History of creatinine clearance: tribute to a forerunner.

It is known to few that the path to the discovery of the long-denied plasma creatinine and its clearance was long and difficult. For quite a long time, related controversies between different groups of researchers were widespread and heated. The scientists who have dealt with the related problems are among the most famous of the last century and some of them are part of the history of medicine. Giovanni Ferro-Luzzi, an Italian clinician, was one of these researchers. He was among the first to detect and dose plasma creatinine and the first ever to measure the clearance of endogenous creatinine (CrCl). Unfortunately, due to a series of unforeseeable events, he has been completely forgotten together with his undertakings. In this review we retrace the steps that led to the measurement of plasma creatinine, and CrCl. With brief biographical notes we try to explain the oblivion of this important figure and of his nephrological accomplishments.

Italian Pioneers in Cardionephrology: how some fundamental Italian cardiorenal researches have passed into oblivion.

A historical research was made on papers published by Italian scientists on cardiorenal diseases. The investigated period is between the beginning of the 20th century and the entry of Italy into the Second World War, 1940. 34 papers dealing with the relationship between the kidney and the cardiovascular system were retrieved. All but two articles were published in Italian medical periodicals. The topics covered are varied and range from cardiotoxicity of substances in uremia to the role of renal disease in vascular damage. Some articles are forerunners of later pathophysiological concepts and research technologies. These concern early atherosclerotic vascular damage and the presence of dialyzable cardiotoxic substances in renal insufficiency. Unfortunately, these highly innovative researches have had little diffusion and have fallen into oblivion in Italy and abroad. In conclusion, our research shows that in the first half of the 20th century in Italy there was a lively interest in cardio-renal diseases and that some researchers had produced precursor results of what was confirmed many years later.

[Interview with Vito Cagli: his life as a nephrologist and more].

This interview describes the numerous and important contributions that Vito Cagli, who was born in Ancona in 1926, has given to the Italian Nephrology and to other fields of Medicine. These contributions, that are very poorly known today, were produced especially in the years in which Cagli worked as deputy director of the Centre for the Investigation and Treatment of Hypertension and Renal Diseases at Policlinico Hospital Umberto I in Rome. This interview also describes the early phase of Italian Nephrology before the introduction in our country of renal biopsy and of hemodialysis.

Nephrology and nephrologists in Italy between the two World Wars.

The First World War was a turning point for medicine worldwide and the following 20 years brought many important innovations. Kidney studies in Italy were part of this general trend. In this contribution, all the papers relating to kidney physiology, pathology and therapeutics produced by Italian scientists in the years between the two World Wars are retrieved and examined. The authors who produced strictly nephrological articles are also singled out and their activity described. This research retrieved 638 articles dealing with kidneys and published by Italian scientists over the period described. The topics covered were up-to-date, and the level was consistent with that of foreign contemporaries. Among the authors, a group of young scientists particularly dedicated to the study of the kidney emerges. Most of them would subsequently be among the founders of the Italian Society of Nephrology and leaders of Italian nephrology.

[Interview to Attilio Losito: my half-century life as a nephrologist in Perugia].

In this interview Attilio Losito tells us about his first nephrological experiences gained in the late sixties of the past century in the Institute of Patologia Medica in Perugia directed by Giovanni Gigli, and his subsequent experiences, which also included a period at Guy's Hospital in London. The interview also describes the important contributions that the school of Perugia produced in the field of nephrology and its main protagonists. This nephrological life story highlights: the role that internal medicine, with its multidisciplinary approach, had in the development of nephrology in its beginnings; the importance of cooperation with foreign institutions; the contributions that specialised research laboratories attached to renal units have given to the improvement of the diagnosis and to the understanding of the pathogenesis of nephropathies.

The origin of the modern Italian nephrology at the dawn of the 20th century.

The author singled out the first decade of the 20th century as the time in which the renewal of academic medicine in post-unification Italy was concluded, while the changes that would be induced by the following war had not yet started. A bibliographic research relating to this period was undertaken with the aim of investigating the number and the quality of the studies on kidneys published by Italian scientists. A total of 176 publications of Italian scientists dealing with kidney diseases or physiology was retrieved, 10.8% of which was published on foreign journals. The analysis of the topics treated shows that they were up to date and comparable with the contemporary studies across Europe. Moreover, the issues raised remained of interest throughout the following decades up to our day. Top Italian researchers were fairly cited, especially if they published on international journals. While at the time the state of other organs was mainly assessed by examining physical signs and symptoms, kidney studies required laboratory facilities. This limitation meant that kidney scholars usually belonged to well established medical faculties. From these schools, a few figures stood out among the others for the importance of their studies, both physiological and clinical in nature. The same figures also gave birth to the major Italian schools of internal medicine from which, half a century later, originated the Italian Society of Nephrology. The findings of this research support the conclusion that the basis of modern nephrology can be traced back to that decade.

[Interviewing Professor Enrico Malizia, one of the fathers of Italian nephrology].

This article contains an interview to Professor Enrico Malizia (born in 1926), who played an important role in the birth of nephrology in Italy. On April 27th, 1957 Professor Malizia was in fact among the founders of the Italian Society of Nephrology, which he also served as secretary for some years, together with Professor Luigi Migone (1912-2002). In addition, he participated in the organization of the First International Congress of Nephrology, which took place in Geneva and Evian from September 1st to 4th, 1960. Professor Malizia devoted himself to nephrology for many years, both as clinician and as researcher, by publishing many original papers and monographs on different nephrological topics, a few of which are described in detail in the present article. In addition, his interest in renal diseases led him to frequent the institutions of eminent renal scientists of the period such as the physiologist Homer Smith (1895-1962) and the pathologist Jean Oliver (1889-1976) in the United States, and the clinician Jean Hamburger (1909-1992) in Paris.

Cardiovascular morbidity and long term mortality associated with in hospital small increases of serum creatinine.

BACKGROUND: The cardiovascular risk associated with an increase in serum creatinine below the acute kidney injury (AKI) threshold, during hospitalization, has not been studied in depth. We assessed patients' features and outcomes associated with these changes. METHODS: Retrospective cohort study of 12,493 consecutive patients admitted to hospital throughout 12 months. We investigated the patients who had a small creatinine increase (SISCr) between 1.2 and <1.5 times the admission value, and tested the association of creatinine changes with the prevalence of cardiovascular disease (CVD). In a follow-up study, we assessed the all-cause mortality and its relationship with SISCr. RESULTS: Among patients with two or more creatinine measurements, 14.9% showed a SISCr. Older age, female gender and higher estimated glomerular filtration rate (eGFR) at admission were characteristics of these patients. The prevalence of CVD was 14.6% in patients with SISCr vs. 10.7% in those with stable creatinine (p < 0.001). SISCr was detected in 36, 26.6 and 18.9% of chronic heart failure (CHF), chronic ischemic heart disease (CIHD) and acute myocardial infarction (AMI) patients, respectively. The follow-up was 26.7 ± 10.6 months with 770 all-cause deaths. Serum creatinine increase above 20% was associated with a significant higher mortality compared to changes below 20%, adjusted hazard (HR) ratio 1.577 (p < 0.001). A higher risk was found associated with creatinine increases >1.5 times the baseline: HR 1.704 (p < 0.001). CONCLUSIONS: In hospitalized patients, increases in serum creatinine below the AKI threshold are associated with CHF, CIHD and long-term mortality.

Association of reduced kidney function with cardiovascular disease and mortality in elderly patients: comparison between the new Berlin initiative study (BIS1) and the MDRD study equations.

BACKGROUND: New creatinine based equations for estimating glomerular proposed for aged subjects have not been assessed in their association of reduced eGFR with cardiovascular (CV) morbidity or all cause (AC) mortality. PATIENTS: All subjects ≥70 years old (2998) who had been admitted to the hospital during a 12 month period were examined. METHODS: In a cohort study we applied the new Berlin Initiative Study (BIS1) equation. We compared the association of reduced eGFR estimated by BIS1 and MDRD equations, with cardiovascular (CV) disease and all cause (AC) mortality. RESULTS: eGFR was 57 ± 17 mL/min/1.73 m2 by MDRD and 71 ± 28 mL/min/1.73 m2 by BIS1 (P < 0.001). A diagnosis of CV disease was present in 947 patients. CV disease was associated with eGFR < 60 mL/min/1.73 m2 by both formulas: OR 1.179 (CI 1.001-1.390) for BIS1 and OR 1.440 (CI 1.223-1.696) for MDRD. In survival analysis a significant association of eGFR < 60 mL/min/1.73 m2 with AC mortality was found for both equations: MDRD (HR = 1.270, CI 1.111-1.453, P < 0.001), BIS1 (HR = 1.174, CI 1.031-1.338, P = 0.016). The analysis repeated with groups of age showed that the association of mortality with eGFRBIS1 < 60 mL/min/1.73 m2 was lost over 80 years. CONCLUSIONS: In patients >70, admitted to hospital, the implementation of the new BIS1 estimating equation does not modify the relationship, observed with the MDRD formula, of reduced GFR with CV disease or AC mortality.

Characteristics of the Relationship of Kidney Dysfunction with Cardiovascular Disease in High Risk Patients with Diabetes.

We aimed at comparing the relationship of reduced estimated glomerular filtration rate (eGFR) with cardiovascular disease (CVD) and mortality between high risk patients with and without type 2 diabetes mellitus (T2DM). The cross-sectional study evaluated 16,298 participants (1,627 T2DM) acutely admitted to hospital. The longitudinal study comprised 7,508 patients (673 with diabetes and 6,835 without). eGFR was categorized into 6 stages from >90 to <15 mL/min/1.73 m2. Kidney dysfunction was defined by an eGFR < 60 mL/min/1.73 m2. Patients with T2D showed a higher prevalence of CVD (37.9% versus 23.6%; P < 0.001) and kidney dysfunction (25% versus 13.2%; P < 0.001) than in the general population. An association with CVD was found with eGFR stages from 30 to 90 mL/min/1.73 m2 in T2D and from <15 to 90 mL/min/1.73 m2 in general population, in whom the association of eGFR with coronary heart disease was in an inverse relationship (P < 0.01 for trend). Survival, in diabetes, was lower (P = 0.037) but not associated with kidney dysfunction. Conclusions. In a high risk population, patients admitted to hospital, the relationship of kidney function with CVD is different between T2D and the general population. Competing mortality and the presence of other major risk factors in diabetes may be responsible for this difference.

Postdialysis Hypertension: Associated Factors, Patient Profiles, and Cardiovascular Mortality.

BACKGROUND AND OBJECTIVES: A postdialytic increase in blood pressure (BP) is a recognized but often an overlooked complication. The epidemiology and predisposing factors are still not well defined. We studied a large sample of Italian dialysis patients to assess the prevalence of postdialysis hypertension (PDHYPER), defined as any increase of systolic BP (SBP) >10mm, Hg above the predialysis value, the associated factors and its role in cardiovascular (CV) mortality. PATIENTS AND METHODS: In this observational study, we assessed dialysis associated changes in BP in 4,292 hemodialysis (HD) patients over 1 month (51,504 sessions). We compared the clinical characteristics of the patients with stable BP values during the HD session with those with PDHYPER. We also assessed the impact of PDHYPER on CV mortality. RESULTS: A total of 994 (23.1%) patients had PDHYPER. Patients with PDHYPER were more likely to be hypertesive, older, have a shorter dialysis vintage, be male, have lower SBP, lower changes in weight during HD, and receive more antihypertensive medications. These predictive factors were shown to be associated with an interaction between weight loss and dialysis, suggesting a volume-related mechanism in its pathogenesis. PDHYPER was also associated with CV mortality. CONCLUSIONS: In our study on a large Italian cohort of dialysis patients, the prevalence of PDHYPER was higher than what was previously reported and is a significant risk factor for CV mortality in dialysis patients. The pathogenesis is multifactorial but hypertensive state, antihypertensive medications, and extracellular volume expansion appear to play a major role.

Blood pressure and cardiovascular mortality in dialysis patients with left ventricular systolic dysfunction.

BACKGROUND: In patients chronically treated with hemodialysis, the prevalence of heart failure is high with a consequently poor prognosis. The role played by blood pressure (BP) on cardiovascular (CV) mortality of these patients has not been clearly defined. METHODS: In this follow-up study, we investigated the relationship of pre- and postdialysis measurements of BP with CV and all-cause mortality in a cohort of 557 dialysis patients with a left ventricular (LV) ejection fraction <50%. RESULTS: During the follow-up (mean = 21.6 ± 8.8 months), 179 deaths were recorded. Ninety-eight patients died from CV causes. By the Cox multivariable analysis, we constructed a predictive model of CV mortality including age, duration on dialysis, diabetes, serum albumin, diffusive dialysis technique, predialysis mean arterial pressure (MAP) (hazard ratio (HR) = 0.978; 95% confidence interval (CI) = 0.956-0.999), and postdialysis MAP (HR = 1.035; 95% CI = 1.010-1.061). The relationship with mortality was inverse for predialysis MAP and direct for postdialysis MAP. In a subsequent analysis, we found that pre- and postdialysis systolic BP, but not diastolic BP, were predictive of CV mortality. Predialysis MAP was in a direct relationship with body mass index. Postdialysis MAP had an inverse relationship with weight loss during dialysis session. CONCLUSIONS: CV mortality in dialysis patients with LV dysfunction is associated with both pre- and postdialysis BP interacting in a complex relationship. Nutritional state and fluid balance and removal are possible clues to this relationship.

Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.

Pulmonary arterial hypertension (PAH) and renal thrombotic microangiopathy (rTMA) are rare diseases in childhood, frequently leading to death and end-stage renal disease, respectively. Their combined occurrence has been reported anecdotally. We investigated the clinical, biochemical, and genetic aspects of 5 children with the rare combination of PAH and rTMA. Onset of disease ranged from 1.5 to 14 years of age. The 2 youngest patients presented with concomitant pulmonary and renal disease; in the older patients, PAH was preceded by rTMA from age 2.5 to 7 years. Three patients presenting at ≤ 3 years of age died of right ventricular failure secondary to progressive PAH. In 2 patients, cobalamin C (cblC) deficiency was diagnosed postmortem. Three patients were treated with hydroxocobalamin; 1 died 2 weeks after diagnosis, 1 patient exhibited progressive pulmonary vasculopathy, and 1 patient is currently in stable condition. cblC deficiency was diagnosed biochemically 2 days to 18 years after initial presentation. Genetic analysis confirmed mutations in MMACHC in all patients; 4 patients were compound heterozygous, with all having base-pair substitutions (G>A or G>T) at nucleotide 276 in addition to frame-shift mutations. One patient had homozygous nonsense mutations of MMACHC. We established cblC deficiency as the denominator in the rare combination of PAH and rTMA in these children. Early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may beneficially affect the course of this devastating disease.

Systolic blood pressure and mortality in chronic hemodialysis patients: results of a nationwide italian study.

Studies on the relationship between blood pressure (BP) and mortality among hemodialysis patients have yielded conflicting results. Reports have come mostly from North America and have dealt with dialysis patients as a homogenous population and differed in methods and time of BP measurement and the optimal BP target. In a prospective nationwide study in 3674 unselected Caucasian patients with end-stage renal disease undergoing chronic hemodialysis from 73 dialysis units, the authors sought to examine the relationship between the different measurements of BP and mortality according to antihypertensive treatment. The mean age of patients was 67.2±14.1 years and the prevalence of diabetes was 19.5%. During follow-up (26.5±10.5 months), 977 deaths were recorded. In the whole cohort, BP was not associated with mortality. After grouping the patients according to antihypertensive treatment, the analysis showed that only in patients who did not take antihypertensive medications (1613) was there an inverse relationship between postdialysis systolic BP and mortality. These patients differed from the others in BP, dialysis vintage, prevalence of diabetes, and type of dialysis technique. This study suggests that with respect to the relationship of BP with mortality, dialysis patients are not a homogenous population. Differences in demographic characteristics and in dialysis technique may therefore explain the reported variability of previous results.

Prevalence of hypertension in a large cohort of Italian hemodialysis patients: results of a cross-sectional study.

BACKGROUND: Hypertension is very common among patients receiving hemodialysis; however, little is known about its prevalence and control following the publication of the Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations. METHODS: This was a multicenter, observational, prospective, cross-sectional study aimed at evaluating the prevalence of hypertension and its awareness in a large sample of hemodialysis patients in Italy, and assessing possible relationships between high blood pressure (BP) values and traditional and nontraditional cardiovascular risk factors. Predialysis hypertension was defined as systolic BP (SBP) / diastolic BP (DBP) =140/90 mm Hg, and postdialysis hypertension as SBP/DBP =130/80 mm Hg or the use of antihypertensive medications. RESULTS: We collected data for 4,022 patients (men/women 2,478/1,544, mean age 67.14 ± 14.08 years) from 77 dialysis centers. Of these, 2,832 patients (70.3%) were defined as having predialysis hypertension. At logistic regression analysis, diabetes, months on dialysis, serum albumin levels and treatment with erythropoiesis-stimulating agent (ESA) were independent factors predicting predialysis hypertension. Antihypertensive agents were used in 57.7% of the patients, leading to adequate BP control in only 40% of them. Factors independently predicting inadequate BP control were diabetes, ESA therapy, high serum cholesterol and higher Kt/V values. CONCLUSIONS: Hypertension is highly prevalent in this Italian hemodialysis population; achievement of adequate BP control is inadequate. It is unclear whether this may reflect suboptimal diagnosis or treatment of hypertension or, more likely, the allowance of higher predialysis BP values to try to avoid abrupt BP falls during the dialytic session.

Thrombotic microangiopathic nephropathy, pulmonary hypertension and nephromegaly: case report of a patient treated with endothelin receptor antagonist.

The coexistence of thrombotic microangiopathic nephropathy and pulmonary hypertension has only been described in association with malignancy and its treatment. Here we describe a 14-year-old boy with no prior medical history who presented with hypertension, proteinuria and nephromegaly, and then developed progressive pulmonary hypertension. Renal histology showed lesions consistent with glomerulopathy due to thrombotic microangiopathy (TMA). Pulmonary hypertension was controlled by the use of an oral endothelin receptor antagonist (bosentan). Although renal function deteriorated at the onset of pulmonary hypertension, an improvement was observed after the bosentan treatment. Nephromegaly persisted, but current creatinine clearance values are within the normal range. While this case exemplifies how thrombotic microangiopathic nephropathy may be associated with pulmonary hypertension, a therapeutic role of endothelin antagonists is suggested, not only for pulmonary hypertension but also for microangiopathic nephropathy.

Reduced kidney function and outcome in acute ischaemic stroke: relationship to arterial hypertension and diabetes.

BACKGROUND: Stroke is a dangerous long-term complication of kidney failure, yet its occurrence early in disease is poorly characterized. Our aim was to investigate the association of reduced kidney function, hypertension and diabetes with acute ischaemic stroke and the outcome thereof. METHODS: In this prospective cohort study, the association of reduced kidney function, hypertension and diabetes with stroke and 2-year all-cause mortality was investigated. Glomerular filtration rate (eGFR) was estimated by the simplified Modification of Diet in Renal Disease formula in 13 365 consecutive patients (671 with acute ischaemic stroke) admitted to our clinical facility over a 12-month period. RESULTS: Ischaemic stroke, after adjustment for age and gender, was significantly associated with eGFR <60 mL/min/1.73m(2) [odds ratio (OR) 1.53, 95% confidence interval (CI) 1.30-1.81], hypertension (2.77, 95% CI 2.33-3.28) and diabetes (1.30, 95% CI 1.04-1.63). Multivariate analysis of interaction indicated the absence of an additive effect between eGFR, hypertension and diabetes, on the risk of stroke. Age and gender-adjusted survival analysis by Cox regression showed an association of mortality with reduced eGFR alone (HR = 4.29, 95% CI 1.02-19.60). CONCLUSIONS: In patients acutely admitted to hospital, reduced kidney function, hypertension and diabetes are independently associated with ischaemic stroke, but do not exert a synergic effect. After hospital discharge, mortality is strongly associated with reduced eGFR but with neither hypertension nor diabetes.

Kidney function and mortality in different cardiovascular diseases: relationship with age, sex, diabetes and hypertension.

BACKGROUND: The aim of this study was to investigate the association of reduced kidney function, diabetes and arterial hypertension with mortality in cardiovascular disease patients admitted to hospital. METHODS: This was a prospective cohort study. The setting was the reference hospital for the population area. Unselected consecutive patients (n=7,487) admitted to the hospital over 12 months were enrolled. In all subjects, the estimated glomerular filtration rate (eGFR) was determined, and the association of acute and 36-month mortality with kidney function impairment, diabetes and arterial hypertension was assessed. RESULTS: Short-term mortality (314 deaths) was significantly associated with reduced eGFR only in patients with chronic ischemic heart disease. The study of 36-month survival in the whole cohort showed that mortality (918 deaths) was significantly associated with age, male sex and reduced eGFR. The study repeated for the individual CV conditions showed that reduced eGFR was associated with mortality only in chronic ischemic heart disease. No association with sex of patient, diabetes or arterial hypertension was found. CONCLUSIONS: Although the association between reduced kidney function and CV diseases was confirmed, the analysis of survival in the individual conditions shows that only in chronic ischemic disease is mortality associated with reduced eGFR. Any interaction with 2 major predisposing diseases - diabetes and arterial hypertension - has not been shown.

[The DASCO meetings: a contribution of industry to Italian nephrology]. / Gli incontri DASCO: un contributo dell'industria alla formazione dei nefrologi italiani.

Between 1971 and 1977 eight DASCO meetings were held in different cities in Italy. The meetings dealt with the technical aspects of renal dialysis, then in its early days. They were organized as round tables and the proceedings were published timely. Lively discussion among the audience was a characteristic feature. Most of the attendants, who came from all over Italy, later pursued careers in nephrology and held posts in the Italian Society of Nephrology. The meetings contributed to the development of national standards for dialysis and ended in 1977 with the definitive establishment of renal dialysis in Italy.