Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

Lipid peroxidation after acute renal ischemia and reperfusion in rats: the effect of trimetazidine.

Lipid peroxidation is a critical pathway of reactive oxygen species inducing tissue injury in postischemic acute renal failure. In order to evaluate the effect of renal ischemia reperfusion on kidneys, renal tissue malondialdehyde (MDA, nmol/g wet weight) concentration was measured in 29 male Wistar rats subjected to a midline abdominal incision and 60 min occlusion of the left renal artery. A right nephrectomy was performed at the beginning of the ischemic period. The animals were separated in four groups. Groups 1 (n = 7) and 3 (n = 7) underwent 60 min of ischemia and 15 min of reperfusion, respectively. Groups 2 (n = 8) and 4 (n = 7) were subjected to the same procedure but, in addition, they received 2.5 mg/kg TMZ into the tail vein 2 h prior to the left renal artery occlusion. A significant elevation of MDA after 60 min of ischemia (1.43 vs. 2.1, p < 0.001), which was augmented after 15 min of reperfusion (1.4 vs. 3.72, p < 0.001) was observed. Furthermore, there was a significant reduction of renal tissue MDA in ischemic rats treated with TMZ (group 3) (2.1 vs. 1.52, p < 0.001). The maximum reduction of renal tissue MDA was observed in ischemic-reperfused rats (group 4) that had received TMZ (3.72 vs. 1.36, p < 0.001). It is suggested that lipid peroxidation is a critical event in postischemic acute renal failure, and TMZ is a useful protective agent of renal damage from oxygen free radicals.

Renal hemodynamics in hypertensive renal allograft recipients: effects of calcium antagonists and ACE inhibitors.

Hypertension present in more than 50% of successfully renal transplanted patients and its prevalence has slightly increased since the introduction of cyclosporine A. Twenty patients, 9 women and 11 men aged from 30 to 58 years, with stable cadaveric renal allograft function and moderate to severe hypertension, were included in the study. Renal artery graft stenosis causing hypertension were excluded. All patients were given triple drug immunosuppressive treatment with methylprednisolone, azathioprine and cyclosporine A (CsA) and their hypertension was treated with a nifedipine dose of 20 mg twice daily. To evaluate the effect of ACE inhibitors on renal hemodynamics and hypertension, a 4 mg/daily dose of perindopril was added to the above regimen for two months. Effective renal plasma flow (ERPF) decreased from 208 +/- 54 to 168 +/- 61 ml/min and renal vascular resistance (RVR) increased from 75 +/- 12 to 88 +/- 17 mm Hg/ml/min (P < 0.05 and P < 0.01, respectively). Mean blood pressure was significantly (P < 0.001) reduced by the combination of both agents in comparison to the blood pressure control by monotherapy with nifedipine. It is suggested that the combination of both antihypertensive agents was more effective than monotherapy with nifedipine in controlling blood pressure, but less favorable on the renal hemodynamic response in hypertensive renal transplant patients who were maintained on CsA.

Management of moderate to severe hypertension and proteinuria by nifedipine retard and perindopril after renal transplantation.

Clinical studies of treatment with angiotensin converting enzyme (ACE) inhibitors in patients with glomerular disease have shown the clinical efficacy of these agents. Fifteen renal transplant hypertensive and proteinuric patients on triple drug treatment with cyclosporin (CSA), azathioprine and methylprednisolone entered the therapeutic protocol of this study. All patients followed up last year had stable graft function (serum creatinine less than 2 mg/dl). Hypertension was treated by nifedipine retard and occasionally by furosemide. Patients with a renal artery graft stenosis, at least as judged by technetium-scan imaging were excluded. In order to evaluate the possible role of ACE inhibitors on hypertension and proteinuria, perindopril 4 mg/daily was added for two months to the above regimen. Two patients, who showed a reversible deterioration of renal function during treatment and three who did not comply to the therapeutic protocol were excluded. Systolic and diastolic blood pressure as well as 24 h urine protein was found to be significantly (p < 0.01) reduced at the end of the two-month combined treatment with perindopril and nifedipine retard in comparison to the result of monotherapy with nifedipine retard. GFR and ERPF showed no significant difference (NS) between the two modes of treatment. It is suggested that the combined treatment with nifedipine retard and perindopril is more effective than the monotherapy with nifedipine retard in the management of moderate to severe post-transplant hypertension and proteinuria of renal transplant patients.

Renal transplantation in asymptomatic carriers of hepatitis B surface antigen.

The aim of the present study was: (a) to assess the effect of HBsAg on the survival of both renal grafts and patients, and (b) to determine the outcome of HBV chronic infection after renal transplantation. Fourteen patients seropositive for HBsAg but asymptomatic before renal transplantation (group A) were included in the study. The results were compared to those of 14 transplanted patients (group B) seronegative for HBsAg with similar age and immunosuppressive treatment. Four patients received a graft from a living-related donor and 10 patients from a cadaver donor in each group. Eight of 14 patients of group A showed, after renal transplantation, chronic hepatitis, which was not observed in any of the group B patients (p < 0.01). The rate of acute rejection episodes was significantly greater (p < 0.05) in group B than in group A. The graft survival was found to be similar in both groups at the 1st year, but significantly less (p < 0.01) in group B than in group A at the 5th year after transplantation. The survival of patients was found to be significantly less in group A than in group B at the 1st (p < 0.05) and 5th years (p < 0.01) after transplantation. In 2 patients of group A and 1 of group B anti-HCV was found, while HDAg plus anti-HD was found in 1 patient of group B. The HBV-DNA was found in 4 of 8 alive patients of group A.(ABSTRACT TRUNCATED AT 250 WORDS)

Influenza vaccination on renal transplant patients is safe and serologically effective.

Since immunosuppressed patients are at higher risk of serious influenza virus infection than healthy subjects, we decided to study the serological effectiveness of influenza vaccination on renal transplant patients, despite the theoretical aspect that such treatment could induce glomerular lesions through an immunological process. Forty transplant patients aged from 20 to 50 years with well functioning renal graft and no febrile episode were studied. Blood samples were collected before the intramuscular injection of 0.5 ml of multivalent influenza vaccine (PASTEUR MERIEUX SERUM VACCINS), at one and at two months after the vaccination. Before vaccination, the antibody titers to influenza virus ranged from 0 to 1/20 and after vaccination from 1/20 to 1/320. One month after vaccination 17/40 (42.5%), 18/31 (58%) and 16/33 (48%) patients showed a four-fold or greater increase of serum influenza antibody titers to antigens A/H3N2, A/H1N1 and B, respectively. A similar response at two months in relation to the first month response rate after vaccination was found in 15/17 (88%), 18/18 (100%), and 15/16 (93%) of transplant patients for the above mentioned three antigens. Side-effects were observed in two of the studied patients. Serum creatinine and urine protein were not changed. Also acute graft rejection episodes were not observed. It is suggested that influenza vaccination is safe and serologically effective on renal transplant patients.

Treatment of urinary tract infections with ciprofloxacin after renal transplantation.

As urinary tract infections in immunosuppressed renal transplant patients present a major therapeutic problem for clinicians in charge of renal units, the efficacy of the antibiotic ciprofloxacin in such cases was tested in this study. Twenty-six patients, 16 women and 10 men, aged 20 to 56 years, who developed urinary tract infection (UTI) from 6 months to 10 years after renal transplantation were included in the study. Of these patients, 20 (77%) showed cystitis and/or prostatitis and 6 (23%) clinical symptomatology of acute or recurrent pyelonephritis. Patients with obstructive uropathy were excluded. Urine culture was positive for E. coli in 16/26 patients (61.5%) and for proteus mirabilis, klebsiella, staphylococcus aureus in 10/26 (38.5%). All patients were given ciprofloxacin 250 mg x 2 daily for 10 days and the results of the treatment were compared to those of 60 nontransplant patients (controls) with UTI. Fourteen patients (54%) were completely cured and 10(38%) showed improvement, while the respective results in the controls were 68% (41/60) and 28%. Relapses occurred in two patients, one in each group. Serious side effects were not observed. It is concluded that ciprofloxacin is an effective and safe drug for the treatment of UTI in renal transplant patients.

Psychiatric and psychosocial status of elderly patients undergoing dialysis.

We investigated the psychiatric and psychosocial status of 31 elderly (age > 65 years) end-stage renal disease patients undergoing hemodialysis (HD) (17 patients) and continuous ambulatory peritoneal dialysis (CAPD) (14 patients). There was no difference between the two groups in terms of age (67.3 +/- 2.3 and 68.5 +/- 4.3 in HD and CAPD groups, respectively), duration of dialysis treatment, and biochemical profile. The psychiatric and psychosocial status of the patients was assessed using the standardized psychiatric interview (SPI), Hamilton's depression scale (HRS-D), and a questionnaire for the evaluation of the psychosocial impact of the method of treatment. Sixteen of 31 patients presented with psychiatric morbidity (9 mild, 5 moderate, 2 severe). However, there was no significant relationship between psychiatric morbidity and method of dialysis (HD or CAPD). The mean values of SPI (21.47 +/- 16.38 and 17.14 +/- 13) and HRS-D (20.91 +/- 17.33 and 15.41 +/- 13.13) scores for the HD and CAPD groups, respectively, did not differ significantly. The analysis of the results of the questionnaire regarding the impact of the method of treatment on psychosocial status indicated that the HD patients felt that their lives were more dependent on factors that they could not influence (i.e., the dialysis equipment, etc.). Our findings suggest that the psychiatric status of elderly patients undergoing chronic dialysis treatment is not affected by the method of treatment, a factor that should be taken into consideration when deciding the proper dialysis treatment for these patients.

Effect of calcium antagonist on renal graft function.

Studies in experimental models of renal ischemia have shown that calcium antagonists are effective in the protection from the ischemic insult. Thirty-five patients who received a kidney graft over a 2-year period (nifedipine group) were compared with 35 consecutive transplanted patients (control group). The two groups were compatible with regard to age, sex, duration of hemodialysis, graft matching, and total number of blood transfusions. The patients in the nifedipine group were given 0.2 mg nifedipine (10% solution) through the renal artery immediately after revascularization, and also nifedipine per os during all the study periods. Adequate diuresis (1 mL/min) was obtained in 14.5 +/- 37.2 and 43.9 +/- 46.8 h after transplantation in the nifedipine and control groups respectively (p < 0.01). The frequency of acute tubular dysfunction and the mean serum creatinine concentrations were found to be higher in the control group. Fractional excretion of sodium was not found to be different in the two groups on the first day, but it was significantly lower by the first week after transplantation in the nifedipine group (p < 0.05). Acute rejection episodes were found to be more frequent in the control group during the first 6 months after transplantation (p < 0.05). It is suggested that nifedipine is effective in the protection of renal function after transplantation.

Reduction of CyA nephrotoxicity by nifedipine during and after experimental in situ renal preservation.

In order to evaluate the role of nifedipine in the nephrotoxic effect induced by both ischemia and CyA, 18 healthy mongrel dogs were used. The kidneys were exposed and subjected to 1 h of ischemia by clamping both renal vessels. To the renal artery of the first group of kidneys (n = 9), 300 mL of cold Euro-Collins solution, in which nifedipine (Bay a 1040-10 mg) was diluted, was infused for 15 min (nifedipine group), while 300 mL of cold Euro-Collins solution plus 10 mg of placebo (Bay a 1040-placebo) was infused to the renal artery of the second group (n = 9) of kidneys (placebo group). Venous drainage was effected through a plastic cannula. All animals received through a nasogastric catheter 20 mg/kg cyclosporine A at the beginning of the ischemia. The 1 h of ischemia was divided in a 15-min period of cold ischemia and 45-min of warm ischemia, at the end of which the clamps were removed. During the 2 h (30 min x 4) after reperfusion, 10 mg of nifedipine and placebo was administered additionally by a peripheral vein to the nifedipine and the placebo group, respectively. Then the kidneys were removed for histological study. Urine volume and creatinine and urea clearances of the nifedipine group were significantly higher than the placebo group (p < 0.001) while TxB2 levels were higher in the placebo group in all studied periods (p < 0.001). Urine sodium, FENa, osmolar clearance, and LDH values were significantly different (p < 0.01), but the urine potassium concentration was not different in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute cyclosporin A renal dysfunction in dogs reversed by calcium antagonists and antiplatelet agents.

The aim of this study was to assess the effect of nifedipine and piracetam alone or in combination in the protection of renal function and morphology after cyclosporin A (CyA) administration. Thirty healthy mongrel dogs with a mean body weight of 15 kg were sacrificed. Six animals (group C) were given CyA 20 mg/kg body weight per os, while the remaining groups (8 animals each) were given concomitantly 20 mg nifedipine (group CN) or 4 g of piracetam (group CP), or both drugs in combination (group CNP). After 5 days of drug administration the animals were anesthetized, both kidneys were exposed, and functional tests were performed. Then the kidneys were removed for histological study. The mean plasma CyA levels in the four groups were 1765 +/- 685 ng/mL, 1300 +/- 324 ng/mL, 1116 +/- 491 ng/mL and 1600 +/- 290 ng/mL, respectively. Urine volume, creatinine, urea, and osmolar clearances were significantly higher in the groups CN, CP, and CNP compared to the control group C (p < 0.01). Urine sodium concentration was significantly higher (p < 0.05 or p < 0.01) in nifedipine groups than in the other two groups of animals, while the fractional excretion of sodium (FENa%) was significantly higher (p < 0.01) in all treated groups compared to controls. Plasma thromboxane-B2 levels were significantly reduced by each drug alone or in combination (p < 0.01). Morphological lesions, similar in all groups, did not correlate with the functional improvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Influenza vaccination in chronic hemodialysis patients. The effect of zinc supplementation.

Since influenza increases the mortality of chronically ill patients we decided to study the effectiveness of influenza vaccination in hemodialysis (HD) patients. Nineteen HD patients aged from 20 to 60 years, on unrestricted diet and with no febrile episode, were studied. Blood samples were collected before the intramuscular injection of 0.5 mL multivalent influenza vaccine (Inflexal Berna) and every 2 weeks thereafter. At the end of 4th week a second vaccination was done and a dosage of 200 mg of zinc acetate (60 mg elemental zinc) was given daily to each patient for at least 4 weeks. Before vaccination the antibody titers to influenza virus ranged from 1:10 to 1:80 and after vaccination from 1:20 to 1:640. Four weeks after vaccination 6/19 (31.5%), 8/19 (42%), and 10/19 (52.5%) patients showed a fourfold or greater increase at serum antibody titers to antigens A/Singapore, A/Sichuan, and B/Beijing, respectively. The zinc supplementation after the second vaccination induced a similar increase of serum antibody titers to the A/Singapore but some even greater increase of the antibody titers to the A/Sichuan and B/Beijing. Serum immunoglobulins and complement components C3/C4 were not changed during this study. It is suggested that about 50% of uremic patients respond to the influenza vaccination and that zinc treatment does not increase this responsiveness.

A pilot study of piracetam in cuprophan hemodialysis.

Twelve patients, 8 male and 4 female, aged from 26 to 70 years were studied. They were on hemodialysis (HD) 4 h three times weekly with cuprophan hollow fiber dialyzers (Gambro 120M) and dialysate containing 35 mEq/L of acetate. The study compares two random HD sessions on each patient. Sixty minutes prior to one random session a placebo was administered orally, and prior to another random session piracetam was given at a dose of 8 g. Heparin dosage was not reduced during HD using QB 200 ml, QD 500 ml, and no ultrafiltration. Blood samples for leukocyte and platelet counts, serum C3, arterial paO2 and paCO2, thromboxane-B2 (TxB2), and beta-thromboglobulin (beta-TG) were taken from the arterial line before and at 15, 60, and 240 min during HD. Leukopenia at 15 min of HD was found to be less severe (p less than 0.01) in the piracetam study than in the placebo, whereas platelet count did not change. Serum C3 was slightly increased in both studies. Arterial oxygen was preserved close to the initial levels by piracetam (91.66 mm Hg versus 81.08, p less than 0.01 at 60 min, and 93.08 versus 80.17 mm Hg, p less than 0.01 at 240 min of HD sessions) but paCO2 did not change significantly. TxB2 increased less with piracetam in comparison to placebo (p less than 0.01 or p less than 0.001), but beta-TG was reduced significantly by piracetam at any time during HD (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)