EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Recent studies suggest a link between chronic kidney disease and brain dysfunctions such as depression and cognitive problems. A review of medieval and early-modern historical figures with aspects of both kidney disease (gout and edema [dropsy]) and depression (melancholia) shows that these conditions were observed together in the past.
Materials and Methods: References to the diseases of gout, dropsy, and melancholia were compared in literature on historical subjects. Case studies are reported to detail a previously unremarked com-bination of current kidney disease and depression comorbidity in historical writings.
Results: The poet Boccaccio had gout and melancholia, and some descendants of the Portuguese Avis and Spanish Trastàmara dynasties, known for melancholia and madness, also had gout and dropsy. Historical case series of causes of death for sultans of the Ottoman Empire suggest an association among dropsy, gout, and melancholia.
Conclusions: In this article, we reviewed the medical research on the comorbidity of kidney disease and depression and shared case studies of historical figures with these conditions and posit not previously noted data supporting comorbidity observations in historical writings.

Key words : Bibliometric, Literature search, Research publications

Recently, an association between kidney diseases and various alterations of brain functions has been observed. Specifically, many patients (up to 25%) with chronic kidney disease (CKD) show cognitive impairment.¹ Similarly, up to 20% of CKD patients have depression.² Furthermore, anxiety is also highly prevalent in CKD, in up to 19% to 43% of patients.³ The cause of this connection is unclear. However, the prevalence of brain dysfunction is so high that it may represent the only symptoms in early kidney diseases.

Because of the otherwise indolent course of kidney diseases, historical accounts of kidney diseases can be traced back only to the forms accompanied by edema (as in nephrotic syndrome), gout, hematuria (nephritic syndrome), kidney stones, and oliguria. Therefore, we will explore the cases of plausible kidney alterations (edema, gout, hematuria, stones) in historical figures with depression, which is a symptom frequently recorded in ancient records.

Dropsy and Gout: In Search for Kidney Disease

Dropsy or hydropsy (ὕδρωψ, from water, υδωρ) was a term possibly introduced first by Hippocrates of Kos (~460 to ~370 BC) and reported by Celsus
(fl. 175-177 AD), before being adopted by Galen (Pergamon 129 to Rome 216 AD), and is still used today in some instances (such as hydrops fetalis, gallbladder hydrops). Hippocrates distinguished water (υδωρ) among the muscles or anasarcal dropsy (υδρωψ ανα σαρκα), water in the belly or hydrops, and tympanites (“there are two kinds of dropsy, the one anasarca, which, when formed, is incurable”).⁴ Hippocrates made the observation that dropsy succeeded by epileptic attacks was very serious, which was interpreted by Comrie in 1928 as a form of uremia and may be considered the first historical observation of a connection between uremia and brain alterations.⁵

Celsus described dropsy as “a chronic malady [which] may develop in those patients who suffer from a collection of water under the skin.”⁶Later, the term dropsy was used by Galen and followers interchangeably to indicate ascites (from liver diseases) or edema from other causes⁷:

“Thus it is clear what errors in regard to the subject of dropsies logically follow this carelessness. For, does it not show the most extreme carelessness to suppose that the blood is prevented from going forward into the liver owing to the narrowness of the passages, and that dropsy can never occur in any other way? For, to imagine that dropsy is never caused by the spleen or any other part, but always by induration of the liver, is the standpoint of a man whose intelligence is perfectly torpid and who is quite out of touch with things that happen every day.”

A recent reanalysis of Galenic authors suggests that many observed the association between dropsy and thirst (“thirsty dropsy”), which may be due to early accounts of heart failure.⁸

Therefore, the historian often faces the problem of distinguishing dropsy from heart failure, liver disease (ascites), and kidney disease (terminal kidney failure or nephrotic syndrome). Our communication suggests that the presence of melancholia (today’s depression), stones, apoplexy (today’s stroke), ascites, age, and use of alcohol may guide the historian (Table 1).

We suggest that (1) dropsy by heart diseases may be suggested by a stroke (apoplexy in old terminology) and by thirst; (2) dropsy by liver disease may be suggested by alcohol consumption or the direct use of the term ascites; (3) dropsy of kidney diseases may be suggested when occurring in a young prepuberal subject (nephrotic syndrome); and (4) writings on historical figures with melancholia may provide a new starting point for historians of nephrology to explore potential links to early-modern kidney disease symptoms.

The historian should also consider that CKD causes an increase serum uric acid levels, resulting in gout with very high prevalence, up to 23% of CKD patients.⁹ Galen describes gout in the aphorisms and suspects it has something to do with gonads (“Eunuchs do not take the gout” and “A woman does not take the gout, unless her menses be stopped” and “A youth does not get gout before sexual intercourse”).¹⁰ Therefore, up to 24% of gout accounts in Galenic literature are due to kidney disease¹¹ (see Table 1).

Example cases
Having described the overall idea of reclassification of some historical cases, we present a few examples.

In the Gospel of Luke (14:1-6), Jesus healed a man diagnosed with dropsy: “ 2 There in front of him was a man suffering from dropsy or abnormal swelling of his body. […] 4 So taking hold of the man, he healed him and sent him on his way.” At the time of the Gospel, the symptom of “dropsy” was part of the Hippocratic terminology. At about the time of Christ’s birth, Celsus described in detail the technique of paracentesis.⁶ Therefore, the account of the Gospel might resemble the immediate relief of excessive abdominal water (ascites) through paracentesis. This allows the interpretation of this example as a form of liver disease.

The Roman Emperor Trajan (53-117 AD) died of dropsy. Friedrich Hoffmann (1660-1742), in a chapter dedicated to dropsy (“de hydrope”), discussed the relevance of hemorrhoids for dropsy reporting an observation of Cassius Dio (~155 to ~235 AD) that Trajan had ascites and hemorrhoids, which were so severe to lead to death: “Thus the Emperor Trajan got ascites from the retention of hemorrhoids; once the patient suffered a relapse and died from it.”¹² Furthermore, Dio Cassius remarked, “I know, of course, that he was devoted to boys and to wine [...] he drank all the wine he wanted; He had also suffered a stroke, so that a portion of his body was paralyzed, and he was dropsical all over.”¹³ In this case, the anasarca and stroke suggest that, in addition to the liver disease (caused by wine and appeared as ascites and hemorrhoids), heart disease or nephritic syndrome (which may give hypercoagulability) was also present.

Some historical figures presented with dropsy or gout with no evidence of behavioral problems:

The Roman emperors Teodosio Flavio (347-395)²² and his son Flavio Onorio (384-423)²³ both died of dropsy. No additional information is available to establish the cause of the dropsy, except for the presence of the same symptom in relatives.

Giovanni Boccaccio (1313-1375) in his final years was troubled by illnesses and dropsy, which have recently been interpreted as caused by liver or heart disease.¹⁴ However, the same source reported the presence of itching, “unremitting kidney pain,” “mental confusion,” loss of memory, and depression. These may well be part of chronic, terminal kidney disease and uremic state. Miguel Cervantes-Saavedra (1547-1616) died of an intense thirst and of dropsy^15,16 without signs of depression or mental disease, leading to the hypothesis of a heart disease or diabetes and leaving uremia as a far possibility. Ludwig van Beethoven (1770-1827) in 1827 had ascites and underwent large volumes of paracenteses. His physician, Andreas Ignaz Wawruch, wrote about him as “Beethoven had almost immediate relief, and when he saw the stream of water [during paracentesis], cried out that the operation made him think of Moses, who struck the rock with his staff and made the water gush forth.” The autopsy showed a liver “shrunken to half its normal volume … it was beset with knots the size of a bean … the spleen was double its proper size and dark coloured and firm.”¹⁷ From the cognitive point of view, he kept working on a tenth symphony up to the very end.¹⁸ The major interpretation here is a liver disease.

Finally, the King of England George III (1738-1820) had, toward the age of 45, acute mania/bipolar disorder, dementia, progressive blindness and deafness, rheumatism/gout, stomach pain, cramps, rashes, edema, and brown urine. Although this was interpreted as a possible form of porphiria,^19-21 the presence of edema, urinary alterations, gout, and dementia might resemble a kidney disease.

Familial Cases of Melancholia Comorbidity
It is also notable that the presence of dropsy in relatives in the same family was sometimes associated with melancholia.

The Trastàmara family is an interesting case of a family with melancholy and possible kidney problems (see Figure 1 and Table 2).^24-28 Isabel of Portugal or of Aviz (Isabel de Avis y Braganza, 1428-1496, queen consort of Juan II of Castile and Leòn) was called “la reina maldita” and had a “profunda tristeza” and attacks of dementia. The daughter of Isabel of Portugal, Isabel I the Catholic, Queen Regnant of Castile (1451-1504), once wrote that she was only saved from the same disease by her strong faith. The change in Isabel I’s face reflected in sequential portraits suggests signs of edema. Isabel I’s eldest daughter, named Isabella of Aragon or of Trastàmara (1470-1498), queen consort of Portugal and granddaughter of Isabel of Portugal, was also described as having a severe depression. Another Aviz granddaughter and Isabel I’s second daughter, Juana of Castile or of Aragon (1479-1555), Queen Regnant of a united Spain, also called “Juana la Loca” or “Joanna the Mad,” also had severe behavioral issues, described as melancholia, which were exploited by the men around her. She is noted as having a swollen body at her death that made movement difficult. Isabella and Juana’s sister and Isabel I’s youngest daughter, Catherine of Aragon, queen consort of Henry VIII of England, joined her family in having signs of melancholia and dropsy. An autopsy found a blackened heart, which may be related to kidney dysfunction as noted above. The daughter of Catherine of Aragon was Mary I Tudor (1516-1558), Queen Regnant of England, who experienced deep sadness throughout her life and descriptions of her stoutness in her middle age, when compared with earlier pictures of a slimmer young Mary, suggest a similar familial tendency to bodily swelling.

Therefore, 4 generations of the same matrilineal family displayed symptoms melancholia and dropsy comorbidities. This does not take into the account comments on and by their children (including Emperor Charles V, d. 1558 and Maria of Hungary, d. 1558), grandchildren (including Juana of Austria, Princess of Portugal, d. 1573), and cousins (including Joao II, King of Portugal, d. 1495) regarding their health or concerns with the familial proclivities. For example, a junior branch of the Trastàmaras continued the pattern. Isabella of Naples (1470-1524), Duchess of Milan, died of dropsy in Naples and Federico IV of Aragon, King of Naples (1452-1504) died of the same disease in exile in France.

Finally, another interesting historical case series concerning the association between dropsy and depression is regarding the Sultans of the Ottoman empire. In a book from Alderson,²⁹ the cause of death of 37 sultans from 1324 to 1944 are listed. Among the sultans, depression or suicide was highly prevalent (9 sultans: 34%), as well as apoplexy (7 sultans: 19%). Stones were present in 1 sultan (Murad III, d. 1595). Gout was diagnosed in 3 sultans: Osman I (1324), Orhan (1360), and Mehmed II (1481); Orhan had comorbid depression. Three brothers who were successive sultans also showed the gout, dropsy and depression combinations: Suleyman II died in 1691 of gout and depression, Ahmed II died 1695 of dropsy and depression, and Mehmet IV died in 1693 of dropsy. Mehmet’s son Mustafa II also died of dropsy (died in 1703).

It is also interesting to note that changes in the nosological system over time have influence in this analysis: diabetes (an important risk factor for nephropathy) is mentioned only in 1904 (Murad V), and the last 4 sultans all had been diagnosed with heart failure, a diagnosis that was absent before 1900.

The known links between gout, CKD, and depres-sion might lead to a better modern classification of ancient pathologies described on the bases of the Galenic system. Dropsy and melancholy often occured together in historical figures; at least in some instances, the presence of kidney disease might explain these cases. Familial occurrences of dropsy and melancholia are also interesting under the modern view of a link between CKD and depression.

Volume: 21 Issue: 6 June 2023 - Supplement - 2

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