Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness.

H+-ATPases are ubiquitous in nature; V-ATPases pump protons against an electrochemical gradient, whereas F-ATPases reverse the process, synthesizing ATP. We demonstrate here that mutations in ATP6B1, encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis. Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac. Our data, together with the known requirement for active proton secretion to maintain proper endolymph pH, implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function. ATP6B1 is the first member of the H+-ATPase gene family in which mutations are shown to cause human disease.

Henoch-Schönlein nephritis: a nationwide study.

BACKGROUND/AIM: The aim of this retrospective study was to evaluate the presentation, clinical and pathological manifestations and outcome of the Henoch-Schönlein purpura (HSP) nephritis in children. METHODS: Clinical and laboratory data of 443 children with HSP nephritis aged between 3 and 16 years from 16 pediatric nephrology reference centers were analyzed retrospectively. The biopsy findings were graded according to the classification developed by the International Study of Kidney Disease in Children (ISKDC). RESULTS: Renal biopsy was performed in 179 of the patients with HSP nephritis. The most common presenting clinical finding in patients who were biopsied was nephrotic range proteinuria (25%) which was followed by nephritic-nephrotic syndrome (23.5%). The biopsy findings according to the ISKDC were as follows: class I: 8.3%; II: 44.1%; III: 36.3%; IV: 6.7%; V: 3.3%; VI: 1.1%. All of the patients who developed end-stage renal disease had nephritic-nephrotic syndrome at presentation. Of 443 patients, 87.2% had a favorable outcome and 12.8% had an unfavorable outcome. The overall percentage of children who developed end-stage renal disease at follow-up was 1.1%. Logistic regression analysis did not show any association of initial symptoms and histology with outcome. CONCLUSION: In the presented cohort, the presence of crescents in the first biopsy or presenting clinical findings did not seem to predict the outcome of HSP nephritis in children. We conclude that children with HSP nephritis even with isolated microscopic hematuria and/or mild proteinuria should be followed closely.

The effects of dialyzer reuse on plasma antioxidative mechanisms in patients on regular hemodialysis treatment.

The effects of antioxidative mechanism are known to be reduced in patients on regular hemodialysis treatment (RHT). The data about the effects of reuse on antioxidative mechanisms are limited. Twelve patients on RHT (age range: 16-50 years) were included in the study. The basal and after 4 months of dialyzer reuse period, plasma antioxidant activity (AOA), myeloperoxidase (MPO) activity, ceruloplasmin (Cp), copper (Cu), transferrin (TF), and sulphydryl group (SH) levels were detected. The basal plasma AOA (110.92 +/- 17.19 microliters), TF (1.23 +/- 0.23 g/l), and SH (307.11 +/- 51.81 mumol/l) levels were lower than the levels of the control subjects (73.75 +/- 9.07 microliters, 2.38 +/- 0.25 g/l, 690.59 +/- 84.18 mumol/l) (p < .001). The basal Cp (0.47 +/- 0.08 g/l) and MPO activity (86.31 +/- 9.57 U/l) levels were higher than the levels of the control subjects (0.34 +/- 0.07 g/l and 65.90 +/- 7.28 U/l) (p < .001). The basal Cu levels (1.19 +/- 0.24 mg/l) were similar to the levels of the control subjects (1.11 +/- 0.13 mg/l) (p > .05). The difference between plasma AOA (83.33 +/- 14.71 microliters), Cp (0.38 +/- 0.08 g/l), and MPO activity (64.43 +/- 10.01 U/l) after the reuse period and the control values were not statistically significant (p > .05). The TF (1.87 +/- 0.15 g/l) levels after the reuse period were significantly lower than the control values (p < .001), although the levels were increased after the reuse period. Our findings may indicate some beneficial effects of hemodialyzer reuse process on plasma antioxidative mechanisms in patients on RHT.

Oxidative stress in hemodialyzed patients and the long-term effects of dialyzer reuse practice.

OBJECTIVES: To investigate the existence of an altered oxidant/ antioxidant balance in patients on regular hemodialysis treatment (RHT) and whether there is any effect of dialyzer reuse on oxidative damage and antioxidative mechanism. DESIGN AND METHODS: Malondialdehyde (MDA) levels and glutathione peroxidase (GPx) activities in both plasma and erythrocytes, plasma selenium (Se) levels, and erythrocyte superoxide dismutase (SOD) activities of RHT patients were determined at the beginning and end of 4-month reuse period. RESULTS: When compared to healthy controls, both plasma and erythrocyte MDA levels were found to be significantly higher in RHT patients before the dialyzer reuse practice; whereas both plasma and erythrocyte GPx activities, erythrocyte SOD activity, and also plasma Se levels were lower in the same patient group than those of controls. When statistical comparison was made on RHT patients between before and after the reuse period, the decreases in MDA levels but increases in the enzyme activities and also an increase in plasma Se levels were observed after the reuse period. However, erythrocyte SOD activities and plasma Se levels measured after the reuse period were not found to be statistically different from the control values; MDA levels still remained elevated above the control values, and GPx activities were not attained to those of controls, after the reuse practice. In addition, positive correlations were found between activities of erythrocyte SOD and GPx enzymes, between GPx and Se levels and negative correlations between the activities of both enzymes and MDA levels in erythrocytes of patients on RHT. CONCLUSION: These findings may indicate that dialyzer reuse may provide, at least partly, an improvement on oxidative stress in patients on RHT.

Evidence of central hypothyroidism in children on continuous ambulatory peritoneal dialysis.

This study investigated the effects of chronic peritoneal dialysis on thyroid function and thyroid volume of patients with chronic renal failure (CRF). We measured the levels of serum and dialysate thyroid hormones [total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (fT4), and free triiodothyronine (fT3)], thyrotropin (TSH), thyroglobulin (Tg), and thyroid volume in 10 children on chronic peritoneal dialysis [9 continuous ambulatory peritoneal dialysis (CAPD), 1 continuous cycling peritoneal dialysis (CCPD)] at baseline and after one year. Serum levels in patients were compared with those in age- and sex-matched healthy children and were scored as normal, low, or high. At the beginning of study, serum levels were low for TT3 in 1 patient, for fT3 in 8 patients, for fT4 in 3 patients, and for Tg in 1 patient; serum TSH was high in 1 patient. At the end of study, serum levels were low for TT3 in 2 patients, for TT4 in 2 patients, for fT3 in 9 patients, for fT4 in 4 patients, for TSH in 2 patients, and for Tg in 3 patients. At the start of the study, only TSH and Tg levels could be detected in peritoneal dialysate; other parameters could not be measured. One year later, levels of TSH had decreased in 6 patients and increased in 3 patients, and Tg had increased in 8 patients, compared with baseline levels. To determine the effect of CAPD, baseline results were compared with mean levels at the end of the study. Although the mean levels of all parameters, except Tg, had decreased after one year, only the decrease in serum TSH was statistically significant. On the other hand, only the levels of Tg increased significantly in peritoneal dialysate. The mean value of thyroid volume also decreased after a year, but all values were within the normal range, and the decrease was not significant. No correlation was found between dialysis duration and any parameter after one year. In conclusion, we found a decrease in serum thyroid hormones, thyroid volume, and TSH in chronic peritoneal dialysis patients. We suggest that the low TSH levels cannot be explained by loss in peritoneal dialysate and may be due to impairment of pituitary function.

Effects of recombinant human erythropoietin on physiological inhibitors of coagulation in children on continuous ambulatory peritoneal dialysis.

The effects of recombinant human erythropoietin (rHuEPO) on plasma and peritoneal effluent levels of antithrombin III (AT-III), protein C (PC) activity, and protein S (PS) activity were evaluated in 10 uremic children on continuous ambulatory peritoneal dialysis (CAPD). The findings were compared with values obtained from ten healthy children. Levels of AT-III and of PC and PS activity in plasma and peritoneal effluent were measured before, and at 8 and 12 weeks after, rHuEPO treatment. Baseline levels of AT-III and PC activity in plasma were lower than the control values. Levels of PC activity increased during the trial, while levels of AT-III remained unchanged, and levels of PS activity decreased. Baseline levels of PC activity in peritoneal effluent were lower than those obtained during rHuEPO treatment, while no change in peritoneal levels of PS activity and AT-III was observed after rHuEPO treatment. A significant positive correlation was seen between plasma and peritoneal levels of PC activity at baseline. A significant positive correlation was also seen between plasma levels of PS activity and hemoglobin at week 12, and a significant negative correlation between plasma levels of AT-III and albumin at week 8. No correlation was found between the plasma natural coagulation inhibitors and CAPD duration. These results suggest that plasma PS activity can be decreased, and plasma PC activity increased, by rHuEPO treatment in children.

Effects of recombinant human erythropoietin on fibrinolytic system in children on continuous ambulatory peritoneal dialysis.

We studied tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) levels in plasma and peritoneal effluent in 10 children on continuous ambulatory peritoneal dialysis (CAPD) before, and 8 and 12 weeks after, treatment with recombinant human erythropoietin (rHuEPO). Plasma t-PA and PAI-1 levels were lower in patients than in controls during the study. The plasma t-PA levels were increased by rHuEPO treatment. Although PAI-1 levels showed a tendency to increase in the early phase of rHuEPO treatment, they later returned to near baseline levels. Peritoneal effluent t-PA levels were decreased at week 8 of treatment, but returned to baseline levels at week 12. Peritoneal effluent PAI-1 levels were not changed by the rHuEPO treatment. No correlation was observed between levels of t-PA and PAI-1 in plasma and in peritoneal effluent. No correlation was seen between plasma PAI-1 levels and duration of CAPD. A significant negative correlation was found between the plasma PAI-1 levels and hemoglobin levels at week 8 and week 12. These results suggest that plasma t-PA levels can be increased by rHuEPO treatment, while plasma PAI-1 levels are associated with hemoglobin levels.

Serum levels of C3 and factors I and B in minimal change disease.

BACKGROUND: Relapses are an important problem in minimal change disease, which accounts for most of the cases of childhood nephrotic syndrome. Because of defects in the humoral immune system, patients are predisposed to infection in nephrotic syndrome and infection is the most important complication that determines mortality and morbidity. METHODS: In this study, serum levels of Factors I and B and C3 were studied to evaluate the relationships between nephrotic syndrome and infection in 17 children with nephrotic syndrome (24-96 months of age) and 10 healthy children (27-84 months of age). RESULTS: Serum levels of Factors I and B were found to be lowered in the active disease group compared with the control group. These values were lowest for the infection group. Although it was observed that these values increased with steroid treatment, they did not reach normal levels. The parameters in remission were not different from the parameters in the control subjects. The serum level of C3 was found to be high during the active disease state and returned to normal levels during remission. CONCLUSIONS: The patients with active minimal change disease had infections such as peritonitis, septicemia and urinary tract infection because of low concentrations of Factors I and B in their sera.

The hormonal and radiological evaluation of adrenal glands, and the determination of the usefulness of low dose ACTH test in patients with renal amyloidosis.

Amyloidosis is a multisystem disease which may cause organ loss. Renal involvement is the most common clinical problem in amyloidosis, however involvement of endocrin organs is possible. In this study to assess adrenocortical function and to evaluate the usefulness of low dose ACTH test in patients with renal amyloidosis, we determined cortisol, 17-hydroxyprogesteron (17-OHP) and 11-deoxycortisol (11-DOC) responses to both 1 microg and 250 microg Synacthen. We also determined the size of adrenal glands radiologically by using computerized tomography. Twenty one patients with renal amyloidosis and 16 healthy subjects for hormonal evaluation, and 20 patients with renal amyloidosis and 22 healthy subjects for radiologic evaluation were included in the study. In four patients (19%) peak serum cortisol levels following stimulation with the low dose of Synacthen were less than 20 microg/dL (550 nmol/L). Two of them had also subnormal cortisol response to the 250 microg Synacthen stimulation test. Basal and stimulated levels of 11-DOC were lower than those of control values (p=0.000 and p<0.01 respectively). The mean 11-DOC responses to stimulation with 1 microg Synacthen were also significantly lower than the values obtained after the simulation with 250 microg Synacthen (p<0.01 and p=0.000). Cortisol responses to the stimulation with 250 microg Synacthen were also lower than the control responses (p<0.05). 17-OHP responses were similar to the control values in both tests. In the radiological evaluation the mean maximum width of right adrenal glands and the mean anterior and maximum width of left adrenal glands were significantly greater in the patient group (p<0.01). In conclusion, adrenal involvement and adrenal insufficiency is common in amyloidosis. Low 11-DOC levels in amyloidosis is a new finding and further detailed studies is required to explain its cause.