[The origins of the Renal Immunopathology Group of the Italian Society of Nephrology].

This article describes the birth and development of the Renal Immunopathology Group of the Italian Society of Nephrology. It collects the stories of nephrologists and pathologists who, since the early Seventies up to the first decade of this century, devoted their professional lives to the study of renal pathology with a strong personal involvement, characterized by enthusiasm, commitment, ability, strong spirit of cooperation, and friendship. All this enabled the Group to: propose the criteria for a standardized histological and immuno-histological examination of renal biopsies and reporting; produce several multicenter studies, whose results were also published in important international journals; to set up a national registry of renal biopsies; to organize a number of courses, some of which were associated with the publication of monographs, on various renal diseases. This article also traces the history of renal pathology in Italy from the second half of the Sixties - when young Italian nephrologists and pathologists from different institutions moved to French laboratories to learn new techniques to apply to renal biopsies - up to the present days. It also shows us how Italian renal pathology has been an essential tool for the development of the nephrological clinical practice and the advancement of scientific research.

Assessment of kidney volume in polycystic kidney disease using magnetic resonance imaging without contrast medium.

BACKGROUND/AIMS: Total renal volume (TRV) is an important index to evaluate the progression of autosomal-dominant polycystic kidney disease (ADPKD). TRV has been assessed by manually tracing renal contours from CT or MR scans, often employing contrast medium (CM). We developed a fast and nearly automated technique based on the analysis of MR images acquired without CM injection for TRV quantification. METHODS: 30 ADPKD patients underwent MRI. After the selection of one point inside each kidney for the entire volume, the automatic extraction of kidney contours was performed on each acquired slice; the segmentation procedure was based on region growing and on the application of morphological operators and curvature-based motion. The area inside each contour was calculated and TRV was derived. Volume measurements were validated by comparison with measurements obtained by stereology. RESULTS: TRV estimated in patients was 768 ± 545 ml (range 161-3,111 ml). The automatic measurements were in excellent correlation with the manual ones (r = 0.99, y = x - 0.7), with a small bias and narrow limits of agreement in both absolute (-5 ± 37 ml) and percentage (-0.6 ± 9.6%) terms. CONCLUSION: This preliminary study showed the feasibility of a fast and nearly automated method for determining TRV; importantly it does not require the use of potentially nephrotoxic CM.

[Solid tumors and paraneoplastic glomerulonephritis]. / Le glomerulonefriti paraneoplastiche nelle neoplasie solidel.

Neoplastic diseases can cause renal damage directly or indirectly. Also their treatment can provoke renal damage. The incidence and prevalence of paraneoplastic glomerulonephritis, especially associated with solid tumors, are a matter of debate and the causal link between cancer and glomerular diseases remains unclear. Paraneoplastic glomerulonephritis is a rare occurrence, with a slightly higher prevalence in the elderly. The most common cancer types associated with paraneoplastic glomerular disease are carcinoma of the lung and the gastrointestinal tract. Membranous nephropathy is the most frequent but not the only presentation of paraneoplastic glomerulonephritis. Patients with unexplained nephrotic syndrome, especially if older than 60 years, with membranous nephropathy and/or with their own risk factors for malignancies should be screened for occult cancer at diagnosis and be followed up carefully after the diagnosis. The primary treatment of paraneoplastic glomerulopathy must be aimed at the cancer and immunosuppressive treatment must obviously be avoided.

The effect of on-line high-flux hemofiltration versus low-flux hemodialysis on mortality in chronic kidney failure: a small randomized controlled trial.

BACKGROUND: Given the paucity of prospective randomized controlled trials assessing comparative performances of different dialysis techniques, we compared on-line high-flux hemofiltration (HF) with ultrapure low-flux hemodialysis (HD), assessing survival and morbidity in patients with end-stage renal disease (ESRD). STUDY DESIGN: An investigator-driven, prospective, multicenter, 3-year-follow-up, centrally randomized study with no blinding and based on the intention-to-treat principle. SETTING & PARTICIPANTS: Prevalent patients with ESRD (age, 16 to 80 years; vintage > 6 months) receiving renal replacement therapy at 20 Italian dialysis centers. INTERVENTIONS: Patients were centrally randomly assigned to HD (n = 32) or HF (n = 32). OUTCOMES & MEASUREMENTS: All-cause mortality, hospitalization rate for any cause, prevalence of dialysis hypotension, standard biochemical indexes, and nutritional status. Analyses were performed using the multivariate analysis of variance and Cox proportional hazard method. RESULTS: There was significant improvement in survival with HF compared with HD (78%, HF versus 57%, HD) at 3 years of follow-up after allowing for the effects of age (P = 0.05). End-of-treatment Kt/V was significantly higher with HD (1.42 +/- 0.06 versus 1.07 +/- 0.06 with HF), whereas beta(2)-microglobulin levels remained constant in HD patients (33.90 +/- 2.94 mg/dL at baseline and 36.90 +/- 5.06 mg/dL at 3 years), but decreased significantly in HF patients (30.02 +/- 3.54 mg/dL at baseline versus 23.9 +/- 1.77 mg/dL; P < 0.05). The number of hospitalization events for each patient was not significantly different (2.36 +/- 0.41 versus 1.94 +/- 0.33 events), whereas length of stay proved to be significantly shorter in HF patients compared with HD patients (P < 0.001). End-of-treatment body mass index decreased in HD patients, but increased in HF patients. Throughout the study period, the difference in trends of intradialytic acute hypotension was statistically significant, with a clear decrease in HF (P = 0.03). LIMITATIONS: This is a small preliminary intervention study with a high dropout rate and problematic generalizability. CONCLUSION: On-line HF may improve survival independent of Kt/V in patients with ESRD, with a significant decrease in plasma beta(2)-microglobulin levels and increased body mass index. A larger study is required to confirm these results.

Patients with complex arrhythmias during and after haemodialysis suffer from different regimens of potassium removal.

BACKGROUND: Although sudden death is one of the most frequent causes of death in haemodialysis (HD) patients, the problem of cardiac arrhythmias, the major cause of these outcomes, has been little discussed. METHODS: In 30 arrhythmia-prone HD patients, we compared the arrhythmogenic effects of two dialysis techniques differing in dialysate potassium (K) content. Each patient underwent Acetate-Free Biofiltration sessions with constant (2.5 mEq/l) K (AFB) and sessions with decreasing intra-HD K (AFBK), according to a crossover single blind design. Holter ECG recording and plasma electrolyte measurements were performed during each dialysis session. RESULTS: There was a tendency in the whole sample for arrhythmia appearance in AFBK to be reduced as compared to AFB throughout the 24 hr period, although this reduction was not statistically significant. In the subset of patients sensitive to dialysis as far as arrhythmia onset is concerned, AFBK was systematically less arrhythmogenic than AFB (P < 0.01). The highest difference was achieved around the 14th hour after the end of dialysis, when the premature ventricular contractions in AFB were 3.9 times higher than in AFBK (P < 0.05). Potassium kinetics differed between the two procedures. At the first hour of treatment, the plasma K concentration was lower in AFB than in AFBK (3.67 +/- 0.15 mEq/l in AFB vs 4.06 +/- 0.13 mEq/l in AFBK, P = 0.05). CONCLUSIONS: Our study shows a greater arrhythmogenic activity with the use of a constant and relatively low K concentration as compared to decreasing K profiling in dialysis-sensitive arrhythmic patients. Smoother K removal may well engender a kind of protective effect.

Agalsidase therapy in patients with Fabry disease on renal replacement therapy: a nationwide study in Italy.

BACKGROUND: In Fabry disease, end-stage renal disease (ESRD) and severe neurologic and cardiac complications represent the leading causes of late morbidity and mortality. A comprehensive Italian nationwide survey study was conducted to explore changes in cardiac status and renal allograft function in Fabry patients on renal replacement therapy (RRT) and enzyme replacement therapy (ERT). METHODS: This study was designed as a cross-sectional survey study with prospective follow-up. Of the 34 patients identified via searches in registries, 31 males and 2 females who received RRT and ERT (agalsidase beta in 30 patients, agalsidase alpha in 3) were included. Left ventricular mass index (LVMI), interventricular septal thickness at end diastole (IVSD), left ventricular posterior wall thickness (LVPWT) and renal allograft function were assessed at ERT baseline and subsequently at yearly intervals. RESULTS: The patients in the dialysis and transplant groups had been started on dialysis at age 42.0 and 37.1 years (mean), respectively, and patients in the transplant group received their renal allograft at age 39.8 years (mean). The mean age at the start of ERT was similar, 44.1 and 44.6 years, respectively. The mean RRT follow-up was 61.1 and 110.6 months for dialysis and transplant patients, respectively, whereas the ERT duration was 45.1 and 48.4 months, respectively. Cardiac parameters increased in dialysis patients. In transplant patients, mean LVMI seemed to plateau during agalsidase therapy at a lower level as compared to baseline. Decline in renal allograft function was relatively mild (-1.92 ml/min/year). Agalsidase therapy was well tolerated. Serious ERT-unrelated events occurred more often in the dialysis group. CONCLUSIONS: Kidney transplantation should be the standard of care for Fabry patients progressing towards ESRD. Transplanted Fabry patients on ERT may do better than patients remaining on maintenance dialysis. Larger, controlled studies in Fabry patients with ESRD will have to demonstrate if ERT is able to change the trajectory of cardiac disease and can preserve graft renal function.

Predictors of outcome in Henoch-Schönlein nephritis in children and adults.

BACKGROUND: Factors predictive of renal outcome were investigated in 219 cases of biopsy-proven Henoch-Schönlein purpura nephritis (HSPN); 83 children and 136 adults enrolled in a national study were followed up for up to 27 years (median, 4.5 years). METHODS: The criterion for defining disease progression was time elapsed until doubling of baseline creatinine level and until dialysis therapy. Age, sex, data at onset (renal function, proteinuria, hematuria, hypertension, and crescents), and data during follow-up (proteinuria and therapy) were tested as covariates. RESULTS: Multivariate Cox regression analysis indicated the following parameters as independent prognostic predictors: age (adults versus children, relative risk, 3.57; 95% confidence interval, 1.18 to 10.79; P = 0.024 for creatinine level doubling; relative risk, 14.89; 95% confidence interval, 1.72 to 129.07; P = 0.014 for dialysis therapy), sex (females versus males, relative risk, 5.71; 95% confidence interval, 1.67 to 19.55; P = 0.006 for creatinine level doubling; relative risk, 26.03; 95% confidence interval, 2.64 to 256.73; P = 0.005 for dialysis therapy), and mean proteinuria during follow-up (for each 1 g/d of protein increase, relative risk, 1.77; 95% confidence interval, 1.35 to 2.32; P < 0.001 for creatinine level doubling; relative risk, 1.73; 95% confidence interval, 1.18 to 2.52; P = 0.005 for dialysis therapy). Information for mean proteinuria levels during follow-up increased the sensitivity at logistic regression to 62.5%, with dialysis therapy as the end point. No data detected at diagnosis, including renal function impairment, proteinuria, hypertension, and crescentic nephritis (involving > 50% of glomeruli in only 2.6%), were significantly related to functional decline at multivariate Cox. CONCLUSION: This analysis indicates that, even more than when decreased renal function, severe proteinuria, hypertension, or crescents are present at onset, the risk for progression of HSPN (greater in adults and females) was associated with increasing mean proteinuria levels during follow-up.

Cardiac response to hemodialysis with different cardiovascular tolerance: heart rate variability and QT interval analysis.

A therapy-specific worsening of cardiovascular stability during bicarbonate dialysis (BD) with respect to acetate-free biofiltration (AFB) have been previously reported. We further investigated the impact of the 2 therapies on electrocardiographic parameters in order to gain novel insight into the cardiac responses. Holter ECG acquired during hypotension-free sessions (12 BD + 12 AFB) were retrospectively analyzed. R-R intervals were extracted from ECG recordings. An autoregressive spectral technique was used to compute low- and high-frequency (LF and HF) components of heart rate variability (HRV). QT interval duration was measured with a computer-assisted technique and corrected for HR. In BD the LF component of HRV after an initial increase was slowly depressed with respect to AFB (p < 0.05). QT duration showed a significant (p < 0.01) hemodialysis-induced reduction. QT shortening was more pronounced (p < 0.05) in BD than in AFB (-31 vs. -10 ms), even after correction for HR (p < 0.05). Cardiac electrical activity is significantly affected by the hemodialysis technique. The decrease in the LF component of HRV and the QT shortening are coherent with the worse cardiovascular tolerance observed in BD and with the hypothesis of an enhanced production of endogenous nitric oxide.

Enzyme replacement therapy in Fabry's disease: recent advances and clinical applications.

Fabry's disease is a rare X-linked recessive disorder resulting from deficient lysosomal enzyme, alpha-galactosidase A (alpha-Gal A) activity. The deficiency leads to progressive glycosphingolipid globotriaosylceramide (Gb3) accumulation in fluids and tissues, including vascular endothelium, connective tissue, kidney, heart, brain and peripheral nerves. Classic Fabry's disease in hemizygous males has high morbidity and mortality due to end-stage renal disease (ESRD) requiring hemodialysis (HD) or kidney transplantation, myocardial involvement and central nervous system (CNS) complications. Most heterozygous females can also suffer from this severe disease deterioration. Until recently, Fabry's disease management consisted of symptomatic and palliative treatment, but this has changed with the availability of the recombinant human alpha-Gal A enzyme, agalsidase. Two different agalsidase formulations have been obtained: one from human fibroblast (agalsidase alpha), and one from Chinese hamster ovary (CHO) cells (agalsidase beta). Both preparations underwent clinical trials that documented the feasibility, efficacy and safety of the treatment. In addition, several clinical observations have proved that agalsidase reduces the storage of the substrate from several organs and tissues and, consequently, improves signs and symptoms of Fabry's disease. Additional clinical experiences have confirmed the initial clinical trial results, but further studies are needed to evaluate the long-term outcome of enzyme replacement therapy (ERT). We reviewed the clinical trial observations, as well as subsequent clinical experiences with ERT in patients with Fabry's disease.

Calcium profiling in hemodiafiltration: a new way to reduce the calcium overload risk without compromising cardiovascular stability.

BACKGROUND: Low and high dialysate calcium (Ca²âº) content may have positive and harmful effects depending on the considered pathological aspect: hemodynamic instability, cardiac arrhythmias, parathormone release, adynamic bone disease, cardio-vascular calcifications. We hypothesized that a time-profiled Ca²âº concentration would keep the cardiovascular advantages of high Ca²âº but would reduce the risk of calcium overload. METHODS: A prospective, multicenter study using a particular hemodiafiltration technique that allows the profiling of electrolytes was designed. Patients (n = 22) underwent randomly a 3-week dialysis session with low and high constant dialysate Ca²âº (Ld(Ca,), 1.25 mM and Hd(Ca,), 2 mM) and profiled Ca²âº (Pd(Ca)), respectively. Plasma and spent dialysate Ca²âº, systolic and diastolic arterial pressure (SAP, DAP) and QT interval corrected for heart rate (QTc) were analyzed. RESULTS: Plasma Ca²âº concentration decreased in Ld(Ca), whereas it increased in Hd(Ca) and to a lesser extent, in Pd(Ca). Total amount of Ca²âº given to the patient in Pd(Ca) (15.5 ± 1.0 mmol) was higher than in Ld(Ca) (4.3 ± 1.6 mmol) but lower than in Hd(Ca) (21.9 ± 3.3 mmol). SAP and DAP decreased in Ld(Ca), whereas it was almost constant in both Hd(Ca) and Pd(Ca·). QTc significantly increased, up to critical values (>460 msec), only during Ld(Ca·). CONCLUSIONS: Pd(Ca) seems to retain the advantages of high Ca²âº in terms of hemodynamic stability and modification of QTc while reducing the excessive positive calcium balance typical of dialysis with high Ca²âº content.

[Parainfectious glomerulonephritis]. / Le glomerulonefriti parainfettive.

Acute postinfectious glomerulonephritis is uncommon in adults especially in developed countries. Streptococcus is the most frequently identified infectious agent in younger patients and staphylococcus in older patients. The most common sites of infection are the upper respiratory tract and skin in younger patients and skin followed by respiratory and urinary tract in older patients. The prognosis is often poor in older patients and in those with an immunocompromised background including diabetes, malignancy, alcoholism, AIDS, or intravenous drug use. Outcome does not seem to correlate with steroid treatment.

Isolated microalbuminuria as the first clinical presentation of Fabry disease in an adult heterozygous female.

Fabry disease (FD) is a rare X-linked disorder characterized by low or absent activity of the lysosomal enzyme α-glycosidase-A that leads to progressive accumulation of glycosphingolipids in different organs and tissues. Clinical manifestations vary from classic to atypical forms characterized by one prevalent organ involvement, and a renal variant has been described in men but not in women. However, little is known about renal manifestation in females affected by FD. We herein report a case of a 22-year-old female with isolated and persistent microalbuminuria as the only sign of FD. In light of the importance of early recognition and treatment of FD organ damage, this case should call for future studies to determine how to assess organ damage, investigate the existence of a 'renal variant' in FD female patients and determine when best to start enzyme replacement therapy (ERT).

Prevention of dialysis hypotension episodes using fuzzy logic control system.

BACKGROUND: Automatic systems for stabilizing blood pressure (BP) during dialysis are few and only control those variables indirectly related to BP. Due to complex BP regulation under dynamic dialysis conditions, BP itself appears to be the most consistent input parameter for a device addressed to preventing dialysis hypotension (DH). METHODS: An automatic system (ABPS, automatic blood pressure stabilization) for BP control by fluid removal feedback regulation is implemented on a dialysis machine (Dialog Advanced, Braun). A fuzzy logic (FL) control runs in the system, using instantaneous BP as the input variable governing the ultrafiltration rate (UFR) according to the BP trend. The system is user-friendly and just requires the input of two data: critical BP (individually defined as the possible level of DH risk) and the highest UFR applicable (percentage of the mean UFR). We evaluated this system's capacity to prevent DH in 55 RDT hypotension-prone patients. Sessions with (treatment A) and without (treatment B) ABPS were alternated one-by-one for 30 dialysis sessions per patient (674 with ABPS vs 698 without). RESULTS: Despite comparable treatment times and UF volumes, severe DH appeared in 8.3% of sessions in treatment A vs 13.8% in treatment B (-39%, P=0.01). Mild DH fell non-significantly (-12.3%). There was a similar percentage of sessions in which the planned body weight loss was not achieved and dialysis time was prolonged. CONCLUSIONS: In conclusion, FL may be suited to interpreting and controlling the trend of a determined multi-variable parameter like BP. The medical knowledge of the patient and the consequent updating of input parameters depending on the patient's clinical conditions seem to be the main factors for obtaining optimal results.

Enzyme replacement therapy with agalsidase beta in kidney transplant patients with Fabry disease: a pilot study.

BACKGROUND: We sought to assess the safety and efficacy of enzyme replacement therapy (ERT) with recombinant human-alpha-galactosidase A (rh-alpha-Gal A) in kidney transplant recipients with Fabry disease, a previously unstudied population. METHODS: Three male kidney transplant recipients with biochemically, genetically, and histologically confirmed Fabry disease and documented Fabry myocardiopathy received the rh-alpha-Gal A, agalsidase beta, 1 mg/kg of body weight every 2 weeks by intravenous infusion and were monitored biochemically, clinically, and electrocardiographically and echocardiographically for 18 months. RESULTS: Patients showed biochemical, clinical/functional, and morphologic response to ERT. Plasma globotriaosylceramide decreased 23% to 50%. Extremity pain resolved within 2 months in the patient with this manifestation. On echocardiography, left ventricular mass, end diastolic diameter (EDD), and cardiac contractility, shown by ejection fraction (EF), improved in 2 of the 3 patients receiving essentially all planned infusions. EDD and EF remained basically stable, but cardiac morphologic abnormalities progressed in the other patient, who had a 5-month interruption in ERT after the initial month. Mild mitral insufficiency persisted in all patients, as did atrial fibrillation in the affected individual. After a combined total of 116 infusions, no treatment-related adverse event, intolerance, or seroconversion was seen. Renal function remained stable and the immunosuppression regimen unchanged in all patients. CONCLUSION: Our pilot study provides preliminary evidence that ERT with agalsidase beta, 1 mg/kg every 2 weeks, is safe and often effective against extra-renal manifestations in kidney transplant patients with Fabry disease. Studies with longer courses of this and higher doses of ERT are merited in this population.

Model-based study of the effects of the hemodialysis technique on the compensatory response to hypovolemia.

BACKGROUND: Hemodialysis technique (dialysate composition, filter, convection/diffusion ratio, etc.) can have an impact on the patient's tendency to acute hypotension. We have examined the hypothesis that the dialysis technique affects the hypotension risk by altering the cardiovascular compensatory response to hemodialysis-induced hypovolemia. METHODS: Twelve hypotension-prone subjects were studied during six sessions of conventional bicarbonate dialysis (BD) and six sessions of acetate-free biofiltration (AFB). Blood volume (BV) control system was used in AFB to provide a BV change equivalent to the BV change observed in BD. The efficacy of reflex compensatory mechanisms was assessed by a model-based computer analysis of the BD and AFB sessions. RESULTS: BD sessions were complicated by hypotension more frequently than the AFB ones (34/66 BD vs. 18/66 AFB). Hypotension arose about 60 minutes earlier in BD (123 +/- 41 minutes in BD vs. 183 +/- 25 minutes in AFB, P < 0.01), and after a smaller BV reduction (hypotension BV 7.9%+/- 2.0% in BD vs. 10.9%+/- 2.6% in AFB, P < 0.05). Model-based computer analysis of the sessions without hypotension revealed differences in peripheral resistance adaptation (9%+/- 9% BD vs. 19%+/- 7% AFB, P < 0.05) as well as in the stroke volume reduction (19%+/- 8% BD vs. 10%+/- 8% AFB, P < 0.001). Model analysis of sessions with hypotension indicated that compensatory mechanisms were almost inoperative in BD, whereas a residual capacity to control peripheral resistance and cardiac contractility was present in AFB. Model simulations demonstrated that hypotension occurred later in AFB since the residual compensatory capacity in AFB was able to sustain the arterial pressure for larger BV reductions (8.3% BD vs. 11.2% AFB). CONCLUSION: The increased risk of acute hypotension in BD compared to AFB is caused by a therapy-induced inhibition of reflex compensatory response to hypovolemia.