Carmelo Giordano (1930-2016): uremia therapy by protein alimentation and sorbents

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Natale Gaspare De Santo

Natale G. De Santo1, Ernesto Quarto2, Malcolm E Phillips3, Carlo de Pascale4, Biagio Di Iorio5

1Emeritus Professor, Department of Medicine, University of Campania Luigi Vanvitelli, Naples, Italy;
2Retired Professor of Bioengineering, University Federico II, Naples, Italy;
3Retired Nephrologist and Medical Director of Charing Cross and Hammersmith Hospitals Trust London, United Kingdom;
4Retired Physician in Chief of the Renal Unit at Cotugno Hospital, Naples, Italy;
5Division of Nephrology, Solofra General Hospital, Avellino, Italy.

Corresponding Author:
Natale G De Santo, MD
Emeritus Professor University of Campania Luigi Vanvitelli
Via Pansini 5, Pad 17, Nephrology, 80131 Naples, Italy,
phone +393484117376,
E-mail: nataleg.desanto@unicampania.it

 

Abstract

Carmelo Giordano was born on August 23, 1930 in Naples and died there on May 12, 2016. He qualified MD in 1954 and then trained with Professor Magrassi and later Professor John Merrill in the USA.

Returning to Naples he established a clinical research laboratory at the University Federico II which was funded for many years from the National Institute of Health in Bethesda. In 1969 he became a full Professor of Nephrology and established the postgraduate school of nephrology.

Giordano developed a worldwide reputation for his work on dietary management of uremia, recognised by the eponym “the Giordano–Giovannetti diet”. In this field he followed on from a galaxy of clinicians dating from antiquity and he worthily followed their high reputations.

He studied treatment of chronic renal failure (CRF) with low protein diets, essential amino acid diets/supplements and was the first to use ketoacids. The effect of these diets was assessed by nitrogen balance studies. He collaborated with other centres in this work including London and Stockholm.

Giordano’s other major interest and contribution to the conservative management of CRF was in the field of sorbents. He manufactured and studied, in patients and animals, the sorbent effects of oxidised starch-oxystarch and oxycellulose in removing, through the gut, significant amounts of nitrogenous waste. These studies raise the possibility of managing CRF using a combination of oral sorbent treatment and hemoperfusion. The latter is discussed in this paper as is dialysate regeneration and “portable” dialyzers.

Keywords: Carmelo Giordano, Low Protein Diet, ketoacids in CKD, oxystarch, oxycellulose, cold carbon apparatus, portable artificial kidneys, wearable artificial kidneys

A Short Biography

Carmelo Giordano (Carmine, Luigi, Giuseppe Giordano) (Figure 1) was born in Naples on August 23, 1930 in the house of Raffaele and Anna Tirone. He received the MD cum laude in 1954, at the Faculty of Medicine of the University Federico II of Naples, the oldest state university of the world. He was fellow and assistant to Professor Flaviano Magrassi (1908-1974). From 1958 to1960 he trained in nephrology with Professor John P. Merrill (1917-1984). At the Peter Bent Brigham Hospital of Harvard University where “no institution had done more for propagating dialysis in the United States”, he was viewed by some as “the father of nephrology as a discipline” (1). The relationship between Giordano and his mentor was extraordinary, both from the intellectual and the professional points of view. It was strengthened by the fact that Giordano during the first year in USA stayed in Merrill’s home. So, he had the privilege to learn directly from the maestro not only during the working hours at the university but also at home (2-8).

On his return to Naples Giordano organized a clinical research laboratory at the Department of Medicine of the University Federico II, where he developed a program of low protein alimentation for patients with CKD, utilizing a grant from the National Institute of Health of The United States in Bethesda. The laboratory was subsequently financed with a series of 33 grants by the National Institutes of Health till 1985 (2-8). He also started hemodialysis for AKI by utilizing an artificial kidney (Brigham Merrill rotating drum) which was a personal gift to him by Mr. Olson, the manufacturer. Maintenance hemodialysis and peritoneal dialysis were started in 1966.

In 1961 Giordano was enrolled as assistant professor of medicine at the university Federico II in Naples where, in the years 1969-1985, he was Professor of Nephrology and chief of the renal unit. There he also established the postgraduate school of nephrology and the kidney transplantation program. In the years 1986-2002 he was Professor of Medicine at the Second University of Naples and physician in chief of the Division of Nephrology. After retirement he continued to attend congresses of medicine and nephrology and directed a successful renal unit in a private hospital until his death in 2016. In 2016 he participated in Survival is Not Enough, an event organized by the Italian Institute for Philosophical Studies on the occasion of World Kidney Day. In his welcome address to the participants he underlined the need to increase the number of renal transplants because of the quality of life this treatment provides, its lower cost and the longer patient survival.

Details about his achievements in science and clinical medicine, the investigators he trained and promoted in the academy and hospitals, the papers and the books he published, the selective Capri Conferences on Uremia (1973-1980), the guest professors, his hobbies and his family have been described elsewhere (1-8). Historical reconstruction of Giordano’s contributions to nephrology have been presented by De Santo at the Congress of the International Society of Nephrology in Milan (2010), at the meetings of the International Association for the History of Nephrology (IAHN) in Wloclawek (2017) and at the 58th ERA-EDTA Congress in Madrid (2017). Biagio di Iorio highlighted the Giordano-Giovannetti diet at the IAHN Congress in Olympia-Patras (2012). Giovambattista Capasso illustrated Giordano’s achievements at the 2017 annual meeting of the Campania-Sicily branch of the Italian Society of Nephrology in Avellino.

Giordano’s name is known worldwide for his contributions to uremia therapy by means of low protein diets and by sorbents (2-8). His name is linked to the eponym: the Giordano-Giovannetti Diet (9).

 

Prehistory of renal nutrition

We have already traced the timeline of the progress in the field (2-4). Herein we will expand on some of his forerunners listed in Table 1, compiled taking also advantage of a recent paper on history of uremia research (10). Forerunners are important in science. Only Archimedes did not have one thus he started everything on his own. Indeed John of Salisbury (Methalogicon, 1159 AC) recounts that his maestro Bernard of Chartres used to say that “we have seen further and farther since we stood on the shoulders of giants”.

 

Galen (c129-c.130-c.200/216 AC Pergamon and Rome): Food and Diet (after 168 AC)

Excessive food intake is harmful. In Ian Johnston’s translation and editing of Galen’s On Diseases and Symptoms (11) one reads:

“.. the excessive intake of what are to the animal the most useful and nourishing foods is a cause of cold diseases. However, many of the things eaten and drunk that are too cold in nature (VII.14K) are also causes of cold diseases. These, then, are the causes of dry diseases. All the opposites (are causes) of moist diseases: an abundance of foods that are moist in capacity, an excess of drinks, an altogether more luxurious way of life”.

 

Prospero Alpini (1563-1616)

In 1591 the printing house of Franciscus De Franciscis in Venice published a book entitled De Medicina Aegyptiorum Libri quatuor/Egyptian medicine, four books (12). It was the opera prima of a young physician who later became professor of medicine, lecturer in simples and prefect of the Botanical Garden (the first worldwide) at the University of Padua (13). The book―an innovative output of a travelling physician (14)― reported on the personal experience of Alpini in Cairo from March 1581 to October 1584 as physician to Giorgio Emo, Consul of Venice. The book, dedicated to Antonio Morosini Senator of Venice, described for the first time the use of coffee, a popular drink in Cairo. Coffee was previously unknown in the western world. We have translated into English some passages related to various medical practices of Egyptian physicians. In Book I, Chapter X, Alpini describes Egyptian alimentation:

“They prepare their meals using milk and eat all dairy products. They eat very simple foods, many of them at lunch and dinner may eat a water melon or corn bread, which is utilized by everyone. They also use broth made of the roots of colocassia, of the bamnia fruit or barley corn or lentils or other legumes or with the green part of the sugar cane, or they feed themselves with grapes, figs, cucumbers and similar. As a beverage the Egyptian followers of Mohammed use Nile water which for its quality is to be preferred to all others”.

In Book I, Chapter XI, Alpini reports on Egyptian longevity:

“Therefore I think that the main reason which grants long life to Egyptians is their sobriety and abstention from an abundance of meat (…), the water of the Nile. In fact in Europe by much eating and drinking excessive quantities of wine, inhabitants of Germany and Poland live less”.

This is the first description of what in the twentieth century was defined as a Mediterranean diet. In Egypt they made use of corn bread, consumed great amounts of fresh or cooked vegetables including lentils and other legumes, and of fruits. They also used milk and dairy products, drank the Nile water or coffee prepared with the same water. Such a diet links to the longevity of the population giving a preventive role to abstention from meat and wine.

 

Mariano Semmola (1831-1895)

Semmola was born in Naples, studied at the University Federico II and obtained the MD in 1852. He studied in France under Claude Bernard, Trousseau and Rayer, and later was Professor of Pharmacology in Naples. He is credited with 28 national and international papers on Bright’s disease.

As a medical student he illustrated at the Academy of Medicine and Surgery in Naples (on January 26, February 23 and April 22, 1850) seminal experiments on the effects of different protein intakes on: (i) urinary specific gravity, (ii) urinary urea excretion and (iii) albuminuria in patients with primary albuminuria receiving either a) a usual mixed diet, or b) a meat diet (600-700 g of boiled meat), or c) a vegetable soup based on greens and bread, or d) a nitrogen-free diet based on fat, tomatoes and chestnuts. Urinary specific gravity was highest under the meat regimen, whereas albuminuria and urinary urea excretion were lowest under the nitrogen-free diet (15-17).

These studies were well received in France and were praised by Sigismund Jaccoud (1630-1930), François Henri Hallopeau (1842-1919), and Georges Dieulafoy (1839-1911). The studies were described at the Academy of Medicine in Paris and appeared in its Bulletin in 1892. That means that Semmola worked in the field for 42 years after 1850 (16).

 

Fernand Widal and Adolphe Javal

These scientists made significant contributions to the patho-physiology of Bright’s disease demonstrating that blood urea increased with the protein content of the diets, and that knowing the composition of the latter was a prerequisite to understanding the meaning of blood urea concentration. These studies were important for Leo Ambard during his studies on the urea-secretory constant (19, 20).

 

The history of low protein nutrition in CKD: The role of Carmelo Giordano

Coming back to the origins of the Giordano-Giovannetti diet, we now illustrate the experiments Giordano performed in the years 1961-1963 which shook the world of uremia specialists. His debut was unexpected, pregnant scientifically, and promised a new perspective for patients with chronic renal disease. Giordano’s studies opened a new era and further results are still expected.

Giordano’s first study (21) was a self-experimentation on one healthy subject (himself). He undertook a 4 period protocol (A,B,C,D) for a total of 53 days. In A he ingested a diet made from essential amino acids + 3 g of nitrogen (N) in the form of glycine. In Period B only 0.5 g of N as glycine supplemented the essential amino acids. In C essential amino acids were supplemented with 2 g of N as ammonium citrate. In D essential amino acids were supplemented with 2 g of N derived from urea. Nitrogen balance was positive and body weight remained constant throughout the experiment.

In the same year Giordano (22) reported on two patients with advanced renal failure treated with essential amino acids (a total of 2 g of N a day) along with 2500 calories. A significant reduction of blood urea concentration occurred during the treatment.

At the Second Congress of the International Society of Nephrology in 1963 in Prague, Giordano (23) reported studies on 23 CKD patients (Table 2) followed with a dietary protocol for 5 weeks. In week 1 and 5 they ate a low protein diet providing 3.8 g of N (23 g of proteins of high biological value (HBV) rich in energy (2,300-3,100 calories). In weeks 2,3 and 4 they consumed a diet containing 2.4 g of N (85% as L-essential amino acids) and providing a high energy supply. Blood urea was reduced by the amino acid diet which normalized N balance after 1 week. At this world convention there were no other presentations on low protein alimentation in renal disease.

In September 1963 Giordano published a paper in the Journal of Laboratory and Clinical Medicine (24). He reported data on 8 CKD patients (eGFR 3-26 ml/min) seven of whom were hypertensive (Table 3). They received for 7 weeks a diet providing L-essential amino acids (2 g of N a day). The energy content provided 2,300 calories in women and 3,100 in men. Thereafter they were given a low protein diet providing 23 g of HBV proteins. Blood urea was reduced under amino acids, nitrogen balance started to be positive after 3 weeks.

A series of seminal studies were presented by Giordano and his initial group of fellows at the 3rd Congress of the International Society of Nephrology in Washington 1966 (25). They reported on 221 patients followed for 60 months. The patients started with 0.3g/Kg of HBV proteins associated with 35 kcal/kg and were followed by assessing the nitrogen balance. When the N balance was negative, 2-3 g of proteins were added (in total 24 g for a 70 kg man). The study reported on more than 1000 days of N balance in 25 of the patients, given various dietary intakes (free intake, 8-11-g L-essential amino acids, and low protein diets providing 17-g, 20-g, 23-g and 25g). 85.7% per cent of the patients were in positive nitrogen balance with 25 g of proteins. This anticipated the evidence that with a 40g protein diet all CKD patients would receive an adequate amount of protein, as demonstrated in 1968 by Kopple et al (26). The study of Giordano et al (25) also disclosed a reduced phenylalanine to tyrosine ratio and a loss of 10-20 g of amino acids and peptides during a dialysis session of six hours.

Three studies documented for the first time the potential of ketoacids in the treatment of CKD. The first was a study on amino acids L and DL, the remaining two mark the origin of ketoacid therapy by using the ketoacids of phenylalanine and valine (27-29). The experiments were made in collaboration with the group of Peter Richards at the St. Mary Hospital in London, where the ketoacids of phenylalanine and valine were administered and their effects evaluated by nitrogen balance studies and 15N incorporation. Plasma albumin was broken down and their constituent amino acid were separated in Naples. Peter Fürst evaluated the 15N enrichment of each amino acid at the Institute for Mass Spectrometry of the Karolinska Institute in Stockholm directed by Garnar Ryhage.

The concept began with a paper on the effects on nitrogen balance of D-isomers of essential amino acids in uremia (27). It was hypothesized that it was the ketoacid of the D-isomers of amino acids that would be utilized. Two papers were published in 1971 showing the feasibility of a low protein diet based on ketoanalogues (28, 29). Ketoacids of the essential amino acids valine and phenylalanine could be utilized in studies with nitrogen balance and 15N incorporation. It was shown that phenylalanine and valine may be synthesized by healthy and uremic individuals. Walser et al. brought strong additional evidence to the importance of ketoacids (30) and nurtured the field for the subsequent 30 years. However, the initial enthusiasm of Giordano et al. for ketoacids diminished since anoxic infants on ketoacid formulations failed to achieve catch-up growth whereas with amino acid formulations they did (31). Thus a new reference pattern was proposed (32). In this way Giordano and his associates lost the advantage they had generated in 1964 (27) and it took many years for Giordano to acknowledge the importance of ketoacids (33).

 

Prehistory of sorbents

Athanasios Diamandopoulos, historian of nephrology, once wrote:

“nature uses various natural membranes to eliminate toxic substances. The membranes used for this purpose are those of the gastrointestinal system and of the skin. Humans tried to imitate nature… the beginnings of these practices can be dated to at least 4000 years ago. Herodotus described the practices of enemas among Egyptian who preserve good health by clystering themselves 2-3 times a month”. He also quotes Aetius Amidanus (6th Century AD) for treating acute renal failure with clysters made of “mallow, linseed oil, peeled barley, warm water, reed, camomille and dill”, a practice also suggested by Albucasis (10th century) and by Avicenna (11th century). On the other hand Hippocrates suggests to “purge to get rid of the rest from above and from below” (34).

Terra sigillata/ sealed earth from the Island of Lemnos in Greece, packed together and bearing the head of Artemis should be considered as the first sorbent for medical use as reported by Dioscorides in De Materia Medica (40 BC).

Spyros Marketos, a founder and president of the Hippocratic Foundation of Kos, produced a seminal paper on purgatives, charcoal and artificial kidney (35). He says that Hippocrates in Aphorisms suggests “Bodies that are to be purged must be rendered fluent… If the matters purged be such as should be purged, the patient profits and bears up well. If not, the contrary”.

Therein one also learns that charcoal was a recognized drug in Ancient Egypt (36) and Pliny the Elder in Naturalis Historia (90 AD) described its virtues for “disease of the spleen, of the kidney abundant menstruation, poisonous serpents’ wounds”. Its use was supported by Thonery, a French pharmacist who used it in the course of self-experimentation by ingesting it along with strychnine before the Medical Academy of France (37). But it was Yatzidis who introduced carbon hemoperfusion for intoxication (38, 39).

Santorio Santorio (1561-1636) in De statica medicina (1514) started a medicine based on measurements by measuring food intake, drinks, urine, feces and calculating perspiration and by suggesting remedies capable to affect the quantity of excreta (40).

 

On the history of sorbents and the contribution of Carmelo Giordano in the years 1968-1984

A total of 31 papers (41-71) represent an incomplete list of the output of a strong, motivated team which included Carmelo Giordano, Renato Esposito (chief of the laboratory, Associate Professor of Nephrology, nutritionist, immunologist and expert in clinical chemistry), Ernesto Quarto (Associate Professor of Bioengineering), Giovanni Demma and Piero Bello (both doctors in Chemistry), Giacomino Randazzo (Full University Professor of Biochemistry), Miss Maria Pluvio (Dr in biology and medicine, nephrologist and Ph. D in Nephrological Sciences), Mrs Norina Lanzetti (physician, nephrologist and Ph. D in Nephrological Sciences), Mr. Tonino Ariano (laboratory technician).

 

Lavage of intestinal wastes

Lavage of intestinal wastes was reported by Kolff in New Ways of Treating Uremia (20). (Kolff created a double ended ileostomy in an isolated ileal loop with an intact blood supply in a 57 year old uremic man. As much as 0.48 g of urea/hour was removed by the patient who performed home intestinal dialysis assisted by his wife for two months until his death. Prolongation of life by intestinal dialysis has been accomplished in dogs (73) and man (74, 75). Clearances during isolated jejunal loop dialysis in uremic patients were reported by Schloerb (74) as 5 to 10 ml/min for creatinine and 3.2 to 5.0 ml/min for uric acid, values about one third and one eighth as efficient, respectively, as obtained with peritoneal and hemodialysis. Intestinal perfusates contain smaller but significant amounts of larger molecules including aldosterone and 17-oxyhydroxycorticosteroids.

By 1960, hemodialysis was made practical by the development of an external plastic arteriovenous shunt. A slowly increasing number of patients were sustained (albeit suboptimally) by periodic intestinal dialysis. Analyzing 15 cases in the literature plus five of their own, Clark et al. (75) reached the conclusion that intestinal dialysis “remains the best method of adjunctive management of progressive uremia.” Thereafter, the improving success rate of maintenance hemodialysis diverted interest from the quest for nitrogenous waste extraction from the gut.

 

Removing urea from blood and/or intestinal tract and the birth of oxystarch and oxycellulose

Activated charcoals have a low sorption capacity for urea although they effectively remove other uremic toxic substances. To provide a urea-reactive adsorbent, a chemically modified oxystarch with albumin or gelatin was prepared. Elemental analysis and Fourier transform infrared (FT-IR) spectroscopic analysis demonstrated that the reaction of a small amount of protein (albumin or gelatin) with oxystarch had taken place possibly by chemical combination (41-46).

The influence of the dialdehyde content of the oxystarch on urea sorption, its sorption isotherm, and the adsorption rates were investigated. It was found that the swelling factor of oxystarch is closely related to the sorption activity under physiological conditions (pH 7.2-7.4 at 37° C). Adsorption studies showed that sorption capacity was increased by surface treatment and can reach 6-8.2 g urea/kg-dried adsorbent (initial urea concentration was 70 mg/dL). The oxystarch had 49.2% of glucose unit oxidized and was surface treated with albumin. These results suggested that the newly prepared surface-treated oxystarch would be utilized as an effective chemisorbent for urea removal under physiological conditions.

Sorbents in the Management of Uremia (60) documented easy transfer of urea from plasma into the intestinal lumen. The potential for treating renal failure by extraction of nitrogen waste from the gut became self-evident. Urea in the gut is degraded to ammonia by bowel bacteria to the extent that normal human feces contain no urea. In healthy volunteer subjects given an antibiotic cocktail, stool urea concentrations increase to blood levels while the fecal ammonia content decreases. This supports the inference that urea in the bowel is biodegraded by luminal microorganisms. Estimates of the quantity of urea converted to ammonia in the gut have been computed by Man et al. (79) from 4 to 7 g/day in normal patients and from 17 to 50 g/day in uremic patients.

Promising additional data indicating that gastrointestinal sorbents can bind to and remove, in the feces, clinically important amounts of nitrogenous wastes were demonstrated by Giordano and associates (5, 41-46) using oxidized starch (oxystarch) and oxidized cellulose (oxycellulose) (Figure 2 and Figure 3).

Corn starch or potato starch suspended in a solution of sodium periodate at 4’C for 24 hours slowly oxidizes to dialdehyde starch (oxystarch). Cellulose treated similarly, oxidizes to oxycellulose. At body pH and temperature, each repeat unit of oxystarch binds 1.5 to 1.9 moles of ammonia in vitro in an 0.3N ammonia solution; when present in excess, oxystarch will bind all the ammonia in a 0.3N solution. Oxystarch also adsorbs urea.

Oxystarch adsorbs aspartic acid in vitro, but it does not bind creatinine, uric acid, L-lysine or albumin. In weanling mice fed 2 per cent oxystarch in a casein diet, growth and development are normal. In rats fed 2 per cent oxystarch in a casein diet severe diarrhoea develops, whereas dogs tolerate as much as 5 per cent dietary oxystarch without apparent adverse effect. Explosive diarrhoea and a cholera-like fluid and electrolyte depletion syndrome occur in dogs fed more than 10 per cent of oxystarch in their diets. In uremic patients fed 20 to 35 g of oxystarch in divided doses stool volume increases by 200 to 600 ml/day and the frequency of bowel movements is increased, but frank diarrhoea does not develop. Giordano’s initial trials of oxystarch manufactured in his laboratories (42-44) showed that uremic patients (creatinine clearances of 0.4 to 3.2 ml/min) tolerated divided doses of 20 g/day well for two months and that, in each case, there was a significant fall in the blood urea nitrogen level. Fecal nitrogen content increased to a mean of 1,450 mg/day (range 730 to 8,050 mg/day). Confirmation of increased stool nitrogen content during oxystarch treatment was provided by a double blind starch/oxystarch full balance study (76-80). In this study seven uremic patients (creatinine clearances of 6 to 30 ml/min) were fed 29 g of oxystarch or starch daily in four equal doses added to a diet containing 40 to 50 g of protein and 2 to 4 g of salt. Blood urea nitrogen levels fell 33 per cent during oxystarch treatment from a mean of 93.1 mg/ 100 ml to a mean of 62.1 mg/100ml. There was no significant change in serum creatinine, plasma amino acid, uric acid and plasma glucose levels during oxystarch ingestion. Oxystarch significantly increased fecal nitrogen from a control mean of I.4 g/24 hours to 2.5 g/24 hours. A concomitant decrease in urinary nitrogen excretion, however, from a control mean of 7.6 g/24 hours to 5.5 g/24 hours during oxystarch treatment prevented development of negative nitrogen balance.

During minimal nitrogen ingestion, uremic patients fed oxystarch (28 g) daily have an increased fecal excretion of nitrogen and potassium, and a counterbalancing decrease in urinary nitrogen and potassium excretion (81). There was a significant increase in the fecal potassium content when oxystarch was ingested, ranging from 5 to 22 mEq/day, which was also counterbalanced by a decrease in urinary potassium excretion. To exclude the possibility that increased fecal nitrogen content noted during oxystarch treatment was due to direct binding of unabsorbed undigested dietary nitrogen rather than bound intestinal nitrogen, four uremic patients were fed oxystarch while ingesting a “no protein” diet (82). In these patients the increases in fecal nitrogen and potassium were similar to those in the previous group indicating that the origin of the extra fecal nitrogen was indeed nitrogenous waste. Will feeding oxystarch to uremic patients have clinical import? In urine-producing patients the counterbalancing decrease in urinary nitrogen excretion tends to detract from the benefit of increased fecal nitrogen content. What will be the effect on nitrogen balance in anuric patients?

 

Oxystarch in bilaterally nephrectomized rats

While awaiting completion of sorbent trials in functionally anephric (undergoing dialytic maintenance) patients, several helpful animal experiments have been completed. To date, chronically uremic animals in need of dialysis have not been sustained by sorbents alone. Gavage feeding of oxystarch alone or in combination with charcoal will prolong the life of anephric rats of three days to five days. Friedman et al. (81) investigated the mechanism of sorbent-induced life extension in bilaterally nephrectomized rats fed charcoal (1 g daily), oxystarch (1 g daily) or oxystarch plus charcoal (1 g of each daily). In sorbent-treated rats the increase in blood urea concentration was less than in untreated nephrectomized controls, but they also had lower serum potassium concentrations throughout their increased life span. Both actions of oxystarch, increased fecal excretion of nitrogen and potassium, were detectable in this in vivo model of fatal acute renal failure.

 

Charcoal as an oral sorbent and for hemoperfusion

The work of Yatzidis on charcoal (38, 39) is important. Administered in oral doses of 20 to 50 g daily, with or without sorbitol as a vehicle, Yatzidis (82) was also able to manage patients with end-stage renal failure for 4 to 20 months without resorting to dialysis.

For completeness in this survey, the technique of direct exposure of blood to a sorbent, termed hemoperfusion, will be mentioned. During a single passage over granular activated charcoal, creatinine, uric acid, indican, phenols, guanidines and organic acids are nearly totally extracted from the blood. Only negligible quantities of urea, magnesium and phosphate are adsorbed on charcoal from blood. Each gram of powdered charcoal will in vitro bind simultaneously 9 mg of creatinine, 8 mg of uric acid, 1.75 mg of phenols, 1 mg of guanidines and 35 mg of urea.

Yatzidis (38, 39) devised a hemoperfusion device containing 200 g of activated charcoal in a siliconized glass cylinder 20 cm in length and 6 cm in diameter. Based on an experience of 20 humans undergoing hemoperfusion, Yatzidis estimated that 60 minutes of blood exposure to two or three 200 g charcoal columns had about the same extraction efficiency (for uremic patients) as a 4 to 6 hours hemodialysis. Hemoperfusion was advocated for the treatment of renal insufficiency, gouty arthritis, and intoxications with salicylates, barbiturates and glutethimide (82-84).

 

Charcoal microencapsulation

Chang et al. (85, 86) have systematically studied several approaches to microencapsulation of charcoal and they developed a blood-compatible albumin-complexed polymer. Chang’s microencapsulated “kidney” contains 300 g of double coated charcoal granules 2 to 5 mm in diameter with a surface area of 2.25 m2. This device achieves clearances in vitro, which are superior for middle molecules (MW 200 to 1,800), to hollow fiber, coil or parallel flow hemodialyzers. Periodic hemoperfusion as a sole treatment for uremia is inadequate because of the need to extract water and probably urea to maintain acceptable morbidity. Combination of hemoperfusion in series with ultrafiltration of blood for water removal might prove a workable therapy for uremic patients who ingest ammonia binding sorbents such as oxidized starch. The efficiency advantage (shorter treatments) of hemoperfusion over hemodialysis in renal failure is sufficiently attractive to consider sorbents in the management of uremia, coupling hemoperfusion with oral sorbent ingestion.

 

Dialysate regeneration

The field of closed circuit artificial kidneys was opened by Yatzidis (38, 39) who introduced carbon to remove uremia waste products. Gordon (87, 88) introduced the use of zirconium phosphate which adsorbs ammonium ions in presence of sodium and releases Na+ and H+. This allowed regeneration of dialysate through a sorbent cartridge.

A remarkable reduction in dialysate volume to 1.5 liters was devised by Gordon and co-workers by the clever means of converting urea in dialysate to ammonium ion and carbonate by urease treatment. Ammonium ion is adsorbed by zirconium phosphate which also extracts calcium and magnesium necessitating continuous reinfusion of these ions. Zirconium oxide binds phosphate and fluoride while charcoal extracts uric acid, creatinine, guanidines, organic acid and phenols. The total weight of the sorbent cartridge is less than 2 kg. The importance of the Gordon (89) system is not only the size reduction, which makes a “travel-suitcase” artificial kidney practical, but it is also a clear demonstration of the value of sorbents in simplifying the therapy of uremia. Zirconium phosphate could also be used in association with charcoal, starch and oxystarch (48-58) by Giordano and his associates for portable artificial kidneys (Figure 4, Figure 5 and Figure 6).

 

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Carmelo Giordano (1930-2016): a giant in Nephrology

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Natale G. De Santo

Natale G. De Santo1, Carlo De Pascale2, Ernesto Quarto3, Malcolm E. Phillips4, Biagio Di Iorio5

1 Department of Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
2 Retired Physician in Chief, Renal Unit Cotugno Hospital, Naples,  Italy
3 Retired Professor of Bioengineering, University Federico II, Naples , Italy
4 Retired Nephrologist and Medical Director of Charing Cross and Hammersmith Hospitals Trust London, UK
5 Division of Nephrology, Solofra General Hospital, Avellino, Italy

Correspondence: Natale Gaspare De Santo, MD, Emeritus, Chair of Nephrology, Via Pansini 5, Pad 17, 80131, Naples, Italy;

E-mail: nataleg.desanto@unicampania.it - Phone: +393484117376

 

Abstract

Carmelo Giordano (Carmine, Louis, Joseph Giordano) was born in Naples on August 23, 1930 in the house of Rafael and Anna Tirone He received the MD cum laude in 1954. He was Fellow and assistant to Professor Flaviano Magrassi and studied nephrology at the Peter Bent Brigham Hospital, University of Harvard in Boston, under the guidance of John P. Merrill (1958-1960). He was nominated Professor of Nephrology at the University Federico II, Naples in 1975 and Professor of Medicine at the Second University of Naples (1986-2002). The National Institutes of Health of the United States in Bethesda financed his research for more than 20 years. He started low protein alimentation (Giordano-Giovannetti diet according to Geoffrey M. Berlyne) with or without addition of amino acids and ketoacids and devised formula diets for CKD infants and children. He demonstrated that 85% of CKD patients receiving a 25 g protein diet were in positive nitrogen balance. Later he introduced the concept of energy load from dialysate in CAPD and the assessment of amino acid losses during hemodialysis and peritoneal dialysis. He also researched the minimum protein requirement under CAPD regimens. He synthesized, with Professor Renato Esposito, oxystarch and oycellulose and introduced the use of carbon at low temperature and its regeneration at 90 ˚C. He introduced wearable and portable artificial kidneys. He died in Naples on May 12, 2016.

Key words: amino acids, carbon, ketoacids, low protein diets, nitrogen balance, oxycellulose, oxystarch, peritoneal dialysis belt, wearable and portable artificial kidneys

Giordano’s life

Carmelo Giordano (Carmine Louis, Joseph Giordano) (Figure 1) was born in the house of Rafael and Anna Tirone in Naples on August 23 1930 (Figure 2). His father held the title of Baron. He was baptized on the 28 September in the Catholic Parish of the Holy Cross and Saint Rita (Figures 3 and 4). Giordano attended primary, junior high and grammar schools in Naples. In the same city he studied medicine at the feet of Professor Flaviano Magrassi (Figure 5), at the University Federico II, and in 1954 he obtained the MD cum laude. During the fourth medical course he had joined the Institute of Medical Pathology directed by Professor Flaviano Magrassi, an expert in infectious diseases and leukaemia, originating in the famous Roman School of Cesari Frugoni. Magrassi, a forerunner of medical specialists in the university, had just arrived in Naples from Sassari in Sardinia. He attracted many talented young students who prepared their Ph.D theses with him and later achieved chairs in many specialties. After obtaining the MD Giordano started a laboratory for the assessment of renal function (mainly devoted to clearance studies) in various human models of renal and vascular disease.

In 1958 Giordano moved to Boston (MA, USA) and remained there for the next 3 years (Table 1). There he studied clinical nephrology, dialysis and transplantation at the feet of Prof. John Putnam Merrill (Figure 5) the “father of nephrology as a discipline” (Prof. Murray Epstein, Nobel prize in medicine in 1991), at the Peter Bent Brigham Hospital of the Harvard Medical School (“no Institution has done more for propagation of dialysis in the United States”- again Professor Epstein).

He had been able to contact Professor Merrill while the Harvard professor was travelling to conferences throughout Italy. Merrill was very impressed by the talents of the young Italian physician and even offered him hospitality at his home (1958). This resulted in a daily scientific exchange with the man who, in association with Professor Joseph E. Murray, had made the first successful renal transplant between identical twins: the brothers Herrick, namely Richard (the recipient) and Ronald (the donor). So Giordano was at the right time in the most prestigious place in the forefront of modern nephrology. There he learned and practiced at the same time dialysis and transplantation from top investigators.

Upon his return to Naples (1961) he developed a laboratory devoted to nutrition in renal disease, which was located in 3 large rooms on the 3rd floor of the Institute of Medical Pathology. Available equipment included a flame photometer, an osmometer, a spectrophotometer, laboratory centrifuges and one ultracentrifuge, a Warburg apparatus, equipment for acid base measurement in blood and urine, an amino acid analyser and Kjeldhal apparatus for measuring nitrogen in urine and faeces. However the most important piece of equipment was a Kolff-Brigham artificial kidney, which had been donated to Giordano by Mr. Edward Olson, its manufacturer. The artificial kidney was located in a special room (called room no. 6) on the fourth floor of the institute where dialysis for acute renal failure was performed. Dialysis for ESRD was started in 1966.

In 1959 Giordano applied a project for nutrition of patient with chronicc kidney disease to the National Institutes of Health of the United States of America. He was financed. He received grants and a contract for projects on nutrition, sorbents and peritoneal dialysis for the next 21 years (1959-1980).

At the University of Naples Federico II Giordano (Table 1) was ordinary assistant (1964-1971), and then Professor of Nephrology-after the national examination in 1975- until 1986. He was invited to take up the chair in Medicine and Nephrology at the Catholic University in Rome but he declined. Thus he was made full Professor of Medicine in Naples in the years 1986-2002. He was Dean for Curricula and founded the postgraduate school of nephrology. He was a member of the board of professors for the Ph. D. Program In Nephrological Science (1980-2002). He was one of the 10 founders of the Italian Society of Nephrology over which he subsequently presided. He was also a founder of the Italian Society of Artificial Organs, a founder of the International Paediatric Nephrology Association, International Society of Artificial Organs and the International Society of Peritoneal Dialysis. In addition he was instrumental in starting academic paediatric nephrology in Italy.

With Wichtig Editore he set up the International Journal of Artificial Organs, the International Journal of Pediatric Nephrology (later changed by Karger AG into Child Nephrology and Urology), and Giornale Italiano di Nefrologia. There were problems in breaking the collaboration with the group of Minerva Nefrologica. However, as pointed out in the letter to the readers, this was just the act of independence of the Italian Society of Nephrology as confirmed by the nomination of Prof. Giuseppe Piccoli as Editor in Chief to express continuity with the work of the previous editorial staff.

 

Fellows and Collaborators

His first fellow was Dr Renato Esposito, a talented investigator with a great interest in clinical chemistry. Giordano also attracted two medical students working on their theses (Natale G. De Santo and Carlo de Pascale) who were the first to be tutored by Giordano for the MD. The initial group also included Mr. Antonio Ariano (laboratory technician), Ada Crescenzi (Ph.D in chemistry), Maria Pluvio and Lia Poderico (nutritionists). An incomplete list of collaborators is given in Table 2.

 

Table 3 lists some of Giordano’s achievements in science. Table 4 lists his active membership in various societies, and the congresses that he organized personally.

 

Investigators on sabbatical

Various creative clinical scientists worked during sabbaticals at the nephrology department directed by Carmelo Giordano (Table 5). The first was Prof. Kazimierz Backzyk, later Professor of Nephrology at the Medical University of Poznan (Poland). He arrived in Naples at a time when Eastern Europe began to separate from the West with the construction of the Berlin wall.

Dr. Malcolm Phillips came to Naples from London as a Welcome Trust Research Fellow for 2 years (1970-1972). His fellowship was arranged between Professors Hugh de Wardener and Carmelo Giordano. He studied amino acid losses on dialysis, the effects of essential amino acid supplements in hemodialysis patients and the utilisation of keto-acids in healthy and uremic subjects. Later, when back in London, Dr. Phillips was, for varying periods General Manager of the Charing Cross Hospital and Medical Director of the Charing Cross and Hammersmith Hospitals Trust.

Prof. Otto Busato came from the Department of Nephrology at the University of Porto Alegre, Brazil, to work on nutrition and peritoneal dialysis. Also Prof. Alejandro Trevino Becerra came with the same goal and subsequently was anchored long term to the topic. Francisco Gonzalez, Professor of Medicine and Chief of Nephrology at Louisiana State University in New Orleans, during his stay attracted many young investigators to study acid-base balance in HD and PD and focused his research on pharmacological means to augment peritoneal dialysis clearances.

The collaboration with Professors Ciro Balestrieri and Domenico Cittadini of the Department of Biological Chemistry at the University of Naples was long-lasting and produced outstanding results.

Drs. Gianfranco Romagnoli and Domenico Di Landro came from the Hospital of the University of Padua to learn about sorbent therapy.

The list of visiting scientists includes, among many others, Professors Jan Brod, Jan Roguski, Thadeus Orlowski, Geoffrey M. Berlyne, Karl Julius Ullrich, Shaul Massry, Klaus Hierholzer, Jules Traeger, Gerhard Malnic and Willem Kolff who was attracted by the use of sorbents for wearable kidneys from Professor Renato Esposito and wrote on this experience in Dialysis and Transplantation.

 

Giordano’s hobbies

Giordano had many interests. He enjoyed to play with words and look into their etymology, a reflection of his days at the grammar school (in Italian Liceo Classico). He was interested in soccer and had season tickets for the home matches of the Naples Soccer Club at the time of the great player Armando Maradona.

He also enjoyed driving Porsche cars, and sailing. He had a boat constructed in Finland (Black Swan), described in the Treccani Lexicon-where photos of Giordano and his crew appear- for its outstanding technical characteristics. He participated in many national and international races and developed an international reputation. Once, with a crew made of young investigators and professors including the famous Professor of Modern History, Giuseppe Galasso (a member of Accademia dei Lincei-Linx) who was responsible of the fiocco (jib), Giordano made third place in the Giraglia Cup. For those not experts the jib is a triangular sail placed in the ship’s bow and the Giraglia Cup is a race starting in St. Tropez, France, passes through the Îles d’Hyères off the French coast near Toulon, then around Giraglia, and finishes in Genoa, Italy, a total of 243 nautical miles.

Giordano also loved to cook simple Neapolitan dishes and from time to time he prepared, late in the evening, spicy spaghetti for his colleagues and guests.

He aspired to perfection in work and used to say “we shall do without mistakes”. This imposed a strong work ethic and mental concentration in his collaborators.

 

The University Federico II: a university with two medical faculties

In Naples, for reasons difficult to explain in a few words, there were two medical faculties at the University Federico II. There was competition between the two schools (normal healthy university life) but there were also frictions, which surpassed the politically correct and affected the academic life of fellows. In 2014 there was finally peace, but it was too late. The wounds had healed with ugly scars.

 

Publishing or perish

Giordano had a great interest in teaching medical students and fellows. He was convinced that the best way to teach was through writing books. A complete list is given in Table 6. The frontispiece is depicted in Figures 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. The first book (Figure 6) was the nicely printed Nefrologia. The outline was that of a U.K. manual, being fresh, modern and easy to read. It included dietary treatment for acute and chronic renal failure

 

The second book was a concise monograph on nutrition in renal disease (Figure 7), the first of its kind worldwide. It could be easily read by students and by practitioners. Giordano put great emphasis on electrolytes and acid base balance (Figures 8 and 12).

 

His most important book was Sorbents and their clinical applications (Figure 10), which opened the field to the use of sorbents in the clinical setting. It was the work of a renowned specialist in the field.

 

For many years Giordano laid great store in participating in congresses, including the Annual Contractors’ Conference in Bethesda, the Congress of the EDTA and of the International Society of Nephrology, the Italian Society of Nephrology, Giornate Nefrologiche of the Saint Carlo Hospital in Milan, as well as those relating to artificial organs work. Many outstanding data are contained in the proceedings of those congresses.

 

Nutrition in chronic kidney disease

Diets in CKD

In 1959 Giordano applied to the National Institutes of Health of the United States in Bethesda for funding for a project devoted to nutrition in kidney disease. He proposed the use of low protein diets in the form a) essential amino acids and b) as proteins of high biological value, both rich in energy. The project was financed and was the first of a series of grants (1959-1980). Giordano’s first study with L-essential amino acids was a classical example of self-experimentation. For 53 days Giordano ingested L-Essential amino acids in a quantity classically defined by Rose. The basic formulation was supplemented either with 3 g of nitrogen (N) derived from glycine (period A), or 0.5 g of N derived from glycine (period B), or 2 g of N in the form of ammonium citrate (period C) or 2 g of N in the form of urea (period D). Nitrogen balance was calculated by daily analysis of urine and fecal nitrogen. The study was published in the Bollettino della Società Italiana di Biologia Sperimentale (1).

The subsequent experiment (2) with amino acids (2 g of N/day) was carried out in two patients with very low GFR’s and this produced positivity of nitrogen balance.

The third crucial experiment was performed in one healthy person (C. Giordano himself) and in 8 patients with eGFRs of 9-26 ml/min (Table 7). These subjects received L- essential amino acids (2g N/ day – period A) followed by a diet (period B) containing 23 g of protein of high biological value. The energy intake was high in both periods. In that paper (3) there are data on the effects of a synthetic diet containing essential amino acids (17.7g/ 2g of N), 2300 calories in women, 3100 in man-followed by a low protein diet (3.8g/N, 68 % from milk, 23g of protein in total). The paper published in J Lab Clin Med  was cited 401 times. A typical experiment in 1 subject is depicted in Figure 18.

At the second congress of the International Society of Nephrology in Prague in 1963 Giordano presented unique work on low protein alimentation. This consisted of data in 23 patients with chronic kidney disease (plasma creatinine 2.6 to 9.0 mg/dl) treated for a total of 236 months. The patients underwent a dietary schedule for 5 weeks: in weeks 1 and 5 they ate a low protein diet (23g day in the form of protein of high biological value) and in weeks 2-4 a diet providing 2 g of N/day as L-essential amino acids (4). A typical experiment in 1 subject is depicted in Figure 19.

In 1964 Giovannetti and Maggiore published data on CKD patients with GFRs of 3-6 ml/min who received a protein poor diet (N 1.0-1.5 g/day) for 10-15 days followed for 2 weeks by a low nitrogen intake (1.74 g/day) as L- essential amino acids and then (indefinitely) by a restricted protein intake (2.2 g of N/day) in the form of egg protein, or egg albumen. Amino acids promoted a positive nitrogen balance, which was maintained under the low protein regime (5).

In the same year Giordano published the aforementioned book on La Dieta nelle Malattie Renali/ Nutrition in Renal Disease, in which he suggested the use of L-essential amino acids for 2-3 weeks followed by a low protein diet with natural foods providing 23 g of protein/day (6). Additional data from the groups in Naples and Pisa were published in Minerva Nefrologica in 1965 (7, 8). This was the genesis of the Giordano-Giovannetti Diet, as said first by Geoffrey M. Berlyne (9, 10, 11, 12, 13). The pioneering nature of this work has been described elsewhere (14, 15, 16).

At the III Congress of Nephrology in Washington Giordano, De Pascale, Esposito and De Santo (14) presented data in 25 CKD patients kept on diets providing up to 25g proteins a day. It was shown that 85% of patients achieved a positive nitrogen balance when the diet provided 25g of protein/day (Table 8). Many other studies (17, 18, 19, 20, 21, 22, 23) confirming the feasibility and the usability of low protein diets were published in the years 1967 and 1968. Kopple at that time was ready to prescribe a 40g protein diet (20). Of course this diet was easy to take since 0.6g/kg is, according to nutritionists, a normal intake in adults.

At the Scottsdale Conference on Nutritional Aspects of Uremia (23) Giordano was applauded as is apparent from the proceedings, published in the American Journal of Clinical Nutrition, which contained favorable comments by very eminent scientists (Table 9).

 

Studies on ketoacids

Giordano had many doubts on the long-term usability of ketoacid analogs in CKD. However he worked hard on this topic. The first experiments dated back to 1968. At that time there was uncertainty about the possibility of utilizing D amino acids for protein synthesis in man (24). An experiment was devised on a young patient with chronic glomerulonephritis who underwent various amino acid regimens (Table 10). The diet provided 5 DL-essential amino acids and 3 L-essential amino acids (Period A), 8 L-Essential amino acids (Period B), 8 L-Essential amino acids with urea (Period C). In period D 8 L-essential amino acids + urea where given in association with paromomycin to sterilize the gut. Nitrogen balance was positive in periods A, C and D, negative in B (Figure 20). The experiment demonstrated that the α-amino nitrogen of D amino acids was fully utilized indicating that nitrogen balance was enhanced by the extra nitrogen of D-isomers.

In 1970 experiments were carried out at St Mary Hospital in London study in nitrogen balance and 15N incorporation in patients receiving the keto analogs of valine and phenylalanine in health and CKD. Nitrogen balance rapidly became negative when either or both phenylalanine and valine were withdrawn from the diet of healthy persons and patients with chronic renal failure. Replacement of these essential amino acids by their α-ketoacid analogs ameliorated or normalized nitrogen balance (25). Data on N incorporation went in the same direction as nitrogen balance pointing to the possibility of substituting amino acids with their keto analogues (26). However, with time, the enthusiasm for this was cooled by data, which showed absence of catch-up growth in infants switched from an amino acid to a ketoacid diet (27). In that study 6 children with GFRs of 0.9 -3 ml/min and two babies (GFRs of 22 and 15 ml/min) were fed either with a formula diet (28) according to the data of Holt and Snyderman (diet D) or according to the uremia reference pattern (29) of Giordano, De Santo and Pluvio (diet C). Both formulae (27) were made either with amino acids or amino acid + 4 ketoacid analogs and a hydroxyacid: alfa-keto-isocraproic acid, L-ketoβmethylvaleric acid, alfa-ketoisovaleric acid, phenylpyruvic acid, αhydroxy-γmethylbutiric acid as keto analogues of L-leucine, L-isoleucine, L-valine, L-phenylalanine, and as the hydroxyacid of L-methionine, respectively.

In children taking formula C diets (amino acids) nitrogen balance was +0.54+018g whereas with the formula C (keto analogues) it averaged +0.14+0.16g (Table 10). In infants formula C (amino) and fomula D (amino) provided growth superior to formula C (keto) and formula D (keto) diets, as indicated in Table 11.

However the results of the studies data of Professor Mackensie Walser on ketoacids were more and more convincing and were confirmed in other laboratories. Thus on the occasion of the plenary lecture at the Athens Congress of the International Society of Nephrology Giordano, while acknowledging the impossibility for nutrition to compete with dialysis and transplantation, made the point that appropriate alimentation should be used very early in the course of chronic kidney disease. He was finally able to bring opinions together from available studies on the use of ketoacids and supported their use as one modality of nutrition in chronic kidney disease (30).

 

Further studies on nitrogen metabolism in health and uremia

Plasma aminograms from uremic patients showed, for the first time, an impaired tyrosine to phenylalanine ratio, an increase in 3- methylhistidine and a depression of the histidine to methylhistidine ratio. Loss of free amino acids and small peptides was 15-20 g per each hemodialysis session (31).

Labeled molecular nitrogen was administered subcutaneously in a CKD patient (creatinine clearance 7.5 ml/min). Labeled nitrogen was subsequently found in amino acids of plasma albumin, indicating that molecular nitrogen is not an inert gas in humans (32).

In another study the energy load from dialysate (800 cal/day) in CAPD patients was described (Figure 21). The patients were undergoing 2 liters exchanges five times a day (33). Nitrogen balance studies were performed for the first time in CAPD patients and it was demonstrated that a protein intake of 1 g/kg/day was sufficient (Figure 22) to keep a neutral or positive nitrogen balance (34).

Giordano was also first to describe (i) amino acid losses in CAPD in children, (ii) the protein requirements of children on CAPD, (iii) the energy load of children on CAPD. In addition he showed that nitrogen balance of diabetic patients on CAPD was maintained by prescribing a diet containing 1.3 g/kg of protein per day (35).

Although dialysis and transplantation (a procedure available to a minority of patients) are vital treatments they are expensive. Giordano continuously searched for improvements in renal nutrition. Even one year of dietary treatment would spare relevant resources. This interest was not lessened by the negative results of the very publicized MDRD study (14, 15).

 

Giordano’s last thoughts of low protein alimentation

The last time Carmelo Giordano participated in a scientific meeting (Survival is not Enough no.10, Naples March 10, 2016 at the Italian Institute for Philosophical Studies) he declared his interest in promoting transplantation because of the quality of life it offered (36). However he declared himself very pleased by the paper of Denis Fouque and William E Mitch which stated: “In the history of medical sciences fewer topics have been the focus of so many clinical trials, reviews, speculation, and discussions than the question of what constitutes an optimal protein intake for patients with kidney disease… But probably we are reaching a consensus” (37).

He felt that this tenet was strongly supported by: (i) the studies of Massimo Cirillo et al. in middle aged subjects of the Gubbio Population Study (the whole population of that city in central Italy) showing that higher protein intake is associated cross-sectionally with higher GFR but longitudinally with greater GFR decline over time (38); (ii) data of Bruno Cianciaruso et al (39); (iii) data of Vincenzo Bellizzi et al. (40), (iv) a report on the costs of CKD therapy in the Campania Region co-authored by many authorities and coordinated by Giorgio Liguori (41), and (v) by data of Vincenzo Bellizzi and Biagio Di Iorio et al. (42) as well as (vi) by the data of Di Iorio’s team on the effects of very low protein diets on Fibroblast Growth Factor 23 (43) and on indoxyl sulphate (44).

 

Studies on sorbents in uremia

Giordano was interested in the use of sorbents in uremia, having developed the idea that the intestine could be used as a third kidney, and having been fascinated by Professor Yatzidis and his studies on carbon. He imprinted this enthusiasm in Professor Renato Esposito, nephrologist and expert in clinical chemistry, Professor of Nutrition and Immunologist (Table 2). He was chief of the laboratory for the development of sorbents (Table 2) which included doctors in chemistry (Pietro Bello, Giovanni Demma, C. Rufolo), a mathematician, bioengineer and associate professor (Ernesto Quarto), a full university Professor of Biochemistry (Giacomino Randazzo), a Ph. D and nephrologist (Norina Lanzetti), a doctor in biological science, Ph.D and nephrologist (Maria Pluvio), a technician (Antonio Ariano) and Carmelo Giordano. We provide here a synopsis of their major achievements (45-75).

 

Oxystarch

Oxystarch -binding urea and nitrogenous substances- was obtained by oxidizing potato or maize starch (Figure 23). Oxystarch reacts with urea in a manner proportional to the concentration. The isotherm of oxystarch is given in Figure 24. At urea concentrations typical of uremia the reaction yields interesting results at low and neutral pH values. Oxystarch was developed in 1968 and data was published in Bollettino Società Italiana di Biologia Sperimentale (45). Oxystarch administered to uremic patients caused increased fecal nitrogen excretion (Figure 25) along with decreased blood urea nitrogen. In a patients treated by peritoneal dialysis (Figure 26) increased fecal nitrogen and reduced blood urea nitrogen were observed and dialysis was postponed by 3 weeks. In a patient on HD oxystarch allowed a prolongation of the interdialytic interval (Figure 27). The data were confirmed by different groups and were shown to be dependent on the fecal mass and the quality of foods. Sorbents bind urea in the stomach and ammonia in the colon. It was shown that the amount of oxystarch could be increased in order to obtain up to 4 g. of nitrogen in feces, which is equivalent to the quantity of urea generated by a protein intake of 24g/day (46, 47, 48, 61, 53, 54).

 

Oxycellulose

Oxycellulose-binding urea and nitrogenous toxins-was obtained by treating wood cellulose with hot acids, cellubiase and cellulase (Figure 28). It reacted with urea at blood concentrations typical of uremia (Figure 29). The reactivity was pH dependent and higher at pH 1 than at pH 7.4 (Figure 30) and is maximal at pH 1 (Figure 31). Oxycellulose could be administered orally (49, 50, 53, 54).

 

Carbon reactivity with urea between 1 and 90 ˚C

The group on sorbents studied carbon reactivity towards urea (Figure 32) and introduced the use of carbon at 0˚C to bind urea and nitrogenous waste products (Figure 33). They also introduced the concept that working between 1˚C (maximal adsorption) and 90˚C (complete desorption they could indefinitely regenerate carbon (Figure 34), as described in references nos. 54,56, 60.

 

Studies on a carbon based portable artificial kidney

The study allowed the construction of a cold carbon apparatus (35). Carbon is very active at 0˚C so it can be used to regenerate dialysis fluid in a closed circuit. With this approach catabolic products are adsorbed onto cold carbon without interfering with electrolytes which are not adsorbed on carbon. Carbon can also be treated to avoid adsorption of useful metabolites. Adsorption and desorption of solutes is an independent operation for each solute, thus the strategy resembles a natural process. Therefore a portable artificial kidney was envisaged using only a few liters of tap water with low expenditure of energy (around 100 watts) by recovery of energy via a thermal exchanger (52, 54, 59, 60, 61, 62, 63).

 

A combination of sorbents for portable and wearable artificial kidneys

A portable as well as a wearable kidney were also built by combining, resins, carbon, oxycellulose, oxystarch and 2 liters of dialysis fluid (Figure 36) continually regenerated (55, 56, 61, 62, 63).

 

A peritoneal dialysis belt

The group on sorbents finally proposed a peritoneal dialysis belt by using a cartridge containing oxycellulose, active carbon and ion exchange resins. It could work without sorbents for urea as oxystarch and oxycellulose could be given orally. Thus the peritoneal dialysis belt was devised to remove urea and non-urea toxins and to restore fluid and electrolyte balance (Figure 37). The belt was assembled using a strong cation exchange resin in H+ form, oxycellulose and a weak cationic resin in Na+ form. The first resin acidified the fluid to pH so that oxycellulose was able to react maximally, the second resin would reconstitute the pH and the electrolytes (62, 63).

 

Sorbents and their clinical applications

The group gained international reputation. Their place in academic medicine is indicated by an incomplete list of papers (ref. from 45 up to 75), published in the years 1968-1984 and the details of congresses to which they were invited. Pim Kolff came to visit Renato Esposito and Carmelo Giordano and their group and worked with them. He wrote in Dialysis and Transplantation of his cultural experience in Naples. Finally in 1980 a provocative book-mentioned before-was edited by Carmelo Giordano (64) on Sorbents and their clinical application (Figure 10 and Table 6) and this included a broad view of future applications. The book, dedicated to Arthur Gordon, was published even in Russian. It hosted papers from thirty illustrious specialists including Renato Esposito (66, 68), Carmelo Giordano(66, 68), Pietro Bello (67), Ernesto Quarto (65), Thomas Ming Swi Chang, Eli A. Friedman, R.E. Sparks, William J Asher, Kenji Maedaand Roger Williams.

 

References

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  2. Giordano C. Metabolismo nell’uremia cronica. III. L’utilizzazione dell’urea endogena in pazienti affetti da grave insufficienza renale. Boll Soc. Ital Biol. Sper. 1961; 3: 1296-1297
  3. Giordano C. Use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J Lab Clin Med. 1963; 62: 231-246.
  4. Giordano C. Treatment of uremia using L-essential amino acid and low protein diets. Proc 2ndInt Cong Nephrol, Prague. Excerpta Medica International Congress series no.78, Karger Basel 1964; 752-765.
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  35. Giordano C, De Santo NG, Capodicasa G, Di Leo VA. Studies in end stage diabetic nephropathy. Data on nitrogen balance during CAPD therapy. In Friedman EA and L’Esperance FA Jr, Eds. Diabetic Renal Retinal Syndrome vol 2. Grune and Stratton Inc, New York, 1982; pp.345-351.
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  38. Cirillo M, Lombardi C, Chiricone D, De Santo NG, Zanchetti A, Bilancio G. Protein intake and kidney function in the middle-age population: contrast between cross-sectional and longitudinal data.Nephrol Dial Transplant (2014) 29 (9): 1733-1740.DOI:https://doi.org/10.1093/ndt/gfu056
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  51. Giordano C, Esposito R, Pluvio M. Further studies with oxystarch. Kidney Int 1976 Dec;(7):S266-8
  52. Giordano C, Esposito R, Bello P. A cold charcoal depurator for the adsorption of high quantities of urea. Kidney Int 1976 Dec ;(7):S284-8.
  53. Giordano C, Esposito R, Pluvio M, Gonzalez F. Oxycelluloses: a group of sorbents to remove extracorporeal urea. Kidney Int 1976 Dec;(7):S348-50
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  74. Capodicasa G, Daví G, Picone F, Mattina A, Giannetto V, Vinti V, Vaccaro F, Strano A, De Santo NG, Giordano C. Platelet thromboxane formation and BTG levels after intensive charcoal HP in uremics on regular hemodialytic treatment (RHT). Int J Artif Organs. 1983 Jul;6(4):183-6.
  75. Giordano C, Esposito R, Cirillo D, Betuel H, Fredel A, Pluvio M, Mazzola G, Longhi R, Manzo M. Active carbon and its controversial ability to adsorb uremic toxins. Int J Artif Organs. 1984 Jul;7(4):177-8

 

Tables

Table 1 – Roles and functions (research, clinical duties and teaching) at the University Federico II in Naples, at the Second University of Naples (Italy) and at the University of Harvard in USA.
Year                       Role and functions

1955-1957           Voluntary Fellow Institute of Medical Pathology

1958                                      On August 2, married Liliana Pistone (4 children were born: Dario, Diego, Mauro and Laura)

1958-1960           Investigator Peter Bent Brigham Hospital of the University of Harvard, Boston USA

1961-1963           Extraordinary assistant of the Institute of Medical Pathology

1964-1971           Ordinary assistant of the Institute of Medical Pathology

1971-1975           Ordinary assistant at the institute of Clinical Medicine

1969-1985           Professor of Nephrology (yearly renewable by the Faculty of Medicine)

1975                      Professor of Nephrology (after the National Contest)

1975-1978           Extraordinary Professor of Nephrology

1983-1986           Director of the Institute of Internal Medicine and Nephrology

1978-1985           Full Professor of Nephrology

1984-1986           Dean for Curricula Faculty of Medicine

1985-1986           Full Professor of Medical Pathology

1987- 2002          Full Professor of Internal Medicine

1975-2002           Director of the Postgraduate School of Nephrology

1987-2002           Director Department of Clinical and Experimental Medicine

Table 2. Giordano’s collaborators
  • Fellows
  • Renato Esposito, (expert in renal nutrition, sorbents, tissue typing, member of the transplant team, Associate Professor of Nutrition and chief of unit for nutrition of surgical patients
  • Natale Gaspare De Santo, physiologist, space physiologist, nephrologist, expert in peritoneal dialysis, member of the transplant team, full Professor of Pediatric Nephrology and full Professor of Nephrology
  • Carlo de Pascale, nephrologist, expert in nitrogen balance, amino acid analysis and peritoneal dialysis, Chief of Nephrology of the Cotugno Hospital for Infectious Diseases in Naples.
  • Giuseppe Capodicasa, nephrologist, expert in renal transplantation, vascular access, hemodialysis, and hemoperfusion, Associate Professor of Nephrology (Deceased)
  • Domenico Cirillo, Expert in renal transplantation, vascular access, hemodialysis and renal pathology, Associate Professor of Nephrology
  • Nicola Perna, cardiologist, nephrologist, forerumner of cardionephrology. Associate Professor of Nephrology
  • Daria Acone, nephrologist, expert in hypertension and hemodialysis University Investigator
  • Vincenzo Calderaro, nephrologist, expert in peritoneal dialysis and ultrasonography, renal pharmacologist. University Investigator (Deceased)
  • Ferdinando Cocco, virologist, nephrologist, expert in renal transplantation. University Investigator, Chief Renal Division at Nocera and Nola Hospitals
  • Ugo Cocco, diabetologist, endocrinologist. University Assistant
  • Francesco Saverio Di Maio, nephrologist, expert in hypertension and hemodialysis. University investigator
  • Sonia Garzoni, nephrologist, expert in hypertension and hemodialysis, University Investigator
  • Mario Landolfi, nephrologist, expert in tissue typing, member of the transplant team, University Investigator (Deceased).
  • Norina Lanzetti, nephrologist, expert in sorbents. University Investigator
  • Massimo Manzo, expert in vascular access, tissue typing and hemodialysis, member of the transplant team University Investigator
  • Anna Papa, nephrologist, expert in peritoneal dialysis. University Investigator. (Deceased)
  • Teresa Troiano Rattazzi, (expert in nutrition), subsequently in Brooklyn with E.A. Friedman and in Seattle with B. Scribner. Director of a dialysis unit. (Deceased)
  • Sabino Rinaldi, nephrologist, expert in amino acid analysis.University Investigator. (Deceased)
  • Antonio Saggese, nephrologist, immunologist, member of the transplant team. University Investigator
  • Pietro Castellino, nephrologist, expert in protein related kidney hyperfiltration. Full Professor of Medicine, University of Catania
  • Maria Pluvio, biologist, nutritionist, nephrologist, Ph.D in nephrology, University Technician. (Deceased)
  • Paolino Raiola, nephrologist, expert in hemodialysis. Clinical Assistant in Nephrology of the Campania Region
  • Amalia Poderico, nutritionist, chief nurse
  • Antonio Ariano, expert in biochemical analyses for nitrogen balances, Laboratory technician (deceased)

 

  • Group on Sorbents
  • Renato Esposito, Coordinator
  • Giacomino Randazzo, Advisor, Full Professor of Biochemistry Faculty of Science
  • Giovanni Demma, Doctor in Chemistry, investigator Faculty of Agriculture
  • Rufolo, Doctor in Chemistry
  • Piero Bello, Doctor in Chemistry, high school professor
  • Ernest Quarto, Engineer, University Professor of Mathematics. Professor of Medical Engineering
  • Norina Lanzetti
  • Maria Pluvio
  • Antonio Ariano
  • Mario Landolfi
  • Massimo Manzo
  • Antonio Saggese

 

  • Group for physiology, peritoneal dialysis, pediatric nephrology, epidemiology of renal disease and space research
  • Natale G De Santo, Coordinator
  • Giovambattista Capasso, physiologist, expert in acid-base and electrolytes and peritoneal dialysis. Full Professor of Nephrology University of Campania Luigi Vanvitelli, Scientific Director Biogem at Ariano Irpino (AV)
  • Massimo Cirillo, nephrologist, internist, epidemiologist, expert in hypertension, biostatician. Associate Professor and Chief of Nephrology at the University of Salerno
  • Pietro Anastasio, nephrologist, pediatric nephrologist, urologist, expert in GFR assessment and hemodialysis. University Investigator
  • Rosa Maria Pollastro, nephrologist, expert in glomerular disease and renal pathology, Ph.D in Space Physiology. University Investigator
  • Alessandra Perna, nephrologist, Ph.D in nephrological sciences, expert in homocysteine. Associate Professor University of Campania Luigi Vanvitelli
  • Biagio Di Iorio, nephrologist, Ph.D in Nephrological Sciences, uremia specialist, Professor Postgraduate School of Nephrology at the Second University of Naples. Chief of Nephrology Solofra Hospital
  • Daniela Molino, nephrologist, Ph.D in Nephrological Scienes, expert in coagulation. Pediatric Nephrologist Santobono Hospital Naples
  • Francesca Nuzzi, nephrologist, Ph.D. in Nephrological Sciences, expert in renal pathology. Pediatric Nephrologist of Santobono Hospital Naples
  • Teresa Cicchetti, nephrologist, expert in peritoneal dialysis. Chief of Nephrology at the General Hospital at Rossano Hospital
  • Raffaele Senatore, nephrologist, expert in peritoneal dialysis. Former Chief of Nephrology at the General Hospital at Cariati Hospital
  • Maria Damiano, nephrologist, expert in peritoneal dialysis. Anesthesiologist San Carlo Hospital Potenza
Table 3 – Gordano’s achievements
(ii)          Honors

  • Doctor Honoris causa of the Polish Academy of Sciences
  • Golden Kidney Award from the European Society of Pediatric Nephrology
  • Domenico Cotugno Award from the University of Bari
  • President and Hon President of the Italian Society for Artificial Organs
  • President of the Italian College of University Professors of Nephrology
  • member of the German Society of Nutrition

 

  • Main Lectures

Polish Academy of Sciences, Nephrological Societies of Italy, Sweden, Brazil, Argentina, Japan, Czechoslovakia, Singapore, EDTA (1975, 1985), International Society of Nephrology, International Society of Artificial Organs, European Society of Nutritionists

 

  • Editorial boards

Minerva Medica, Nephron, Clinical Nephrology, Kidney International, Giornale Italiano di Nefrologia (founder), International Journal of Artificial Organs (founder), Artificial Organs International Journal of Pediatric Nephrology (founder), Diabetic Nephropathy, Diabetes Complications, Medizin und Ernhaung, Peritoneal Dialysis Bulletin

 

  • Funding

He received 50 scholarships among them 33 research grants and contracts from the National Institutes of Health Bethesda. He was also supported from the National Research Council of Italy, Regione Campania, Italian Ministry of Health

Table 4. Scientific societies and congresses
  • Scientific Societies
  • International Society of Nephrology (A founder in Geneva)
  • European Dialysis and Transplant Association (Councillor)
  • European Society for Paediatric Nephrology (President)
  • International Society for Pediatric Nephrology (Founder)
  • International Society for Peritoneal Dialysis (Founder and President of the Venice congress)
  • International Society for Artificial Organs (Founder)
  • Italian Society of Nephrology (Founder and President)
  • Società Italo-Americana di Nefrologia (Secretary)

 

  • Congresses (as organizer)
  • The Second Italian Congress of Peritoneal Dialysis
  • The Italian Congress of Nephrology
  • The Capri Conferences on Uremia in 1974, 1977, and 1980
  • The Sorrento International Workshop on Artificial Organs in 1980
  • The Venice Congress of the International Society for Peritoneal Dialysis
Table 5. Visiting Scientists and most productive collaborations
  • Visiting scientists from abroad and from Italy
  • Kazimierz Backzyk, 2nd Medical Clinic, University of Poznan, Poland
  • Otto Busato, Professor of Nephrology, University of Porto Alegre, Brazil
  • Malcolm Phillips, Consultant Nephrologist at Charing Cross Hospital, Medical Director Charing Cross and Hammersmith Hospitals Trust in London
  • Alejandro Trevino Becerra, Chief Division of Nephrology, Mexico City, DF, Mexico
  • Francisco Gonzales, Professor of Medicine, Louisiana State University, USA
  • Shaul Massry, Professor of Medicine, Keck School of Medicine, Los Angeles
  • Domenico di Landro, Assistant in Nephrology at the Polyclinic Teaching Hospital in Padua. Chief of Nephrology at Cannizzaro Hospital in Catania for studies on sorbents
  • Gianfranco Romagnoli, assistant in nephrology at the Polyclinic Teaching Hospital in Padua, Chief of the same, for studies on sorbents

 

(iI)          Most productive collaborations

  • Peter Richards, St Mary’s Hospital London, for ketoacids
  • Peter Fürst, St. Eriks Sjukhus, Stockholm, for nitrogen incorporation into proteins
  • Garnar Ryhage, Director Institute for Mass Spectrometry, Karolinska Institute, Stockholm, for studies on nitrogen utilization in healthy and uremic men
  • Staley M. Levenson, Albert Einstein College of Medicine, New York, for nitrogen incorporation in germ-free rats
  • Jules Traeger, University of Lyon, France for renal transplantation
  • Herve Betuel, Immunologist, University of Lyon, for renal transplantation and for genetic studies
  • Jean-Michel Dubernard, University of Lyon, for Renal transplantation
  • Eli A. Friedman, State University of New York, for amino acid losses in hemodialysis and for sorbents
  • Ciro Balestrieri, Full Professor of Medical Chemistry, at both medical faculties in Naples, for studies on nitrogen balance and amino acid synthesis and degradation
  • Domenico Cittadini, Associate Professor of Medical Chemistry at both medical faculties in Naples, for studies on nitrogen balance and amino acid synthesis and degradation
Table 6. Giordano’s books
  • For medical students and fellows
  1. Giordano C. Nefrologia. Idelson, Napoli, 1963, pp VIII+ 290+IV (Figure.2)
  2. Giordano C. La nutrizione nelle malattie renali, Edizioni Minerva Medica, Torino, 1964, pp. IV+70+IV (Figure 3)
  3. Giordano C. Fisiopatologia dell’apparato urinario. In Magrassi F, Ed, Trattato di Fisiopatologia Medica. Società Editrice Universo, Roma 1966, pp. 1241-1390 (Figure 4)
  4. Giordano C. Nefrologia. Idelson, Napoli,1979; pp XV+325+II (Figure 5)
  5. Giordano C. Sorbents and their clinical applications. Academic Press, New York, 1980 (Figure 6)
  6. Giordano C. Nefrologia. In Zanussi C, Ed, Medicina Interna. UTET, Torino, 1986 pp XV+372+IV (Figure 7)
  7. De Santo NG, Capasso G, Giordano C. Alterazioni del ricambio Idroelettrolitico. USES, Firenze,1988. pp. VII+271+IV (Figure 8)

 

 (ii) Conference Proceedings

  1. Giordano C, Friedman EA. Uremia. Pathobiology of patients treated for 10 years or more. Wichtig Editore, Milan 1981, pp X+311+IV (Figure 9)
  2. Giordano C and De Santo NG. Dialisi Peritoneale. Atti II Congresso Nazionale di Dialisi Peritoneale, Capri 1983, Wichtig Editore Milan, 1984 (Figure 10)
  3. Giordano C, De Santo NG. Nefrologia, Dialisi Trapianto. Atti XXVII Congresso SIN, Napoli 23-25 maggio 1986; pp. XV+447+IV (Figure 11)
  4. Friedman EA, Beyer M, De Santo NG, Giordano C. Prevention of Progressive Uremia. Vol I and II. Field and Wood, New York, 1989. Vol I pp XIV+ 179 +IV, Vol II XVIII+ 229 pp+ II (Figure 12)
  5. Avram MM, Giordano C, Eds, De Santo NG, Mittman N, Bazzato G, Co-eds. Ambulatory Peritoneal Dialysis. Plenum, New York, 1990, pp.XVI+349+IV (Figure 13)
Table 7. Studies on low protein nutrition. Data from reference no. 3.
Persons               eGFR/MDRD)    Hypertension

Healthy                120                       no

Pat. 1                    26                                         yes

Pat. 2                    22                                         yes

Pat. 3                    15                                         yes

Pat. 4                    17                                         yes

Pat. 5                     9                                           yes

Pat. 6                      6                                           yes

Pat. 7                     8                                           no

Pat. 8                     3                                           yes

 

Financed by National Heart Institute Grants H-5773 (C1- C2), HE-05773-03

Table 8. Nitrogen balance (reference no.20)


Table 9. Some comments on Giordano’s work as it emerged at the Scottsdale Conference on the Nutritional Aspects of Uremia (Am J Clin Nutr 1958; 21 pp. 640-642).
Lewis E. p.350. “Giordano had previously presented evidence to support the concept that urea nitrogen can be utilized for protein anabolism in attaining positive nitrogen balance when the diet is adequate calorically”. “Our special thanks to Dr. Carmelo Giordano who came from afar to make an important contribution”.

 

Hemmett L and Holt JR, p..375 “We did not have the wit which Dr. Giordano had to apply this to uremia

problem. I was very impressed when his paper came to my attention and I would like to congratulate

him for making this use of it”.

 

Swendseid M. p. 382. “It is quite possible that in chronic renal failure the optimal amino acid requirements are different than in health. The innovating experiments of Giordano are indications in this direction”

Ginn EA, Frost A, Lacy WF, p.385. “Our effort was based on the possibility of treating uremic subjects with a diet that permitted the use of endogenous urea for protein synthesis as was earlier suggested by Giordano and after by Giovannetti and Maggiore”.

Berylne G, Gaan D, Ginks WR, p. 547. “We have put over 100 patients suffering from chronic renal failure on the Manchester modification of the Giordano-Giovannetti diet”.

Kopple JD et al, p. 560. “This conclusion was buttressed by the demonstration of marked decrease in SUN, intact or only slightly negative nitrogen balance and possibly endogenous urea for protein synthesis”.

Gulyassi PF et al, p. 565. “Rigid reduction of protein intake can produce considerable clinical improvement in patients with moderately or far advanced uremia”

Salteri P and Pittaluga L, p. 590. “Dietetic products, treatment of Chronic Uremia, and the Giordano Giovannetti-Diet.

Lonergan ET and Lange K, p. 595. “In the last 10 years a diet developed by Giordano and Giovannetti and later modified by Berlyne”

Table 10 – Amino acid and keto acid in uremic children and infants

Table 11 - Growth in infants on various amino acid and keto acid formulations. Growth was superior with amino acid diets (Modified from reference n. 36).

FORMULA*                                                       DAILY GROWTH (g)

Pat 7                     Pat 8

Control Similac                                                 13.3                       10

Formula C           amino                                  25.3                       38.6

Formula C           keto                                      10                           8.3

Formula C           amino                                  40                           25

Formula D           amino                                  50                           31.5

Formula D           keto                                      30                           30