gout Archivi

Gout in the Corpus Hippocraticum

Posted on Monday August 4th, 2025Scarica PDF

Natale Gaspare De Santo

DOI: 10.69097/42-04-2025-10

Natale G. De Santo¹, Carmela Bisaccia², Luca S. De Santo³

1 Emeritus Professor of Nephrology, University of Campania Luigi Vanvitelli
2 Istituto Mazzini
3 Division of Heart Surgery University of Campania Luigi Vanvitelli and Monaldi Hospital, (all in Naples, Italy)

Corresponding author:
E-mail: natalegaspare.desanto@unicampania.it

Abstract

Gout is the oldest recorded form of inflammatory arthritis to affect humankind, with roots stretching back to 2640 BC and known in Greece by 1700 BCE. It is due to deposition of sodium monourate driven by hyperuricemia.
The association of humours with causation stems from Hippocrates (460-370 BCE). More specifically, a toxic humour was suspected by Celsus (25 BCE-50 CE) and Rufus of Ephesus (98-138 CE), and confirmed by Alfred Garrod in 1849.
Its therapy has been based on colchicine since Severus Iatrosophista, Theodosius the Philosopher, and Jacobus Psychrestos, introducing Colchicum as an innovative treatment for podagra in the early Byzantine period. A breakthrough in treatment was the introduction of allopurinol in 1966.
This study aimed to examine gout in the Corpus Hippocraticum. For Hippocrates, gout is a disease caused by bile and phlegm, not by the wrath of a god. Gout is mentioned in the Corpus 20 times, and a total of five Aphorisms are dedicated to podagra. In Affections, “Gout is a disease that induces burning pains in the joints; it comes to paroxysms, now in one limb, now in the other, where it causes ailments of variable severity”. In Prorrhetics, it is described as a disease not amenable to cure in the elderly patients with tophi – a goal achievable in the young patient willing to adhere strictly to the therapy suggested by the physician.

Keywords: Gout, Tophi, Corpus Hippocraticum, Aphorisms, Affection, Prorrhetic II

Dedicated to the memory of Professor Simon Byl (1940-2018),

Belgian Hellenist at the Université Libre de Bruxelles.

On gout and joint diseases in the Corpus Hippocraticum

he knew and taught the most.

Introduction

“Gout (ποδάγρα/podagra): an illness which may appear in the upper limbs (cheiragra) or more commonly in the lower limbs (podagra) and is characterized by a red, hot swollen joint at the base of the big toe; it was thought to be caused mainly by an excess of yellow bile” [1].

The history of gout parallels that of the history of medicine. Gout is the oldest recorded inflammatory form of arthritis to affect humankind, with roots stretching back to 2640 BCE. Kettridge and Downs by examining in 1957 an Egyptian mummy discovered a urinary stone dated 7000 years ago. Its nucleus was made of uric acid [2, 3].

Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis in adults, for which many therapeutic options are now available. It is due to the deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia (at or above 6.8 mg/dl). Hyperuricemias may result from: (i) renal overload (overproduction or extrarenal underexcretion due to dysfunctional variants of transporters in the gut and intestine); (ii) renal underexcretion; or (iii) a combination of both renal overload and renal underexcretion.

The kidney can be both a cause and a target of hyperuricemia (calculi, renal disease and its progression). At onset, gout affects one joint, frequently the metatarsophalangeal joint of the great toe that is self-limited, and heals in 2 weeks. Flares subsequently affect two or more joints. Gout becomes a chronic disease when tophi and joint erosions appear. Risk factors include conditions with high cell turnover, as well as a high intake of purine-rich foods (such as meat, crustaceans, alcohol, and fructose-containing syrup). Prevalence increases with age and women become hyperuricemic after menopause [4, 5].

Gout known as “the unwalkable disease” (Hippocrates), for which protection was granted by the Goddess Artemis Podagra (Clemens Alexandrinus), a disease with a heritable trait recognized by Galen, and by Aretheus. Soranus of Ephesus was the first who described tophi, later widely discussed by the Byzantine physician Alexander of Tralles (525-605 AD) who illustrated the virtues of hermodactyl. Its name derives from the Latin word gutta (meaning drop to indicate the drop of a humour in excess precipitating in the joint).

The goal of this study

This study aims to shed light on the contribution of Hippocrates to the knowledge of gout. It is a part of a program [6-9] on establishing the timeline of Podagra from the Corpus Hippocraticum to Renaissance, encompassing no less than 25 authors (Table 1).

Gout was present in Greece since 1700 BC [10]. Many mythological Greek heroes suffered with the gout: Priam of Troy, Achilles (as suggested by Lucian of Samosata), Bellerophon, Oedipus King of Tebe. Thus we are not surprised by its significant presence in the Corpus Hippocraticum.

Hippocrates (460–370 BCE)

Teophrastus (371-287 BCE)

Nicander (2nd century BCE)

Celsus (25 BCE–50 CE)

Aretaeus of Cappadocia (1st half, 1st century CE)

Scribonius Largus (1st century CE)

Dioscorides of Anazarbus (1st century CE)

Anonymus Parisinus (1st century CE)

Galen (c. 129–c. 216 CE)

Lucian of Samosata (c. 120–after 180 CE)

Oribasius (c. 320–400/403 CE)

Severus Iatrosophista (5th century CE)

Theodosius the Philosopher (5th century CE)

Jacobus Psychrestus (5th century CE)

Aëtius (mid-5th to mid-6th century CE)

Caelius Aurelianus (6th century CE)

Evagrius Scholasticus (6th century CE)

Paulus of Aegina (625–690 CE)

Rhazes (c. 854-925/935)

Avicenna (980–1037 CE)

Michael Psellus (1018–1078 CE)

Constantinus Africanus (floruit 1020–1087 CE)

Matthaeus Platearius (d. c. 1161 CE)

Demetrios Pepagomenos (13th century CE)

Nikolaus Myrepsos (floruit 1240–1280 CE)

John Actuarius (end of the 14th century CE)

Table 1. On the Timeline of Podagra from the Corpus Hippocraticum to the Renaissance.

Hippocrates’ short biography

Hippocrates (c.460-c.370), the father of medicine, was born in the age of Pericles, a bright period of prosperity, science and arts in Greece. He was born in Kos near the coast of Asia Minor. In the heart of the city, an Oriental Plane tree still stands, said to have provided shade for his public lectures.

“His contemporaries constituted perhaps the most remarkable galaxy of Genius ever known. They included Pericles, the statesman builder of Acropolis, the poets and playwrights Aeschylus, Sophocles, Euripides, Aristophanes, and Pindar, whose nephew was one of Hippocrates’ students, the philosopher Socrates with his disciples Plato and Xenophon, the venerable father of history (Herodotus) with his youthful rival Thucydides, the sculptor Phidias, and Chrysippus and Euryphon of Cnidos. Hippocrates’ writings are free of the prevailing superstitions which associated the cause of disease with divine wrath for sin, and much of contemporary therapy was magic” [11].

His grandfather (Hippocrates), and his father Heraclides – priest doctors – were descendant of Asclepius and passed down knowledge and skill to the family members, thus Hippocrates received medical training from them. Heleni Tsiompanou and Spyros Marketos [12] in a paper that appeared posthumous, after Marketos death, point out that Plato (Politics) calls him ‘The great Hippocrates, the wise physician’, whereas Aristotle calls ‘the famous physician of Kos’ (Protagoras).

Tsiompanou and Marketos also stress the fact that Hippocrates broke with the tradition of keeping the expertise in medicine within the family. He started the School of Kos where fellows received instruction for a fee [12]. We know very little about Hippocrates’ life. Probably he successfully diagnosed and treated, as court physician, King’s “love-sickness” in Macedonia, and cured Democritus’ madness in Abdera.

“Between 440 BC and 360 BC Hippocrates and his pupils wrote a number of medical treatises, only 60 treatises were saved from the fire that destroyed the Great Library at Alexandria. The surviving text were published under the title of Corpus Hippocraticum. Some of the texts may not be Hippocrates’own writings but all display his influence”. He died in Thessaly, in Larissa [12].

He broke with the oral tradition and collected detailed reports of patients he cared for. He also introduced the need to review and analyze all pre-existing data. According to Hippocrates ‘Full discovery will be made, if the inquirer be competent, conduct his research with knowledge of discoveries already made’ (Ancient Medicine).

Gout in the Corpus Hippocraticum

Simon Byl pointed out [13] that in the Corpus Hippocraticum joint diseases have been described as “arthritis, arthritika, arthron, ponoi, oidemata, and eparseis of the joints, kedmata and ischias”.

These conditions are attributed to an accumulation of phlegm linked to excessive food consumption. However, the text asserts “arthritis is not lethal” (On Diseases).

The Corpus Hippocraticum also differentiates gout from other joint diseases such as acute articular rheumatism and ankylosing spondylitis. Podagra (gout affecting the foot) was identified as the most severe form of joint disease, characterised as a chronic condition. It was noted to affect younger individuals more frequently than the elderly [13]. Gout is mentioned 20 times in the Corpus Hippocraticum, with specific references to podagra appearing 5 times. The terms podagrao and podagriao (indicating affliction with gout) are used 1 and 4 times, respectively, while podagrikos (relating to gout) appears 10 times. Additionally, Simon Byl observed that the corpus contains 314 references to the word arthron (joint). In the Corpus Hippocraticum, podagra associated with tophi is described as nearly incurable [13]. Even the most skilled physicians were unable to provide relief and cautioned against the use of drugs to relieve pain.

In Aphorisms, Hippocrates mentions gout 5 times [14].

“Eunuchs do not take gout, nor become bald” (VI, 28);
“A woman does not develop gout unless her menses be stopped” (VI, 29);
“A youth does not get gout before sexual intercourse”(VI, 30);
“In gouty affections inflammation subsides within 40 days” (VI, 49);
“Gouty affections become active in Spring and Autumn” (VI, 55).

However, the importance of the seasons was rejected by many authors of antiquity including Galen, Celsus and Seneca. “Hippocrates also learned by experience that an excess of wine could exacerbate or even cause gout, as did an excess of sexual activity and that the disease was more severe in the inherited form than in those who contract it by their unsafe lifestyles” [13].

In Affections of the parts, the chapter on Stranguria, sciatica and gout reads (VIII, 32) reads:

“Gout is a disease that induces burning pains in the joints; it comes to paroxysms, now in one limb, now in the other, where it causes ailments of variable severity. Cool compresses will be applied where there is pain, the intestines will be cleansed of the materials found there by giving enemas and administering a suppository; use for drink and liquid food what seems best suited. Once the pain has calmed down, purge him and then have the cooked whey and donkey’s milk taken. Gout is caused by phlegm and moving bile, which rush over the joints”.

“It can be short, acute and is not deadly. It is more frequent in youth than in old age.

Pain in the feet [podagra] is the most violent of all, most long and resistant. It is the effect of a defect in the blood altered in the small veins by the pituitary gland and bile; the disease is all the more fixed and difficult to heal if it establishes itself in small veins and if the violence exerted on many nerves and bone parts is serious. It is treated with the same means used or joint pain. It lasts for a long time, is very painful but is not deadly. Whenever the pain fixes in the fingers, the burning fire is placed above the joint using raw flax”.

In Prognostics (Book 1, Chapter 4, 19), age and conditions required to recover from gout are discussed as for gouty persons, Hippocrates says:

“It is my opinion that the old, those who have lumps in the joints, which leads to a painful life, who are habitually constipated, all these people, I say, cannot absolutely be cured, at least with no human means that I am aware of. They feel relief from the work of the viscera when it occurs, and in general, the downward colliquation of the humours benefits them. The gouty person who is young and free from knots in the limbs, active, vigorous, whose abdominal functions are regular, capable of subjecting himself to the method prescribed by the doctor, can hope for recovery”.

“These complaints are better removed by the occurrence of dysenteries or other evacuations downwards. His principal remedies are purgatives administered by the mouth or by injection, and local applications of cooling nature, and even pouring cold water on the foot. When the pain of the gout becomes fixed in a joint, it directs us to burn it with crude flax”.

In Prorrhetic II, where tophi are described as epiporomata, we are made aware of the difficulties of healing the elderly who have lumps in the joints:

“Elderly gouty sufferers who have tophi around the joints and adopt unhealthy lifestyles and whose bellies are dry are beyond the possibility of the human art… they can’t be healed, at least not by any human means I am aware of. They benefit from evacuations when they occur.

The young gouty sufferer free of tophi in the joints, who adopts a healthy alimentation, is vigorous and practices exercise, has regular bowel movements, and is vigorous and active and accepts to follow the prescription of the doctor, he can hope to be healed”.

Treatments

Treatment was based on appropriate nutrition, abstention from wine, drastic purges, preferably black hellebore (Helleborus niger L.). An attack of dysentery represented the best natural remedy for gout. Burning the area above the joints with raw flax was also a possibility.

“Both cold and hot water poured abundantly over those who have no painful ulcerative tophi are very useful”.“Cold water moderates the pain, numbing the part, since mediocre numbness is a sedative. Hot water attenuates and softens; lotions and baths are used in the case of gout” (Treatise on Liquids).Salt, the ubiquitous simple, has a crucial role in treating podagra and its pains. “Apply salt on the swollen parts, the salt having been mixed with water in a paste. The paste is left in situ for three days, and after its removal, the parts shall be rubbed with red saltpeter mixed with honey for the subsequent three days” (Disease of Women I).

The paper can be concluded with a passage from Affections (first quarter of the fourth century BCE):

“Podagra is the fiercest, longest and most tenacious of all joint diseases; it occurs when blood present in the vein has been contaminated by bile and phlegm, and since these are the thinnest and tightest vessels of the body (the same applies to the neighboring tendons and bones), pain is thus the most intense in this area. The same cure as used for arthritis is suitable in this case; the disease is long and painful, but not lethal. If the pain does not subside in the big toes, then one will cauterize the toe’s vessels above the condyle and this cauterization will be performed with raw flax” [13].

Acknowledgements

We thank Dr. Rosaria Di Martino, Head of Centro Servizio del Sistema Bibliotecario di Ateneo Università degli Studi della Campania Luigi Vanvitelli and Coordinator Biblioteche di Ateneo, for her expert assistance in literature searches. We are also indebted to Professor Joseph Sepe for editing the English version of the manuscript.

Bibliography

Gout From the Corpus Hippocraticum to the Renaissance: The Role of Galen

Posted on Tuesday April 8th, 2025Scarica PDF

Natale Gaspare De Santo

DOI: 10.69097/42-02-2025-14

Natale Gaspare De Santo¹, Carmela Bisaccia² and Luca Salvatore De Santo³

1 Emeritus Professor of Nephrology, University of Campania Luigi Vanvitelli, Naples
2 Istituto Mazzini, Naples
3 Division of Heart Surgery, University of Campania Luigi Vanvitelli, Naples

Corresponding author:
Salita Scudillo, 20, 80131, Naples, Italy
Phone: +39 3484117376
E-mail: natalegaspare.desanto@unicampania.it

Abstract

Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis due to deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia. Gout is the oldest recorded inflammatory arthritis to affect humankind, with roots stretching back to 2640 BCE.
To establish the timeline of gout from the Corpus Hippocraticum to the Renaissance, this study focuses on Galen (129-c.215 CE). A princeps English edition of Galen’s works is still lacking; therefore, this paper provides a translation of the paragraph on gout from the Latin edition [12] by Carolus Gottlob Kühn (Leipzig, 1821-1833).
Galen departs from Hippocrates and displays a vast knowledge of pathogenesis, symptomatology, clinical course, differential diagnosis, therapeutic skills and prognostication. In Galen’s view, gout is due to fluid overflow that infiltrates nerves and causes pain. Overflowing fluid may be blood, phlegm, or a mixture of bile, blood, and phlegm. The prevailing humor is crude, mucous, and thick, and by residing in the joint, causes tophi. The nature of infiltrating humor can be diagnosed through color of the joint, symptoms, effects of heat and cold, effects of drugs, and information related to age, diet, quantity and quality of exercise, attitude towards baths of the patient.
Treatment, according to Galen, required immediate bloodletting by venesection at the elbow, which could be repeated. Purges, enemas, and/or emetics are additionally needed to evacuate the humor(s). Poultices played a role draining the humor(s) as well as for their emollient-softening properties.

Keywords: Galen, gout, humors, venesection, purges, emetics

Introduction

Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis in adults for which treatment options are now available. It is due to deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia at or above 6.8 mg/dL. Hyperuricemia itself results from genetic, environmental factors as well as from urate transporter dysfunction in the gut and in the kidneys.

Hyperuricemia may be due to either renal overload (overproduction or extrarenal underexcretion due to dysfunctional variants of transporters in the gut and intestine), or to renal underexcretion, or a combination of renal overload and renal underexcretion [1–4]. Renal overload may be due to overproduction by dietary purines, endogenous purine synthesis, purine breakdown and purine salvage (Hypoxanthine-guanine phosphoribosyltransferase deficiency and 5-phosphoribosyl-1-pyrophosphate deficiency). Crystal deposition activates the NOD-like receptor protein 3 (NLRP3) inflammasome causing—via caspase-1 —release of the cytokine IL-1β and activates proteinase 3 and elastase. The kidney may cause hyperuricemia, but is also the target of hyperuricemia (calculi, renal disease, and its progression) [1–7].

At onset, gout affects one joint, frequently the metatarsophalangeal joint of the great toe, which is usually self-limited and heals in two weeks. Flare-ups subsequently affect two or more joints, becoming a chronic disease when tophi and erosions of the joint appear. Risk factors are diseases with high cell turnover and high intake of purine rich foods (meat, crustaceans, alcohol, and syrup containing fructose). It increases with age and women become hyperuricemic after menopause. It affects patients with hypertension, diabetes mellitus, and chronic kidney disease. The diagnosis is made by demonstrating sodium monourate crystals in a joint by polarization microscopy or fine needle aspiration of tophi. The prevalence is 1% in Italy and in France, 2.5% in United Kingdom, Spain, Netherland, 3.9% in the USA and 1% in China. It is rare in Portugal, Czech Republic Former Soviet Union, Turkey, Malaysia, Japan, Korea, African countries. The prevalence increases with age up to 70-80 years of age.

Its name derives from the Latin word gutta (drop) to indicate the drop of a humour in excess precipitating in the joint. Garrod made seminal experiments on the role of uric acid (1848). Having found a cure for the disease — allopurinol, still the most used ― Gertrud B. Elion (1918-1999) and George H. Hitchings (1905-1998) received the Nobel Prize for Medicine in 1988 [8, 9].

Galen of Pergamum (129-c216 CE)

The first of doctors and unique among philosophers.
EMPEROR MARCUS AURELIUS

The Prince of Medicine.
VESALIUS, Defabrica corporis humani, 1555

Until the twentieth century he was the most influencial figure
in western medicine and perhaps in western culture.
SUSAN P. MATTERN, 2013 [10]

A Thinking Doctor in Imperial Rome.
VIVIAN NUTTON, 2020 [11]

Biography

Galen (129-c.216 CE), the Greek-Roman physician, was born in Pergamum, Mysia, Anatolia (modern-day Bergama, Turkey), situated on the river Caicus, 16 kilometers from the Aegean Sea. He was the son of Nicon, a wealthy architect and Roman citizen, who owned a house in the city and a large estate. His grandfather had been an engineer. “The city of Attalus and Asclepius, the city that had turned on its Roman inhabitants and slaughtered them by thousands on a dark day in 88 BCE and then became the light of Roman Asia, beloved by Hadrian, adorned with every architecture glory – was Galen’s city” [10].

Between 143 and 144 CE, Galen received his primary education from his father, Aelius Nicon, at home. Initially, the education focused on meticulous skills in both oral and written Greek, as well as providing a foundation in literature, mathematics, geometry, and astronomy. In addition to this foundation, Galen also had tutors in philosophy. One of his teachers was the philosopher Eudemus. His father’s intention was to mold Galen into a rich gentleman and possibly a philosopher. His father, who carefully selected his later teachers and often accompanied him to school, guided his early education. During these formative years, Galen studied Plato, Aristotle, the Stoics, and the Epicureans with great enthusiasm.

At the age of 17 (in 145/146 CE), however, his studies shifted to medicine after his father was told in a dream by Asclepius that his son was destined for a medical career.

Consequently, Galen studied in Pergamum with private physicians personally selected by his father. Later, following Nicon’s death (148 CE), he studied in Smyrna (150 CE), Corinth and Alexandria (152-153 CE), as reported in Table 1.

PERGAMUM
Satyrus	Sophist
Aeschrion	Empiricist
Epicurus	Empiricist
Stratonicus	Empiricist
Aeficianus	Pneumatist
SMYRNA
Albinus	Platonist philosopher
Pelops	Stoic interpreter of Hippocrates

Table 1. Galen’s teachers in medicine [11].

In Alexandria, a city with a vibrant cultural life, Galen remained for 3-4 years. There, he learned anatomy through daily dissections [10]. In 157 CE, he returned to Pergamum and, at the young age of 28, was appointed as the doctor of the local gladiators. A man of independent ideas and means, Galen never belonged to a specific philosophical or medical sect, and he remained independent throughout his life.

From Pergamum to Rome

In 162 CE, he moved to Rome, the capital of the empire, where he cultivated a friendship with the influential senator Flavius Boethus and reunited with his former philosophy teacher, Eudemus. Both relationships opened many doors for him, particularly after Galen was able to restore Eudemus’ health, curing a disease that others had deemed fatal, and subsequently healed Boethus’ son and wife. Furthermore, his masterlful public dissections gained renown throughout the city and attracted important clients. However, this success also sparked the jealousy and resentment of local physicians, toward whom, like Pliny the Elder in the previous century, he openly expressed his disdain. His attacks were mainly directed against Methodists but also towards Erasistrateans.

For unknown reasons, in 166 CE he left Rome and returned to Pergamum, probably the fear of plague and/or the fear of the hatred generated by the envy of his Roman colleagues [10, 11].

He returned to Rome in 169 and was appointed physician of Marcus Aurelius, who valued his medical expertise as much as his philosophy. He was in charge of preparing theriac for the Emperor until the Emperor’s death (in 180 CE).

His subsequent life was not without difficulties, but he safely navigated the tumultuous years of Emperor Commodus. He served in office under Emperor Septimius Severus and likely died during the reign of Caracalla (197-217 CE). According to Arabic sources, Galen died in 216 or 217 CE.

Galen on health and disease

“Health is granted by a system based on the four elements (air, water, fire and earth), four qualities, two opposed pairs namely hot-cold and dry-wet, four humors (blood, phlegm, yellow bile and black bile (melancholy)), four seasons (spring, summer, autumn, winter) and temperaments that were nine (1 for each of the 4 qualities, 1 for each possible combination of the 4 qualities and 1 ideal temperament where all temperaments are in perfect balance [10]).

The temperaments (Figure 1) became 4 in Medieval Europe. Equilibrium between humors is associated with health, imbalance with disease. Galen attributes the humoral theory directly to Hippocrates, not to Polybus, Hippocrates’ son-in-law, as reported by Aristotle.

The liver is central to the body’s function. It generates blood from nutrients derived from food, which then circulates to the entire organism. The heart produces the innate heat that provides the energy for physical and mental health. It diminishes with age and disappears at death. The innate heat is maintained by the nutrients going from liver to the left ventricle and is cooled during respiration. Too much nutriment overheats, too little cools. Nutrients are relevant to acquired heat. Imbalance or excess of humours can be contrasted with drugs. Health is granted also by four faculties: attraction, expulsion, digestion (assimilation) and retention that allow appropriate handling of nutrients, and are present in every living organism, including plants.”

Figure 1. Humours, elemental qualities, and temperaments in Medieval Galen. Modified from De Santo NG, Bisaccia C, and De Santo RM. The Nature of water, New York, Nova 2013.

Between 169 and 180 CE, Galen prepared the theriac for Marcus Aurelius. It was based on that of Andronicus, made of 64 ingredients, including viper’s flesh, Cinnamomum and poppy-head juice (3.4%), equivalent to approximately 33 mg of opium per day.

The author

Galen was a prolific writer. He started as a student, authoring 3 texts respectively on the anatomy of the womb, the diagnosis of diseases of the eyes and a report on a debate between the Empiricist Philippus and the Hippocratic Pelops on the best method to meet patients’ needs. In total, he left more than 300 books, which were revised repeatedly during his life. These works cover a wide range of subjects, including anatomy, ethics, lexicography, logic, and pharmacology. He wrote in Greek, but his thought has been preserved through translations into Arabic, Hebrew, Syriac, Armenian, and Latin. We can say that Arabic translations played a crucial role in preserving his methods. A notable example is the Canon (Al-Quanun fi al-Tibb) of Avicenna (Abu al-Hussayn ibn Abdullah ibn Sina, 980-1037 CE). According to Vivian Nutton it can be considered an outstanding treatise of Galenic medicine [11].

Galen’s success

Galen achieved success in Rome. His prestige was immense, allowing him to care for the most important families. This enabled him to assemble an outstanding personal library in the Palatinum and to purchase a villa in Castellammare di Stabia. Unfortunately, the library, which housed the most important copies of medical books from antiquity and his own works, was located near the Temple of Apollo on the Palatine Hill and in 192 CE caught fire and was irretrievably lost. He lost not only books in the fire but also gold, silver, and other valuables. Luckily, some of his books were housed in the Villa of Castellammare.

Galen provided medical care free of charge, but we know that he accepted gifts – such as the 400 aurei (gold coins) from Senator Flavius Boethus following the recovery of his son and wife. The great anatomist and pharmacologist “never lost the idea that medicine is about treating patients” [8]. Until the twentieth century he was the “most influential figure in western medicine and perhaps in western culture” [10].

Galen’s Text: Regarding sciatica, gout and arthritis

“Arthritis encompasses conditions such as sciatica and gout [12]. Sciatica refers to arthritis affecting the joints connected to the hip, while gout describes arthritis near the foot. Hence, gout typically begins in a single joint and progressively spreads to others, eventually becoming chronic. These three conditions share a common feature of an excessive buildup of fluid in the affected joint. This excess fluid overflows and infects the surrounding nerves, resulting in pain. The fluid that erupts can be sanguine or more commonly phlegmatic, or even a combination of phlegm, bile, and blood. More precisely, it can be said that in arthritis the prevailing humor is not typically phlegmatic but rather the one known as raw. This thick, mucus-like humor, when it remains in the joints for long periods, not only becomes denser but also more viscous. This is the origin of what is known as concretions, and once these develop, there is no hope of restoring the joint to its original condition.

It is evident that the differences in humor affliction can be discerned through color, symptoms, and the effects of administered drugs. Therefore, the description and diagnosis of humor color are widely known and understood. Although not everyone experiences the symptoms firsthand, they are not difficult to learn. For instance, bilious blood produces a sensation of intense heat in the patient, which worsens with the application of heat and is alleviated by cold.

To identify the humor involved, one should consider factors such as diet, physical activities, bathing routines, quantity and quality of exercises and foods, season, climate, age, and overall physical condition. These factors, along with the body’s various faculties, can assist in the diagnosis.

To treat the illness by removing the specific humor causing it, bloodletting is employed for plethoric bodies, followed by purgation. Subsequently, appropriate medications are administered in a specific order and timing to repel the excessive flow of humor. However, special caution is needed when treating the hip joint, as it is deep and forcing the blood out can affect nearby vessels and muscles. Initially, soothing drugs for hip pain are necessary, which neither excessively cool nor heat, as these may exacerbate the secretions.

While the focus here is not on poultices or baths but on the preparation of medicines, it is important to mention the treatment of the hip joint. In cases of sciatica, treatment often involves lancing the veins around the calf or ankles to alleviate the condition. However, in cases where strong drugs were used without evacuating the whole body, the accumulated humor may become thick and viscous due to the heat and dryness of acidic drugs, causing increased pain. Thus, beginning with the evacuation of the entire body, starting with a blood sample from the elbow, is crucial. Vomiting is particularly helpful in treating sciatica, and moderate emetics can be used in the initial stages.

For those who have suffered from improper obstruction of fluids caused by acidic drugs that are difficult to dissolve, enemas and potent infusions, such as coloquintid, can be more effective.With these considerations in mind, medicines are prescribed following the methods passed down by ancient doctors. Andromachus’ writings on external medicines, specifically emollient poultices (malagma), serve as an excellent starting point, providing relief for chronic conditions including sciatica.” [12].

Preparations written by Andromachus for sciatic patients in his own words, from books on external drugs

Seeds of wild rue (Ruta graveolens L.), of silphium (the extinct plant), of laurel (Laurus nobilis L.), saltpeter, southernwood (Artemisia abrotanum L.), coloquintid (Citrullus colocynthis L.), cardamom (Elettaria cardamomum L.), ammi (Ammi visnaga L.), the eighth part of a mina (436.6 g) of green rue (Ruta graveolens L.). Some of these receive a pitch of terebenthine, resin, and the same quantity of wax and taurine fat, copper disulphate, fumes of ammonium salt, of rubber from the hogweed plant (Heracleum sphondylium L.), of native sulfur [12].

The effectiveness and warming properties of the mentioned medicines are well documented and do not require further recent verification. Wild rue seed, silphium, laurel berries, saltpeter foam, southernwood, coloquintide, cardamom, ammi, green rue, and natural sulfur all possess strong heating properties and can draw out the afflicting humors from deep within the hip joint. The poultice containing these ingredients is composed of pitch, turpentine, resin, wax, and fat. Ammonium fumes and galbanum not only contribute to the composition but also have emollient and softening properties. The gum of the hogweed plant is of a similar nature, but with faculties that are more potent.

Another remedy of Andromachus with the same effect

Andromachus provides another preparation for sciatica [12], which includes wax, turpentine, ammonium fumes, propolis, galbanum (Ferula galbaniflua, Boiss. and Buhse), bdellium (Commiphora mukul, Engl.), saffron (Crocus sativus L.), gum from the hogweed plant, sodium carbonate foam, and crushed iris oil (Iris florentina L.).

A remedy of Protas of Pelusium for hip and head pain and all chronic pain

It was made of wax (24 drachmae), seven drachmae of ammonium fumes, seven drachmae of trebentine, eight drachmae of thapsia (Thapsia garganica L.) juice, and 1 cyathus (1 cup, 0,046 l) of oil [12].

Among emollient poultices a remedy for hip pain drawn by Andromachus from Heras of Cappadocia

“Three heminas of liquid pitch, or two and a half, wax, pine resin, wine sulfites, each a pound, six ounces of potassium nitrate, one quart of the green root parasite plant pedicularis (Pedicularis sylvatica L.), one quart of pyrethrum, two quarts of burnt wine dregs, two heminas of cardamom (Elettaria cardamomum L.), one quart of galbanum (Ferula gummosa L.). Liquids are added to the dry component. As Heras wrote near the end of his own book: they are added not in a pitch, or two and a half, but exactly three heminas” [12]. The title is verbatim that he gave.

Discussion

This study highlights Galen’s pivotal role in the historical understanding of gout, bridging the era of the Corpus Hippocraticum and the Renaissance period. His treatise demonstrates a profound understanding of the disease pathogenesis, symptomatology, clinical course, differential diagnosis, therapeutic skills and prognostication. Gout starts in one joint and then, progressively, spreads to other joints becoming chronic.

In Galen’s view, gout is due to fluid overflow that infiltrates nerves and causes pain. The overflowing fluid may be blood, phlegm, or a mixture of bile blood and phlegm. The prevailing humor is crude, mucous and thick and by residing in the joint becomes thicker and thicker and causes concretions (tophi). When tophi appear, the disease cannot be cured.

The nature of infiltrating humor can be diagnosed through color of the joint, symptoms, effects of heat and cold, effects of drugs and specific information about age, diet, quantity and quality of exercise, and bathing habits.

Bloodletting, in Galen’s therapeutic framework, is essential for plethoric patients and should be implemented promptly. A proponent of the procedure, Galen would draw large quantities of blood, preferably overnight, until the patient fainted. To treat gout, an incision was made at the elbow. Venesection might be repeated. Enemas and /or emetics may be needed to evacuate the humor. Poultices have not only a role in evacuating the humor(s) but may have emollient and softening properties.

Galen starts with two medical recipes by the pharmacologist Andromachus the Elder (and probably of his like-named son), physician of Nero in the century before, followed by another Andromachus’ recipe derived from Heras of Cappadocia, himself a pharmacologist of the previous century most valued by Galen, author of Narthex a book of medical remedies.

The subsequent recipe comes from Protas of Seleucium in Egypt, a man who is mentioned in the “litany of names of some authors or providers of drugs listed by Galen” of Vivian Nutton [13] that includes 15 men and one woman (Aquilia Secundilla).

Of great interest are the gouty patients described by Galen. The treatise On the Mixtures and Powers of Simple Dugs reports on an old man with chronic arthritis and chalky stones (tophi) who knocked at his door for immediate help. Galen who, probably, was in the middle of a discussion with his household about the use of the rancid cheese that had accumulated in the kitchen, immediately took a piece of that rancid cheese and pounded it in a mortar along with a piece of pickled pork leg and prepared a plaster that was put on the affected part. The plaster opened the chalky stone rendering incision unnecessary [10]. Galen reported also about another patient with a milder form of gout in an ambulatory patient, who was offered a cure by a street huckster. Galen challenged the charlatan to heal the patient. The cure was not effective, as we learn in Simp. Med 1.29 11.432-33K, as enlightened by Susan P. Mattern [10].

Although Galen considered Hippocrates an infallible physician and cited him 2500 times [10], Galen did not swear by the Hippocratic aphorism related to the absence of gout in eunuchs. He knew by experience that at the time of Hippocrates, nutrition was more appropriate, and wine was never consumed before or at breakfast; conditions that, in his view, protected eunuchs from developing the disease. By contrast, for the eunuchs of Galen’s time, gout became a possibility due to poor nutrition and use of strong wines drank even before breakfast. Galen also observed that many patients with gout had fathers or grandfathers affected by the same disease, suggesting a possible hereditary component.

A very recent paper has identified eight Galenic case reports on inflammatory diseases of the musculoskeletal system selected from the list of 358 cases [14], some of them identified as gouty.

Gout is probably the first known noncommunicable disease that can be discussed in terms of Omran’s “Theory of Epidemiologic Transition” [16, 17]. Omran analyzed the changing patterns of population age distribution in relation to changes in mortality, fertility, life expectancy, and causes of death. The theory has been updated frequently, by taking into consideration poverty along with incomes and education. This made the theory suitable to explain the differences between high prevalence of gout in popes and low but slightly increasing prevalence in the general population. Gout should be discussed in terms of lifestyles, income, and education. In general, rich and educated people, when made aware of the risk, agree to modify their lifestyles, whereas people who are poor and uneducated may not. Those who do not understand the risk factors are more likely to experience higher morbidity and mortality from the disease, while those with access to education are more likely to achieve protection [18].

The above concepts were recently applied to gout in Roman Pontiffs, and it was shown that popes reigning before 1914 had a high prevalence of gout due to lifestyles causing gout. These lifestyles were later corrected through education, and by 1914 gout had virtually disappeared among popes. In contrast, individuals with poor nutrition, mostly those with low incomes, were not prone to gout. Their diets, working conditions, and daily commute to and from work provided them with protection from gout [19–22].

In Rome at the time of Galen, life expectancy at birth ranged between 20 and 33 years [21], and in the poorer quarters it was around 20 years. As a result, gout was primarily a disease affecting elderly aristocrats. However, some cases of gout were probably linked to a high lead concentration in water due to the lead used for water pipelines, tanks and for utensils. Studies have shown that lead content in human skeletons increased significantly between 200 BCE and 200 CE [23].

Conclusion

Galen fixed practical guidelines for the management of gout at the bedside. The goal was possible since he was a “thinker”, “observer”, “good doctor”, “healer”, “dietitian”, and a “pharmacologist going beyond empirism”[11]. Gouty patients presented Galen with opportunities to fully exercise his diagnostic, therapeutic, and prognostic skills. He achieved this through patient communication and meticulous observation during frequent visits, which sometimes occurred multiple times a day. These interactions served as occasions for Galen to critique inferior physicians and charlatans and to show his superior expertise and ingenuity, as shown by the two cases illustrated before [10].

Acknowledgements

We thank Dr. Rosaria Di Martino, Head Centro Servizio del Sistema Bibliotecario di Ateneo Università degli Studi della Campania Luigi Vanvitelli and CoordinatorE Biblioteche di Ateneo, for her expert assistance in literature searches.

Thanks are also due to Professor Joseph Sepe for the editing of the English text.

Bibliography

Hyperuricemia in Chronic Kidney Disease: To Treat or Not to Treat?

Posted on Sunday September 1st, 2024Scarica PDF

Marco Manganaro

DOI: 10.69097/41-s83-2024-05

Marco Manganaro

già Direttore SC Nefrologia e Dialisi, ASO “SS. Antonio e Biagio e C. Arrigo”, Alessandria.

Corresponding author:
Marco Manganaro,
via Giordano Bruno 63/d, 10134 Torino (Italia).
E-mail: giurima@alice.it

Abstract

Numerous studies have shown that hyperuricemia (HU) is an independent risk factor for the development of chronic kidney disease (CKD) and cardiovascular events. However, while some evidence suggests that uric acid (UA) may play not only a predictive but also a causal role in these conditions, a robust and definitive demonstration of this is still lacking.
Moreover, despite what appears to be a logical rationale supporting the use of so-called ‘urate-lowering therapy’ (ULT) for nephroprotection in hyperuricemic patients with CKD, studies and meta-analyses on this topic — sometimes burdened by limitations that may have affected their results — have so far provided highly divergent outcomes, leaving uncertainty about whether drug-induced reduction of uricemia can truly slow the progression of CKD and prevent its cardiovascular complications.
This article summarizes current knowledge on UA metabolism and the drugs that interfere with it, discusses theories on the possible multiple pathogenic mechanisms underlying HU related kidney damage, and reviews the results and limitations of the most recent studies that have supported or refuted the nephroprotective role of ULT in CKD, fueling an ongoing scientific controversy.

Keywords: Uric Acid, Asymptomatic Hyperuricemia, Gout, Chronic Kidney Disease, Urate-Lowering Therapy

Sorry, this entry is only available in Italiano.

Introduzione

I rapporti tra iperuricemia (HU) e malattia renale cronica (CKD) sono complessi e di difficoltosa interpretazione per la presenza di fattori confondenti legati alla duplice potenzialità della prima di poter essere sia conseguenza, sia causa della seconda. Da un lato infatti la riduzione del filtrato glomerulare (GFR) che si verifica nella CKD comporta una ridotta escrezione urinaria di acido urico (UA) che può innalzarne i livelli serici, il concomitante impiego di diuretici aggrava tale difetto e le principali cause di CKD, cioè diabete ed ipertensione, sono spesso già di per sé condizioni iperuricemiche(1-3). D’altra parte, ormai assodato che l’HU costituisca un fattore predittivo indipendente per lo sviluppo della CKD e di eventi cardiovascolari patologici, il suo possibile ruolo causale in tali situazioni resta incerto: in particolare, per quanto attiene quello relativo al danno renale, esso risulta meglio provato nella forma da deposito di cristalli di urato, ma meno definito, anche se con crescenti indizi a suo suffragio, nelle conseguenze ascritte all’azione dell’UA solubile. Analogamente rimane ancora controverso, a causa dei contrastanti risultati sinora forniti da studi e meta-analisi sull’argomento, il possibile ruolo nefroprotettivo dalla cosiddetta urate-lowering therapy (ULT)(4-5).
Nella trattazione che segue esamineremo gli studi più recenti e le motivazioni che sono alla base di differenti punti di vista rispetto alle sopra descritte diatribe.

Fisiologia

L’acido urico o C5H4N4O3 o 2,6,8-triossi-1H-purina, composto organico eterociclico con massa molecolare pari a 168,11 unità di massa atomica, è un acido debole che nel comparto extracellulare, al pH fisiologico, è presente al 98-99% nella forma ionizzata di urato monosodico (MSU).
La sintesi dell’UA, prodotto finale del catabolismo delle purine esogene (da cui derivano quotidianamente circa 100-200 mg di UA) ed endogene (da cui derivano ulteriori 600-700 mg/die di UA) avviene nel fegato ad opera dell’enzima xantina ossidoreduttasi (XOR), mentre l’eliminazione dell’UA è per 1/3 gastrointestinale, poi seguita da uricolisi batterica, e per 2/3 renale. In quest’ultima sede il 95% dell’UA viene filtrato dal glomerulo (la restante quota non filtrata è quella legata alle proteine), poi riassorbito al 99% nel tratto S1 del tubulo prossimale e successivamente secreto nel tratto S2, in entrambi i casi ad opera di trasportatori di membrana specifici per ciascuna delle due direzioni e situati in parte sul versante apicale (URAT1 o SLC22A12, OAT4 o SLC22A11, OAT10 o SLC22A13, GLUT9 o SLC2A9 deputati al riassorbimento e ABCG2, ABCC2 o MRP2, ABCC4 o MRP4, NPT1 o SLC17A1, NPT4 o SLC17A3 deputati alla secrezione) ed in parte sul versante baso-laterale (GLUT9 o SLC2A9 deputato al riassorbimento e OAT1 o SLC22A6, OAT2 o SLC22A7, OAT3 o SLC22A8 deputati alla secrezione) della cellula epiteliale del tubulo; alla fine del processo la quota di UA eliminata con le urine rappresenta circa il 10% di quella filtrata(6-10).

Definizione, cause e conseguenze della HU

Negli esseri umani i livelli plasmatici di UA sono più elevati rispetto a quelli degli animali dotati di attività uricasica che permette loro di trasformarlo in allantoina (rispettivamente 3-7 mg/dl contro 1-2 mg/dl), e sono inferiori nella donna rispetto all’uomo per effetto dell’attività uricosurica propria degli estrogeni.
La mutazione responsabile della perdita dell’uricasi (o urato ossidasi) da parte dell’uomo e dei primati superiori sarebbe avvenuta nel Miocene, tra 25 e 12 milioni di anni fa, comportando almeno quattro rilevanti vantaggi in termini evoluzionistici: il rimpiazzo dell’attività antiossidante conseguente alla perdita della capacità di sintesi della vitamina C, importante per la longevità e la neuro-protezione; la stimolazione mentale dovuta ad analogie strutturali con la caffeina, importante per lo sviluppo dell’intelligenza; la stimolazione del sistema renina-angiotensina-aldosterone (RAAS) per il mantenimento di un adeguato regime pressorio in concomitanza con l’assunzione della stazione eretta nonostante un’alimentazione all’epoca povera di sodio; l’incremento delle capacità di accumulare grasso in risposta alla ridotta disponibilità di frutti causata dal raffreddamento della terra(7,11).
Nella seconda metà del secolo scorso, nei paesi economicamente avanzati, i livelli medi di uricemia della popolazione sono progressivamente saliti con il progredire del benessere(12) e l’incremento dell’assunzione di cibi ricchi in purine (soprattutto proteine animali, crostacei, birra, vino, e bevande alcooliche) e fruttosio (bevande zuccherate).
Benché da lungo tempo siano considerati valori di uricemia patologici quelli superiori a 7.0 mg/dl nell’uomo e a 6.0 mg/dl nella donna, alcuni invitano a considerare l’uricemia normale per entrambi soltanto fino a 6.0-6.4 mg/dl poiché questi sono i limiti di solubilità del MSU rispettivamente a 35° e 37°(13-14); al momento questo orientamento non sembra tuttavia trovare ancora il completo accordo di tutti gli esperti.
Cause acquisite o congenite di aumentata introduzione (dieta iperpurinica) o di aumentata produzione di UA (malatttie mielo-linfoproliferative, neoplasie, chemioterapia, psoriasi, sindrome di Lesch-Nyhan, iperattività della fosforibosilpirofosfato sintetasi), ma soprattutto (90% dei casi) di ridotta eliminazione dell’UA (ipovolemia, CKD, farmaci, saturnismo, tubulopatia autosomica dominante uromodulina-associata) inducono HU, condizione a rischio per il successivo sviluppo di patologie. Come già anticipato in premessa, queste conseguono alla formazione di cristalli di MSU e alla loro successiva precipitazione intra- tissutale (gotta articolare, nefropatia gottosa cronica, AKI da massiva precipitazione intra- tubulare acuta) o nelle vie urinarie (calcolosi), ma potenzialmente anche ad effetti emodinamici e cellulari attribuiti alla forma solubile di UA: questi ultimi comprendono attivazione del RAAS (ipertensione arteriosa), ma anche infiammazione e stress ossidativo con risvolti sia renali (disfunzione endoteliale, glomerulosclerosi, fibrosi tubulo-interstiziale) che sistemici (danno cardiovascolare, aumentata resistenza all’insulina, sindrome metabolica)(15). Va infatti considerato il ruolo ambiguo dell’UA che ha proprietà antiossidanti quando circolante nell’ambiente idrofilo extracellulare, ma ha effetti pro- ossidanti che sarebbero alla base del danno cardio-nefro-metabolico nell’ambiente idrofobico intracellulare(16).

Epidemiologia della HU e della gotta

Nel paziente adulto con GFR normale la prevalenza di iperuricemia asintomatica (aHU) è circa del 20%, mentre quella della gotta oscilla tra lo 0.7 e il 3.9%, con trend complessivo in crescita, ampia variabilità nelle diverse aree geografiche ed etnie, e valori anche superiori nella parte più anziana della popolazione. Nel paziente affetto da CKD la prevalenza di aHU sale fino all’80% e quella della gotta fino al 32% e ciò avviene in modo direttamente proporzionale alla severità della malattia renale. Inoltre, in modo quasi speculare, anche nei pazienti iperuricemici e gottosi si osserva un incremento della prevalenza di CKD dal 6-12% fino al 50% ed al 70% rispettivamente(4,8,17).

Esiste davvero il danno renale cronico da UA?

Come già detto, la patologia da cristalli comprende, oltre al danno renale acuto (AKI) da precipitazione intra-tubulare massiva di cristalli di MSU, e alla calcolosi da precipitazione di MSU nelle vie urinarie, anche la nefropatia da deposizione intra-parenchimale cronica di MSU. Quest’ultima è istologicamente caratterizzata da deposizione focale di cristalli di MSU nei tubuli, flogosi interstiziale evolvente verso la fibrosi dell’interstizio e l’atrofia tubulare, glomerulosclerosi ed arteriolosclerosi di grado variabile, mentre si manifesta clinicamente dapprima con un deficit della capacità di concentrazione delle urine e successivamente con una graduale riduzione del GFR(6).
Benché assai ben descritta già in un lontano passato, la reale esistenza di questa forma cronica di nefropatia è stata tuttavia rimessa in discussione verso la fine del XX secolo prima di essere nuovamente riaffermata. Come riporta un antico testo scientifico(18), infatti, già verso la metà del XIX secolo Robert Bentley Todd, irlandese divenuto professore al King’s College di Londra, descriveva il quadro del rene gottoso come caratterizzato dalla presenza di “linee bianche di materiale simile al gesso nella porzione piramidale del rene che prendono la direzione dei tubuli retti e che risultano cristallizzate in forma di prismi quando osservate al microscopio e costituite da urato di soda quando sottoposte ai test chimici”. L’identità di tale riscontro, poi confermato in ampie casistiche, autoptiche e non, della metà del XX secolo(19-20), venne successivamente confutata negli anni ottanta con la pubblicazione di alcuni articoli(21-23) che formulavano le seguenti obiezioni: il riscontro bioptico di una focale deposizione di cristalli di MSU, peraltro osservabile anche in soggetti senza malattia renale, non può spiegare la diffusa presenza di cicatrici renali; il concomitante danno vascolare renale sembra dipendere da altre più rilevanti cause di nefropatia, quali ad esempio la coesistente ipertensione arteriosa; il danno interstiziale può anche conseguire al largo impiego di antiinfiammatori non steroidei (FANS) nel paziente gottoso. Così, per un certo periodo, l’UA non venne più considerato come possibile causa di CKD e l’HU venne ritenuta piuttosto una mera conseguenza della ridotta escrezione di UA dovuta alla riduzione del GFR(2).
Nuovi elementi a suffragio della possibilità di un nesso causale tra UA e CKD giunsero dall’evidenza che ratti con CKD, se resi iperuricemici, avevano una progressione più rapida della malattia anche in assenza di deposizione intrarenale di cristalli (24): ciò riaprì la ricerca e la discussione sul possibile ruolo nefrolesivo dell’UA non solo nella sua forma cristallina, ma anche nella sua forma solubile.
Dopo un appello di alcuni ad adoperare maggior cautela prima di estrapolare conclusioni valide per l’uomo da studi condotti su roditori dotati di attività uricasica, cioè abituati a uricemie ben inferiori a quelle umane e resi severamente iperuricemici in via sperimentale(25), successive ricerche evidenziarono reali effetti pro-infiammatori e di immuno-attivazione dell’UA solubile nei confronti rispettivamente delle cellule dell’epitelio tubulare e delle cellule mesangiali umane(26-27).
Nuovi studi effettuati nel corrente secolo e qui di seguito descritti, sono poi giunti a identificare la HU come fattore indipendente di rischio cardiovascolare e renale nella CKD. Nel 2012 Kanbay e coll. hanno pubblicato i risultati di uno studio condotto su 303 pazienti con CKD e follow-up medio di 39 mesi che mostravano una significativa associazione tra HU ed eventi cardiovascolari fatali e non in maniera indipendente da altri fattori di rischio(28).
Nel 2014 Zhu e coll. hanno dimostrato, in una meta-analisi di 15 studi di coorte che avevano complessivamente arruolato oltre 99.000 individui, un’associazione positiva tra livelli di UA e sviluppo di CKD, con un rischio relativo di 1.22 per ogni mg/dl di incremento dell’uricemia e in maniera indipendente da altri fattori di rischio(29).

Nel 2018 Srivastava e coll. hanno confermato il suddetto riscontro evidenziando una curva conformata a “J” tra livelli di uricemia e rischio di morte per ogni causa (30).
Più recentemente i risultati del progetto URRAH, uno studio osservazionale multicentrico retrospettivo italiano su una coorte di 26.971 soggetti, hanno evidenziato un’associazione indipendente tra livelli di UA e mortalità cardiovascolare e globale, con soglie di uricemia predittive di mortalità anche inferiori a quello che viene attualmente ritenuto il cut off di normalità dell’uricemia(31), oltre che una prevalenza di HU crescente con il decrescere del GFR e maggiore nei pazienti con macroalbuminuria rispetto a quelli con micro e normoalbuminuria(17).
Anche una meta-analisi condotta da Autori brasiliani su 24 studi osservazionali riguardanti oltre 400.000 pazienti, pubblicata nel 2022(32), ha documentato una significativa correlazione tra uricemie inferiori e minor sviluppo e progressione di CKD.
Uno studio prospettico multicentrico osservazionale del gruppo di studio francese CKD- REIN(33), condotto su 2.781 pazienti con CKD in stadio 3-5 seguiti mediamente per oltre 3 anni, dopo aver pianificato l’esecuzione di una determinazione basale e di almeno 5 successive determinazioni dell’UA per ciascun paziente, ha confrontato in modo longitudinale il rapporto tra uricemia e rischio di insufficienza renale e di morte: ne è emerso che il rischio di insufficienza renale aumenta con il crescere dell’uricemia, con un plateau tra i 6 ed i 10 mg/dl ed un brusco incremento al di sopra degli 11 mg/dl, mentre il rischio di morte palesa una curva conformata ad “U” in cui, al di sotto dei 3 mg/dl (forse per il venir meno dell’azione anti-ossidante dell’UA) e al di sopra degli 11 mg/dl, esso è doppio rispetto a quello osservato con valori di uricemia attorno ai 5 mg/dl. Ne è altresì emerso che analoghe curve, costruite solo in funzione delle uricemie basali, non sono in grado di fornire i medesimi risultati: ciò potrebbe spiegare perché alcuni precedenti lavori non abbiano trovato correlazione tra livelli di UA e insufficienza renale.
Schwartz e coll.(34), in uno studio longitudinale su 693 bambini o adolescenti con CKD ad eziologia glomerulare e non glomerulare, hanno trovato un’importante correlazione tra livelli di UA e rischio di progressione della nefropatia: la perdita annuale di GFR in tre fasce pre-definite (<5.5 mg/dl, 5.5-7.5 mg/dl e >7.5 mg/dl) di uricemia basale era infatti rispettivamente -1,4%, -7,7% e -14,7% nelle glomerulopatie e -1,4%, -4,1% e -8,6% nelle nefropatie ad eziologia non glomerulare. Esaminando poi la perdita di GFR osservata per ogni successivo mg/dl di incremento dell’UA nei pazienti che al controllo basale appartenevano alle prime due fasce si evinceva una significativa perdita del GFR, di -5,7% e -4,3% nelle glomerulopatie e di -5,1% e -3,3% nelle nefropatie non glomerulari.
Assodato il ruolo dell’UA come fattore di rischio per lo sviluppo della nefropatia, sono in molti a ritenere plausibile un suo ruolo attivo e non solo predittivo in tal senso, ipotizzando differenti e coesistenti meccanismi lesivi per la sua forma cristallina e per quella solubile. Da un lato la precipitazione a livello tubulare di cristalli di MSU in grado di indurre flogosi interstiziale. Dall’altro una duplice possibilità, immunologica la prima, non immunologica la seconda, che l’UA solubile, identificato come sostanza pericolosa dai recettori dell’immunità innata, inneschi una risposta infiammatoria evolvente verso la fibrosi, ma anche che, attraverso l’attivazione del RAAS e l’avvio di stress ossidativo, induca vasocostrizione, disfunzione endoteliale e proliferazione delle cellule muscolari lisce vascolari alle quali conseguono glomerulosclerosi e fibrosi interstiziale (9,15,35,36).

Una recente divergente osservazione sostiene invece la possibilità che la forma solubile dell’UA abbia effetti soppressivi, e non stimolanti, sull’immunità innata e che sia implicata, insieme ad altri fattori, nello sviluppo della cosiddetta immunodeficienza secondaria alla malattia renale (SIDKD), tipica dell’uremia in fase avanzata, che si caratterizza per alterate difese nei confronti dei patogeni, scarsa risposta ai vaccini e attenuazione delle patologie infiammatorie croniche non infettive(37). Questo contrasta con gli studi citati in precedenza conferendo invece all’UA solubile effetti anti-infiammatori e anti-ossidanti e avvalorando l’ipotesi che la produzione di specie reattive dell’ossigeno (ROS) e il rilascio di citochine pro-infiammatorie non derivino dalla HU, bensì dalla contestuale attivazione della XOR(5).
Per quanto attiene invece la patologia da cristalli, i noti limiti della biopsia renale nei riguardi dell’identificazione della nefropatia gottosa, difficoltosa soprattutto nelle fasi iniziali di malattia perché il prelievo di tessuto renale avviene perlopiù in sede corticale mentre la patologia ha prevalente estrinsecazione midollare, ed anche perché alcuni fissativi causano la dissoluzione dei cristalli stessi(15), sembrano oggi superabili grazie alla Dual-energy computed tomography (DECT) e/o all’impiego combinato dell’ultrasonografia B-mode e Power Doppler-mode. La DECT è infatti in grado di fornire immagini dei depositi di MSU consentendo di applicare loro un codice colore che li distingua dalle calcificazioni, mentre con l’ultrasonografia l’iperecogenicità midollare apprezzabile in B-mode
corrisponde alla presenza di artefatti scintillanti all’indagine in modalità Power Doppler (38- 39).

Il possibile ruolo della XOR

La XOR è un enzima del peso molecolare di 300 kDa regolato a più livelli e dotato di due forme, la xantina deidrogenasi (XDH) presente nell’ambiente intracellulare e la xantina ossidasi (XO) che deriva dalla conversione della precedente quando rilasciata a livello plasmatico. La sua struttura è composta da due sub-unità identiche, ciascuna delle quali costituita da un duplice gruppo Fe/S all’estremo N-terminale, da un cofattore flavin- adenina dinucleotide (FAD) dotato di attività NADH-ossidasica nella porzione intermedia e da un cofattore molibdopterinico all’estremo C-terminale responsabile delle attività enzimatiche xantino-deidrogenasica, xantino-ossidasica e nitrito/nitrato-reduttasica.

La XOR provvede al catabolismo delle purine trasformando l’ipoxantina in xantina e quest’ultima in UA. Essa è inoltre in grado di interferire sullo stato ossido-riduttivo e sulla dinamica dei segnali dell’ambiente cellulare mediante la produzione di ROS e di specie reattive dell’azoto (RNS). Ne deriva che un’eventuale inadeguata attivazione della XOR possa indurre danni tissutali sia di tipo ossidativo che di tipo infiammatorio, assumendo dunque un ruolo patogenetico nelle fasi iniziali della CKD e nelle altre patologie HU- correlate (ipertensione arteriosa, obesità, resistenza all’insulina) che potrebbero quindi anche conseguire più all’iperattività della XOR che non alla HU di per sé.
In questa differente prospettiva, il trattamento con farmaci inibitori della XOR (XORi) quali allopurinolo e febuxostat, oltre a ridurre l’uricemia prevenendo la deposizione tissutale di cristalli di MSU, ridurrebbe la produzione di ROS indotta dalla XOR prevenendo il danno ossidativo tissutale. In aggiunta, gli XORi non competitivi (febuxostat), attraverso l’azione della ipoxantina-guanina-fosforibosil-transferasi (HGPRT) del cosiddetto “purine salvage pathway”, promuoverebbero il riutilizzo dell’ipoxantina, convertita in inosin-monofosfato (IMP) utilizzabile per incrementare la produzione di ATP. Quest’ultima azione potrebbe anche spiegare gli eventi cardiaci sfavorevoli, descritti in alcuni pazienti al momento della sospensione della terapia con febuxostat, come conseguenti ad un disturbo della conduzione e della contrazione da improvvisa ridotta disponibilità di ATP(40-41).

L’approccio terapeutico alla HU sintomatica nel paziente con CKD

L’approccio terapeutico alla HU sintomatica(6,9,10,42,43) deve sempre innanzitutto prevedere l’analisi delle sue possibili cause, l’adozione di appropriate variazioni dello stile di vita e dell’alimentazione (incoraggiamento dell’attività fisica e del calo ponderale; eliminazione di birra, vino, alcoolici e bevande zuccherate; riduzione dell’apporto di proteine animali; mantenimento di un adeguato apporto di fluidi, frutta e verdura), nonché la ricerca e il governo di eventuali altri fattori di rischio concomitanti (fumo, ipertensione, iperglicemia, dislipidemia, obesità). Poiché queste prime obbligatorie misure possono non essere sufficienti, si rende spesso poi necessario anche il ricorso anche alla ULT che può contare sull’esistenza di farmaci appartenenti a tre distinte categorie: XORi, uricosurici e uricasi ricombinanti. Una recente review di Jenkins e coll.(43) ha censito l’esistenza di 36 sostanze ipouricemizzanti, 10 delle quali approvate da una o più organizzazioni nazionali di controllo del farmaco (allopurinolo, febuxostat, topiroxostat, benzbromarone, lesinurad, dotinurad, probenecid, sulfinpirazone, pegloticase, rasburicase) e 26 in studio; di particolare interesse tra queste ultime nuove forme di uricasi ricombinante a minor immunogenicità e farmaci con duplice meccanismo d’azione.
Tra i farmaci finora approvati, gli XORi restano al momento la prima scelta per la buona efficacia nella riduzione dell’uricemia, la semplicità d’utilizzo e, nonostante tutto, la relativa buona sicurezza d’impiego se somministrati nel rispetto di alcune ben specificate cautele.
L’allopurinolo è un analogo purinico, inibitore competitivo non specifico di XOR, che agisce tramite il suo metabolita attivo ossipurinolo ad eliminazione renale. Oltre alla nota interferenza con il metabolismo di altri farmaci (azatioprina, warfarin, diuretici), la sua complicanza più temibile è la sindrome da ipersensibilità all’allopurinolo (AHS): essa è legata alla presenza dell’allele HLA-B*58.01, peraltro più frequente nelle popolazioni asiatica e afro-americana, le sole per le quali ha indicazione il test genetico per ricercarlo, mentre si riscontra solo nello 0.7% dei soggetti di razza bianca. Anche il supposto ruolo della CKD nel favorire la AHS è oggi ridimensionato e ritenuto limitato ai casi di avvio del trattamento a dosi troppo alte, più che non alla necessità di adeguare al GFR la successiva dose di mantenimento. Nella CKD è pertanto indicato iniziare con 100 mg/die se il GFR è 30-60 ml/min e con 50 mg/die se il GFR è <30 ml/min, salendo con gradualità ogni 2-5 settimane fino alla dose che consente di raggiungere il target di uricemia <6 mg/dl, e potendo arrivare anche sino a 300 mg/die finché il GFR resta >15 ml/min. Nel paziente in trattamento sostitutivo occorre ricordare che la dialisi rimuove l’UA, ma che, mentre la dialisi peritoneale lo fa in modo continuo, l’emodialisi lo fa ad intermittenza, con una modalità che potrebbe da sola non essere sufficiente nelle forme di gotta severa; a questo proposito va quindi tenuto presente che l’eventuale assunzione dell’allopurinolo deve avvenire dopo la seduta dialitica perché l’emodialisi rimuove il suo metabolita attivo(9,10,43).

Il febuxostat è un inibitore selettivo non purinico di XOR, più costoso dell’allopurinolo, per il quale occorre ricordare che, come quest’ultimo, interferisce con il metabolismo dell’azatioprina. Esso è anche in grado di inibire ABCG2 e di rallentare così l’eliminazione dei propri metaboliti senza tuttavia innalzare significativamente l’uricemia. Avendo un metabolismo prevalentemente epatico è utilizzabile nella CKD a 40 mg/die, ma probabilmente anche a dosi maggiori, con buon profilo di sicurezza, finché il GFR si mantiene >15 ml/min. Se l’avvio del trattamento avviene quando il paziente ha già GFR <30 ml/min, è opportuno farlo a posologia ridotta; in dialisi, pur con pochi dati al riguardo, dosi di 20-40 mg sembrano ben tollerate(9,10,43).
Il topiroxostat è un altro inibitore selettivo non purinico di XOR, approvato solo in Giappone e con profilo di sicurezza non dissimile dai precedenti, che si somministra alla dose di mantenimento di 60-80 mg due volte al dì (9,43).
Gli URICOSURICI sono farmaci ULT di seconda scelta che non funzionano se il GFR è inferiore a 20-30 ml/min, possono indurre nefrolitiasi e vengono generalmente impiegati, pur con tutti i limiti appena descritti, in caso di intolleranza agli XORi o in associazione a questi ultimi quando la monoterapia si rivela insufficiente.
Il probenecid è un inibitore non selettivo di URAT1, che in minor misura agisce anche su GLUT9, OAT1 e OAT3, del quale occorre tener presente la capacità di alterare la clearance di altri farmaci quali ad esempio penicilline, furosemide e methotrexate. Si somministra a una dose variabile da 0.5 a 2 g al giorno(43).
Il benzbromarone è un uricosurico non selettivo più potente del precedente, che agisce allo stesso modo e che può dare epatotossicità. Si somministra alla dose 50-200 mg al giorno(43).
Il lesinurad è un inibitore selettivo di URAT1 che si somministrava alla dose di 200 mg al giorno, ma del quale l’industria farmaceutica ha recentemente cessato la produzione(9,10,43). Il dotinurad è un inibitore selettivo di URAT1 in grado di inibire anche l’inflammasoma NLRP3 che si somministra alla dose di 0.5-4 mg al giorno(43).
Il sulfinpirazone è un altro uricosurico non selettivo in via di cessazione di produzione la cui dose quotidiana varia da 100 a 800 mg suddivisi in due somministrazioni(43).
Le URICASI RICOMBINANTI hanno potente attività ipouricemizzante derivante dalla loro capacità di trasformare l’UA in allantoina, ma sono gravate dalla necessità di somministrazione per via endovenosa, da costi elevati e soprattutto dalla loro immunogenicità.
La rasburicase è indicata nelle HU di origine tumorale e nella sindrome da lisi tumorale alla dose endovenosa di 2 mg/kg/die per 1-5 giorni. Non sono consigliati cicli di trattamento ripetuti in quanto può indurre sia reazioni anafilattiche, sia sviluppo di anticorpi anti-farmaco che ne compromettono l’efficacia(43).
La pegloticase è la forma peghilata della precedente utilizzabile nella gotta severa e non responsiva ai farmaci delle categorie precedentemente illustrate. Ha lunga emivita per cui è sufficiente una somministrazione endovenosa di 8 mg ogni 2 settimane e, nel paziente con CKD, non necessita di adeguamento della dose al GFR. Suoi limiti sono rappresentati dalla necessità di infusione della durata di almeno 2 ore, dal costo elevato, dalle frequenti reazioni infusionali, dal rischio di sviluppo di anticorpi anti-farmaco che ne compromettono l’efficacia e dalla controindicazione all’impiego nei pazienti con favismo nei quali può scatenare crisi emolitiche(43).
Occorre poi tenere presente che esistono svariati farmaci concepiti per altre scopi che possiedono anche un effetto ipouricemizzante mediato dall’inibizione di URAT1. La conoscenza di questa loro caratteristica può consentire di sfruttarli laddove, insieme alla patologia per la quale sono primariamente indicati, coesista anche una HU: tra essi il losartan, i calcio-antagonisti diidropiridinici, gli SGLT2-inibitori (soprattutto empaglifozin), il fenofibrato e l’atorvastatina, le alte dosi di aspirina, la leflunomide, alcuni FANS (indometacina e fenilbutazone), il desametasone e gli estrogeni(10,44).
Parimenti esistono farmaci e sostanze che inducono HU, sempre mediata dell’interazione con trasportatori dell’UA della parete tubulare, effetto collaterale del quale è opportuno essere a conoscenza: i diuretici tiazidici e dell’ansa, alcuni beta-bloccanti (propranololo, atenololo, metoprololo e sotalolo), alcuni antitubercolari (pirazinamide e etambutolo), gli inibitori delle calcineurine, le basse dosi aspirina (effetto peraltro trascurabile rispetto al beneficio cardiovascolare indubbiamente offerto dal farmaco), l’insulina, il testosterone e il lattato(44).

È plausibile che la somministrazione della ULT nella CKD possa esercitare anche un’azione nefroprotettiva?

Un piccolo trial randomizzato e controllato (RCT) del 2006 condotto a Hong Kong su 54 pazienti iperuricemici con CKD(45) documentava un rallentamento del calo del GFR rispetto ai controlli dopo 12 mesi di trattamento con allopurinolo.
Giungevano ad analoghe conclusioni, dopo 24 mesi di trattamento con allopurinolo, anche due studi spagnoli del 2010 e del 2015, peraltro non disegnati in doppio-cieco, rispettivamente su 113 e 107 pazienti con CKD(46-47).
Lo studio RENAAL, disegnato per valutare gli effetti antiipertensivi del losartan(48-49), evidenziava anche un effetto ipouricemizzante del farmaco che determinava una riduzione del 6% del rischio di progressione della CKD per ogni 0.5 mg/dl di riduzione dell’uricemia. Le linee guida KDIGO per la gestione della CKD, la cui stesura risale peraltro ormai al 2012, riportavano tuttavia l’inesistenza di sufficienti evidenze sia per supportare, sia per controindicare l’impiego della ULT allo scopo di rallentare la progressione della nefropatia nel paziente con CKD ed HU sintomatica o asintomatica(50), lasciando del tutto all’orientamento personale di ogni medico la scelta del comportamento da adottare di fronte a ciascun singolo caso. Purtroppo, anche l’ormai lunga serie di studi al riguardo successivi a quella data ha continuato a fornire dati non univoci e spesso criticabili.
Nel 2017 uno studio con 7 anni di follow up condotto con il criterio della randomizzazione mendeliana su 3.896 caucasici finnici affetti da diabete di tipo 1(51) concludeva che la HU è indipendentemente associata al calo del GFR, ma non con un rapporto causale.
Anche da una revisione a ombrello di precedenti meta-analisi di Li e coll. del 2017(52) emergeva un nesso causale tra livelli di UA e sviluppo di gotta o nefrolitiasi, ma non tra livelli di UA e ipertensione o CKD, la cui semplice associazione veniva ritenuta insufficiente ad autorizzare la prescrizione della ULT a scopo nefroprotettivo.
Un’altra meta-analisi cinese del 2017(53) su 16 RCT comprendenti 1.211 pazienti con CKD trovava invece un tasso di declino significativamente inferiore nei pazienti trattati con ULT.

I risultati dello studio FEATHER, un RCT di confronto tra febuxostat e placebo su 443 pazienti con HU asintomatica e CKD in stadio 3, pubblicati da Kimura e coll. nel 2018(54), non mostravano differenze significative nel tasso di riduzione del GFR tra i due gruppi, anche se emergeva invece un significativo beneficio in un sottogruppo di pazienti con malattia meno avanzata, cioè senza proteinuria e con creatininemia inferiore alla media complessiva.
Uno studio retrospettivo del 2018(55) su 12.751 pazienti con CKD stadio 2-4, confrontando quelli trattati con ULT fino a raggiungere un’uricemia inferiore a 6 mg/dl rispetto ai non trattati, concludeva che i primi avevano una significativa maggior probabilità di miglioramento del GFR, soprattutto negli stadi 2 e 3, ma non nello stadio 4.
Kojima e coll hanno pubblicato nel 2019 i risultati dello studio FREED(56), un RCT multicentrico giapponese con 3 anni di follow up su 1.070 anziani iperuricemici con ipertensione, diabete, CKD o patologia cardiovascolare, nell’ambito del quale l’andamento del gruppo di quelli trattati con febuxostat è stato confrontato con quello dei non trattati, dimostrando che il raggiungimento di un end-point composito, costituito dal tasso di eventi cerebrali, cardiovascolari, renali o mortali, era significativamente inferiore tra i primi. Una meta-analisi di studi condotti su pazienti di origine europea eseguita con il metodo della randomizzazione mendeliana e pubblicata nel 2019(57) dimostrava invece nuovamente, pur in presenza di un nesso causale tra livelli di UA e rischio di gotta, l’assenza di un analogo nesso rispetto al rischio di riduzione del GFR per cui gli Autori giudicavano improbabile un effetto nefroprotettivo da parte della ULT.
Due importanti studi pubblicati nel 2020(58-59), a seguito descritti, sui quali erano riposte le aspettative di molti per una definitiva dimostrazione della possibile utilità della ULT per rallentare il calo del GFR nella HU della CKD non hanno invece raggiunto questo traguardo. Lo studio PERL(58), RCT effettuato su 530 pazienti statunitensi e canadesi con diabete tipo 1 e CKD stadio 1-3a, non ha mostrato differenze significative nel tasso medio di declino del GFR tra il gruppo trattato con l’allopurinolo e quello trattato con il placebo. Lungo l’elenco delle successive osservazioni riguardanti i limiti che potrebbero aver inficiato le conclusioni di questo studio: casistica relativamente piccola, reclutamento pianificato per pazienti con uricemia >4.5 mg/dl (quindi anche con uricemia normale) ed attuato in soggetti con diabete mediamente di lunga durata, mal controllato e con nefropatia ad andamento fast- progressive(4,9,36,60).
Lo studio australiano e neozelandese CKD-FIX(59), RCT su 363 pazienti con CKD in stadio 3- 4 senza gotta, diabetici e non, trattati in parte con allopurinolo ed in parte con placebo e seguiti per 2 anni, ha ottenuto una riduzione delle uricemie nel braccio con allopurinolo senza ottenere differenze significative nel tasso annuo di riduzione del GFR rispetto al braccio con placebo. Anche in questo caso sono stati elencati svariati limiti che potrebbero aver inficiato le conclusioni dello studio: casistica relativamente piccola e comprendente pazienti con CKD già troppo avanzata, arruolamento avvenuto in modo incompleto (solo al 60% rispetto al numero preventivamente pianificato), elevata (17-30%) percentuale di interruzione della terapia senza conseguente esclusione di questi pazienti dalla casistica, eccessiva eterogeneità delle uricemie basali per mancata adozione tra i criteri di inclusione di un range ben definito(4,9,36,60).

Da segnalare a questo proposito anche altre non dirette e più generali osservazioni, valide per ottimizzare il disegno di eventuali futuri studi, sul fatto che i benefici del trattamento con ULT potrebbero anche variare in funzione dell’età(60), della durata(60) e della tipologia della nefropatia di base(35,61), oltre che del tipo, della dose e della durata(4) del trattamento ipouricemizzante.
Sempre nel 2020 Chen e coll.(62) hanno effettuato una revisione sistematica con meta- analisi di 28 RCT, tra i quali erano inclusi anche gli studi FEATHER, PERL e CKD-FIX e complessivamente riguardanti 3.934 pazienti, senza trovare benefici cardio-nefroprotettivi della ULT. Anche un successivo aggiornamento di questo studio, riportato nelle linee-guida CARI messe a punto in Australia e Nuova Zelanda nel 2022(63), nel quale sono stati selezionati 17 dei 28 RCT analizzati nel lavoro precedente, nello specifico quelli nei quali almeno il 66% dei soggetti reclutati risultasse affetto da CKD, e ne sono stati aggiunti 2 con analoghe caratteristiche, pur appurando che la ULT riduce gli attacchi gotta e non è meno sicura del placebo, ha confermato l’assenza di benefici cardionefroprotettivi e la non indicazione al suo impiego con questo scopo. Costituisce tuttavia un limite di entrambi questi studi il fatto che non tutti i pazienti avessero una HU e una CKD(4).
Nel 2022 Tien e coll. di Taiwan(64) hanno pubblicato una revisione sistematica con meta- analisi di 13 RCT riguardanti complessivamente 2.842 pazienti con aHU rilevando benefici nefroprotettivi della ULT rispetto al placebo, dove però raggiungevano la significatività quelli trattati con allopurinolo, ma non quelli trattati con febuxostat.
Un’altra revisione sistematica con meta-analisi di Tsukamoto e coll.(65) su 10 RCT che includevano 1.480 pazienti con CKD ha documentato una significativa azione nefroprotettiva del topiroxostat e del febuxostat nei pazienti con HU, ma non dell’allopurinolo e della pegloticase.
Al contrario, uno studio retrospettivo statunitense su 269.651 pazienti con GFR >60 ml/min e senza albuminuria non solo non mostrava benefici nefroprotettivi nell’avvio della ULT, ma addirittura rilevava un maggior rischio di insorgenza di CKD(66).
Sempre nel 2022, il trail randomizzato ALL-HEART ha arruolato 5.721 ultrasessantenni del Regno Unito con cardiopatia ischemica e senza gotta non trovando differenze nel raggiungimento di un endpoint composito, riguardante eventi cardiovascolari sfavorevoli, tra trattati anche con allopurinolo e trattati solo con le cure usuali(67).
Nel 2023 una meta-analisi, eseguita da Autori brasiliani(68) su 18 RCT complessivamente riguardanti 2.463 pazienti con CKD, ha documentato significativi effetti nefroprotettivi della ULT rispetto al placebo.
Ancora nel 2023 i risultati pubblicati da Yang e coll.(69), relativi ad un RCT multicentrico cinese su 100 pazienti con CKD in stadio 3-4 seguiti per 12 mesi, mostrano un rallentamento del declino del GFR nel gruppo trattato con febuxostat rispetto a quello trattato con placebo.
Per quanto attiene il confronto tra i diversi farmaci utilizzabili per la ULT nella CKD, sia in termini di sicurezza di impiego, sia in termini di maggior o minor efficacia cardionefroprotettiva, alcuni articoli di più recente pubblicazione forniscono indicazioni, anche anche in questo caso non tali da consentire di trarne univoche conclusioni.
Lo studio CARES del 2018(70), un RCT su 6.190 pazienti con gotta e patologia cardiovascolare, stratificati per livelli di GFR, dimostra la non inferiorità del febuxostat rispetto all’allopurinolo per tasso di eventi cardiovascolari avversi, ma ne palesa una maggior mortalità totale e cardiovascolare. I risultati di questo studio sono stati peraltro messi in discussione per l’alto tasso di sospensione del trattamento e di perdita al follow- up, la mancanza di un gruppo di controllo con placebo e l’insufficiente associata prescrizione di farmaci cardioprotettivi nei cardiopatici arruolati per lo studio(43).
Nel 2021 Pawar e coll., per rivalutare il problema della sicurezza cardiovascolare in un contesto reale, hanno esaminato retrospettivamente i dati relativi a 467.461 pazienti del sistema statunitense Medicare giungendo alla conclusione che il febuxostat non aumenta il rischio cardiovascolare rispetto all’allopurinolo(71).
La già citata revisione sistematica con meta-analisi di Tsukamoto e coll. del 2022(65) su studi relativi a pazienti con CKD documenta una significativa azione nefroprotettiva del topiroxostat e del febuxostat, ma non dell’allopurinolo e della pegloticase.
Altri 2 RCT cinesi pubblicati nel 2022 e condotti per 6 mesi rispettivamente su 100 e 120 pazienti con CKD mostrano nel primo caso(72) la superiorità del febuxostat rispetto all’allopurinolo sia come effetto nefroprotettivo, sia come sicurezza d’impiego, e nel secondo caso(73), la maggior nefroprotezione offerta delle basse dosi di febuxostat rispetto a quelle di allopurinolo (20 mg e 200 mg rispettivamente) con sicurezza d’impiego non inferiore.
Uno studio retrospettivo del 2023 condotto da Lai e coll.(74) su 13.661 pazienti di Taiwan con aHU in trattamento con ULT evidenzia minor rischio di sviluppare CKD con il benzbromarone che non con l’allopurinolo.
Un’analisi post-hoc del 2023 di Kohagura e coll.(75), riferita a 707 dei 1.070 pazienti dello studio FREED(56) che avevano un GFR <60 ml/min, evidenzia che il rischio relativo di sviluppo o peggioramento della macroalbuminuria era del 56% inferiore nel gruppo con febuxostat rispetto ai controlli.
In un altro studio randomizzato di Kohagura e coll. su 95 pazienti con ipertensione, HU e CKD in stadio 3(76) non sono emerse differenze nel declino del GFR fra quelli trattati con febuxostat e quelli trattati con benzbromarone. Il declino del GFR era peraltro significativamente inferiore con febuxostat nel sottogruppo con CKD in stadio 3a, ma non in quello in stadio 3b: tutto sommato una non trascurabile conferma che, anche i farmaci che mostrano un’efficacia nefroprotettiva nelle fasi più precoci della CKD, tendono a perderla nei pazienti con CKD in stadio più avanzato.
La già citata meta-analisi di Bignardi e coll.(68), che documenta l’utilità della ULT ai fini nefroprotettivi, non ha trovato differenze di efficacia in tal senso fra i tre XORi studiati. Va infine per completezza ricordato che, una recente ricognizione dello stato dell’arte sui rapporti tra HU e CKD anche nell’ambito del trapianto renale, riporta un analogo clima di incertezza caratterizzato dall’evidenza che la HU, presente nel 28% dei casi, costituisca un indubbio fattore di rischio indipendente per lo sviluppo di insufficienza del rene trapiantato, ma con rapporto di causalità e indicazioni all’impiego della ULT ancora oggetto di dubbi(77).
In conclusione, come ben dimostrato non solo dall’insieme dei risultati delle ricerche sin qui citate, ma anche dall’accesa diatriba consegnata alla Letteratura(78-80) da gruppi di Autori in dissenso su quali caratteristiche conferiscano maggiore o minore attendibilità agli studi (degne di menzione, a questo proposito, anche le critiche ai lavori nei cui gruppi di controllo non era avvenuta, come lecito attendersi, una significativa progressione della nefropatia), e come ben riporta il titolo di un’ampia revisione sull’argomento recentemente pubblicata(4), probabilmente molto resta ancora da fare.

Quali comportamenti clinici e quali future ricerche gli esperti suggeriscono di adottare alla luce dell’attuale stato delle conoscenze?

Alcuni Autori(4) suggeriscono di affrontare il problema del trattamento della HU nella CKD distinguendo i comportamenti da adottare nei pazienti con gotta da quelli nei pazienti con aHU: nel primo caso la ULT, che trova comunque indicazione per ridurre il rischio di ricorrenza degli attacchi artritici e di peggioramento del danno articolare perseguendo un target di uricemia <5-6 mg/dl(81-85), ha buona probabilità di interferire favorevolmente sulla patologia da deposito di cristalli che si sviluppa anche in sede extra-articolare (renale e vascolare)(4,39); nel secondo caso, poiché i controversi risultati delle meta-analisi si spiegherebbero anche con il fatto che alcuni sottogruppi di pazienti potrebbero giovarsi più di altri della ULT, sembra trovare crescenti consensi l’idea che la ricerca venga orientata verso l’individuazione di tali sottogruppi(4,9,36,60). In particolare, secondo Johnson e coll.4), potrebbero essere da tenere in maggior considerazione quelli con patologia tissutale da cristalli ancora silente, oggi meglio identificabili con le indagini ecografiche e DECT già in precedenza citate, quelli con cristalluria ricorrente e/o nefrolitiasi uratica e quelli con aumentati livelli intracellulari di UA, questi ultimi indirettamente individuabili attraverso il rilievo di un’incrementata attività plasmatica della XOR. Altri punti fondamentali da tenere presente nel disegnare futuri studi sono rappresentati: dal momento d’inizio della ULT (4,9,36,41), che dovrebbe essere quanto mai tempestivo e precoce perché il danno renale da UA solubile, una volta avviato, progredisce poi indipendentemente dai livelli di uricemia per l’iperfiltrazione e l’ipertensione glomerulare; dalla durata del trattamento(4) che sembra possa offrire benefici maggiori se protratto per almeno due anni; dalla verifica se il target di uricemia per ottenere l’effetto nefroprotettivo può essere o meno il medesimo adottato per la prevenzione della gotta(42).
Altri Autori(5,40,42) suggeriscono inoltre di chiarire fino a che punto gli effetti dei farmaci XORi dipendano in modo diretto dalla loro azione ipouricemizzante e non da altri effetti quali ad esempio l’azione anti-ossidante indotta dal blocco di altri substrati della XOR.

Conclusioni

E’ assodato che la HU costituisca un fattore di rischio indipendente per lo sviluppo della CKD con crescenti anche se non definitive dimostrazioni di causalità legate a possibili plurimi meccanismi patogenetici.
In considerazione delle differenze nel metabolismo delle purine tra una specie e l’altra va ricordato che, qualunque risultato ottenuto in proposito da esperimenti su animali dotati di attività uricasica, necessita comunque di essere riconfermato nell’uomo.
A dispetto della presenza di un logico razionale per l’impiego della ULT ai fini del rallentamento della progressione della nefropatia nei pazienti con HU e CKD, i risultati controversi e i limiti degli studi a ciò rivolti non hanno finora portato a robuste e definitive dimostrazioni di reale efficacia in tal senso.

Poiché il danno renale UA-correlato, una volta indotto e consolidato, sembrerebbe mantenuto da meccanismi indipendenti dai livelli di uricemia, resta da confermare se un precoce avvio della ULT nelle fasi iniziali della nefropatia abbia maggiori probabilità di fornire reale nefroprotezione. Analogamente occorre appurare se esistano altri specifici sottogruppi di pazienti che per età, sesso, tipologia di danno, nefropatia di base o altre caratteristiche abbiano maggiori probabilità di potersi giovare di tale trattamento.
Sono pertanto auspicabili futuri più ampi RCT che, adeguatamente disegnati, e dotati di criteri di inclusione tali da superare i limiti di alcuni di quelli sin qui prodotti, analizzino la risposta ai differenti farmaci somministrati in fase iniziale di malattia, per un tempo sufficiente e in dosi idonee al raggiungimento di un target di uricemia che va anch’esso meglio ridefinito.
Nel frattempo, nella pratica clinica quotidiana, è opportuno tenere sempre presente che quella dell’utilità della ULT a scopo nefroprotettivo nella CKD rimane una questione aperta e che tale terapia, per ora non raccomandata dalle linee guida per il protrarsi della mancanza di sicure evidenze, potrebbe in realtà essere di grande utilità almeno per alcuni dei nostri pazienti.

Bibliografia

Kanbay M, Solak Y, Dogan E et al. Uric acid in hypertension and renal disease: the chicken or the egg? Blood Purif 2010;30(4):288-295. https://doi.org/ 10.1159/000321074.
Johnson RJ, Nakagawa T, Jalal DI et al. Uric acid and chronic kidney disease: which is chasing which? Nephrol Dial Transplant 2013;28:2221-2228. https://doi.org/ 10.1093/ndt/gft029.
Jalal DI. Hyperuricemia. The kidneys, and the spectrum of associated diseases: a narrative review. Curr Med Res Opin 2016 Nov;32(11):1863-1869. https://doi.org/ 10.1080/03007995.2016.1218840.
Johnson RJ, Sanchez Lozada LG, Lanaspa M et al. Uric Acid and Chronic Kidney Disease: Still More to Do. Kidney Int Rep 2023;8(2):229-239. https://doi.org/ 10.1016/j.ekir.2022.11.016.
Anders HJ, Li Q, Steiger S. Asymptomatic hyperuricaemia in chronic kidney disease: mechanisms and clinical implications. Clin Kidney J 2023;16(6):928-938. https://doi.org/ 10.1093/ckj/sfad006.
Delbarba E, Terlizzi V, Dallera N et al. Iperuricemia e Gotta. G Ital Nefrol 2016;33(S68).PMID: 27960024.
Zacchia M, Capolongo G, Rinaldi L et al. Fisiologia dell’handling renale dell’acido urico. G Ital Nefrol 2015;32(S62). PMID: 26005871.
Dalbeth N, Gosling AI, Gaffo A et al. Gout. Lancet 2021 May 15;397(10287):1843-1855. https://doi.org/10.1016/S0140-6736(21)00569-9.
Ponticelli C, Podestà MA, Moroni G. Hyperuricemia as a trigger of immune response in hypertension and chronic kidney disease. Kidney Int 2020 Nov;98(5):1149-1159. https://doi.org/10.1016/j.kint.2020.05.056.
Sun H, Wu Y, Bian H et al. Function of Uric Acid Transporters and Their Inhibitors in Hyperuricaemia. Front Pharmacol 2021 July;12:667753. https:// doi.org/ 10.3389/fphar.2021.667753.
Kratzer JT, Lanaspa MA, Murphy MN et al. Evolutionary history and metabolic insights of ancient mammalian uricases. Proc Nat Acad Sci USA 2014 March 11;111(10):3763- 3768. https://doi.org/10.1073/pnas.1320393111.
Glynn RJ, Campion EW, Silbert JE. Trends in serum uric acid levels 1961-1980. Arthritis Rheum 1983 Jan;26(1):87-93. https://doi.org/10.1002/art.1780260115.
Desideri G, Castaldo G, Lombardi A et al. Is it time to revise the normal range of serum uric acid levels? Eur Rev Med Pharmacol Sci 2014;18:1296-1306. PMID: 24867507.
Bardin T. Hyperuricemia starts at 360 micromoles (6 mg/dL). Joint Bone Spine 2015 May;82(3):141-143. https://doi.org/10.1016/j.jbspin.2015.01.002.
Piani F, Johnson RJ. Does gouty nephropathy exist, and is it more common than we think? Kidney Int 2021;99:31-33. https://doi.org/10.1016/j.kint.2020.10.015.
Chen C, Lu JM, Yao Q. Hyperuricemia-Related Diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview. Med Sci Monit 2016;22:2501-2512. https://doi.org/
Russo E,Viazzi F, Pontremoli R et al. Association of uric acid with kidney function and albuminuria: the Uric Acid Right for heArt Health (URRAH) Project. J Nephrol 2022;35:211-221. https://doi.org/10.1007/s40620-021-00985-4.
Garrod AB et al. The Nature and Treatment of Gout and Rheumatic Gout. Br Foreign Med Chir Rev 1860 Apr;25(50):419-435.
Talbott JH, Terplan KL. The kidney in gout. Medicine (Baltimore) 1960 Dec;39:405-467. PMID: 13775026
Barlow KA, Beilin LJ. Renal disease in primary gout. Q J Med 1968 Jan;37:79-96. PMID: 5657765.
Reif MC, Constantiner A, Levitt MF. Chronic gouty nephropathy: a vanishing syndrome? New Engl J Med 1981 Feb;304:535-536. https://doi.org/10.1056/NEJM198102263040909.
Porter GA. Gouty nephropathy: fact or fiction? Am J Kidney Dis 1983 Mar;2(5):553-554. https://doi.org/10.1016/s0272-6386(83)80099-7.
Beck LH. Requiem for gouty nephropathy. Kidney Int 1986 Aug;30:280-287. https://doi.org/10.1038/ki.1986.179.
Kang DH, Nakagawa T, Feng L et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13:2888–2897. https://doi.org/10.1097/ 01.asn.0000034910.58454.fd.
Moe OW. Posing the Question Again: Does Chronic Uric Acid Nephropathy Exist? J Am Soc Nephrol 2010;21:395-397. https://doi.org/10.1681/ASN.2008101115.
Xiao J, Zhang X, Fu C et al. Soluble uric acid increases NALP3 inflammasome and interleukin-1β expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway. Int J Mol Med 2015 May;35(5):1347-1354. https://doi.org/10.3892/ijmm.2015.2148.
Xiao J, Fu C, Zhang X et al. Soluble monosodium urate, but not its crystals, induces toll like receptor 4-dependent immune activation in renal mesangial cells. Mol Immunol 2015 Aug;66(2):310-318. https://doi.org/10.1016/j.molimm.2015.03.250.
Kanbay M, Ylmaz MI, Sonmez A et al. Serum Uric Acid Independently Predicts Cardiovascular Events in Advanced Nephropathy. Am J Nephrol 2012;36:324-331. https://doi.org/10.1159/000342390.
Zhu P, Liu Y, Han L et al. Serum Uric Acid is Associated with Incident Chronic Kidney Disease in Middle-Aged Populations: A Meta-Analysis of 15 Cohort Studies. PLoS One 2014 Jun 24;9(6):e100801. https://doi.org/10.1371/journal.pone.0100801.
Srivastava A, Kaze AD, McMullan CJ et al. Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD. Am J Kidney Dis 2018 Mar;71(3):362-370. https://doi.org/10.1053/j.ajkd.2017.08.017.
Del Pinto R, Viazzi F, Pontremoli R et al. The URRAH study. Panminerva Med. 2021 Dec;63(4):416-423. https://doi.org/10.23736/S0031-0808.21.04357-3.
Gonçalves DLN, Moreira TR, da Silva LS. A systematic review and meta-analysis of the association between uric acid levels and chronic kidney disease. Sci Rep 2022 Apr 15;12(1):6251. https://doi.org/10.1038/s41598-022-10118-x.
Prezelin-Reydit M, Combe C, Fouque D et al. Longitudinal uric acid has nonlinear association with kidney failure and mortality in chronic kidney disease. Sci Rep 2023 Mar 9;13(1):3952. https://doi.org/10.1038/s41598-023-30902-7.
Schwartz GJ, Roem JL, Hooper SR et al. Longitudinal changes in uric acid concentration and their relationship with chronic kidney disease progression in children and adolescents. Pediatr Nephrol 2023 Feb;38(2):489-497. https://doi.org/10.1007/s00467- 022-05620-3.
Tsukamoto SI, Wakui H, Tamura K. Effects of Uric Acid-Lowering Therapy on the Kidney (HTR-2023-0096.R2). Hypertens Res 2023 Jun;46(6):1447-1449. https://doi.org/ 10.1038/s41440-023-01252-8.
Leoncini G, Barnini C, Manco L et al. Uric acid lowering for slowing CKD progression after the CKD-FIX trial: a solved question or still a dilemma? Clin Kidney J 2022;15(9):1666–1674. https://doi.org/10.1093/ckj/sfac075
Steiger S, Rossaint J, Zarbock A et al. Secondary Immunodeficiency Related to Kidney Disease (SIDKD) – Definition, Unmet Need, and Mechanisms. J Am Soc Nephrol 2022 Feb;33(2):259-278. https://doi.org/10.1681/ASN.2021091257.
Bardin T, Tran KM, Nguyen QD et al. Renal medulla in severe gout: typical findings on ultrasonography and dual-energy CT study in two patients. Ann Rheum Dis 2019 mar;78(3):433-434. https://doi.org/10.1136/annrheumdis-2018-214174.
Bardin T, Nguyen QD, Tran KM et al. A cross-sectional study of 502 patients found a diffuse hyperechoic kidney medulla pattern in patients with severe gout. Kidney Int 2021;99:218-226. https://doi.org/10.1016/j.kint.2020.08.024.
Furuhashi M. New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity. Am J Physiol Endocrinol Metab 2020 Nov;319(5):E827- E834. https://doi.org/10.1152/ajpendo.00378.2020.
Polito L, Bortolotti M, Battelli MG et al. Chronic kidney disease: Which role for xanthine oxidoreductase activity. Pharmacol Res 2022 Oct; 184:106407. https://doi.org/ 10.1016/j.phrs.2022.106407.
Vettoretti S, Pontremoli R, Messa P. Treatment of hyperuricemia in CKD. G Ital Nefrol 2015;32 Suppl 62:gin/32.S62.9. PMID: 26005876.
Jenkins C, Hwang JH, Kopp JB et al. Review of Urate-Lowering Therapeutics: From the Past to the Future. Front Pharmacol 2022;13:925219. https://doi.org/ 10.3389/fphar.2022.925219.
Leung N, Yip K, Pillinger MH et al. Lowering and Raising Serum Urate Levels: Off-Label Effects of Commonly Used Medications. Mayo Clin Proc. 2022 July;97(7):1345-1362. https://doi.org/10.1016/j.mayocp.2022.02.027.
Siu YP, Leung KT Tong MKH et al. Use of Allopurinol in Slowing the Progression of Renal Disease Through Its Ability to Lower Serum Uric Acid Level. Am J Kidney Dis 2006; 47:51–59. https://doi.org/10.1053/j.ajkd.2005.10.006
Goicoechea M, De Vinuesa SG, Verdalles U et al. Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk. Clin J Am Soc Nephrol 2010;5:1388–1393. https://doi.org/10.2215/CJN.01580210
Goicoechea M, De Vinuesa SG, Verdalles U et al. Allopurinol and Progression of CKD and Cardiovascular Events: Long-term Follow-up of a Randomized Clinical Trial. Am J Kidney Dis 2015;65:543–549. https://doi.org/10.1053/j.ajkd.2014.11.016.
Miao Y, Ottenbros SA, Laverman GD et al. Effect of a Reduction in Uric Acid on Renal Outcomes During Losartan Treatment: A Post Hoc Analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial. Hypertension 2011, 58, 2–7. https://doi.org/ 10.1161/HYPERTENSIONAHA.111.171488.
Smink PA, Bakker SJ, Laverman GD et al. An initial reduction in serum uric acid during angiotensin receptor blocker treatment is associated with cardiovascular protection: a post-hoc analysis of the RENAAL and IDNT trials. J Hypertens 2012;30:1022-28. https://doi.org/10.1097/HJH.0b013 e3283 5200f 9
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3 1-150. https://doi.org/10.1038/kisup.2012.73
Ahola AJ, Sandholm N, Forsblom C et al . The serum uric acid concentration is not causally linked to diabetic nephropathy in type 1 diabetes. Kidney Int2017 May;91(5):1178-1185. https://doi.org/10.1016/j.kint.2016.11.025.
Li X, Meng X, Timofeeva M et al. Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies. BMJ 2017; 357:j2376. https://doi.org/ 10.1136/bmj.j2376.
Su X, Xu B, Yan B et al. Effects of uric acid-lowering therapy in patients with chronic kidney disease: A meta-analysis. PLoS One 2017 Nov 2;12(11):e0187550. https:// doi.org/10.1371/journal.pone.0187550.
Kimura K, Hosoya T, Uchida S et al. Febuxostat Therapy for Patients With Stage 3 CKD and Asymptomatic Hyperuricemia: A Randomized Trial. Am J Kidney Dis 2018;72(6):798- 810. https://doi.org/10.1053/j.ajkd.2018.06.028
Levy G, Shi JM, Cheetham TC et al. Urate-lowering therapy in moderate to severe chronic kidney disease. Perm J 2018;22:17-142. https://doi.org/10.7812/TPP/17-142.
Kojima S, Matsui K, Hiramitsu S et al. Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy. Eur Heart J 2019;40:1778–1786. https://doi.org/ 10.1093/eurheartj/ehz119
Jordan DM, Choi HK, Verbanck M et al. No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study. PLoS Med 2019 Jan 15;16(1):e1002725. https:// doi.org/10.1371/journal.pmed.1002725.
Doria A, Galecki AT, Spino C et al. Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes N Engl J Med. 2020 June 25; 382(26): 2493–2503. https://doi.org/10.1056/NEJMoa1916624.
Badve SV, Pascoe EM, Biostat M et al. Effects of Allopurinol on the Progression of Chronic Kidney Disease. N Engl J Med 2020;382:2504-13. https://doi.org/ 10.1056/NEJMoa1915833
Russo E, Verzola D, Leoncini G et al. Treating Hyperuricemia: The Last Word Hasn’t Been Said Yet. J Clin Med 2021;10:819-826. https://doi.org/10.3390/jcm10040819.
Watanabe K, Nakayama M, Yamamoto T et al. Different clinical impact of hyperuricemia according to etiologies of chronic kidney disease: Gonryo Study. PLoSOne 2021;16(3):e0249240. https://doi. org/10.1371/journal.pone.0249240.
Chen Q, Wang Z, Zhou J et al. Effect of Urate-Lowering Therapy on Cardiovascular and Kidney Outcomes: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol. 2020 Nov 6;15(11):1576-1586. https://doi.org/10.2215/CJN.05190420.
Stanley IK, Phoon RKS, Toussaint ND et al. Caring for Australians and New Zealanders With Kidney Impairment Guidelines: Rapid Development of Urate Lowering Therapy Guidelines for People With CKD. Kidney Int Rep 2022 Oct 5;7(12):2563- 2574. https://doi.org/10.1016/j.ekir.2022.09.024.
Tien YY, Shih MC, Tien CP et el. To Treat or Not to Treat? Effect of Urate-Lowering Therapy on Renal Function, Blood Pressure and Safety in Patients with Asymptomatic Hyperuricemia: A Systematic Review and Network Meta-Analysis. J AM Board Fam Med 2022;35:140-151. https://doi.org/10.3122/jabfm.2022.01.210273.
Tsukamoto S, Okami N, Yamada T et al. Prevention of kidney function decline using uric acid-lowering therapy in chronic kidney disease patients: a systematic review and network meta-analysis. Clin Rheumatol 2022 Mar;41(3):911-919. https://doi.org/ 10.1007/s10067-021-05956-5.
Hassan W, Shrestha P, Sumida K et al. Association of Uric Acid-Lowering Therapy With Incident Chronic Kidney Disease. JAMA Netw Open2022 Jun 1;5(6):e2215878. https://doi.org/10.1001/jamanetworkopen.2022.15878.
Mackenzie IS, Hawkey CJ, Ford I et al. Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open- label, blinded-endpoint trial. Lancet. 2022 Oct 8;400(10359):1195-1205. https://doi.org/ 10.1016/S0140-6736(22)01657-9.
Bignardi PR, Ido DH, Lopes Garcia FA et al. Does uric acid-lowering treatment slow the progression of chronic kidney disease? A meta-analysis of randomized controller trials. Nefrologia 2023;43(2):167-181. https://doi.org/10.1016/j.nefroe.2022.04.005.
Yang H, Li R, Li Q et al. Effects of febuxostat on delaying chronic kidney disease progression: a randomized trial in China. Int Urol Nephrol 2023 May;55(5):1343-1352.https://doi.org/10.1007/s11255-022-03437-5.
White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med 2018;378:1200-1210. https://doi.org/0.813rem;”>10.1056/NEJMoa1710895.
Pawar A, Desai RJ, Liu J et al. Updated Assessment of Cardiovascular Risk in Older Patients With Gout Initiating Febuxostat Versus Allopurinol. J Am Heart Assoc 2021;10:e020045. https://doi.org/10.1161/JAHA.120.020045
Liao Z, Xu L, Wan B et al. Comparison of Febuxostat and Allopurinol in the Treatment of Patients with Chronic Kidney Disease Stage 3∼5 with Hyperuricemia. Emerg Med Int 2022 Oct 11;2022:1177946. https://doi.org/10.1155/2022/1177946.
Yang N, Cao B. Low-dose febuxostat exhibits a superior renal-protective effect and non-inferior safety profile compared to allopurinol in chronic kidney disease patients complicated with hyperuricemia: A double-centre, randomized, controlled study. J Clin Pharm Ther. 2022 Dec;47(12):2214-2222. https://doi.org/10.1111/jcpt.13794.
Lai SW, Liao KF, Kuo YH et al. Comparison of benzbromarone and allopurinol on the risk of chronic kidney disease in people with asymptomatic hyperuricemia. Eur J Intern Med 2023 Jul;113:91-97. https://doi.org/10.1016/j.ejim.2023.04.025.
Kohagura K, Kojima S, Uchiyama K et al. Febuxostat and renal outcomes: post-hoc analysis of a randomized trial. Hypertension Res 2023;46:1417–1422. https://doi.org/ 10.1038/s41440-023-01198-x.
Kohagura K, Satoh A, Kochi M et al. Urate-lowering drugs for chronic kidney disease with asymptomatic hyperuricemia and hypertension: a randomized trial. J Hypertens 2023 Sep 1;41(9):1420-1428. https://doi.org/10.1097/HJH.0000000000003484.
Imasuen UJ,Swanson KJ, Parajuli S. Serum uric acid levels in kidney transplant recipients: A cause for concern? A review of recent literature. Transplant Rev 2023 Jul; 37(3):100775. https://doi.org/10.1016/j.trre.2023.100775.
Sato Y, Feig DI, Stack AG et al. The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD. Nat Rev Nephrol. 2019 Dec;15(12):767-775. https://doi.org/ 10.1038/s41581-019-0174-z.
Steiger S, Ma Q, Anders HJ. The case for evidence-based medicine for the association between hyperuricaemia and CKD. Nat Rev Nephrol 2020 Jul;16(7):422. https://doi.org/ 10.1038/s41581-020-0288-3.
Sato Y, Feig DI, Stack AG et al. Reply to ‘The case for evidence-based medicine for the association between hyperuricaemia and CKD’. Nat Rev Nephrol 2020 Jul;16(7):422-423. https://doi.org/10.1038/s41581-020-0289-2.
FitzGerald JD, Dalbeth N, Mikuls T et al. 2020 American College of Rheumatology Guideline for the Management of Gout Arthritis Care Res (Hoboken)2020 Jun;72(6):744-760. https://doi.org/10.1002/acr.24180.
Ughi N, Prevete I, Ramonda R et al. The Italian Society of Rheumatology clinical practice guidelines for the diagnosis and management of gout. Reumatismo 2019 Sep 23;71(S1):50-79. https://doi.org/10.4081/reumatismo.2019.1176.
Afinogenova Y, Danvea A, Neogi T. Update on gout management: what is old and what is new. Curr Opin Rheumatol 2022, 34:118–124. https://doi.org/10.1097/ BOR.0000000000000861.
Stamp LK, Farquhar H. Treatment advances in gout. Best Pract Res Clin Rheumatol 2021 Dec;35(4):101719. https://doi.org/10.1016/j.berh.2021.101719.
Stamp LK, Farquhar H, Pisaniello HL et al. Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities Nat Rev Rheumatol 2021 Oct;17(10):633-641. https://doi.org/10.1038/s41584-021-00657-4.

Pius X (1835-1914): the last gouty pope

Posted on Tuesday February 1st, 2022Scarica PDF

Corresponding author:
Natale Gaspare De Santo
Salita Scudillo 20,
80131, Napoli
E-mail: NataleGaspare.Desanto@unicampania.it

Abstract

Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis in adults. It is due to the deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia. Gout is the oldest recorded inflammatory arthritis to affect humankind, with roots stretching back to 2460 BC. It is known as “the rich man’s disease”, “the patrician malady”, “a disease of plenty”, “disease of kings”, “disease of Western Society”, and also “a life-style disease”. Few studies have addressed the problem of gout among popes, affluent people who usually live longer than their contemporaries and are among the most scrutinized persons. Pius X (1835-1914) was the last pope with gout.

Gout seems to have affected 26 out of 265 popes (9.81%) from Saint Peter to Benedict XVI (34-2013 AD). The first was Gregory I Magnus, who was pope in the years 590-604, the last was Pius X, who reigned from 1903 to 1914 at age 79. Their age at death was 71.7 ±9.2 years (Mean ± SD). All popes were elderly men, some had voracious appetites and/or were wine drinkers. Several were sedentary and obese, while others were sober eaters, who took long walks or went riding. Chiragra (arthritic pain in the hands), podagra (arthritic pain in the big toe) and renal stone disease were among the most frequent disturbances.

The causes of death, due to CKD, strokes and infections are discussed along with the fact that gout disappeared from the Vatican Palace on August 22, 1914. However, in accordance with the Theory of Epidemiological Transition, gout seems likely to become a problem for the general population, increasingly adopting unhealthy lifestyle choices, in the absence of a correct education.

Keywords: gout, popes, Pius X, renal death, death due to infection, death due to stroke

Introduction

Gout is a chronic, painful, non-infectious, non-lethal disease associated with crystal deposition of uric acid, when uric acid concentration exceeds 6.8 mg/dl plasma. The kidneys may cause hyperuricemia – the prevalence of which increases in the old and very old, – but are also the target of hyperuricemia (renal stones, renal disease and its progression). Hyperuricemias are due to either renal overload, renal underexcretion or a combination of both; renal overload may be due to overproduction by dietary purines, endogenous purine synthesis, purine breakdown and purine salvage [1–6]. Gout, known also as the “patrician malady” and the “disease of distinction” [7,8] is the oldest recorded inflammatory arthritis to affect humankind, with roots stretching back to 2640 BC [9].

Popes by definition belong to the most affluent class and their lifespan is longer than their contemporaries. In fact, a total of 51 pontiffs reigning in the years 1493 to 2005 lived to a mean age of 63.9 years and died an average of 10.0 years after being enthroned [10]. We have studied the narratives around popes, from Saint Peter to Benedict XVI [11–15], and demonstrated a high prevalence of gout. In a recent review [16] we identified a total of 25 gouty popes: 14 out of 25 (58%) had risk factors; 5 out of 25 (25%) had comorbidities; 21 out of 25 (84%) were unable to perform their duties; 8 out of 25 (32%) died of stroke; 12 of them (68%) had renal disease; 12 out of 17 (70.6%) underwent a renal death. Renal disease did not affect age at death [16].

This paper focuses on the last gouty pope, Pope Pius X. His death has been traditionally but wrongly attributed, even by us, to acute pneumonia. The present study now points out that his death was most likely linked to uremia, due to lasting gout, the final straw being acute pulmonary infection.

Historical case report – Pius X (1835-1914), Pope (8/4, 1903-8/22,1914)

Pius X (Figure 1), born Giuseppe Melchiorre Sarto on June 2, 1835 at Reise (Province of Treviso), was ordained priest in 1858 and, in the same year, became parish priest. Later he was nominated bishop of Mantua (1884), cardinal and patriarch of Venice (June 1893) and elected Pope on August 4, 1903; he reigned until August 22, 1914. A renowned orator, he is remembered for his expertise in sacred music and for hiring Lorenzo Perosi for the Choir of the Sistine Chapel, for his antimodernism and the refusal of science, for the letters sent to European powers to avoid the First World War, and for the wide pastoral care and the love for the poor. In his last will and testament wrote “born poor, lived poor, want to die poor”. Roger Aubert, the Belgian historian Roger Aubert (1914-2009) has defined Pius X as the greatest reformer of the internal life of the Church after the Council of Trent [17].

His health has been described as good until the end of his days and his death ascribed to “acute tracheitis, bronchitis, infection-inflammation of the lower left lung lobe”, a disease of acute onset followed by rapid worsening. He was under the care of Andrea Amici (1870-1920), archiater and chief of medical services in the Vatican, and of Ettore Marchiafava (1847-1935), professor of pathology at the University La Sapienza in Rome. His disease lasted from Saturday August 15 (he celebrated the last mass) to the night of August 20, 1920. The course was characterized by a worsening fever that, in his last hours, peaked at 40°C and was associated with dyspnea [18-20].

Figure 1: Picture of Pope Pius X (1835-1914), October 1903, from Herder Verlag, Freiburg im Breisgau: Die katholischen Missionen (digitally colored). Image in the public domain, https://commons.wikimedia.org/wiki/File:Pius_X,_by_Francesco_De_Federicis,_1903_(retouched,_colorized).tif

However, we now know that Giuseppe Sarto, since his early years of priesthood, had suffered from gout, which flared painfully from time to time and was tolerated by him. As a pope, for obvious state reasons, he was forced to frequent health checks and restrictive dietary impositions [21]. The disease flared up in August 1920 and was associated with chest pain, fever, nephritis (uncurable at that time). The disease extended to the bronchial tree and caused the pneumonia that killed him [22]. So, the diagnosis was pneumonia, heart failure, pericarditis and uremia due to gout.

He was beatified in 1951 by Pius XII. As far as we know, he was the last gouty pope and after him the disease was never again associated with the papacy.

Discussion

Recent studies have defined gout as a “papal disease” [16]. Pope Pius X is the last in the list of 26 gouty popes of the Catholic Church between the years 590-1914 (Table 1). Gout affected 9.77% of all popes and he was the 18^th out of 26 (69.3%) gouty popes to die of a renal cause. The disease left him, like 22 out of 26 (84.6%) other popes, unable to perform his duties.

No.	Popes	Family name	Start of pontificate	End of pontificate	Inhability to perform	Renal/non renal death**	Age of death
1	St Gregory I	Anici	9/3, 590	3/12, 604	yes	Non-renal	64
2	Sisinnius	NK	1/15, 708	2/4, 708	yes	Non-renal	58
3	Sergius II	Sergio	1/2 844	1/17 847	yes	Non-renal	57*
4	Boniface VI	NK	4/5, 896	4/20 896		Non-renal	NK
5	Honorius IV	Giacomo Savelli	4/2, 1285	4/3, 1297	yes	Non-renal	77*
6	Boniface VIII	Benedetto Caetani	12/24, 1294	10/11, 1303	yes	Non-renal	73
7	Clement VI	Pierre Roger	5/7, 1342	12/6, 1352		Non-renal	62
8	Nicholas V	Tommaso Parentucelli	3/6, 1447	3/24, 1455	yes	Renal	58
9	Callistus III	Alonso de Borja	4/8, 1455	8/6, 1458	yes	Renal	80
10	Pius II	Enea Silvio Piccolomini	8/19, 1458	8/15, 1464	yes	Renal	66
11	Sixtus IV	Francesco della Rovere	8/9, 1471	8/12, 1484	yes	Renal	70*
12	Pius III	Francesco Todeschini Piccolomini	9/22, 1503	10/18, 1503	yes	Renal	64
13	Julius II	Giuliano della Rovere	11/1, 1503	2/21, 1513		Non-renal	70
14	Julius III	Giovanni Maria del Monte	2/7, 1550	3/23, 1555	yes	Non-renal	68
15	Marcellus II	Marcello Cervini degli Spannoni	4/1, 1555	4/30, 1555	yes	Renal	54*
16	Pius IV	Giovanni Angelo Medici di Marignano	12/25, 1559	12/9, 1565	yes	Renal	66
17	Clement VIII	Ippolito Aldobrandini	1/30, 1592	3/3, 1605		Renal	70*
18	Gregory XV	Alessandro Ludovisi	2/9, 1621	7/8, 1623	yes	Renal	69
19	Innocent X	Camillo Pamphilj	10/4, 1644	1/7, 1655	yes	Non-renal	80
20	Clement X	Lorenzo Altieri	4/29, 1670	7/22, 1676	yes	Non-renal	86
21	Innocent XI	Benedetto Odescalchi	9/21, 1676	8/12, 1689	yes	Renal	78
22	Innocent XII	Antonio Pignatelli	7/12, 1691	9/28, 1700	yes	Non-renal	85*
23	Clement XII	Lorenzo Corsini	7/12, 1730	2/6, 1740	yes	Renal	88*
24	Benedict XIV	Prospero Lorenzo Lambertini	8/17, 1740	5/3, 1758	yes	Renal	83*
25	Pius VIII	Francesco Saverio Castiglioni	3/31, 1829	11/30, 1830	yes	Non-renal	69
26	Pius X	Giuseppe Melchiorre Sarto	8/4, 1903	8/20, 1914	yes	Renal	79
All popes					84.6%	50% Renal	71.9 ±9.2^#

Table I: Gouty popes (no. 26). Data for popes nos. 1-25 in reference no.16. (* affected by stroke; ** presumed Renal/Non Renal death; ^#Mean ±SD; NK = not known).

The mean age at death of the 26 popes listed in Table I was 71.7 ±9.7 years and no difference was found between the age at death of popes who died of a renal cause and those who died of a non-renal cause. Pius X died from an acute infectious disease, which is always a risk for a gouty person. In fact, compared to the general population, gout patients have an increased association with all-cause disease mortality, especially attributed to cardiovascular diseases, cancer, and infectious diseases [23].

In a study by Vargas-Santos et al. [24] enrolling 19,497 people with a new diagnosis of gout and 194,947 controls, a strong association was found between gout and risk of death due to renal disease. Furthermore, a study by Spaetgen et at. [25] investigated the risk of various types of infections (pneumonia and urinary tract infection), and infection-related mortality in patients with gout using data from the UK Clinical Practice Research Datalink. Their study was the first evaluating the risk of community-acquired infections in patients with gout versus matched controls. Gout was associated with a 34% increased risk of pneumonia. Also, in a national study across the United States [26], the most common infection was pneumonia (52%) in 1998-2000 and sepsis (52%) in 2015-2016. Older age was associated with a greater risk.

There is a strong suspicion, still to prove, of an association between lung infection and the lung dysfunction described in uremia for the first time in 1932 by Ehrich and McIntosh in 3 patients with Bright’s disease [27]. They believed that some toxic or metabolic factor resulted in edema and congestion with “formation of an exudate which failed to resorb and then went on to organization” [27], a dysfunction that has been extensively studied in recent years. A restrictive dysfunction, associated with gravity of CKD, was disclosed by Mukai et al. [28], whereas Zoccali et al. [29] have shown, by systematically applying chest ultrasound in ESRD patients, that hidden or clinically manifest lung congestion is exceedingly frequent in this population an may be detected at a preclinical stage.

Gout, probably the first known non-communicable disease, might not represent in principle the best candidate to be discussed in terms of “Theory of Epidemiologic Transition”. This theory was advanced in a landmark paper by Abdel R. Omran [30] after infectious diseases were conquered [31] after World War II and degenerative and “man-made diseases” started emerging. Using demographical tools, Omran analyzed the changing patterns of population age distribution in relation to changes in mortality, fertility, life expectancy, causes of death. He identified 3 ages in humankind: the age of famine and pestilence (life expectancy <30 years), the age of “receding pandemics” (life expectancy 30-50 years), and the “age of degenerative diseases and man-made disease” (life expectancy >50 year). The theory has been updated frequently, and finally poverty (initially neglected) has been taken into consideration along with incomes and education [30–36].

This is relevant and makes the theory suitable to explain the high prevalence of gout in popes and the low, but slightly increasing, prevalence in the general population. The data shall be discussed in terms of lifestyles, income and education. It has been shown that affluent and educated people also adopt immoderate lifestyles causing non-communicable diseases associated with morbidity and mortality [30–36]. However, these people, when made aware of the risks, often agree to modify their lifestyles choices, whereas poorer, uneducated people do not. Thus, the latter group tends to experience the morbidity and mortality of the disease (third transition phase) at the time when rich well-educated individuals achieve protection [36].

By applying the above concepts to gout (Figure 2), we can say that popes before 1915 had a high prevalence of gout due to lifestyles choices causing it. These were later corrected through education and gout disappeared. Thus, in 2021, gout has no room in the apostolic palaces. At the same time, poor people, because of undernutrition, working conditions, and frequent movements back and forth from the workplace, were “protected” from gout, and therefore, before 1915, the prevalence of gout was zero. After World War II the general population has become sedentary, while the availability of proteins and the abuse of spirits, wines and other alcoholic beverages, as well as beverages rich in glucose, has sharply increased. Therefore, in the USA, Italy and France, the blood concentration of uric acid has been slightly but steadily increasing; the prevalence of gout is still minimal, but increasing, and will continue to do as long as education fails to encourage healthier lifestyles.

Figure 2: Lifestyles causing and preventing gout, and trends in the prevalence of gout in popes and general population before 1915 and in 2021

Acknowledgements

We thank for the English revision Joseph Sepe MD, Professor of Biological Sciences, University of Maryland Global Campus, USA and Adjunct Professor – Department of Mathematics and Physics University of Campania, Luigi Vanvitelli, Naples, Italy.

References

Dalbeth N, Merriman TR, Stamp LK. Lancet 2016; 388(10055): 2039-52 https://doi.org/10.1016/s0140-6736(16)00346-9
Ragab G, Elshahaly M, Bardin T. Gout: An old disease in new perspective – A review. J Adv Res 2017; 8:495-511. https://doi.org/10.1016/j.jare.2017.04.008
Igel TF, Krasnokutsky S, Pillinger MH. Recent advances in understanding and managing gout. F1000Res 2017; 6:247. https://doi.org/10.12688/f1000research.9402.1
Dalbeth N, Choi HK, Joosten LAB, Khanna PP, Matsuo H, Perez- Ruiz F, Stamp LK. Gout. Nature Reviews Disease Primers 2019; 5:69. https://doi.org/10.1038/s41572-019-0115-y
Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystaks activate the NALP3 inflammasome. Nature 2006; 440:237-41. https://doi.org/10.1038/nature04516
McCarty DJ, Hollander JL. Identification of urate crystals in gouty synovial fluid. Ann Intern Med 1961; 54:45-64. https://doi.org/10.7326/0003-4819-54-3-452
Porter R, Rousseau GS. Gout: The Patrician Malady. New Haven, Yale University Press: 1988.
Savica V, Santoro D, Ricciardi B, Ricciardi CA, Calo LA, Bellinghieri G. Morbus dominorum: gout as the disease of lords. J Nephrol 2013; 26(S22):113-16. https://doi: 10.5301/jn.5000349
McKeown T. The origins of human disease. Oxford, Blackwell: 1988.
Retief FP, Cilliers L. Disease and causes of death among popes. Acta Theologica 2006; 26(2):S7. https://doi.org/10.4314/actat.v26i2.52576
De Santo NG, Bisaccia C, De Santo Causes of death due to disease of the genito-urinary system and of the heart among 264 popes in the years 65-2005 AD: First approach. Nephrol Dial Transplant 2019; 34(S1): gfz103.SP804. https://doi.org/10.1093/ndt/gfz103.SP804
De Santo NG, Bisaccia C, De Santo LS. Deaths caused by cardiorenal disease among 264 popes from St. Peter to St. John Paul II. Hellenic Nephrology 2019; 31:158.
De Santo NG, Bisaccia C, De Santo LS. Papal deaths caused by cardiorenal disease. First Approach. Arch Hell Med 2020; 37(S2):177-81.
Bisacccia C, De Santo LS, De Santo NG. Gout a papal disease: a study in 20 pontiffs (540-1830. Nephrol Dial Transplant 2020; 35(S3):gfaa144.P1836. https://doi.org/10.1093/ndt/gfaa144.P1836
De Santo N, Bisaccia C, De Santo (2021). Renal stone disease in 193 pontiffs from Vigilius to Pius VIII (537-1830). Nephrol Dial Transplant 2021; 36(S1):gfab105.001. https://doi.org/10.1093/ndt/gfab105.001
De Santo NG, Bisaccia C, De Santo LS. Gout: a papal disease-a historical review of 25 gouty popes (34-2005 AD). J Nephrol 2021; 34(5):1565-67. https://doi.org/10.1007/s40620-021-01117-8
Aubert R. Documents relatifs au movement catholique italien sous le pontificat de S. P. X. ibid., XII (1958), pp. 202-43, 304-70. In: Pius X, Enciclopedia Treccani online. Accessed on December 9, 2021.
Merry del Val R. San Pio X. Verona, Fede e Cultura: 2012.
Occelli P. Il beato Pio X. Roma, ed. Paoline: 1951, p. 237.
Siccardi C. San Pio X. Roma, San Paolo ed.: 2014, p. 369.
dal Gal G. Pio X il papa santo. Firenze, Libreria Editrice: 1940, p. 283.
Sanguinetti O. Pio X: Un pontefice santo alle soglie del secolo breve. Milano, Sugarco Edizioni: 2014, p. 283
Disveld IJM, Zoakman S, Jansen TLTA, Rongen GA, Kienhorst LBE, Janssens HJEM, Fransen J, Janssen M. Crystal-proven gout patients have an increased mortality due to cardiovascular diseases, cancer, and infectious diseases especially when having tophi and/or high serum uric acid levels: a prospective cohort study. Clin Rheumatol 2019; 38(5):1385-91. https://doi.org/10.1007/s10067-019-04520-6
Vargas-Santos AB, Neogi T, da Rocha Castelar-Pinheiro G, Kapetanovic MC, Turkiewicz A. Cause-Specific Mortality in Gout: Novel Findings of Elevated Risk of Non-Cardiovascular-Related Deaths. Arthritis Rheumatol 2019; 71(11):1935-42. https://doi.org/10.1002/art.41008
Spaetgens B, de Vries F, Driessen JHM, Leufkens HG, Souverein PC, Boonen A, van der Meer JWM, Joosten LAB. Risk of infections in patients with gout: a population-based cohort study. Scientific Reports 2017; 7:1429. https://doi.org/10.1038/s41598-017-01588-5
Singh JA, Cleveland JD. Serious Infections in Patients With Gout in the US: A National Study of Incidence, Time Trends, and Outcomes. Arthritis Care Res 2020; 73(6):898-908. https://doi.org/10.1002/acr.24201
Ehrich W, McIntosh JF. The pathogenesis of bronchiolitis obliterans. Arch Path 1932; 13:69-76.
Mukai H, Ming P, Lindholm B, Heimbürger O, Barany P, Anderstam B, Stenvinkel P, Qureshi AR. Restrictive lung disorder is common in patients with kidney failure and associates with protein-energy wasting, inflammation and cardiovascular disease. PLoS One 2018; 13(4):e0195585. https://doi.org/10.1371/journal.pone.0195585
Zoccali C, Tripepi R, Torino C, Bellantoni M, Tripepi G, Mallamaci F. Lung congestion as a risk factor in end-stage renal disease. Blood Purif. 2013; 36(3-4):184-91. https://doi.org/10.1159/000356085
Mc Keown R. The epidemiologic Transition: Changing Patterns of Mortality and Population Dynamics. Am J Lyfestyle Med 2009; 3(S1): 19S-26S. https://doi.org/10.1177/1559827609335350
Omran AR. The epidemiologic transition. A theory of the Epidemiology of Population Change. Milbank Memorial Fund Quarterly 1971; 49(4):509-38.
Caldwell JC. Population health in transition. Bull World Health Org 2001; 71(1):159-60.
Pearson TA. Education and income: double edged swords in the epidemiologic transition of cardiovascular disease. Ethnicity & Disease 2003; 13(S2):158-63.
Pearson TA. Socioeconomic status and cardiovascular disease in rural population. In Stamler J, Hazuda H (eds). Report on the conference on Socioeconomic Status and cardiovascular disease. Washingtoon DC, National Heart, Lung, and Blood Institute: 1995, pp. 101-08.
Marmot MG, Smith GA, Stansfeld S, Patel C, et al. Health inequalities among British civil servants. Lancet 1991; 337:1387-93. https://doi.org/10.1016/0140-6736(91)93068-k
Kaplan G, Keil J. Socioeconomic factors and cardiovascular disease: a review of the literature. Circulation 1993; 88:1973-88. https://doi.org/10.1161/01.cir.88.4.1973

The use of Water for the treatment of Kidney Disorders

Posted on Monday January 29th, 2018Download PDF (english version)

Athanasios A. Diamandopoulos

Diamandopoulos Athanasios

Corresponding Author:
Prof. Diamandopoulos Athanasios
Hon Professor EKPA,
Louros Foundation for the History of Medicine, Athens
E-mail address: 1453295@gmail.com
Tel +00 302610641364 Mobile phone+00306974026198

Abstract

The treatment of end stage renal failure is always based on the use of water. Both the artificial kidney machine and peritoneal dialysis use a huge amount of water, either in its pure condition (the RDT) or as the main ingredient in PD solutions. As these modalities are rather modern for an article on the history of the topic, we will skip them and proceed to the discussion of more ancient methods, correlating them with more recent times. Recent for us means from the 9^thcentury onwards. The structure of this article was inspired by the Polka dance, originally a Czech dance and a genre of dance and music familiar throughout Europe and the Americas. It is still practiced in many countries and widely in Poland.
In this paper we present extracts from the works of Plato, Hippocrates, Aristophanes, Galen, Pliny the Elder, Paulus Aegineta, Rufus, Alexander, Avicenna with their views on mineral waters in general and their application on renal diseases. Gout and lithiasis figure prominently and were the more prominent indications for that mode of treatment. We followed the evolution of their ideas in time and compared them with the current use of hydrotherapy in various Spas with emphasis on the ones from Central and Eastern Europe.
We conclude that the popularity of hydrotherapy for treating kidney disorders was alternatively increasing and decreasing over centuries, resembling the Back and Forth steps of Polka

Keywords: Hydrotherapy, mineral waters, lithiasis, gout, Galen, Avicenna

Introduction

The treatment of end stage renal failure is always based on the use of water. Both the artificial kidney machine and peritoneal dialysis use a huge amount of water, either in its pure condition (the RDT) or as the main ingredient in PD solutions. As these modalities are rather modern for an article on the history of the topic, we will skip them and proceed to the discussion of more ancient methods, correlating them with more recent times. Recent for us means from the 9^th century onwards. The structure of this article was inspired by the Polka dance, originally a Czech dance and a genre of dance and music familiar throughout Europe and the Americas. It is still practiced in many countries and widely in Poland. Thus, let us consider this structure of the lecture as a tribute to our host country. Polka can be very bouncy and upbeat. Try going Back in the Past and Going Forth in squares, and Front and again. Similarly, we will present various practices and theories about the use of baths for renal ailments back in the past, we will follow their abandonment and then will we witness going forth to their revival.

Discussion

The article starts the discussion with a general view on the therapeutic properties of baths.

Back in the past:

As the use of water treatments combines mythical, religious, medical and social characteristics, it has been a point of discussion since antiquity. We read in Plato’s Cratylus that: “(…) and should be accepted one name only for the god (Apollo) being the god of music, or arching, oracles and of medicine (…) [as] the same tools are used by doctors and oracles like baths and sprinkling with water, as there is a common goal: A person’s soul and body purification” (1).

Going forth, the revival:

Today, ritual purification through water can be found in the religious ceremonies of Jews, Muslims, Christians, Buddhists, and Hindus. These ceremonies reflect the ancient belief in the healing and purifying properties of water. With time, various qualities of natural waters were considered, or advertised, as beneficial for health.

Back in the past:

Plutarch (1^st cent. AD): “Which pain, which abstinence, which drug did solve any disease as quickly as a bath taken timely?” (2) Galen (1^st/2^nd cent. AD): “When there is an increase of impurities the best purgation is via phlebotomy, then baths and fasting (3) and when these are neglected many ailments appear”. (4) And further on: “Who doesn’t remember his (Kointos’) scorn of warm and cold and dry and wet baths, now he announces names of baths without which no treatment is achieved” (5). Rufus of Ephesus (1^st/2^nd cent. AD) repeats the above: “(…) if the patients suffer by an abundance of bad humours, they benefit from (…) warm baths (6).

Natural springs had been classified according to their physical properties. Hippocrates had already commented that: “The next worst will be those whose springs are from rocks–for they must be hard–or from earth where there are hot waters, or iron is to be found, or copper, or silver, or gold, or sulphur, or alum, or bitumen, or soda” (7). A more detailed classification was made by Pliny the Elder (1^st cent. AD) in his famous Natural History. He himself was a fervent advocate for bathing as his nephew Pliny the Younger states “In the country, the only time he took from his work was for his bath, and by bath I mean his actual immersion, for while he was being rubbed down and dried he had a book read to him or dictated note” (8). Also Paulus Aegineta (7^th cent. AD) elaborated on the topic (9). According to Galen, natural waters could also be classified in accordance to their temperature: “The so-called natural springs in some places have a pleasant temperature; in others these are boiling or lukewarm, while the cold ones are everywhere” (4).

Going forth, the revival:

Similarly, nowadays a variety of natural waters is widely advertised as good for health, as we can see from extracts of various pamphlets for spas in Central and Eastern Europe:

The Yeisk resort, on the coast of the Azov Sea, is famous for its healing waters containing hydrogen sulphide (…). The main therapeutic factors of the resort are the unique and rare in the content of iron, mineral waters surpassing in some characteristics all known springs in the world (10).
Carbonaceous: Naturally carbonated waters. Stimulate the appetite and digestion when drunk, increase the digestive secretions of the stomach, pancreas and intestines (11).
Sulphur-containing water reduces gastric secretion, helps digestion, and treats lazy bowels. Less mineralized waters are used for treating calculus (kidney stones) and urinary tract infections (12).
Apart of the variations of waters, baths and bathing always took place in beautiful scenic landscapes and in buildings with works of art.

Back in the past:

Romans took this to the extreme, building huge imperial bath complexes full of mosaics, statues, paintings and other luxuries. In many ways, these were similar to community centers. Because the bathing process took so long, conversation was necessary. Many Romans would use the baths as a place to invite their friends to dinner parties, and many politicians would go to the baths to convince fellow Romans to join their causes. The thermae had many attributes in addition to the baths. There were libraries, rooms for poetry readings, and places to buy and eat food. The modern equivalent would be a combination of a library, art gallery, mall, restaurant, gym, and spa (13). Baths were a site for important sculptures; among the well-known pieces recovered from the Baths of Caracalla are the Farnese Bull and Farnese Hercules and the larger-than-life early 3^rd century patriotic figures somewhat reminiscent of Soviet Socialist realism works (now in the Museo di Capodimonte, Naples). There were also famous artistic works in the baths of Constantinople (14, 15). Later, Avicenna in his Canon of Medicine in the 10^th century elaborated on: The bath-rooms: Temperature of air in different rooms (temperate, warm, hot, and cool); mural decorations (16).

Going forth, the revival:

The use of public baths declined during the Middle Ages, partially revived in the 16^th century and reached its peak in the 19^th. To limit the search only to France, we quote six novels from Philip Albou’s article on “Taking waters in the French literature” (17). Namely, 1. Michel de Montaigne (1533 – 1592) who compares the particular manners of taking water in France, Germany and Italy in 16^th century. 2. Gui Patin (1602 – 1672), the famous Senior of the Faculty of Medicine of Paris, declared to be very perplexed as to the effectiveness of water, going on to declare: “the waters make more cuckolds than they do cure patients!”; 3. The account of Madame de Sévigné (1626 – 1696), from her famous Letters, on taking waters in Vichy in 1676; 4. Thermal treatment (without effect…) of the extinction of voice of Nicolas Boileau (1636 – 1711) at Bourbon-l’Archambault in 1687; 5. The portrait of Irene (alias Madame de Montespan) found in the “Caractères” of Jean de la Buyère’s (1645 – 1696); and finally, 6. An extract of the novel Mont-Oriol by Guy de Maupassant where he evokes the cynical and financial aspects of the creation of a thermal place in the centre of France during the 19^th century. The latter, though cynical, explains in part the frenzy of building huge hotels and other buildings in that era to accommodate the well-off’s desire for cure and recreation. Focusing on the subject of this article, we notice an echo of the bath decorations of the past in the modern trend of the last two decades, as more designers and operators recognize the healing benefits of positive distractions, natural views, and daylight within their care environments (18).
Having dealt in brief as an introduction with the general ideas of the benefits of bathing both in the past and in modern times, we will focus now on our central theme that is the use of waters for kidney problems.

Back in the past:

Hippocrates (5^th cent. BC): The very cold water minimizes and eliminates the tumours and pain of gouty attacks. (19) He also commented on the impact of the quality of drinking water on stone formation: “Men become affected with the stone, and are seized with diseases of the kidneys, strangury, sciatica, and become ruptured, when they drink all sorts of waters, and those from great rivers into which other rivulets run, or from a lake into which many streams of all sorts flow” (5) Galen: For renal diseases you should consume a light diet and very frequent baths. Because drinking too much water is contraindicated in renal disease while purification via the skin is desirable (20). Plutarch refers to the gouty attack of Sulla, the Roman general, who according to Strabo hurried himself to the medicinal waters of the Aedipsos Baths, at the island of Euboea in Central Greece (21). Paul of Aegina (5^th cent. AD): “(…) for retention of urine: add a fifth part of heated oil to the water. Such a bath is highly anodyne” (9). Alexander warns on the over-prescription of hot or cold baths for treating renal problems and suggests moderation (22). Hydrotherapy in Byzantium was a strong therapeutic agent for many ailments, including acute nephritis and attacks of gout (23). Avicenna (10^th cent. AD): “(…) On the presentations of the urinary stone. Know that when the stone enlarges in the kidney it hinders the urine, causes intolerable pain, and may lead to mental confusion from pain. Each occasion of the pain is called an episode (the pain is intermittent). During the episode of pain the patient should sit in a tub of warm water in which the leaves of cabbage…” (24).

Generally, in antiquity methods for alleviation of pain from kidney stones consisted of (…) baths and warm clysters that were sometimes medicated (25). Hence, even the comic play writer of the 5^th cent BC Aristophanes has Dionysus suffer from kidney pains, because of overtiredness, to beg Zeus to permit him to run to the public bath for relief (26).

Going forth, the revival:

In The Principles and Practice of Medicine, William Osler (1849–1919) commented on the topic: “Many patients ﬁnd beneﬁt from a stay at Saratoga, Bedford, Poland or other mineral springs in this country, or at Vichy or Ems in Europe” (27). In Central and Eastern Europe today, bath treatments for kidney diseases flourish. We present indicatively a few such places:

1) Czech Spas – Treatment of kidney and urinary tract diseases has a long tradition in Marienbad with the use of the god-given effects of natural carbon dioxide. The curative springs, in particular, the hypotonic mineral waters in the drinking cure, are the foundation of therapies for urologic and kidney illnesses in children, adolescents, men and women. Due to the cooperation with the dialysis centre Fresenius in Marienbad, it is possible with advance arrangements, to treat patients requiring a dialysis program (sic!). A fine example of the combination between alternative and high tech treatments based on commercial goals (28).
Czech Spas.

2) The Royal Spa hotel in Mariánské Lázně specialises in kidney and urinary tract treatment. Natural mineral carbon dioxide treatment in the form of both water and dry baths helps the vascular system widen and become more flexible. Carbon dioxide, which is absorbed through the body surface, stimulates receptors of even the tiniest capillaries in our body. It is also suitable for curing cysts, kidney stones and sand (lithiasis) or kidney hypofunction in connection with other chronic diseases (29).

3) In the Carpathian Basin in Central Europe, where Hungary is located, the crust of the earth is very thin, so these waters right from the core of the earth rise to the surface very easily. There are more than 200 thermal spas (…) used to cure kidney diseases. Most Hungarian spa resorts use their hot springs complimentary to regular medicinal methods in many type of diseases and conditions like skin diseases, (…) kidney diseases, neurological problems, etc. depending on the composition of their waters. In Hungary, spa treatments are covered by the Hungarian medical insurance plan and regularly prescribed by Hungarian doctors as part of natural rehabilitation protocols (30).

4) There are more than 1300 mineral sources in Slovakia, used as curative waters for (….) renal diseases. There are 21 thermal spas built on these mineral springs, usually divided in three groups according to type: Balneological spas, Climatic spas, mixed spas. The main focus of the “cure” is often drinking water from the spring (it usually tastes like medicine), but all of the spas listed also offer soothing soaks, medicinal massages!) and other restorative therapies, as well as swimming and other recreational opportunities in beautiful natural settings (31).

5) The oldest balneological centres in Russia are the resorts of Caucasian Mineral Waters. The waters in Zheleznovodsk at Stavropol Krai can heal the digestive system, the pancreas, and kidneys. (11) In the same area, the Mashuk Aqua-Therm hosts the only monument in the world commemorating enemas, unveiled in June 2008 (Figure 1). The 770-pound bronze statue stands nearly five feet tall and was created by a local regional artist named Svetlana Avakova. The use of enemas for treating uraemia has been well established since antiquity.

6) Treatment descriptions – Pühajärve Spa & Holiday Resort (…) for heart diseases, high blood pressure and kidney diseases. The discovery of the mineral springs in 1876 marked the beginning of the history of Rymanow-Zdroj. It specializes in the treatment of children with kidney diseases (32).
The main ways in which baths are useful in treating renal failure were perspiration and toxic substance elimination via the skin, which acted as a kind of dialysis membrane.

Back in the past:

Hippocrates: “We should then abstain from the cathartic methods performed from below (that is, diuretic drugs and enemas). The best of all though is to provoke diuresis and perspiration and get the patient walking” (33).

Aristotle (4th cen. BC): “And soon this (alien substance) is separated and discharged. And the latter when is discharged from below is called urine whereas when it is eliminated through the skin is called perspiration. Both are saline for the same reason” (34).

Rufus: “because it is good for them to be able to perspire if diuresis stops. The best of all is a steam bath in a small vat with the head coming out from the top, so that, while the rest of the body is being heated, one can breathe cool air” (35).

Going forth, the revival:

A Clinical/Historical paper we wrote tried to explain the beneficial role of perspiration in renal failure: “(…) Each human kidney has approximately 1.2 million nephrons. In other words, humans have as many nephrons as sweat-glands (…). The role of the skin as an excretory organ is also demonstrated by the fact that the sweat glands as well as the kidneys have receptors for aldosterone and ADH (…). We found a difference of 16 mg/dl in average blood urea between winter and summer months (mean winter urea 182 mg/dl, mean summer urea 166 mg/dl). These differences were statistically very significant (p<10^-27). There was no significant difference in patient body weight between winter and summer months” (36). The following articles back our thesis:

Sauna baths in the treatment of chronic renal failure.

Snyder D, Merrill JP, Trans Am Soc Artif Intern Organs. 1966; 12:188-92.

Sweating treatment for chronic renal failure.

Lacher JW, Schrier RW. Nephron. 1978; 21(5): 255-9. “This removal of urea, water and salt suggests that sweating could be used to treat uraemia in conjunction with charcoal hemoperfusion”;

Stimulated sweating in chronic renal failure

Man in ‘t Veld AJ, van Maanen JH, Schicht IM. Br Med J. 1978 Jul 15; 2(6131): 172-3. “With hot baths and/or saunas the urea and creatinine in RDT patient falls”

Hot bath for the treatment of chronic renal failure

Ting Ye, Weiping Tu & Gaosi Xu, Ren Fail. 2014 Feb; 36 (1):126-30: “(…) Therefore, it offers an adjuvant alternative renal replacement method”.

Local application of footbaths for gout has been also suggested.

Back in the past:

Rhazes (9^th cent. AD) stated that: “Two factors are involved in gout management via application of water to the feet; the temperature of the water and the time of application. Some patients with gout are advised to use extremely cold water during acute episodes, while others need to apply tepid or hot water (37).

Going forth, the revival:

Claridge in the 19^th cent wrote: “A king’s councilor had suffered for six years with the gout (…) repeated cold foot-baths, after some days, caused the inflammation and redness to disappear (38). The method has a modern interpretation: In Foot Bath Therapy, warm water can promote blood circulation, and blood flow after a footbath can increase to 10~18 times above normal, which can improve patient metabolism and Qi-blood circulation. Besides, Foot Bath Therapy can improve the skin functions of mucosa absorption and skin penetration, which can promote the medicine ingredients to be absorbed into the blood (39). Basically, hot therapy is applied when there is no inflammation while cold therapy where there is inflammation/swelling. Contrast Hydrotherapy (CH) has been used for treating and preventing gout besides daily hydration.
The most exotic treatment is via magnetized water. Its ancestor was mesmerism. Practitioners were often known as magnetizers, rather than mesmerists. For about 75 years from its beginnings in 1779, it was an important specialty in medicine, and continued to have some influence for about another 50 years. Hundreds of books were written on the subject between 1766 and 1925. Today it is almost entirely forgotten. Magnetism dressed up as magnetized water, is the new frenzy for treating kidney ailments: In a 19^th cent Commentary on Avicenna’s Canon, there is an implication of the impact of the radiation of the soil over the medicinal waters: “His statement contains an important truth. Certain spas and health- resorts (Carlsbad, Bath, Droitwich, Baden, Bourbonne-les-Bams, Is ancy Wiesbaden) owe their virtue not merely to the chemical composition of the water which is taken by the patients, but also to the locality itself. The radiations which pass outwards at those parts of the earth produce a beneficent influence upon them as they walk over the ground” (17). In a more recent article on the efficacy of naturally magnetized water on kidney function, we read: “(…) a daily regimen of 16 ounces of naturally magnetized water was shown to be significant in lowering urine pH, and promoting excretion of acids and toxic mineral salts suggesting an increased ability of the kidneys to remove toxic wastes from the body …” (40). In another similar article: “They had their patients drink bi-polar (treated with both North and South poles) magnetized water. This simple treatment was very effective in breaking up kidney and gall bladder stones into small enough particles to be passed through urine without any pain or danger to the patient (41).

Conclusions

Ancient and medieval practices on the use of water are reincarnated today in the more general urge for alternative, traditional, mythical treatments. They are those who look and make steps Back in the Past to follow them, there are those who sternly stand for the technological approach turning their back to the past Moving Forwards. Nevertheless, both groups in their contrary movements meet harmoniously in the middle like groups dancing the famous Polka dance Podhale (Figure 2).

References

Plato (5th cent. BC) Cratylus. In: Burnet J (ed) Platonis opera, vol. 1, 2nd edn. Clarendon Press, Oxford:, 1900, Stephanus page 405, section b, line 2.
Plutarchus (1st/2nd cent AD) Quaestiones Convivales (612c-748d), Stephanus page 662, section C, line 3. Available online at: http://data.perseus.org/citations/urn:cts:greekLit:tlg0007.tlg112.perseus-grc1:612c
Galenus Med. (1st/2nd cent AD) De constitutione artis medicae ad Patrophilum. In: Kühn C (ed) Claudii Galeni Opera Omnia vol. I. Cnobloch, Leipzig, 1821, page 299, line 7.
Galenus Med. De sanitate tuenda libri vi. In: Kühn C (ed) Claudii Galeni Opera Omnia, volume 6, Teubner, Leipzig, 1923, page 244, line 12.
Galenus Med., De methodo medendi libri xiv. In: Kuhn C (ed) Opera Omnia. Volume 10. Cnobloch, Leipsig, 1822, page 467, line 8.
Rufus Med., Quaestiones medicinales, Section 25, line 4 Gärtner H. Rufus von Ephesos: Die Fragen des Arztes an den Kranken. Corpus medicorum Graecorum. Akademie, Verlag, Berlin, 1962.
Hippocrates (5th cent BC) De aere aquis et locis. In : Jones W (ed) Airs, waters places – Perseus Digital Library, section 7, p. 87.
Radic B. (2003) The Letters of the Younger Pliny, Penguin Classics, UK.
Adams Fr. (1844 -47) Paulus Med. Epitomae medicae libri septem. Book 1, Syndenham Society, London, chapter 52, section 1.
About the resort of Zheleznovodsk / Plaza SPA Hotels. plazaspa.net.
Carbonated (Sparkling) Water: Good or Bad? (2016) Healthline.
Best Water for Kidney Stones – Water benefits health, www.waterbenefitshealth.com/best-water-for-kidney-stones.
Fagan G. (1999). University of Michigan Press, Michigan.
Kaldellis A (2007) Christodoros on the Statues of the Zeuxippos Baths: A New Reading of the Ekphrasis. Greek, Roman, and Byzantine Studies 47 361–383.
Bassett S.G. (1996) Historiae custos: Sculpture and Tradition in the Baths of Zeuxippos. AJA 100: 491– 506 .
Gonzalez C (1929) Avicenna’s Canon Of Medicine. AMS Press, New York. https://archive.org/stream/AvicennasCanonOfMedicine/ .
Albou Ph. (2005) Taking the waters in the French literature. Book of Abstracts. 3rd Meeting of the ISHM, Patras, Greece.
Di Nardo A. (2015) Healing Masterpiece | HCD Magazine.
Hippocrates (5th cent BC) Aphorisms. Adams Fr (trans) Chapter 5, section 25, line 2.
Galenus Med. De venae sectione adversus Erasistrateos Romae degentes. In : Kühn C (ed) Claudii Galeni. Оpera omnia. Vol. 11. Knobloch, Leipzig, 1826 page 240, line 7.
Plutarchus. Sulla. Perrin, Bernadotte (ed) Harvard University Press, Harvard, 1916. Chapter 26, section 3, line 3.
Alexander Med (6th cent AD) Therapeutics. In: Puschmann T. (ed) Alexander of Tralles, Volume 1, page 481, line 1.
Diamandopoulos A. (1997) Hydrotherapy in Byzantium, Kathimerini Newspapaper June (in Greek).
Ardalan M. et al (2007) Diseases of the kidney in medieval Persia—the Hidayat of Al-Akawayni. Nephrol Dial Transplant, 1.
Touwaide A. et al. (2013) Healing kidney diseases in antiquity. Bios, Cosenza, 115–129.
Aristophanis Ranae (5^th cent BC) Ex recensione Guilielmi Dindorfii.
Osler W (1892) The Principles and Practice of Medicine. Republished 1978. Classics of Medicine Library (publ) Birmingham.
http://www.royalspa.cz/en/24928-kidney-and-urinary-tract- diseases.
http://www.spaseurope.net/czech-spas-information.htm
http://www.spashungary.com/hungarian-spa.htm
http://www.slovak-republic.org/spa
Spa Resorts Russia – Advantour.
Hippocrates. On the Diet of Acute Diseases. In: The Greeks, (1992) Kaktos (pbl), Athens, p. 139.
Aristotle (4th cent BC) Problemata. Bekker I (ed). Gruyter, Berlin,1960, sec 866.
Rufus of Ephesus (1st cent AD) In : Hakkert (ed) De Renum et Vesicae Morbis, Ouevres de Rufus d’Ephese (1963). Amsterdam.
Diamandopoulos A and Goudas P (2000) The substitution of renal function through skin catharsis, a clinicohistorical review. Kidney International 59: 1580 – 1589.
Ashtiyani SnC et al (2012) Rhazes’ Prescriptions in Treatment of Gout. Iran Red Crescent Med J 14(2): 108–112.
Claridge R T (1842) Hydropathy, or the Cold Water Cure. In: Cold Water Gout Cure | Cold Showers www.cold-showers.com/cold-water-gout-cure/, 11 Ιουλ 2012.
Foot Bath Treats Kidney Disease or Kidney Failure – Kidney Disease. Available online at:
http://www.kidney-symptom.com/foot-bath.html
Galitzer M and Reminick H (1999) Efficacy of a naturally magnetized water on kidney function. Available online at: http://www.ihfglobal.com/education_documents.
The Health Benefits of Magnetic Water. Publishing web Life-Sources Inc. Available online at: http://www.life-sources.com/pages/The-Health-Benefits-of-Magnetic-Water.htm

Introduction

The goal of this study

Table 1. On the Timeline of Podagra from the Corpus Hippocraticum to the Renaissance.

Hippocrates’ short biography

Gout in the Corpus Hippocraticum

Treatments

Acknowledgements

Bibliography

Introduction

Biography

Table 1. Galen’s teachers in medicine [11].

From Pergamum to Rome

Galen on health and disease

The author

Galen’s success

Galen’s Text: Regarding sciatica, gout and arthritis

Preparations written by Andromachus for sciatic patients in his own words, from books on external drugs

Another remedy of Andromachus with the same effect

A remedy of Protas of Pelusium for hip and head pain and all chronic pain

Among emollient poultices a remedy for hip pain drawn by Andromachus from Heras of Cappadocia

Discussion

Conclusion

Acknowledgements

Bibliography

Introduzione

Fisiologia

Definizione, cause e conseguenze della HU

Epidemiologia della HU e della gotta

Esiste davvero il danno renale cronico da UA?

Il possibile ruolo della XOR

L’approccio terapeutico alla HU sintomatica nel paziente con CKD

È plausibile che la somministrazione della ULT nella CKD possa esercitare anche un’azione nefroprotettiva?

Quali comportamenti clinici e quali future ricerche gli esperti suggeriscono di adottare alla luce dell’attuale stato delle conoscenze?

Conclusioni

Bibliografia

Introduction

Historical case report – Pius X (1835-1914), Pope (8/4, 1903-8/22,1914)

Discussion

Table I: Gouty popes (no. 26). Data for popes nos. 1-25 in reference no.16. (* affected by stroke; ** presumed Renal/Non Renal death; # Mean ±SD; NK = not known).

References

Table I: Gouty popes (no. 26). Data for popes nos. 1-25 in reference no.16. (* affected by stroke; ** presumed Renal/Non Renal death; ^#Mean ±SD; NK = not known).