Text

The story of spironolactone (SP) and of its derivatives is strictly linked to the story of mineralocorticoids and in particular of aldosterone.

Deoxycorticosterone (DOC) was the first mineralocorticoid synthesized and its properties were studied mostly on electrolyte balance. In 1949 Selye evaluated the role of DOC in the development of certain inflammatory process, like rheumatism: he suggested that mineralocorticoid hormones had an inflammatory activity in contrast to the glucocorticoid compounds, which have an anti-inflammatory action [1].

Subsequently, the interest on the inflammatory effect of mineralocorticoids was lost and all the studies were focused for several decades only on the sodium balance and hypertension. In the recent years the involvement of aldosterone in the inflammatory and autoimmune mechanisms was revaluated and its role in the production of heart and kidney fibrosis, hypertrophy and atherosclerosis was reconsidered, focusing on the fundamental role of aldosterone receptor blockers in the treatment of resistant and essential hypertension.

Aldosterone, spironolactones and the sodium balance

In 1950 Deming and Luetscher found increased sodium retention in patients with heart diseases compared to healthy subjects [2]. Many other researchers showed that DOC has a powerful sodium retentive activity and tested a number of synthetic steroids for their ability to block the sodium retaining and potassium excreting effect of DOC in adrenalectomized rats.

In 1953 Simpson and Tait discovered aldosterone, firstly termed electrocortin for its very strong mineralocorticoid activity, bigger than any other adrenocortical compound previously known[3].

In 1957 Kagawa et al. found two steroid compounds which caused sodium depletion and moderate retention of potassium depending on the action of the mineralocorticoids [4]. These compounds were a 5-membered lactone ring on carbon 17 (17spironolactones), containing, like DOC, no oxygen in the 11 position and possessing a gamma-lactone side-chain in the 17 position, instead of an alfa-keto side-chain and hydroxyl group. Numerous other preparations with similar effects were produced. One of these, SC-9420 spironolactone, had an acetylthio radical at carbon 17 and showed the most potent anti-mineralocorticoid effect; this compound was called aldactone. In the same period, Kagawa and coll. demonstrated that SP was able to block the sodium-retaining and kaliuretic-excreting activity of aldosterone and of other mineralocorticoid active compounds like DOC, cortisol and 9-alpha- fluorocortisol. On the other hand, when used alone these compounds did not produce any effect in adrenalectomized rats [4] [5], while in patients with Addison disease treated with desoxycorticosterone acetate (DOCA) they were able to reverse the effect of DOCA on sodium and potassium excretion.

In 1955 Jerome Conn described the first case of primary aldosteronism, characterized by an aldosterone-producing adrenal adenoma [6]. The unilateral adrenalectomy resolved the clinical symptoms of the syndrome and SP was considered the main treatment of these patients both before surgery to normalize blood pressure and serum potassium both for long-term treatment in patients with bilateral adrenal hyperplasia with or without a marked nodular hyperplasia (idiopathic hyperaldosteronism).

The antagonism of SP is not only evident in renal sodium transport, but also in the ionic equilibrium of other tissues, for example in red blood cells [7] [8], intestine, salivary and sudoripary glands. SP was also used for various clinical situations, as liver cirrhosis, idiopathic oedema [9], ascites, nephrosis, congestive heart failure and various hypertensive vascular diseases; it was also particularly indicated in the hypokalemic state caused by diuretics, in nephritic syndrome [10] and in the treatment of cardiac oedema of patients refractory to the usual diuretics. The only contraindications to SP therapy is in case of renal insufficiency, because of a possible worsening of hyperkaliemia, and when SP is given in association with thiazides, because hypokalemia tends not to improve [11].

An important question raised in the subsequent years is whether SP can affect directly the secretion of aldosterone at the level of adrenal glomerulosa. In 1963 Janigan demonstrated that patients treated with SP do have cytoplasmic inclusions in the adrenal called “spironolactone bodies” [12]. In the same period, we reported that administration of SP in patients with primary aldosteronism reduces the urinary aldosterone in the first period of treatment when renin is still suppressed, while later renin and aldosterone increase due to the diuretic effect of SP [13].

Searle and other companies later tested different analogues of SP and the more interesting derivatives for clinical application were potassium canrenoate, canrenone and more recently eplerenone. SP do also have an important antiandrogen effect, which is lower in potassium canrenoate and canrenone and absent in eplerenone [14] [15].

This different actions increase the use of SP also as an antiandrogen, for example in polycystic ovary syndrome [16] [17], while potassium canrenoate and canrenone are mainly used as antimineralocorticoid drugs.

Aldosterone, spironolactones and inflammation

In the last decades, many studies revaluated the role of aldosterone in the pathogenesis of inflammation. This process is preceded by peripheral blood mononuclear leukocytes (MNL) invasion, but it is still not clear if MNL are activated before tissue invasion or they are attracted in the inflammatory site by local factors.

In 1985 we demonstrated that human lymphomonocytes possess the mineralocorticoid receptor (MR), where aldosterone regulates intracellular electrolytes and volume [18] [19] [20]. Subsequently we demonstrated that coincubation of MNL with canrenone blocked the inflammatory effect of aldosterone, reducing the MNL expression of two markers of oxidative stress, PAI-1 and p22^phox [21].

In the late 1980th Pitt and coll. found that SP and eplerenone are potent anti-inflammatory drugs, blocking the inflammatory effect of aldosterone in non-epithelial cells, such as vascular smooth muscle, renal and myocardial cells. These studies supported the addition of anti-mineralocorticoid drugs to the conventional treatment of many pathological conditions characterized by secondary aldosteronism, reducing the prevalence of a relapse of heart failure and of cardio-cerebrovascular accidents [22] (full text) [23].

Other studies suggested a role of aldosterone in the pathogenesis of atherosclerosis and of anti-mineralocorticoid drugs in blocking this process. In particular, eplerenone induces reduction of oxidative stress and arteriosclerosis progression in apolipoproteins E-deficient mice and in monkey fed with a high cholesterol diet but with normal aldosterone plasma levels [24] [25] (full text). It is well known that MNL and macrophages are mainly involved in vascular inflammation and atherosclerosis. Based on these studies, we suggested that a possible link between aldosterone, inflammation and atherosclerosis could derive by the increased cholesterol concentration at the level of the arterial wall, which induces an inflammatory process, attracting MNL with the MR available for binding of aldosterone, that may act as a pro-inflammatory factor even in tissue which do not have MR [26] (full text).

Many authors are exploring the use of SP as anti-inflammatory drug, being effective for example in the treatment of ocular chorioretinopathy and of arthritis [27] [28] (full text).

More recently we also found that aldosterone can induce remarkable membrane alterations of erythrocytes, leading to their premature removal from circulation. This effect is blocked by coincubation with canrenone, suggesting that also the so-called non-genomic effects of aldosterone could be mediated by the MR [29].

Finally, the relationship between aldosterone and autoimmune disorders is a new area of investigation. Recently Herrada et al. demonstrated that aldosterone can directly increase the capacity of dendritic cells to activate CD8⁺ T cells and induce Th17 polarization of CD4⁺ T cells, which have been associated with the promotion of many organ-specific autoimmune diseases, such as rheumatoid arthritis and autoimmune thyroiditis [30] (full text). In particular, a recent article reported a case of a female affected by primary aldosteronism and autoimmune thyroiditis, to whom surgical removal of an aldosterone-producing adrenal adenoma improved thyroid function and decreased thyroid autoimmunity [31]. These data suggest that SP could ameliorate the evolution of some autoimmune diseases, proposing new therapeutic targets for anti-mineralocorticoid drugs.

Perspective

Actually the normal concentration of aldosterone is not related to the crude value but rather to the aldosterone/plasma renin activity ratio; however, the administration of MR- antagonists is useful to prevent cardiovascular risk even in patients with normal aldosterone values, pointing out on the importance of these drugs not only for hyperaldosteronsim but also for essential hypertension.

Recently, the guidelines of the European Society of Hypertension (ESH) has recommended the use of MR-antagonist only for the treatment of patients with hypertension resistant to the conventional polytherapy. In our experience, we think that some cases of hypertension were resistant because MR were not still blocked. Considering all the benefits of MR-antagonists, their use should be reconsidered not only for the treatment but also for the prevention of many clinical situations [32].

Introduction

During 20th century the average life expectancy significantly increased, which resulted in a constantly growing number of elderly people. Already a population over 65 years old in the United States represent nearly 13% of general population. It is projected that in the next 15 years it will be a 21%.

A good source of information about the incidence and prevalence of chronic kidney disease is ERA-EDTA Registry Database [1]. Registry covers about 71% of the European population and the renal registries for most countries covering more than 98% of the population. It is estimated that one of three Europeans is at risk of developing chronic kidney disease (CKD). It is assumed that one in ten (approximately 74 million people) have already impaired renal function, unfortunately, often without being aware of it. The registry includes also incidence of patients accepted for renal replacement therapy (RRT). In total in 2013 72.698 patients started RRT. In a population of 647 million people it resulted in an overall incidence of 112 pmp (per million population) of whom 24 pmp was RRT for diabetic end stage renal disease (ESRD). The highest incidence of entering RRT among European countries was observed in Belgium, the lowest in Estonia. Overall prevalence of patients undergoing RRT is increasing. ERA-EDTA Registry shows that the prevalence of patients in renal replacement therapy in Europe increased by 2.1% from 2012 to 2013 (716.7 per million population) (Figure 1). This is also a financial challenge, given average costs up to EUR 80,000 per dialysis patient per year. Due to continuous increase in the average age of the population a further rise in ESRD patients should be expected. It complies with trend of` decreasing incidence of CKD but rising prevalence every year. Prevalence of chronic kidney disease in different countries is presented in table (Table 1).

Comparing the population of European countries to the United States of America, the incidence of patients entering the RRT during the period of 1999-2012 was three times higher in the US. The differences were particularly evident in subgroup of patients over 65 year old.

The main cause of end stage renal disease requiring starting renal replacement therapy in 2013 was diabetes mellitus, both in the population below and above the age of 65 it was around 22%. The percentage of patients with diabetic kidney disease increased from the year before. Next cause in the younger population was glomerulonephritis, while in the elderly it was arterial hypertension. Still in almost one-fifth of patients the reason of ESRD remains unknown (19.4% in the group of elderly). Way of RRT – hemodialysis or peritoneal dialysis did not change a lot throughout the years 1999-2013. A gradually increasing incidence of pre-emptive kidney transplantation (KT) was observed, from 3.5 pmp in 1999 to 8.1 pmp in 2013. The group of hemodialysis patients represents the majority of the population of ESRD in subjects over 65 years (67.5%). Unlike the younger population where the biggest group of end stage kidney disease patients is after kidney transplantation. The transplant rate for all European countries included into the registry equals 30 pmp. The highest rate is in Croatia (60 pmp), the lowest in Ukraine (3 pmp). Poland is just above the average with the result of 31 pmp transplant rate [1].

Among kidney transplanted patients the vast majority received organ from deceased donor (74.7%, rate 32.2 pmp). Transplantation from living donation is more common in younger patients with ESRD (the group of patients under 65 year of age at the time of transplantation). Obviously kidney transplantation is an established method of renal failure treatment, it allows to restore homeostasis and thanks to this way of treatment patients are able to return to normal functioning in society. No doubts KT is the best method of ESRD therapy but it does not remain without drawbacks. Complications associated with the surgery procedure and later as a consequence of immunosuppressive therapy significantly affect the survival. However long-term survival benefit in ESRD population is observed regardless of age. The expected remaining lifetime of patients after kidney transplantation is about half longer than ones undergoing hemodialysis (Figure 2). Nevertheless the average life expectancy in transplant recipients is still reduced by 25-30% compared to general population [1].

Even though the dialysis patients and the ones after kidney transplantation comprises the visible expensive component of medical care it seems to be just like the tip of an iceberg. As it was mentioned at the beginning the largest group of patients with CKD, which carries increased risk of ESKD are not aware of any impairment of renal function.

Chronic kidney disease is the most common in elderly population. Deterioration in renal function with age was a subject of many studies in past years [2] [3] [4] [5] Researchers proved that in the elderly there glomerular filtration rate (GFR) and renal blood flow (RBF) reduces. The scale of decline in above mentioned parameters differ between individuals, however it was demonstrated that the average decline in glomerular filtration rate is estimated at 1 ml/min/1.73m² per year and effective renal plasma flow at about 8 ml/min/1.73m² per year [6]. Epidemiological studies attempt to answer the question what is the cause of worsening of the kidney function in elderly. A various factors related the deterioration of kidney function can be enumerate, the ones connected with senility and those which are complications of concominant diseases. It includes: age at the genetic level in the form of telomere shortening and loss of mitochondria, then oxidative stress, glomerular hypertension and hyperfiltration, intrarenal activation of the renin angiotensin system, endothelial dysfunction with the loss of nitric oxide, next renal ischemia, accumulation of advance glycation products and chronic effect of uric acid. Even in the generally healthy elderly, kidneys themselves have features of senescence. Age affect kidneys in the form of nephrosclerosis or altering morphometric aspects. Under the term of nephrosclerosis the constellation of glomerulosclerosis, arteriosclerosis, tubular atrophy, and interstitial fibrosis is found [3]. More than two such changes will be present in light microscopy in 2.7% of group aged 18-29 years, in 44% of 50-59 year-olds and in 73% of population aged 70-77. It seems that age-related loss of renal function might be associated also with loss of renal mass. However decline in overall kidney volume seems to be present only in very elderly [3]. It was found that kidney weight decreases by approximately 19% in male and 9% in female in subjects aged 70-79 years in comparison to 20-29 year-olds individuals [2]. Considering partial sclerosis of glomeruli in many cases kidney volume is preserved by compensatory hypertrophy of intact nephrons which is again related to decreased glomerular density.

Based on the epidemiological study – PolNef, it was found that CKD occurs often in Polish population, in about 18.4% of subjects. Albuminuria appeared in almost 12% of the general population. The incidence of albuminuria was increasing with age [7]. Extremely valuable information about medical and also socio-economic aspects of aging in Polish population was brought by PolSenior study. PolSenior was the first multidisciplinary project focused on ageing in Poland performed in 2007-2011 [8]. Study involved 5695 individuals. On the basis of PolSenior results it was shown that the prevalence of chronic kidney disease in Polish population aged >65 years is 36.5% and eGFR<60ml/ml/1.73m² was observed in 27.7% of this population. In comparison in United State the prevalence of CKD in population age 60-69 is around 20% while in a group over 70 years old it is more than 45% [9]. In PolSenior as might be expected the prevalence of CKD increased with age. The CKD was more common in women than in men. The largest part of the population with impaired renal function was in stage 3 of CKD. Interesting conclusion was that 96.8% subjects were unaware about any impairment of renal function. The co-morbitity, in particular diabetes mellitus, arterial hypertension, prostate hyperplasia was clearly associated with decline in eGFR. Decreased glomerular filtration was also related to heart failure, coronary artery disease, occurrence of myocardial infarction and stroke. Albuminuria was observed in 25% individuals over 65 years old. Albumin-creatinine-ratio (ACR) >300mg was present in 2.3% subjects. The incidence of ACR <300mg increased with age and was significantly higher in men than in women aged > 65 years. What to expect albuminuria occurred more frequently in patients with diabetes. It was also associated with nephrolithiasis, failure and medical history of stroke [10]. Results were comparable in women and men.

Not only coexisting disease must be taken into account when analyzing the frequency of occurrence of CKD. An equally important factor is the socio-economic determinants. Fedewa et. al showed that low income and low income communities are a risk factors of occurrence of end stage renal disease and that chronic kidney disease progression in independently linked to patients socioeconomic status. All cause-mortality in CKD patients was the highest in low income black race population [11]. Crews et. al observed that low socioeconomic status is strictly correlation with occurrence of CKD in African Americans. This correlation was not found in whites [12]. In PolSenior study the correlation between responders’ education and the presence of chronic kidney disease was demonstrated. Researchers noted the highest prevalence of CKD among subjects with no education (55.8%), and the lowest in a group with vocational education (33.9%). What interesting not smoking and lower alcohol consumption were related to higher frequency of CKD. It was also valid for those with no regular physical activity. Results were similar for men and women [8].

Conclusions

Chronic kidney disease is a rather common condition in the elderly. It is found up to 30-40% in this population. PolSenior Study showed that CKD in Polish population was more frequent among elderly urban dwellers, non-smokers, alcohol abstinents and low physical activity. Only in women higher educational status was related to the lower risk of CKD. Potentially modifiable factors like health-related behaviours, comorbid conditions, and health-care access, contribute substantially to the association between low socioeconomic status and CKD. Lower socioeconomic status might lead to poorer self- management and thus greater complications from diabetes or arterial hypertension. Socioeconomic factors seems to be a suitable target for interventions at the national and supranational level aimed at reducing prevalence of CKD.

Introduction

Polycystic kidney disease (PKD) is one of the most common systemic inherited kidney diseases causing end stage renal disease (ESRD). It has been described in all racial and ethnic groups, and there are 13 million autosomal dominant PKD (ADPKD) individuals worldwide [1]. ADPKD is thought to be responsible for one in every twenty cases of ESRD requiring renal replacement therapy in USA [2]. This article will mainly address the possible answers of following questions in light of old and current knowledge;

a) When did we notice this disease?

b) Did we show enough interest to PKD?

c) Does it have the deserved place in the literature?

History of polycystic kidney disease

PKD has been in existence with humanity. It is a natural process to be observed firstly in the animals’ internal organs, since they have been used for nutrition and/or sacrificed for God. Although forbidden meats described very well in several religions, there is no enough information about the abnormalities of kidneys in literature. Nevertheless, hydatid cysts were recognised in animals and humans from very early times [3]. Examination of dead human body to help the living ones is a revolution in understanding of the diseases.

Recognition of PKD begins with the death of King Stephen Bathory. He was born on 27 September 1533, and became the third elected king of Poland in 1576. He reigned for 10 years (1 May 1576-12 December 1586). Within a decade, he was one of the most successful kings in Polish history, particularly in the realm of military history, and the reform of judicial system. He had no children. His father and two brothers had gout, and his brothers died before the age of 50 years. In his personal life, hunting and reading were his favorite activities. Symptoms of the king had began after his last hunting trip, and caused the death within 9 days, at the age of 53 on December 12, 1586 [4] [4] [5] (full text) [6]. King’s symptoms and progress of the disease have been well documented in the article written by Torres and Watson [5] (full text), and summarized in Table 1.

The death of king in a short time caused serious and unpleasant discussions about the diagnosis among his two doctors, Dr. Simon Simonius and Dr. Nicholas Buccella. In fact, both of his doctors had great background. Dr. Simon Simonius was an Italian philosopher and physician educated in Geneva and Heidelberg. Dr. Nicholas Buccella mainly educated in Padua, and also had experience in general surgery. Dr. Simonius was believing in the “humoral theory of diseases” in accordance to his education, as proposed by the ancient Greeks. His diagnosis was “discrasia frigata” caused by overexposure to cold during hunting. Therefore, his suggestion was “the steady warming of the King” [4] [5] (full text) [6]. Dr. Buccella believed that the basis of diseases was of “organic nature”, and the King could be suffering from “meningeal abscess”. He recommended “cooling agents” to treat the King’s symptoms, and accused Dr. Simonius regarding of wrong treatment application. Their suggestions were completely opposite to each other, and led to rumor between royal doctors over many years.The autopsy during mummification in Grodna put an end to these discussions. During the extraction of internal organs, surgeon Jan Zigulitz, assisted by Dr.Buccella, described the cysts in kidneys as; “large like those of a bull, with an uneven and bumpy surface”. They noted that there was a stone in gall bladder, and heart, lungs, liver, stomach, spleen were all normal [4] [5] (full text) [6]. However, the head was not dissected.

The renal findings were not considered to be related to the cause of King’s death at that time. In 1933, 347 years later of this gross definition, Hungary and Poland celebrated the “400^thanniversary of King’s birth”. On this occasion, Prof. Franciszek Walter, at the Krakow Medical School, invited a group of medical specialists and historians to review in detail the description of the disease and autopsy findings of King Bathory. After this meeting, they concluded that the most likely cause of King’s death was “ PKD and uraemia” [5] (full text) [7].

Discussion

It has been well known that uremic patients have high morbidity and mortality rates. Compared to the age adjusted cardiovascular disease mortality in the general population, mortality is approximately 15 to 30 times higher in dialysis patients [8] [9] (full text). Uraemia-specific risk factors, hypertension, left ventricular hypertrophy (LVH), uremic cardiomyopathy and heart failure, increase in prevalence as kidney function declines, and especially LVH is an independent risk factor for cardiac death [8] [9] (full text). Anemia, hyperhomocysteinemia, and increased phosphate (P) level (P> 6.5 mg/dL) are other contributing factors causing increased mortality risk in these patients [8] [9] (full text).

If we re-evaluate the symptoms of King Stephen Bathory in the light of current knowledge, one of the first questions may be whether the King had uremia due to PKD.

There is no enough information about his urinary problems, urinary output, symptoms regarding hypertension, exercise intolerance (he was an active king), no fatigue, shortness of breath and/or chest pain until the date of his death. In fact, there may be some clues that he had PKD before his death. He wore slack suits in his all portraits, suggesting he might have enlarged kidneys (Figure 1).

His father and his brothers had gout, and his brothers died before the age of 50 years. Considering the genetic basis and high uric asid levels in PKD, it is possible that they might have some forms of PKD [10] (full text). It has been noted that he had no children. However, it is hard to say that he had infertility, common in males with PKD, or it was only because of the age of his wife, Anna Jagielleonka. She was 53 years old when married, a late age for childbirth.

The second question to be asked is whether the real cause of King’s death could be anything else.

Two possible scenarios may be written in this regard. One is subarachnoid hemorrhage (SAH) due to vascular aneurysm in brain. Almost 10% of asymptomatic PKD patients have intracranial aneurysms during screening, while it increases up to 25% in patients with a family history of subarachnoid or intracranial haemorrhage [11]. The rupture of these aneurysms may be induced by exercise or trauma. Possible cause-effect relationship is described in detail in Figure 2.

The key question in this scenario may be why he had severe chest pain. Although it is difficult to explain severe chest pain in a patient with SAH with the old knowledge, recent knowledge demonstrates that acute lung injury or the acute respiratory distress syndrome [12] and neurocardiogenic injury [13] can be seen in patients with SAH. Therefore, severe chest pain of the King may be explained by this way.

The second scenario may be written on aortic dissection. Progression of this dissection to aortic arch may explain the following complaints of the King after the first day (Figure 3).

Although the physicians noted his heart as normal (accepting also the examination of the vessels) during the mummification, it does not imply that he did not have aortic dissection. Probably, it might not be recognized since aortic dissection has been firstly described by Frank Nicholls in 1760 [14].

Unfortunately, PKD did not attract the interest of physicians until the 18^th century. In late 18^thcentury, Dr. Matthew Baillie noted that these vesicular cysts in kidney were different from hydatid cysts, and described them as “false hydatids of kidney” in his anatomy book [15]. Rayer quoted the descriptions of PKD in newborns and infants in 18^th century, and “cystic degeneration ” was noted as a “cause of kidney failure” in his book [16]. He also stressed severe functional alterations of other systems, particularly the central nervous system, causing the death of the patient in PKD [16]. This description referring “the relation between structural changes in an organ and the disease” attracted the attention of firstly pathologists. Such a comprehensive approach to the clinical problems of nephrology described as “Pierre Rayer’s innovative method of clinical investigation” by Professor Gabriel Richet in 1991 [17].

With the increase in number of autopsies during the early 19th century, renal cysts began to be defined in more detail, that is “teardrops of the kidney began to be noticed by investigators”.

In 1888, Félix Lejars used the term of “polycystic kidney” for the first time in his doctoral thesis, and stressed that these cysts were bilateral [18]. He also underlined that this disease is not an only anatomo-pathological condition, but also causing clinically identifiable symptoms [18]. Then, in 1899, genetic basis of the PKD was firstly recognised by Steiner (313 years after the King’s death) [19]. However, the researches to understand the mode of inheritance and other genetic abnormalities have taken more than 90 years.

In 1902, W. Osler described two patients having bilateral tumours in the flanks together with cardiovascular changes and differences in the urine content [20]. In parallel to developments in radiology, renal pathologies were identified better and radiological attempts began to be used in treatment of these patients. T. Rovsing shared the results of multiple punctures in 3 PKD patients[21]. Microscopic analysis of specimens obtained during surgery or autopsy has enabled the further identification of cellular pathology in PKD. It has been stated that the reasons of cysts may be “obstruction, neoplasia or developmental abnormality” [5] (full text) [21]. These theories regarding cyst pathogenesis during 19th century explained with details in article of Torres and Watson [5] (full text). They have been summarized in Figure 4.

Significant research breakthroughs into PKD occurred in the 1990s. Cyst formation in this disease began to be better understood at the molecular level. It has been shown that abnormalities of expression and function of the epidermal growth factor – axis, decreased intracellular calcium with aberrant intracellular cAMP signaling, abnormal structure and/or function of the primary cilia and alterations in cell-cell, and cell-matrix interactions resulting in tubular cell hyperplasia, tubular fluid secretion, abnormalities in tubular extracellular matrix, structure, and/or function [1].

PKD-1 gene on chromosome 16, present in approximately 85% of ADPKD patients, has been discovered in 1994 [22] (full text). Subsequently, detailed genetic studies have been achieved regarding PKHD1 gene, causing autosomal recessive PKD (ARPKD) [23] (full text). After the researches in PKD animal models showing the effectiveness of vasopressin V2 receptor antagonist (Tolvaptan) in prevention of kidney enlargement, clinical trials was initiated [24]. The UK ADPKD and ARPKD Study Groups are formed under the Renal Association/Renal Registry in 2012, to increase the attention that this disease deserved.

Conclusion

The reason of the present article titled as “tear drops of kidney” was; PKD has been like an invisible reality until the 18^th century. At the end of 19^th century, the basic clinical signs, and genetic basis of the disease have been better defined. After the recognition of genetic basis, the inheritance pattern was understood almost within a 100 years. Although more than 300 different mutations in the PKHD1 gene have been described in nowadays, further studies are still needed at molecular level regarding the pathogenesis of PKD.

We finally see the teardrops of kidney; cysts, measured by magnetic resonance imaging as total kidney volume, are being accepted as “the best available biomarker of disease progression” [25] (full text).

I believe, further researches will wipe away the teardrops of kidney in the near future.

Introduction

Fabry disease is an X-linked lysosomal storage disorder caused by accumulation of glycosphingolipids due to a deficiency of the lysosomal enzyme α-galactosidase A. Deposition of substrate results in renal failure, stroke and cardiac death. Other symptoms include angiokeratoma or corneal opacities, amongst others. Life expectancy is reduced by an average of 15 and 20 years in female and male patients, respectively [1].

In 1898 first reports of Fabry disease were published by William Anderson and Johannes Fabry, who described patients with ‘angiokeratoma corporis diffusum’, the red–purple maculopapular skin lesion that represents a characteristic feature of this disease [2] [3]. Although the disorder is now simply known as Fabry disease, it is also referred to as Anderson-Fabry disease in recognition of the original descriptions made by both, Anderson and Fabry [4].

After the initial reports of angiokeratoma corporis diffusum, several other disease manifestations were described, (Table 1) until in 1939 Ruiter concluded that angiokeratoma corporis diffusum is the cutaneous manifestation of a systemic disease [5], which in the following years was classified to be a storage disorder [6].

In 1951 Scriba confirmed the lipid character of the storage material [7] and in 1959 Nobel laureate Christian de Duve described the lysosome as an important cellular organelle. Thus, he provided the basis for the concept of lysosomal storage disorders and even at this time suggested enzyme replacement as a therapeutic opportunity [8].

In 1962 Wise and colleagues reported on several families with Fabry disease, including the offspring of the first patient of William Anderson. They also examined the first living female patients with Fabry disease and clearly demonstrated X-linked inheritance, which was confirmed by further pedigree analyses within the next years [9]. Later, Sweely und Klionsky characterised the disease as sphingolipidosis [10].

In 1965, an electron microscopy study by Hashimoto et al. revealed the presence of bodies in endothelial cells, smooth muscle cells, fibrocytes and perivascular cells of patients with Fabry disease. Referring to these structures as “extremely overcrowded lysosomes”, he concluded that malfunctioning lysosomal enzymes had to be the result of a genetic abnormality [11].

In 1967 Roscoe Brady finally elucidated in detail the underlying cause of Fabry disease, the deficient activity of the enzyme catalyzing the hydrolysis of the terminal galactose molecule of ceramidetrihexoside, ultimately leading to multiorgan symptoms and manifestations [12]. Thereafter they purified the enzyme from human placenta cells and demonstrated biochemical effects of the enzyme in patients with Fabry disease [13]. In the meantime the enzyme was identified as α-galactosidase A [14]. Cloning of the GLA gene by Robert Desnick’s group in 1985 provided the basis for molecular genetic diagnosis and specific therapy [15]. Following the introduction of enzyme replacement therapy at the begin of this century by Raphael Schiffmann et al. [16] and Christine Eng et al. [17], molecular chaperone therapy represents the next step forward to provide cure for this devastating disease [18].

The renal lesion of Fabry disease – case reports in the early years

Notably, even the first two cases reported in the literature presented with proteinuria, aside from the back then central manifestation of the disease, the angikeratoma corporis diffusum. William Anderson described the obvious cutaneous lesions of a 39 year-old man, but did not overlook the elevated albumin content of his urine. Even at this time he suggested that the proteinuria may possibly be related to the “diseased condition of the vessels” [2]. In contrast, the first report of Johannes Fabry on a 13 year-old boy highlighted the progressive nature of the cutaneous lesions, while at this point of time, however, the urine of the boy was unremarkable. Following his initial report, Johannes Fabry published two further papers on his patient in 1916 and 1930 [19] [20]. Finally, in 1916 he observed proteinuria in this case, whom he followed until his death in 1928 at the age of 43 years. A pedigree of this family was published in 2001 by Hermann Fabry, a dermatologist and a nephew of Johannes Fabry [21].

In the first decades following the initial description of what is known today as Fabry disease, several authors mentioned the presence of proteinuria or abnormal urinary sediment in patients with angiokeratoma (Table 2). In 1939 Maximiliaan Ruiter reported on three brothers, who presented with angiokeratoma, acroparesthesia, arterial hypertension, left ventricular hypertrophy, edema, and proteinuria with cells and casts in the urinary sediment. He summarized these findings as a cardiac-vascular-renal complex of symptoms and concluded that angiokeratoma corporis diffusum is the cutaneous manifestation of an inherited systemic internal disease [5].

Autopsy reports, kidney biopsies, and electron microscopy

In 1944 one of the three brothers described by Ruiter in 1939, died and in 1947 Pompen, Ruiter, and Wyers reported on autopsy findings of this and a second case, who died the same year from uraemia: “In the kidneys of both cases sclerosis of many glomeruli was found with, probably secondary to this, alterations in the tubule structure, leading to renal failure. Moreover, unexplained pathological changes in many of the glomeruli were found in the first case.” and ” As regards the pathogenesis of this disease, the authors suggest as a hypothesis the existence of a primary congenital disease of the entire vascular system, in which some form of metabolic disturbance occurs in the muscle cells of the heart and vessels. A thesaurismosis, whereby some substance is deposited in these muscle fibres, could also be considered” [6].

The first renal needle biopsy was performed by Colley and colleagues in 1958: “Renal needle biopsy was performed on two men suffering from angiokeratoma. The distinguishing feature was a vacuolation and distension of the cells of the glomerular tufts and distal tubules. In both cases the ability to concentrate the urine was grossly impaired; in one case the glomerular filtration rate was normal and in the other it was moderately impaired. A retrospective re-examination of the kidney of a female relative of these two patients, who had died some years before, showed identical lesions. Her relatives state that she did not suffer from the characteristic skin lesions. It is possible, therefore, that the metabolic disturbance associated with angiokeratoma can also occur in women, perhaps without the typical skin manifestations”[22].

Sweely und Klionsky in 1963 examined kidney lipids from a patient, who died at the age of 28 years of renal failure and whose clinical symptoms were classic ones for Fabry disease [10]. They provided convincing evidence that the major component of the glycolipid fraction is a trihexoside composed of sphingosine, glucose, and galactose at a molar ratio of 1:1:2.

In the same year an electron microscopy study of a kidney biopsy by Henry revealed further resolution of the lipid material, „which has an interesting “lamellar” pattern” [23]. “Despite the inability to concentrate urine above a specific gravity of 1.012, this patient showed preserved ability to acidify and alkalinize urine after oral ammoniumchloride (150 mEq./day) and sodium bicarbonate (158 mEq./day) loading, respectively, over several days. This observation stands in contrast to previous reports and suggests that the regularly observed hyposthenuria in this disease is independent of defects in ion transfer in the distal tubule system”.

A Fabry disease pedigree spanning some 150 years

This family includes the first case described by Anderson in 1898 [2]. Sixty years later Colley and colleagues performed the first kidney biopsies in patients with Fabry disease in affected offspring from Anderson’s original patient and also mentioned the first female suffering from Fabry disease [22]. Further details of this family were described in the same year by Wallace [24]. In 1962 Wise and colleagues reported on eight British families, including Anderson’s family, with a total of 21 affected patients. They showed an X-linked inheritance pattern and also reported the first living woman with a confirmed diagnosis of Fabry disease [9].

Most recently, Rohman and colleagues from the Royal Free Hospital in London described 5 further patients of this family, including one of the first men to start enzyme replacement therapy in 1999 and who died in 2014 from cardiac complications [25]. The sister of this patient, suffering from renal and cardiac disease, has four sons, of which two are affected by Fabry disease. One of her sons started enzyme replacement therapy at the age of three years because of severe acroparesthesia and gastrointestinal symptoms, being the youngest Fabry patient in the UK to start enzyme replacement therapy (personal communication, Figure 1).

Interestingly, this family harbors the GLA mutation p.A143T, the disease-causing role of which was recently challenged by some experts. However, the kindred summarized here, clearly demonstrate that this mutation can result in significant disease burden in hemizygous and heterozygous patients.

Conclusion

In 1898 the cutaneous lesions of Fabry disease, angiokeratoma corporis diffusum, were initially described by two independent dermatologists. The renal involvement of the disease was documented by the presence of proteinuria in these two cases. In 1939 the full-blown picture of the disease was described, suggesting that angiokeratoma corporis diffusum is the cutaneous manifestation of an inherited internal disease. Autopsies and kidney biopsies between 1947 and 1963 elucidated the renal pathology of Fabry disease and indicated that Fabry disease is a metabolic storage disorder. Biochemical studies in 1963 and 1967 explained the characteristics of the accumulated material and the enzyme deficiency in Fabry disease.

Introduction

Diabetes insipidus (DI) is characterized by the kidney inability to concentrate urine leading to consistent hypotonic polyuria greater than 3 liters in 24 hours in adults and persisting even during water deprivation. Three main types of DI can be defined as follows: A. Central DI (CDI) due to a defect in arginin-vasopressin (AVP) synthesis; B. nephrogenic DI (NDI) characterized by kidney resistance to the AVP action; C. gestational DI caused by accelerated AVP degradation.Besides these forms excessive fluid intake can cause DI [1] [2].

Central DI is the most frequent form and can be due to damage at the level of the hypothalamus which might affect the supraoptic or paraventricular nuclei or the osmoreceptors committed to ‘sense’ the alterations in blood osmolality. In rare cases (1-2%) CDI can be due to mutations of the gene coding for the AVP receptor.

On the other hand, AVP resistance due to renal defect characterizes NDI. In NDI the kidney cannot concentrate urine leading to a risk of severe volume depletion, hypernatremia, and hyperchloremia. NDI can be congenital due to mutations in the vasopressin receptor V2R gene causing X-linked NDI accounting for about 90% of congenital NDI [3] or to mutations in the gene coding for the water channel Aquaporin 2 causing autosomal-recessive or autosomal dominant DI responsible for about 10% of congenital NDI characterized by altered expression or trafficking of the AQP2 water channels [4] (full text).

Much more frequent are the forms of acquired NDI associated to a wide range of conditions such as lithium ingestion, urinary obstructions, hypercalcemia and hypercalciuria [5].

Finally about 5% of all cases of NDI are genetically unresolved or have unidentified causative mutations [6].

The key advances in the understanding DI and NDI are shown in Figure 1.

History of Diabetes Insipidus: a disease identified about 200 years ago

DI has been described several thousand years later with respect to the similarly named Diabetes Mellitus (DM), a diseases already known in ancient Egypt, Greece and Asia. In fact, its description is date back to 1794, when Johann Peter Frank of the University of Pavia described patients characterized by “long continued abnormally increased secretion of nonsaccharine urine which is not caused by a diseased condition of the kidneys” and introduced the term “diabetes insipidus” derived from the french word “insipide” [7]. According to the historical documents, in 1841 Lancombe described a family with 8 members displaying the symptoms of DI first focusing the attention to the familial features of DI [8].

The familiarity of DI was subsequently described in a publication by McIlraith in 1892 entitled “Notes on some cases of diabetes insipidus with marked family and hereditary tendencies” [9]. In the following years it became clear that a defect in the hypothalamus was somehow responsible for the DI. In 1901 Magnus and Shaffer demonstrated that the posterior pituitary extract had a pressor and antidiuretic activities [10]. Few years later in 1913 Fariniand van den Velden successfully used posterior pituitary extracts to treat diabetes insipidus [11] [12].Subsequently Bailey and Ranson, two researchers working in Illinois, described a supraoptico-hypophyseal tract in animals that connects the hypothalamic supraoptic nuclei to the posterior pituitary and showed that an injury to this tract produced DI [13] [14]. In parallel in Europe, Camus and Roussy of the Faculté de Médecine of Paris discovered in dogs that, puncturing the hypothalamus but leaving the pituitary intact, produced polyuria [15]. In summary, the available evidence in the 1920s was conclusive enough to define DI as a disorder of the pituitary gland and actually named this disorder as ‘hypopituitary syndrome’ [16] [17].

Central Diabetes Insipidus is distinct from Nephrogenic Diabetes Insipidus

Regarding the two principal forms of diabetes, mellitus and nephrogenic, in 1670s Thomas Willis, professor of Natural Philosophy at Oxford already noted the difference in taste of urine from polyuric subjects compared with healthy individuals [18] [19] [20]. He used the term diabetes in the generic sense, meaning polyuria, however his observations led to the differentiation of diabetes mellitus from the more rare entity of diabetes insipidus a century later.

In the early 1928, a german scientist DeLange, first observed that some patients with DI did not respond to posterior pituitary extracts. Moreover those families appeared not to have a male to male transmission of the disease [21]. These observations were followed by more accurate analysis by Forssman [22] [23], who established that the kidney had a critical role in those forms of DI resistant to treatment with the posterior pituitary extracts. In an original document Waring described patients with “an unusual syndrome” that presented shortly after birth, characterized by polyuria, polydipsia, fever, and constipation vomiting, high serum Na and Cl, rapid dehydration, and inability to excrete hypertonic urine. He concluded that the condition was caused by “a specific defect in tubular reabsorption of water” and appeared more frequently in boys. This description is consistent with what we know today to be the congenital form of the X-linked Nephrogenic Diabetes Insipidus. In 1947 by Williams and Henry introduced the term “nephrogenic diabetes insipidus” for the congenital syndrome characterized by polyuria and renal concentrating defect but unaffected by vasopressin [24]. They noticed the inheritance pattern realizing that the defect was transmitted by asyntomatic female to male offspring. The authors concluded that the disease was due to a congenital defect in the loop of Henle and the distal convoluted tubule.

Purification and synthesis of vasopressin

In 1955, several years later the successful treatment of diabetes insipidus using posterior pituitary extracts in 1913, du Vigneaud of Cornell Medical College, received the 1955 Nobel Prize in chemistry for the first synthesis of a polypeptide hormone vasopressin [25]. With a seminal work, du Vigneaud purified both oxytocin and vasopressin by countercurrent distribution and then chemically synthesized oxytocin in 1953 and vasopressinin 1954 [25]. Further distribution studies on the oxytocic hormone of the posterior lobe of the pituitary gland and the preparation of an active crystalline flavianate [26] (full text) [27] (full text).

Within this scenario of this series of truly landmark achievements, the 2013 marked the 100^thanniversary of vasopressin treatment for DI [28].

Cloning of the V2R and identification of patients with X-linked NDI

The 1971 Nobel Prize in Physiology or Medicine was awarded to Sutherland “for his discoveries concerning the mechanisms of the action of hormones” (Sutherland EW. Studies on the mechanism of hormone action (Nobel Lecture) [29]. Sutherland promoted the idea that hormones activate the adenylyl cyclase molecule. Subsequently Pastan et al [30] introduced the concept that most hormones act at the cell surface and by binding to a finite number of molecules (receptor) on the cell surface.

In 1992 the AVPR2 gene that encodes the V2 vasopressin recep­tor was cloned and mutations in this gene were identi­fied in patients with X linked NDI. Specifically Lolait et al from the National Institute of Mental Health, Bethesda, cloned the rat kidney V2 receptor displaying a transmembrane topography characteristic of G protein-coupled receptors. The human V2 receptor gene was localized to the long arm of the X chromosome close to the locus for nephrogenic diabetes insipidus [31].

In parallel Rosenthal and co-workers from the Baylor College of Medicine, Houston, Texas (USA) also cloned the V2 receptor and reported the case of an affected male of a family with CDI having a deletion in the open reading frame of the V2 receptor gene, causing a frame shift and premature termination of translation in the third intracellular loop of the receptor protein [32]. In parallel van den Ouweland from the University Hospital Nijmegen (The Netherlands) described 3 patients with identified point mutations AVPR2 gene affected by NDI [33]. It became subsequently clear that mutations in AVPR2 are responsible for about 90% of the inherited forms [2] [34]. Since this gene is located on the X‑chromosome, the major­ity of patients with NDI are male.

To date more than 250 different AVPR2 mutations have been described and most of these mutations are missense and based on the in vitro data those mutations apparently encode for functional but misfolded receptors, retained and degraded in the endoplasmic reticulum [35]. These observations opened a research field aimed at correcting those forms of NDI trying to rescue the otherwise functional receptors from the endoplasmic reticulum to the plasma membrane.

Cloning of the AQP2 water channels and identification of patients with autosomal NDI

In 1993 the AQP2 gene was cloned by Sasaki group from the University of Tokyo, Japan, and found to be expressed in the renal collecting duct [36] [37]. In 1994 Deen and co-workers showed that mutations in AQP2 gene were found to be responsible for autosomal recessive NDI demonstrating that AQP2 water channel is required for vasopressin-dependent concentration of urine [38].

The cloning of the vasopressin sensitive water channel AQP2 has been obtained by homology cloning after the identification of the first water channel Aquaporin 1 by Peter Agre [39] (full text). The 2003 Nobel Prize in Chemistry was awarded jointly to Peter Agre, “for the discovery of water channels”, and to Roderick MacKinnon “for structural and mechanistic studies of ion channels”.

The discovery of Aquaporins allowed understanding the etiology of congenital NDI caused by mutation of the AQP2 gene. Using immunogold electron microscopy, Nielsen and co-workers localized AQP2 in intracellular vesicles in collecting duct principal cells. AQP2 vesicles fuse to the apical membrane under vasopressin action leading to an increase in the osmotic water permeability (see schematic model in Figure 2). Removal of vasopressin caused internalization and recycling of the APQ2 protein and markedly diminished water permeability [40] (full text). This mechanism allows water reabsorption from the lumen of collecting duct and concentration of urine. In 1994 Deen and co-workers demonstrated that aquaporin‑2 water channel is required for vasopressin-dependent concentration of urine [38]. In the same year van Lieburg identified mutations of the AQP2 gene that caused the autosomal recessive form of NDI, based on the observations that patients showed increased factor VIII responses to dDAVP, an extrarenal effect suggesting normal vasopressin receptors [41]. Subsequently, in 1998, the autosomal dominant form of NDI was identified [42]. So far 40 known mutations that cause autosomal recessive NDI have been described and 8 known mutations responsible for the autosomal dominant form of NDI [2].

Current treatment of congenital NDI focuses on dietary modification, thiazides and inhibitors of prostaglandin synthesis (see [2]). Treatment with statins have also been suggested to potentially be beneficial for ameliorate NDI [43] (full text) [44].

Novel therapies, such as mutation-specific treatment using molecular chaperones [45], have been investigated in animal models, but few data from clinical studies are currently available.

In the future, gene therapy aimed at delivering kidney-specific wild-type AVPR2 or AQP2 could potentially cure congenital NDI.

Summary and Conclusions

After 3000 years of the description of Diabetes Mellitus, a subset of polyuric patients was considered to be affected by Diabetes Insipidus. About one hundred years ago in 1913, posterior pituitary extracts (containing vasopressin and oxytocin) were used to treat Central Diabetes Insipidus and this approach represented one of the first successful therapies for a peptide hormone deficiency.

About 70 years ago, physicians recognized patients with DI who failed to respond to vasopressin and 60 years ago the Nobel Prize du Vigneaud was successful in isolation, sequencing, and chemical synthesis of oxytocin and vasopressin.

Starting 50 years ago, a multitude of cellular events at the target cell have been elucidated. An error at any step can result in defective water balance. Emerging concepts of receptors and recent genetic analysis led to the recognition of patients with mutations in the genes coding for the vasopressin receptor and for the AQP2 water channel. The etiology of the autosomal form of Neprogenic Diabetes Insipidus was delineated by the discovery of the first Aquaporin by Peter Agre who was awarded with the 2003 Nobel Prize for the discovery of the water channels. Our understanding of the molecular physiology of Diabetes Insipidus has greatly advanced in the past 25 years. It is known today that acquired forms of Neprogenic Diabetes Insipidus are very common and most of those forms are associated to lithium treatment.

Today, Diabetes Insipidus includes a large series of disorders. Many of the known disorders are now susceptible to symptomatic treatments or specific interventions such as on dietary modification, thiazides and inhibitors of prostaglandin synthesis. However these treatment approaches can only ameliorate the clinical phenotype of Neprogenic Diabetes Insipidus. In the future gene therapy to correct the deficiency of AVPR2 or AQP2 genes might potentially represent a successful approach.

Introduction

The first description of Crush syndrome with renal failure is attributed to EGL Bywaters and D Beall because of their paper following the London Blitz [1], wherein the scientist did not acknowledge any predecessor. Following that paper the eponym Bywaters syndrome was generated. Historically the eponym is a mistake acknowledged even by Bywaters who was forced to admit the existence of predecessors in a letter to British Medical Journal [2].

That of Bywaters and Beall “was definitely a landmark paper, which focused attention on acute kidney injury and launched the subsequent cascade of studies that were to lead to the full emergence of acute renal failure during the ensuing decade”. […] “Bywaters and Beall rediscovered injury of the kidney in crush victims” [3].

However kidney injury following rabdomyolysis has a longer history going back to the Messina Earthquake in 1908. Ori S. Better, an authority for crush syndrome, was appropriately distinguished for the studies at 1. traumatic rabdomyolysis, 2. acute renal failure from war injuries and 3. the possible link between muscle damage and renal failure [1]. He pointed out that “traumatic muscle description was apparently first described in casualties of the 1909 Messina Earthquake by the German von Colmers [4]. Frankenthal in 1916 [5] was the first in describing traumatic rabdomyolysis and acute renal failure resulting from war injuries […]. Minami in 1923[6] described further cases of muscle crush injury and renal failure and raised the possibility that the muscle damage somehow contributed to the renal failure”. So it is evident that Better had not read the original paper of Franz von Colmers [7] and admitted that the source of that information was a paper of Bywaters published in 1990 [4].

Also recent papers from Vanholder et al and of Yoshioka et al [8] (full text) [9]. Vanholder and his associates pointed out that “In modern times the first cases of crush syndrome and ARF were reported during the Sicilian earthquake in Messina in 1908 and also in the German military medical literature during World war II. However they quote the paper on Bywaters and Beall of 1941 where such information is lacking [8] (full text). Also Yoshioka et al. [9] started their historical overview pointing out that “The first description of Crush Syndrome is considered to have appeared at the time of the Sicilian Earthquake”. However, they derived the information from the paper of Ori S. Better [1].

Aims

In order to understand who said it first in the field of rabdomyolysis and or acute renal failure we have devised a study to analyze the pertinent literature related to people affected by the Earthquake-Tsunami of Messina and Reggio Calabria. The final goal was that of finding reports on rabdomyolysis and or acute renal failure following that disaster which occurred on December 28, 1908 (magnitude 7.3 on the Richter scale).

Data will be provided indicating that there are 4 excellent scientific reports on the quake by scientists participating in rescue and health services. All of them described the crush of the muscle mass, but only 2 authored by Antonino D’Antona described rabdomyolysis and renal failure.

Results

There were 4 exhaustive medical reports [7] [10] [11] [12]. Franz von Colmers on the activity of the Red Cross Hospital of the German Medical Expedition in Syracuse [7]. Rocco Caminiti’s[10] detailes on activity of his special rescue and care unit rescue of the special unit in Calabria. Antonino D’Antona and his associates reported on the activity of a special Earth Quake Hospital Net in Naples which started its activity on December 30, 1908, at 11.30 AM when the first hospital ship entered in the port of Naples.

Report of Franz von Colmers

Franz von Colmers was chief of the Hospital of the Red Cross during the German Mission to Syracuse. The unit reached Syracuse by train on January 12, 1909. The hospital, not in the front line of the quake, took mainly care of patients already treated by local hospitals. It was operative immediately after arrival and ended its activity 48 days later, on February 28. The hospital took care of 119 persons, 83 of them were hospitalized for fractures, wounds, internal diseases due to the quake (mainly rheumatism) and minor surgeries. For each of them a narrative was reported and available for care. In the report (Figure 1) read to the German Society of Surgery in 1909 [7], v. Colmers referred to fractures, the gangrene due to compression (drückgangrene), the necrotic process of skin and muscles, and on the care and the healing of the wounds. There were 6 deaths. The hospital provided ambulatory care to some 300 patients. From the report, which was enriched by illustrations, emerges a good description of rabdomyolysis. The kidney and the urinary tract are mentioned on 10 occasions. The reasons are highlighted in Table 1. He did not see patients with shock because of the time elapsed from the event (14 days).

Report of Rocco Caminiti

Rocco Caminiti was Chief of surgery at the Loreto Hospital in Naples and Clinical Professor of Surgery at the University of Naples (Figure 2). He was in his native town of Villa San Giovanni probably joining the family for Christmas and New Year 1909. His house was crushed, and he was personally slightly wounded. Caminiti immediately assembled a small and efficient rescue and care unit which was operative until January 28. He and his volunteers took care of 224 wounded persons (Figure 3), 11 of whom (4.5%) were in shock. His report is also special because of its accurate analysis of causes of death in the days immediately following the quake, gangrene being the main cause. “Gangrene was the most serious” [10].

“Muscle lesions were also very severe due to the fact that wounds were contusive in nature, or due to the compression under the debris or under beams for hours and days. Muscle substance was deprived of blood. This tissue, because of its fragility, was the most compromised. Blood vessels participated in the genesis of these primary and deep lesions, and their pathology favored and accelerated the lesions in other tissues and the subsequent gangrene” [10].

Concerning the lesions of internal organs he observed that “among them prevailed the lesions of the bladder, independently of the block of urine flow due to cross section of the spine”. There are many other reasons to read Caminiti’s report. Last but not least because it highlights the courage a surgeon has to generate when confronted with an insurmountable clinical disaster and lack of facilities at disposal, the hard times when even “bandaging was not sterile” [10].

In conclusion the report of Professor Caminiti, heretofore unknown, told how he took care of persons under the debris, some of them in shock, and also nicely described the crush syndrome. However he did not describe persons with kidney injury.

Report of Antonino D’Antona

The day after the quake (December 29) the Sicilian born Antonino D’Antona (Figure 4), professor of surgery and director of the division of surgery at the University of Naples, immediately enrolled a volunteer group of surgeons and nurses to work in his unit, and move directly to Messina. The group even reached the port to embark, but there was no ship available that evening. On the following day (December 30), in accordance with the Prefect of the city and of the Rector of the University, it was decided to organize a net of all Neapolitan Hospitals (29 in total), hospitals [11] [12] to take care of the patients which were transferred by ship to Naples, the first one arrived at 11.30 AM that morning. D’Antona, because of his national and international reputation, was nominated chief of the net. The surgeons of the University Clinic were waiting for the patients on the dock. Private citizens put at their disposal private cars in order to move the patients into the various hospitals. A total of 1862 persons were hospitalized, of which 110 (5.9%) were in shock (Table 2).

D’Antona personally took care of 192 patients (the most critical), 7 of them were in shock (3.7%). The clinical status and the outcome of each of them was described [11] [12]. There were 22 deaths (11.4%). Six out 7 patients in shock died (86.7%). Two patients died because of acute uremia. Patients nos. 116 and 120 [11] [12], (Table 3).

D’Antona et al well described and discussed the pathogenesis crush syndrome (Figure 5, Figure 6, Figure 7). The “Pathogenetic event was for all persons a violent compression-transient or lasting hours and days”. Skin lesions presented “as black or pitch-black irregular spots with distinct borders which did neither protrude nor become hollow in relation to the intact skin, where they appeared as mounted. The contrast health and diseased skin was clear cut. These necrotic spots were leather hard to the touch, but definitely compressible. Surgeon scissors revealed the kind of lesions as well as their extension… However there were also translucent yellow, or amber-yellow- spots always well delimited over the whole skin”. There were “mechanical necrosis as well as anemic necrosis with venous thrombosis”. However “the area of the spots were not indicative to neither the extension nor of the depth of the lesions”. Concerning blood vessels, he pointed out that “small and large arteries may be not affected even when they are deep in a necrotic tissue” [11] [12].

The data on the patients hospitalized in Naples were illustrated by Antonino D’Antona, Luigi Rizzo and Antonio Damascelli at the Congress of the Italian Society of Surgery on October 31, 1909, which took place in Rome. Of the 197 patients under his direct care at the University Surgical Clinic seven were in shock and two of them died of uremia.

Discussion

After the Messina earthquake four outstanding reports were published [7] [10] [11] [12], based on experience made on 2205 patients.

Recognition for the reports on crush syndrome has been continuous for Colmers [1] [2] [3] [1]. Caminiti was never quoted. Giuseppe Armocida quoted D’Antona in the entry of Encyclopedia Treccani [13].

Crush syndrome with renal failure was described by Antonino D’Antona [11] [12], but it was never mentioned. Probably he wrote so many outstanding procedures that historians were never attracted by this primacy. Language difficulties may have played a role. However he had an international reputation and Spencer Watson of the great Northern Hospital in London came to Italy to assist his surgical séances. After assisting at two surgeries by D’Antona in Naples, he wrote “his ability will be not overcome neither in Europe nor in United Sates” [14], however even his main biographer did not catch this novelty [14]. Bywaters had no primacy, no right to the eponym, although he was forced to admit that there were many other scientists who paved the way.

At the time of the earthquake of Messina and Reggio Calabria, little was known about shock. World War I stimulated interest in the topic. Many ad hoc committees were nominated in USA, United Kingdom, France and Germany. Outstanding scientists were attracted to such studies like W. M. Bayliss (General Physiology University College of London), A. N. Richards (University of Pennsylvania), and Walter B. Cannon (Harvard University). The latter published in 1923 an epochal monograph on Traumatic Shock which characterized pathogenesis, laboratory investigations and therapy [3] [15].

From Cannon we learn that leukocytosis, starvation acidosis, increased non-urea non-protein nitrogen emerged as distinct markers. There was an increase of residual nitrogen (total non-protein nitrogen minus urea nitrogen) in non-catabolic cases as well as an increase of urea and non-urea blood nitrogen in the more catabolic patients which was related the low blood pressure. Urine was characterized by increased ammonia and acetone bodies. The toxic effects of nitrogenous substances liberated by the crush were suspected. It was established that it was important to correct body fluid either by forcing oral water intake, or by the intravenous route. Sodium bicarbonate had to be injected for acidosis. Infusion of plasma expanders was seen capable to restore low blood pressure permanently. The use of blood which was highly valuable however, was not superior to plasma expanders in pure shock. It was also learned that surgery was possible in shocked persons, with a low mortality for an operation performed in the early hours after the accident. Fluid resuscitation was a central step in management of patients with crush syndrome and fully adopted by Bywaters. This manoevre has been recently turned into a modern guideline [16].

Biographies of D’Antona, Colmers and Caminiti

Antonino D’Antona

He was born in Riesi, province Caltanissetta (Sicily) on December 18, 1842. High school studies were in Naples, Medical studies in Palermo (1860-1863) and Naples (1863-1865). At the age of 23, he received his MD in 1866. In the years 1866-1869 he trained in surgery in various European Universities: in Vienna with Theodor Billroth, in Leipzig with Karl Tiersch, in Berlin with Bernard Rudolf Conrad Langenbeck, in London with T. Spencer Wells and in Edinburgh with Joseph Lister. Subsequently he became in Naples a member of the university surgical team of Carlo Gallozzi and opened a private office where he taught surgery. In 1884 he was nominated surgeon at the Pilgrim Hospital in Naples where four years later he was additionally appointed pathologist (a very coveted position). In 1881 he won the national context for a professorship in surgery at the University of Padua, in 1884 that for professor of surgery at the University of Naples and in 1885 that at the University of Modena. He opted for Naples. He turned into a surgeon of unsurpassed skill, and opened many fields being excellent in abdominal, brain, and tuberculosis surgery. He mastered ovariectomy. He was particularly known for the nephrectomy using the extraperitoneal route. In 1896 he was nominated by the King Senator of the Kingdom of Italy. In 1903 he became chief of the Surgical Clinic of the University of Naples and occupied the office till death (Naples on December 21, 1913). His last years were saddened by a process because he left a gauze in the abdomen of a very sick cancer patient and for which he was completely acquitted by the tribunal of the parliament. His obituary was published in the year book of the University of Naples 1914-1915 where a total of 73 publications were listed. A monument has been erected by the municipality in Riesi, in front of his family house. For Spencer Watson he “was the greatest European Clinician” [13]. A street on the hill of city and a bust in the Department of Surgery honor him in Naples. On his death he was commemorated in the Senate. The President of the Italian Government, Giovanni Giolitti, presided the ceremony, the King sent a message.

Franz von Colmers

He was born in Berlin Charlottenburg in 1875. A child of Jewish parents, he studied medicine in Erlangen where he obtained his MD in 1899. He specialized in traumatology and war medicine and became assistant to Vincent Czerny in Heidelberg. He directed a Unit of the German Red Cross during the Russian-Japan War and in Sicily 1909 (although not in the forefront of the quake). Thereafter he became director of Surgery in Coburg Regional Hospital. In 1912 he was consultant to Queen Eleonor of Bulgaria for various hospitals in Sofia. With the advent of Nazism, being Jewish, he lost, in 1924, the position of surgeon in Coburg. From that year on he was in correspondence with Thomas Mann [17]. In 1935 he moved to Zurich and in 1936 he opened a surgical practice in New York. He died in 1960 in the Stanford Conn Hospital [18].

Rocco Caminiti

He was born in Villa San Giovanni in 1868. Medical studies were at the University of Messina. During the university studies he was attracted by comparative anatomy, histology, and zoology. He had as a tutor Professor Nikolaus Kleinenberg, a Baltic German zoologist who collaborated with Dohrn in the venture of the Zoological Station in Messina and in Naples [19]. MD, magna cum laude, on July 6, 1896. After the MD, he registered at the Faculty of Science and became a Ph.D.. He finally moved to the University of Rome where he worked under the direction of Marchiafava where he trained in bacteriology, morbid anatomy, and in the practice of autopsy in the years 1899-1902. In 1903 Antonino D’Antona offered him the position of assistant in surgery at the University of Naples where he obtained the venia legendi (reader in surgery) in surgery in 1905. In 1908 he was nominated director of surgery at the Loreto Hospital where he perfected his skill in laryngology and orthopedics. Later he was elected member of the National Senate national and mayor of Villa San Giovanni, where in the years 1920-1930 he started a private clinic bearing his name. It is still active and is managed by his grandchildren. The name and the fame of Rocco Caminiti are perpetuated in Villa San Giovanni by a Junior School and by a bust – gift of the Medical Society of Calabria – in Rosario Square.

Conclusion

The paper supports the notion that the crush syndrome was described years before Bywaters and Beall described it in 1941 and generated the wrong eponym Bywaters Syndrome. The syndrome of crush syndrome with acute renal failure was described by Antonino D’Antona in 1909 well before Bywaters [1] [2] and of many other scientists [20] [21] [22] [23] [24] [25]. The crush syndrome without renal failure was described in 1909 by Colmers [7], D’Antona [10] [11] and by Rocco Caminiti. The data confirm and extend preliminary findings described elsewhere [26].

Acknowledgements

Thanks are due to Rosaria Vollaro of the Biblioteca Universitaria, Naples, Italy; Patrizia Nocera, Angela Pinto and Antonietta Pisani of the Biblioteca Nazionale, Naples, Italy; Rosa Baviello of the Biblioteca Universitaria, Pisa, Italy; Bernadette Molitor of the BIU Santé, Paris, France; Concetta Caltabellotta of the Biblioteca dell’Officina di Studi Medievali, Palermo, Italy; Emeroteca Tucci, Naples, Italy.

Heartfelt thanks are also due to Mrs. Filomena Bisaccia Tucciarone and to Mrs. Ersilia Pifferi, Southington, CT, USA for many helpful suggestions.

Introduction

The most remarkable fact in Prof Eric Bywaters’ career and its relation to the crush syndrome is that he was not a nephrologist but rather a rheumatologist. In a career spanning more than 60 years, he spent only seven working on renal disease. Having qualified in medicine in London in 1933 he found himself immediately prior to World War 2 in the USA working at the Massachusetts General Hospital investigating patients with systemic lupus erythematosis. In 1939 he returned to the UK to work at the Postgraduate Medical School in the Hammersmith Hospital, London, once again pursuing a career in rheumatology. It was here that Bywaters was working when World War 2 began.

The crush syndrome

The concentrated bombing of London, ‘’The Blitz’’, began in September 1940. Within a fortnight Bywaters recalls seeing his first two victims when two casualties were admitted having been buried underneath debris but apparently relatively well when rescued. However, within a few hours they collapsed, became pale and hypotensive. Despite resuscitation with plasma they died from uraemia 5 to 6 days later [1]. Very quickly increasing numbers of cases were seen by Bywaters and colleagues around London with this familiar pattern being repeated. Autopsies although difficult under the circumstances, Bywaters describes taking shelter from a bombing raid under the autopsy table [1], were completed with histological examination of the muscles of the back and pelvis and crucially the kidneys. It was noted that patients rescued from entrapment, developed limb swelling due to the accumulation of serum and that surgical incision revealed muscle necrosis.

In 1941 Bywaters and other colleagues submitted two papers to the British Medical Journal (BMJ) describing the clinical course and pathology of patients admitted to London hospitals after rescue from collapsed buildings. Both papers were published in the same March 1941 edition of the journal. The lesser referenced paper described a single case of the crush syndrome but contained no histology [2]. The second, usually recognised as the Bywaters’ seminal paper on the crush syndrome, was important not only for its written content but for using a photomicrograph of the histology of the kidney demonstrating ‘pigmented casts’ in the tubules [3].

The ‘forgotten’ letter

The four cases presented in the Bywaters’ paper confirmed that crushing injuries, primarily to the limbs, produced shock which despite restoring circulation and even after recovery resulted in the patients developing nitrogen retention and dying. Renal histology showed degenerated changes in the tubules and pigmented casts in the nephron which were subsequently confirmed to be myoglobin.

Most authors would at this point have been content to have been recognised as being the first to have described a ‘new’ pathological entity and satisfactorily described the pathophysiology leading up to renal failure. Bywaters however continued to search the literature, which given the circumstances of bombing, manual searching of documents and language barriers must have been a considerable effort during a period of simultaneous intense clinical work.

Bywaters subsequently identified a substantial body of literature predominantly in German texts describing previous cases mirroring his own experiences. In a letter to the BMJ published in July 1941 [4], just 4 months after his original paper Bywaters clearly and humbly gave credit to a series of German pathologists and surgeons for their earlier descriptions, even more remarkable given the time and circumstances of his writing.

In this rarely referenced letter [4], in comparison to the original BMJ paper [3], he first gave credit to Colmers (Franz Colmers-Coburg) who attended in 1909 casualties of the 28 December 1908 earthquake in Messina, Italy which claimed some 70,000 lives. Colmers described among 83 casualties 19 suffering from “acute pressure necrosis” and one case had a history of bloody urine and oliguria.

Next he gave significant merit to 3 doctors supporting the German Army in World War 1. Firstly, Ludwig Frankenthal who volunteered as an army surgeon in 1914 and in 1916 described serious injuries to three soldiers who had been buried and showed oedema, bloody urine and post mortem ischaemic muscle necrosis. Secondly, Hackradt in 1917 working in Max Borst’s laboratory, who had set up Germany’s systematic ‘war pathology’ service, described tissue from a soldier experiencing a nine-hour burial with oedema of the leg, blisters and bloody urine containing albumin and casts, the patient dying on the fifth day. Necropsy in this case showed muscle necrosis and tubular degeneration in the kidneys with blood casts. The last of this trio was Lewin, a student of Ludwig Pick, who briefly described 3 cases in 1919.

Bywaters’ explanation for these cases not being referenced or commented upon in his original paper lay with them being in inaccessible journals or in “inaugural dissertations”.

Most importantly he gives recognition to Siego Minami a Japanese dermatologist working in Germany, also under Prof Pick in 1923 who summarized the chaotic literature and investigated more completely material from the three cases that had been already described by Lewin. His description of one of these cases tallied exactly with Baywaters’ own; a soldier buried by a grenade explosion for an unknown time, on the second day showed a painful swelling of the left thigh; on the fourth day scanty bloody urine and tenderness in the kidney region; on the fifth day 200 c.cm. of urine only, less pigmented, was found, and on the sixth day, when death occurred, the urine was still scanty (but now yellow) and contained red cells and hyaline casts. Necropsy showed grey muscle necrosis and oedema of the lungs. The kidney showed normal glomeruli, degeneration of the convoluted tubules, and pigmented masses and ribbons in the collecting tubules and in Henle’s loops [5].

It was clearly stated in the letter that by the end of World War 1 the crush syndrome and its consequences for the kidney was well recognized by German pathologists, and included in their textbooks of war surgery. However, in Great Britain it appeared to have been both unrecognized and undescribed. At the time of his writing and in the midst of a second great conflict Bywaters wonders why there was no reference to the German findings in any of the six standard textbooks on war surgery published in Great Britain or the USA.

Recommendations

Bywaters’ work on the crush syndrome did not end with his pathological description and pathophysiological causes. Further work on animal models led him to make recommendations on ways by which the kidney could be protected in these circumstances. His recommendation for early fluid resuscitation, ideally to produce an alkaline diuresis, and crucially whilst the patient remains trapped under the wreckage [6] remains true today.

Bywaters’ letter ends with sage advice for those engaged in providing medical support to casualties of war (or in fact civil catastrophes). He points out that the surgeon under these conditions is often too busy to give detailed consideration to anything beyond what is absolutely necessary for the well-being of the patient. He explains this is where co-operation between surgeons, physicians, and research workers becomes of the utmost importance: clinical, chemical, and pathological observations adequate enough to make any rational deductions regarding treatment are in many of these conditions far beyond the capabilities of any single, even full-time, worker. The advantages of group research were thus obvious to him.

Introduction

Goeury-Duvivier was a doctor in the Faculty of Medicine in the University of Paris and the University of Jena. He also attended the Department of Public Assistance and worked in the Hospital of Varsavia; here he was decorated by Polish authorities with a military order. He was not just a leading figure in the scientific progress and in the development of the knowledge in the nephrology field but was even an accurate and zealous researcher of the history of medicine.

Thanks to this cultural background and to the passion in the study of the old masters he obtained the inspiration for his intuitions.

Duvivier gives us the descriptions of invasive innovative techniques of the time, the «Taille», the lithotripsy and lithotomy of kidney stones and their negative effects or limits for each technique.

He also explains the palliative methods and solutions to relieve the symptoms with less pain to improve the condition of the patients.

He describes how the management of kidney stones has always been a big problem for physicians of all time. The history of urinary stones almost begins and goes parallel with the history of civilization. Ammonius of Alexandria (276 BC) was the first person to suggest treat the renal stone disease to facilitate its expulsion.

Ammonius was called «The lithotomus» from the instrument he developed to break the calculi. It is said that the Arabists used a diamond, placed on the edge of a rod, to shatter the calculus.

The first recorded details of “perineal lithotomy” were those of Cornelius Celsus (25 BC-40 AD), who lived in Rome and wrote encyclopaedia of medicine (De Medicina).

Duviver also reports that in 1580 Sanctorius extracted a calculus thanks to a new kind of tool. It was made of three branches and its centre had a “stiletto” used to break the calculus in order to facilitate its expulsion.

In XIX century Martin and Gruithuisen demonstrated the great extensibility of the urethra. This suggested them the use of a straight cannulas for the extraction of the calculus from the bladder.

The different kind of invasive operation

The original route of approach was through the perineum, first through the mid-line and later from the left side. The suprapubic or high operation started to be used in the early 18^th century. The first median perineal lithotomy was known as the “Lesser operation” or “operation by the Apparatus Minor” as only two instruments were essential, a knife and a hook. For the Greater operation many were needed.

The author highlights the list of the main methods that characterized the treatment of renal calculi in the history.

For instance the «Cutting technique», the «Taille», probably developed for the first time in Alexandria.

This kind of operation passed into the annals of history for the tragic death of king Antiochus V, who lost his life when the technique was at its dawn. At the beginning, the technique did not get so much acclamation and the opinions were not positive until the influence of two prestigious doctors: Frere Jacques de Baulie and Jean Baseilhac.

Frere Jacques de Baulie refined the previous methods introducing the lateral cut of the perineum. Jean Baseilhac invented a particular kind of lithotome with an hidden blade, bringing great benefits to the operation: this surgical cut, which can be suprapubic or perineal, represented the classic method for the therapy of kidney stones.

The most immediate way to expel the calculus was to find out the exact moment when the patient gets the stimulus to urinate.

The physicians had to push in the point of the urine tract where they can assume there was the obstacle and ask him to exercise a vigour pressure in order to distend the canal and expel it; if this procedure did not give a satisfactory result, it was possible to use the «Hunter» pincer. This instrument is made of a cannula with a protective sheath that has two clamps on the edge. The Hunter has two functions: the first one is to dilate the urethral channel and the second one is to grab the small calculus once the pincer is in the urethra.

The lithotripsy was the preferable method to grind the calculus and allow expulsion. It includes four basic rules: perforation, isolation, eclatement, and the écrasement, which may be used individually or together.

The limit of the lithotripsy was that it was impossible to pulverize the calculi. For this reason this technique has often required in many cases a suprapubic cut or hypo-gastric one. Another possibility was a cut under pubic or perineal area to help the extraction of the most voluminous stone fragments.

The Lithotrisy represents the evolution of Lithotripsy, also called the elder sister; in fact the Lithotrisy, using more accurate procedures, could break, split and pulverize the stones, so that they could be eliminated by the expulsive action of the bladder. To achieve better results Duvivier realized a special chair that gave to the patient the possibility to stay sat with less pain (Figura 1).

Palliative methods

If calculi are located in different sites (kidneys, ureters, bladder, prostate), or if the clinical condition does not allow the use of the above-named techniques, or if the patient obstinately refuses surgery, Duvivier advices, for duty and for humanity, the use of hygienic and palliative procedures (Figura 2).

This kind of approach could sometimes give unexpected and satisfactory results for both patient and the caregiver. Such methods included the palliative anti-inflammatory drugs, the dilators, and diuretics.

The ingestion of too much uric acid could be reduced by avoiding nitrogen and using hard and fermented liquor in the diet. Instead of meat, starches and plants were to be preferred.

To increase the urinary secretion, the author found advisable to use decoctions of chiendent (the elymus repens), of cherry juice, parietaria, flaxseed, which increase diuresis and help the dissolution of the calculi. It was also recommended the use of mineral waters such as the Carlsbad and the Eau de Vichy, which were capable of neutralizing the uric acid; to saturate the urinary uric acid, it was recommended the use of alkaline carbonates such as potassium and sodium. Another solution was to adopt measures to treat renal stone disease like common baths, body exercises, or going horseback riding.

Goeury Duvivier used to say: «They (patients) have two alternatives: To heal imposing themselves a hard and different way of living or to accept all the inevitable complications and the progression of the bad consequences of the diathesis».

Conclusions

The author gives us an important details concerning the view that ancient physicians had about the urinal tract diseases. He also shows us the view that a great personality of the time like him had about the development of these techniques. The application of these studies in the clinical cases of the 19^th is a relevant look back, and clarify how the medicine of the 20^th was inspired from these older techniques.

References

Goeury- Duvivier JL, Guide des maladies: atteints d’affetions des voies urinaires et des organes de la generation. Paris; 1852

Introduction

Abū Bakr Muḥammad ibn Zakariyyā al-Rāzī (865-925) (Figure 1 [1]), known in the West as Rhazes, was one of the most important figures of the golden age of Islamic science and medicine during the medieval ages. Kiṭab al-Ḥāwī fī al-Ṭibb (Figure 2 [2]), Kitāb al-Ṭibb al-Manṣūrī and Kitāb al-Judarī wa al-Ḥasba are his well-known works on medicine, which were translated into Latin respectively under titles of Liber Continens, Liber Medicinalis ad Almansorem and Liber de Pestilentia [3]. He also wrote the first book on pediatrics, Risāla fī Ṭibb al-Aṭfāl / Practica Puerorum[4] [5] and a book containing several medical case histories, Kitāb al-Tajārib (The Book of experiences / The Casebook) [6] [7].

Rhazes’ Kiṭāb al-Ḥāwī fī al-Ṭibb / Liber Continens contains a chapter entitled “Al-juzʿ al-ʿāshir: fī amrāḍ al-kilā wa al-majarī al-bawl wa ġayrihumā (The 10^th Section: On diseases of the kidney and the urinary tract and others) [8]/ “Liber vigesimus tertius praefati continentis Rasis: de dispositionibus renum et vesice et aliqualiter veretri (The 23^rd chapter of Rhazes’ Continens: On diseases of the kidney and the bladder and others)” [9] Kitāb al-Tibb al-Manṣūrī / Liber medicinalis ad Almansorem contains chapters regarding “fī ʿusr al-bawl / de difficultate mingendi (On difficulty of passing urine), fī al-ḥaṣāṭ / de lapide (On the stone), fī waram al-kilā wa al-mathānā / de nascentiis renum et vesice (On swelling of the kidneys and the bladder), fī ḥarqa al-bawl / de ardore qui fit in mictu (On burning sensation during micturition), fī bawl al-dam wa al-midda / de mictu sanguinis et puris (On urinating blood and pus) and fī salas al-bawl / de his qui non possunt retinere urinam (On incontinence of urine)” in “Al-maqāla al-tāsiʿa / Tractatus nonus (The 9^th discourse) [10] [11].” Rhazes also wrote a separate discourse “On stone in the kidney and the bladder” under the title “Maqāla fī al-Ḥaṣā fī al-Kulā wa al-Maṭhāna / Dissertatio de calculis in renibus et vesica [12] [13].” The 21^st chapter, “fī awjāʿ al-kulā wa al-mathana wa al-bāh,” of Kitāb al-Tajārib is “On pains of the kidney and the bladder and coitus [14] [15].” Evaluation and presentation of the cases in this chapter regarding the kidney and the bladder are the aims of this report.

Material and Method

Kitāb al-Tajārib was collected and arranged by Rhazes’ pupils and includes approximately 900 cases [6] [7]. Cases, classified and presented under title of each chapter, contain the gender, age, the complaints of each patient, and Rhazes’ diagnosis and suggested treatment. [7] [16]. Kitāb al-Tajārib was written in Arabic and one of its copies is Ahmed III Nr. 1975 manuscript in Topkapı Palace Library in Istanbul (Figure 3) [14]. Ms. Ahmed III Nr. 1975 of Kitāb al-Tajārib is 126 folios. It was copied by ʿAlī ibn Ayyūb ibn Yūsuf al-Ḳonawī al-Mawlawī and completed in 7 Ṣafar 656 / 13 February 1258, Wednesday (Figure 4) [7] [14]. A physician by the name of Ali Munshi of Bursa translated Kitāb al-Tajārib into Turkish in the 18^th century, and Hamidiye Nr. 1013, Veliyuddin Efendi Nr. 2487 and Çorum Nr. 2909 manuscripts are the copies of its Turkish translation available in different libraries in Turkey [17]. Both the book and its Turkish translation contain 31 chapters; 30 of them concerning diseases a capite ad calcem and the last one on pharmaceutics [6] [7] [14] [15][16].

Ms. Ahmed III Nr. 1975 of Kitāb al-Tajārib (Figure 5) [14] and its Turkish translation, Ms. Hamidiye Nr. 1013 [15] were examined for this report. The chapters “On pains of the kidney, the bladder and coitus” in these copies were compared and translated into English. The literature also was reviewed. The numbers of the following reported cases were assigned by the author and were not in the Arabic and Turkish copies.

Findings

Forty-one cases were presented under the title of “On pains of the kidney, the bladder and coitus [fī awjā‘ al-kulā wa al-mathana wa al-bāh]” in Kitāb al-Tajārib by Rhazes, but the Turkish translation has only 40 cases, missing is Case XXXVII. Of the 41 cases, 34 are male and 7 female [Cases IX, XIV, XX, XXI, XXXI, XXXIV, XXXVIII]. Of the 41 cases, 4 are children (M: 3 [Cases V, XXV, XXXII]; F: 1 [Cases XXXI]); 4 are young male patients [Cases XXII, XV, XVI, XIX]; 1 is a middle-age male patient [Case XXIX]; are 3 are elder male patients [Cases X, XXVI, XXXX]. The rest are adult male or female patients.

The cases are related to the urinary system more than the genital system. The chapter also includes cases of spinal trauma [Case XXI] and diabetes [Cases II, VIII, XI, XXIII], which are not directly related to the urogenital tract. Each case report, usually includes the gender, age, symptoms and signs of the patient, and features of the urine, followed by Rhazes’ diagnosis, treatment and nutritional advice. Simple and compound medicines frequently were used in the treatment of the various diseases.

Symptoms and signs of kidney and bladder diseases were accepted as diagnoses of some cases (Table 1) [14] [15] [18].

[Case I] A man complained of difficulty of passing urine [ʿusr al-bawl] and burning sensation [ḥarqa] when he urinated and a little blood passed from the urethra. And he [Rhazes] ordered him balls of the seeds [banādiq al-buzūr] and to sit in warm water three times a day and to eat all the cold and moist food and isfīdbāc [a kind of dish made of meat, onions, butter, cheese &, or of bread and milk] with fatty fowl [dajaj samīz] or almond oil [duhn lawz] [14, f. 73b; 15, f. 90a].

[Case XIX] A young man complained of frequent urination of blood [tabawwul al-dam] with burning sensation in the penis [ḥarqa fī al-qaḍīb]. And he [Rhazes] ordered phlebotomy of the saphenous [vein] on the side of the burning sensation and to drink lozenges of the yellow amber [aqrāṣ al-kahribā] and summāqiyya [the food cooked with summach] [14, f. 76a; 15, f. 93a].

In some cases a diagnosis was given in addition to the reported symptoms and signs.

[Case II] A man had urinary incontinence [salas al-bawl] and his urine was straw colored and he had extreme thirst [ʿatash shadīd] and the dry mouth [Jafāf al-fam]. He [Rhazes] ordered him to be assiduous [in using] barley water [māʾ al-shaʿīr] with a quarter [amount] of it the bitter pomegranate juice [māʾ al-rummān al-murr] and the food summāqiyya and he [Rhazes] said: “This is diabetes [dayābīṭis] [14, f. 73b; 15, f. 90a].”

In some cases, with polyuria, the differential diagnosis of diabetes is considered and a different treatment prescribed.

[Case XXXIV] A woman brought her urine which was white and thin. And he [Rhazes] asked her: “Do you thirst a lot? And she said: “No.” Then he [Rhazes] said: “This is polyuria [idrār al-bawl].” And he ordered a warm ischuretic [māsik al-bawl al-ḥārr] drug and to cook rue [saẕāb] with olive-oil [zayt] and to anoint her bladder with it and to foment with warm rags and to eat dry yellow figs [tīn aṣfar yābis] [14, f. 78a; 15, f. 95a].

Cases directly related to kidney diseases are few in number.

[Case XVI] A young man complained of difficulty in passing urine [ʿusr al-bawl] for ten years and he felt heaviness when he lied down face downward and was not able to prostrate and sometimes, pus exited from him. And his urine was raw and a little turbid. He [Rhazes] said: “This is the pain in the kidney [wajaʿ fī al-kulya] from a wound [qarḥa].” Then, he ordered him three drachms of lozenges of the winter cherry [aqrāṣ al-kāknaj] with boiled wine [mayfūchtaj] in the daytime and three drachms of weight of balls of the seeds [banādiq al-buzūr] with the rose-water [julāb] at the night time [14, f. 75b-76a; 15, f. 92b].

[Case XX] White urine similar to pus [midda], he [Rhazes] asked her: “Do you find heaviness in the back [ẓahr]?” She said: “Yes.” Then he [Rhazes] said: “This is an abscess in her kidneys [dubayla fī kulā].” He ordered her balls of the seeds [banādiq al-buzūr] and a diet of greasy food isfīdbājāt [a kind of dish made of meat, onions, butter, cheese &, or of bread and milk] [14, f. 76a; 15. f. 93a].

Cases about kidney and the bladder stones are also presented.

[Case XXV]Blackish urine of a boy who complained of difficulty in passing urine presented. And he [Rhazes] said: “This urine is the best evidence of stone in the kidney.” He [Rhazes] claimed that he had found it in some of Rufus’ books, and had himself repeatedly experienced. And he [Rhazes] ordered him balls of the seeds [banādiq al-buzūr] [14, f. 76b-77a; 15, f. 93b-94a].

Only one case includes complications and prognosis of the kidney disease.

[Case XXVI] An old man had pain in the kidneys [wajaʿ al-kulā] with severe burning in the penis [iḥtirāq shadīd fī al-qaḍīb] and redness of the urine, then, dysentery [zakhīr] followed this. And he [Rhazes] said: “He will not survive, because the kidney was adhered to the bowel and the bowels were perforated from the heat of the kidney.” And he died after ten days [14, f. 77a; 15, f. 94a].

A probable spinal trauma case was included in this chapter because of urinary incontinence.

[Case XXI] He [Rhazes] reported a woman who fell into a well and her feet / [legs] became flaccid and she did not hold her urine. And he [Rhazes] said: “Does the stool involuntarily come out?” They said: “No.” Then, he [Rhazes] ordered the purgative clyster [ḥuqna mushila] and water of the seeds [māʾ al-buzūr] with rinds of the cassia [fulūs al-khiyārshanbar] and a little almond oil [duhn lawz]. Then he [Rhazes] said: “Perhaps there is a swelling.” He ordered ten drachms rinds of the cassia [fulūs al-khiyārshanbar] with thirty drachms of the violet syrup [sharab al-banafsaj] and to put almond oil [duhn lawz] on it and to anoint the painful site with lukewarm oil of the yellow wallflower [duhn al-khīrī] [14, f. 76b; 15, f. 93a-b].

Diabetes was accepted as a kidney disease and a probable case of juvenile diabetes was presented without diagnosis.

[Case XXXI] A skinny eight-year-old female child came and he [Rhazes] was told that she slimmed and emaciated without nutrient deficiency and she was frequently thirsty [ʿaṭash] and when she slept, her urine flowed until the morning. And he [Rhazes] made her drink barley water [māʾ al-shaʿīr] and pomegranate juice [māʾ al-rummān] or the sour unripe grape juice and he included other treatments for this illness of the food ḥisrimiyya[a dish flavored with green grapes] and summāqiyya or the beef [14, f. 77a-77b; 15, f. 94b].

Discussion

Case histories in medical literature go back to Greco-Roman era. Álvarez-Millán informs us that the earliest samples of case histories are in seven books of Epidemics of the Hippocratic Corpus (5^th-4^th centuries BC). Twenty-one cases of Rufus of Ephesus (the first century AD) are another sample of case histories. Galen also wrote case histories in his works, such as On Prognosis, On the Affected Parts and On the Method of Healing [19].

Rhazes, who according to Meyerhof, “was a pupil of Galen in medical theory, but a pure Hippocratist in practical observation and therapy” used case histories based on his observations in his monumental work, al-Ḥāwī fī al-Ṭibb [20]. Meyerhof [20] published 33 cases from al-Ḥāwī -and their Latin translations also were published by Temkin [21]– who evaluated Cases I and XXIV as of “renal abscess, perforating into the renal pelvis” and “acute glomerulonephritis following measles,” respectively. Eknoyan [22] then evaluated same cases as “renal abscess or severe pyelonephritis” and “Schönlein-Henoch purpura” and he also proposed Case XXXIII as “hepatorenal syndrome,” which was considered as “cholangitisis (?); infectious icterus” by Meyerhof.

Rhazes’ Kitāb al-Tajārib (The Book of Experiences/ The Casebook), with Álvarez-Millán’s words [7], is “the largest and oldest collection of case histories, so far as is known, within medieval Islamic medical literature contains many cases.” Álvarez-Millán [19] evaluates that “the cases in the Tajārib reminds us of those in Epidemics II, IV, and V in their sketchy style, their concern with pathology as it manifests in real cases, their link with instruction in therapy rather than in diagnosis and prognosis” and states that “al-Rāzī’s case histories as a whole are Hippocratic in essence.”

The treatments of the cases in the chapter “On pains of the kidney, the bladder and coitus” were based on principles of humoral paradigm and reflect that Rhazes had a good knowledge of the literature of his era. He refers to Rufus when he diagnosed kidney stone in [Case XXV]. Rufus of Ephesus indeed wrote about the diagnosis in the chapter “On kidney stones” in his book, Diseases of the Kidney and Bladder: “…In general, black urines determine (diagnose) the disease, other urines also determine the disease, but they are more tenuous than diagnostic… [23]” It is also known that the term “diabetes” was first used by Aretaeus of Cappadocia (the second century AD) [24] (full text) [25] (full text), and Rhazes used this term as a diagnosis.

Acknowledgements

I thank Assoc. Prof. Kemal Tuzcu Ph.D. and Assist. Prof. Çağatay Aşkit Ph.D. for reviewing original Arabic and Latin texts in comparison with their English translations, respectively.