Franz Volhard: 150th Birth Anniversary of a Father of Nephrology and Hypertension.

Franz Volhard (May 2, 1872, to May 24, 1950) was a German clinician and researcher who made outstanding contributions to the field of nephrology and hyper-tension. His studies led to important developments in knowledge about the pathophysiology of the kidney and its relationship to cardiovascular disease. He contributed to a better understanding of the mechanisms underlying renovascular hypertension by explaining the crucial relationship between the decrease in renal blood flow and the increase in blood pressure. He also introduced a precise classification of the different types of hypertension and the associated renal involvement. In collaboration with Karl Theodor Fahr (1877-1945), he developed a new classification of Bright's disease (nephritis), which was published in the book Die Brightsche Nierenkrankheit. Klinik, Pathologie und Atlas, and revolutionized the concepts behind the mechanisms of glomerulonephritis. During his distinguished career, Volhard headed departments of internal medicine at the Luisenhospital in Dortmund (1905-1910) and in Mannheim (1910-1918). In 1918, he became chairman of the Department of Internal Medicine at the University of Halle, his alma mater, until 1928, the same year he became chairman of the Department of Internal Medicine at the University of Frankfurt until 1938. Volhard continued his successful career until 1950, when he died of complications from a car accident. The worldwide medical com-munity greatly appreciated Franz Volhard's scientific contribution. The International Society of Hypertension posthumously presented him with the "Franz Volhard Award." The aim of this article is to commemorate the importance of this giant of nephrology 150 years after his birth.

The Mysterious Life of Jeronimus Ruscelli and His Contribution to Nephrology (1504-1566).

Jeronimo Ruscelli was a mysterious humanist of great fame. He was born in Viterbo between 1504 and 1518 and died in Venice in 1566. Very little is known about Ruscelli's life, but based on his extensive literary output we can assume that he was endowed with remarkable intellectual abilities and a propensity for varied interests. At a young age, he developed a strong interest in classical studies and attended the court of Cardinal Marini Grimani in Utini. After completing his studies at the University of Padua, he participated in the founding of a humanist academy, the Accademia degli Sdegnati (the Scornful Academy). After his fruitful experience in Rome, he moved to the Neapolitan residence of Marquis Alfonso D'Avalos. Here, Ruscelli founded an "Academy of Secrets", composed of a group of humanists and nobles who had an extensive culture and had different experiences but similar interests. During these productive years, under the pseudonym Alexius Pedemontanus, he wrote one of his masterpieces, The Secreti, an important historical documentary manual of great value. In this book, the author proposes therapies for a wide variety of diseases, claiming in most cases that they have been experimentally and successfully tested in the presence of witnesses in at least 3 clinical cases. Ruscelli composed an extensive version of The Secreti, the Secreti Novi. In this book he reported more than a thousand recipes, the substances used were of a great variety and sometimes curious. According to Ruscelli, the recipes in this updated version of the book were "easy for anyone to make, of little effort, and useful for all kinds of people." The topics of this masterpiece range from general medical suggestions to more specific indications, with a wide variety of recipes and treatments of nephrological and urological interest.

Horseshoe Kidney: 500 Years From the First Report in the Literature.

Horseshoe kidney or ren arcuatus is the most common renal fusion anomaly, with an incidence of 1:500 in the normal population and a male predominance of 2:1. In >90% of cases, the fusion occurs along the inferior pole. It may vary in location, orientation, and arterial and venous anatomy. In 1522, Berengario da Carpi described this renal malformation for the first time in his masterpiece "Isagogae breves" (Introduction to Anatomy). He reported the results of a postmortem examination in the public autopsy room of the University of Bologna, describing "kidneys that are continuous as if they were a kidney, with two emulsifying veins, two emulsifying arteries, two ureteral outlets." In 1564, Leonardo Botallo described and illustrated the features of this atypical anatomical representation, and later, in 1602, Leonard Doldius added further details by examining this anatomical feature during an autopsy. In 1761, Giovanni Battista Morgagni discussed this condition not only as a rare anatomical curiosity found only in necroscopy but also discussed its physiological aspect. In the nineteenth century, with the advent of renal surgery, the horseshoe kidney played a more important role in urological diagnosis and treatment, and its identification became more frequent. With the advent of pyelography, imaging reports of the horseshoe kidney allowed a more accurate representation of the anatomical variants, which was particularly useful in preoperative assessment and outcomes. Berengario da Carpi laid the foundation for a better knowledge of this anatomical anomaly. Five hundred years after the first report in the literature, relevant advances have been made in the management of complications associated with horseshoe kidney and in diagnosis, confirming the need to monitor individuals with this condition who are at higher risk of developing chronic kidney disease.

Utility of Urine: From Antiquity to the Moon.

In ancient times, religious traditions considered urine a useful distilled product from the body. It has been used as a form of medicinal therapy for many years and is still used by millions of people worldwide who drink their urine for therapeutic purposes. The positive effects of urine on health were reported since the Renaissance for its bactericidal effects on wounds, healing effects on gastric ulcers, improved protein synthesis, regression of liver tumors, and ability to block the growth of tuberculosis mycobacteria. Urine contains a large number of chemical agents, some of which have already been identified, although others are still unknown. It is important to identify these agents through new technological methods, such as mass spectrometry, as new biomarkers of diseases. Recently, the use of urine has been discovered as a "green" element to produce electricity, agriculture fertilizers, generation of water, and building material for lunar bases for future space explorations.

Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease.

The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial variability suggesting that environmental factors may play a role. We hypothesized that a prevalent form of renal insult may accelerate cystic progression and investigated tubular crystal deposition. We report that calcium oxalate (CaOx) crystal deposition led to rapid tubule dilation, activation of PKD-associated signaling pathways, and hypertrophy in tubule segments along the affected nephrons. Blocking mTOR signaling blunted this response and inhibited efficient excretion of lodged crystals. This mechanism of "flushing out" crystals by purposefully dilating renal tubules has not previously been recognized. Challenging PKD rat models with CaOx crystal deposition, or inducing calcium phosphate deposition by increasing dietary phosphorous intake, led to increased cystogenesis and disease progression. In a cohort of ADPKD patients, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition which could be therapeutically controlled by relatively simple measures.

The management of kidney stones as suggested by Goeury-Duvivier.

The management of kidney stones has always been a big problem for doctors of all time. Goeury Duvivier in his masterpiece "Guide des malades atteints daffections de voie urinaires ou des organes de la gnration chez lhomme et chez la femme shows us the different kind of diseases which affects the urinary tract and in particular highlights the list of the main methods that during the history characterized the treatment of renal calculi. Duvivier gives us the descriptions of invasive innovative techniques of the time, the Taille, the Lithotripsy and Lithotomy and their negative effects or limits for each technique. He also describes the different kind of palliative methods used in the 19th century to treat renal lithiasis and the clinical case reports of the time.

The concept of the urine test and specific reaction of the urine in various diseases according to Enrico Cauchi - member of the medical council of Malta (1933).

The Study of urine from the outset has always aroused the interest of scientists and physicians all over the world, from ancient Greeks and Romans to Hindus , Hulcos in Mexico, Australian native etc. The urine in such case was considered not only as a waste product but also as a therapeutic product. In the late XIX century scientific knowledge had already identified the function of substances that favor the increase of urinary output, and physicians over the centuries have always tried to analyze urine in various ways. In Cauchis work in 1933 all chemistry and pathophysiological knowledge of the time was condensed. Cauchi signed the preface as Member of the medical council of Malta. He was a medical doctor of the early20thcentury, He wrote about the physiopathology of urine ranging from chemical and physical behavior, to the analysis of sediments and the special reactions of the urine in various pathologies. In particular Cauchi emphasizes the main diseases of the time combines the behavior of the reaction of urine as a diagnostic and prognostic instrument, stressing the importance of the urine test and describing the method used for analysis at the time. The analyses of the text in the issue seems to belong to archaic medicine, and it is difficult to think today, that what was presented as very up-to-date- science at that time, took place only 80 years ago. Reading the full original text with today experience we are led to consider the increasing importance that scientific community gave in the past, and still gives to urine test.

Between the utility and hazards of phosphorus through the centuries.

Phosphorus has been shown to be a predictor of cardiovascular mortality in kidney disease subjects. Phosphorus was discovered in 1669 and was considered a philosophers stone, it was used as medicament but there were reported deaths after its use. High serum levels of phosphorus are associated with increased risk for cardiovascular disease in the general population in subjects free from chronic kidney disease. Phosphorus can be defined as a useful and hazardous element for public health.

Socio-Economic Factors, Food Habits and Phosphorus Levels in Patients on Hemodialysis.

BACKGROUND: Hyperphosphoremia is one of the most important risk factors for morbidity and mortality for chronic kidney disease (CKD) patients, and also, for the general population. Excessive dietary intake of phosphate (P) is one of the key factors. In particular, P in its inorganic form, which is contained in food additives, is more readily absorbed. Unfortunately, these food additives are mostly present in convenience so called "fast foods" (pre-cooked), soft drinks, which represent the typical food consumed by our hemodialysis (HD) population, composed by elderly people, mostly low-socio economic class, who often live alone. OBJECTIVES: We performed an observational retrospective multicenter study to find any association between social, cultural and economic situation, as well as food habits, and P levels in a cohort of patients on HD. Secondarily; we also examined the association between the fast food consumption and increased P levels, as well as patient compliance for P binding products. PATIENTS AND METHODS: To explore the association between socio-economic factors and serum P levels, we enrolled 100 patients on periodic HD treatment from three different units. Information on social, cultural, economic, diet habits, therapy for hyperphosphoremia and hematological and clinical parameters had been collected through specific questionnaires, administered by a physician. RESULTS: Results showed serum P level was reduced in patients who live alone compared to patients in family (P = 0.04), in self-sufficient (P = 0.05) and in patients belonging to middle-upper class, versus low-class (P = 0.003). Fast foods intake correlates with increase in P serum levels (P = 0.002), whilst the same correlation was not found for cheese intake. Our data show that socio-economic status and food habits are useful predictors of P serum levels. CONCLUSIONS: In conclusion, dietary counseling of patients on HD is mandatory. Interventions that consider the socio-economic situation allow delivering important messages on foods with the least amount of P and adequate protein content, and they may be a successful strategy in targeting patients at a higher risk of hyperphosphoremia.

Erythropoiesis-stimulating agents: dose and mortality risk.

Hypo-responsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality in end-stage renal disease patients. It is not clear if this effect is related to the elevated ESAs dosage for targeting hemoglobin levels or underlying morbid conditions that lead to ESA resistance. We retrospectively evaluated from 2008 to death or December 2011, 28 consecutive incident hemodialysis patients. We identified 2 cohort of patients based on their mean annual ESAs dosage. The correlation between data was evaluated with the Spearman's rho test. Kaplan-Meier curves were generated to assess survival in subjects with high and low ESAs mean dose. Median ESAs dosage, used as a cutoff point between patients at high and low ESAs dose, was at 11.000 IU/week for epoetin alfa and beta, 55 mcg/week for darbopoietin, and 220 mcg/month for cera. Mean hemoglobin (Hb) level was 10.58 ± 0.13 g/dL. Of 28 patients, during follow-up, 6 (21,4%) died of all causes. High-dose ESA therapy was associated with increased all-cause mortality (P = .047). Moreover, there was a negative correlation between ESAs dose and Hb levels (rho = -0.825; P < .001). Higher ESAs dose for the treatment of anemia in incident hemodialysis patients was associated with higher mortality risk. ESAs and Hb serum levels were inversely correlated with mortality. Together, these findings suggest that ESAs dosage and Hb level may play a role through an independent manner or an interactive effect that adversely affects mortality.

Expert opinion of nephrologists about the effectiveness of low-protein diet in different stages of chronic kidney disease (CKD).

No clinical trials have specifically explored the benefits of low-protein diet in patients with different stages of chronic kidney disease (CKD) 3B. In the absence of RCTs, expert opinion may be a valid surrogate to estimate treatment effectiveness. A questionnaire-based survey of a large sample of nephrologists from Southern Italy was conducted to explore benefits of low-protein diet (LPD) in delaying dialysis entry in different CKD stages. For the case vignettes describing eight different patient profiles with various CKD stages, nephrologists reported expected benefits as time delay of dialysis entry. Information was collected through questionnaires filled by 88 nephrologists from different Southern Italian hospitals. On average, nephrologists estimated the highest delay in starting dialysis due to LPD in stages 3B (15 months) and 3A (14 months), and the lowest for 5 stage (3 months). According to opinion of a large sample of Southern Italian nephrologists, low-protein diet may be more efficacious if started in CKD stage 3B than 4 and 5.

Vitamin D receptor gene polymorphism and left ventricular hypertrophy in chronic kidney disease.

FokI and BsmI polymorphisms of vitamin D receptor (VDR) gene are regarded as reliable markers of disturbed vitamin D signaling pathway. Left ventricular hypertrophy (LVH) is a strong cardiovascular risk marker in end stage renal disease (ESRD) patients. Since BsmI polymorphism has been associated with LVH in ESRD patients, we addressed this study in patients with chronic kidney disease (CKD) not yet on dialysis. One hundred and forty five patients with CKD stage 3 were genotyped for FokI and BsmI VDR polymorphisms, in order to assess the relationships between these VDR polymorphisms, some markers of mineral bone disorders, and LVH measured by echocardiography. Patients bearing either the Ff heterozygous or FF homozygous genotype had significantly higher PTH values than those bearing the ff genotype. The relationships between VDR genotypes and LVH revealed a highly significant association of the BsmI Bb heterozygous genotype with LVH. In patients with CKD stage 3 BsmI B allele was independently related to LVH. Since LVH is a frequent finding in dialysis population due to several mechanisms, the presence of the same relationship in patients with CKD strengthens the hypothesis that alterations of vitamin D signaling are implicated in LVH development in patients with renal diseases.