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Since the efficacy of mycophenolate mofetil (MMF) to treat immunoglobulin A (IgA) nephropathy is controversial, we extended our original study by following 40 Chinese patients with established IgA nephropathy for 6 years. All patients were maintained on their angiotensin blockade medication and half were randomized to receive MMF for 6 months. After 6 years, 11 patients required dialysis (2 from the MMF and 9 from the control group). Significantly, only 3 treated (as compared to 10 control) patients reached the composite end point of serum creatinine doubling or end-stage renal disease. Linear regression showed the annualized decline in the estimated glomerular filtration rate was significantly less in the MMF-treated group. Urinary protein excretion and the albumin-to-creatinine ratio were lower with MMF treatment during the first 24 months, beyond which there was no difference between groups. Multivariable Cox regression analysis showed that the baseline estimated glomerular filtration rate and proteinuria, and change in the urine albumin-to-creatinine ratio at 1 year to be important predictors of progression to end-stage renal disease. We found that among Chinese patients with IgA nephropathy who had mild histologic lesions and persistent proteinuria despite maximal angiotensin blockade, MMF treatment may result in transient and partial remission of proteinuria in the short-term and renoprotection in the long-term.

Background: Hyperuricemia is an independent risk factor for renal progression in IgA nephropathy (IgAN). However, no study has evaluated the effect of allopurinol on the clinical outcome in hyperuricemic IgAN. Methods: First,a retrospective cohort study of 353 IgAN patients was conducted to explore the relationship between uric acid (UA) and the progression of renal disease over a mean period of 5 years. Then, 40 hyperuricemic IgAN patients were randomized to receive allopurinol (100–300 mg/day) or usual therapy for 6 months. The study outcomes were renal disease progression and/or blood pressure. Results: Hyperuricemia independently predicted renal survival at 1, 3, and 5 years after adjustment for different baseline estimated glomerular filtration rates. In the randomized controlled trial, allopurinol did not significantly alter renal progression or proteinuria. The antihypertensive drug dosage was reduced in 7 of 9 cases with hypertension in the allopurinol group compared to 0 of 9 cases in the control group (p < 0.01). UA levels correlated with mean arterial pressure in normotensive patients (r = 0.388, p < 0.001). Conclusion: Hyperuricemia predicts the progression of IgAN independently of baseline estimated glomerular filtration rate. Allopurinol may improve the control of blood pressure. Further studies are required to explore the effects of lowering UA on renal protection in IgAN.

Mycophenolate mofetil in IgA nephropathy: Results of a 3-year prospective placebo-controlled randomized study. Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF). A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2g per day (N = 21) or placebo (N = 13). After 36months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis. Therapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d. In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results.

Treatment remains uncertain for IgA nephropathy patients with mild to moderate proteinuria, for whom anti-hypertensive medication or the RAS blocker is not applicable due to low blood pressure. A double blinded randomized trial. The anti-proteinuric effect of tacrolimus was explored for 40 biopsy-proven mild IgA nephropathies for 16 weeks. We randomly assigned patients either to receive tacrolimus or placebo with stratification by using a renin angiotensin system blocker. The primary outcome was the percentage change of final UACR compared to the baseline value (pcUACR). The mean value of pcUACR at 12-week and 16-week visits (primary outcome) was decreased more in the Tac group compared to the control group (-52.0±26.4 vs -17.3±29.3%, p = 0.001). At each visit, pcUACR was also decreased more in the Tac group compared to the control group. In the Tac group, the pcUACRs were -60.2±28.2%, -62.2±33.9%, -48.5±29.8%, and -55.5±24.0%, and, in the control group, -6.8±32.2%, -2.5±35.9%, -12.7±34.2%, and -21.9±30.6%, at 4-week, 8-week, 12-week, and 16-week visits, respectively. The pre-defined secondary outcomes were better in the Tac group compared to the control group. The frequency of decrease in pcUACR and percentage change of UPCR (pcUPCR) ≥50% at 16 weeks were 65.0% (13/20) and 55.0% (11/20)in the Tac group, and 25.0% (5/20) and 15.0% (3/20), in the control group, respectively (p = 0.025 for pcUACR and p = 0.019 for pcUPCR). However, tacrolimus wasn't effective with a dose of 0.05 mg/kg/day in patients taking ARB. The adverse events were tolerable. Tacrolimus effectively reduced proteinuria in IgA nephropathy with normal blood pressure. This suggested that tacrolimus could be an alternative to corticosteroid and RAS blocker for IgA nephropathy patients who cannot endure anti-hypertensive medication. Clinicaltrial.gov NCT1224028.

The immunosuppressive drug tacrolimus has the short-term effect of reducing proteinuria in patients with immunoglobulin A nephropathy (IgAN). Our study investigated the effects on proteinuria and kidney function after discontinuation of tacrolimus. Patients with biopsy-proven IgAN were included in the study and randomly divided into two treatment groups. There was a corresponding control group for each treatment group. The first group included patients treated with tacrolimus (Tac vs non-Tac group) and the second group included patients with a renin angiotensin system blocker (RASi vs non-RASi group). The Tac group received treatment for up to 16 weeks, with the administration of tacrolimus being ceased at the final visit (trial phase). We tracked the patients at 12, 24, 52, and 240 weeks (observational phase). The primary outcomes examined were the percentage change (from the trial phase to the observational phase) of time-averaged proteinuria (TA-proteinuria; g/g creatinine [cr]) and the estimated glomerular filtration rate (eGFR). Time-averaged proteinuria was defined as the average of urine protein to creatinine ratio (UPCR), measured every 3 months during both the trial and observational phases of the study. A significant reduction in UPCR was observed in the Tac group compared to non-Tac group at the 4 and 8 week visits during the trial phase (p = 0.023 and p = 0.003, respectively). However, the difference between the Tac group and non-Tac group was not evident in the other review periods, estimated by linear mixed effect model. The percentage change in TA-proteinuria was greater in the Tac group than that in the corresponding control group (116 ± 96% vs. 63 ± 239%, p = 0.004). Therefore, during the observational phase, TA-proteinuria was not significantly different between the Tac group and the non-Tac group (1.150 ± 0.733 g/g cr vs. 1.455 ± 2.017 g/g cr, p = 0.775). The levels of eGFR throughout the observational phase were not significantly different between the two groups. Furthermore, the mean rate of eGFR change throughout both phases of the study was -6.4 ± 5.9 mL/min/1.73 m2/year in the non-Tac group and -5.4 ± 7.9 mL/min/1.73 m2/year in the Tac group (p = 0.988). The anti-proteinuric effect of tacrolimus was promptly reversed 3 months after discontinuing the drug. The use of tacrolimus for a short period of time for patients with IgAN temporarily reduces proteinuria, but the data showed no long-term efficacy regarding proteinuria reduction and improvement of renal function.

Background and aim IgA nephropathy (IgAN) is one of the world’s most common glomerular diseases. Hyperuricemia was recently defined as risk factor for chronic kidney disease. We aimed to investigate the impact of baseline serum uric acid levels on progression of IgAN. Materials and methods A total of 93 patients with IgAN were screened. Demographic information and biochemical data were recorded. eGFR (using the CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration formula) was used as renal function marker. Baseline and sixth month eGFR values were calculated. Progression of renal disease was defined as the difference between baseline eGFR and sixth month eGFR (delta eGFR). Results Mean age of the patients was 40 ± 11 years (60 % were males). Baseline mean eGFR was 77.9 ± 30.2 mL/min, and baseline mean serum uric acid was 5.65 ± 1.68 mg/dL. Importantly, baseline serum uric acid levels were found to be associated with the change in eGFR ( r  = 0.252, p  = 0.01). In multivariate analysis (adjusted R 2  = 0.171, p  = 0.031), adjusting for age, gender, baseline eGFR, blood pressure, baseline albumin concentration and ACEI and/or ARB use revealed that the baseline serum uric acid levels significantly predicted the change in eGFR. Conclusion Baseline serum uric acid concentration is directly proportional to the rate of decline in renal functions in patients with IgAN. Uric acid-lowering treatments may be beneficial for the prevention of progression of IgAN. However, randomized controlled studies are needed for this purpose.

Background The significance of immunosuppressants as an adjunct treatment with corticosteroids for IgA nephropathy (IgAN) has not been well demonstrated. This study was performed to compare two treatment regimens, steroid-pulse therapy or combined with mizoribine (MZR) in progressive IgAN. Methods Study design was a prospective randomized controlled trial of 40 patients with moderate to severe glomerular injuries who were randomly administered either pulse methylprednisolone followed by a 25-month course of oral prednisolone (P group, n  = 20) or in combination with MZR (150 mg/day for 24 months, M + P group, n  = 20). The primary endpoint was a reduction of proteinuria by ≥50 % of the baseline value. Secondary endpoints were increased serum creatinine (Cr) by ≥50 %, or a decrease in estimated glomerular filtration rate by ≤50 %. Results Twenty-five months after the initiation of treatment, urinary protein excretion significantly declined from the median of 0.98 to 0.17 g/gCr in the P group ( P  < 0.05) and from 1.01 to 0.38 g/gCr in the M + P group ( P  < 0.05). There was no statistical difference in the serial changes of proteinuria between two groups ( P  = 0.81). All patients reached the primary endpoint, and the cumulative incidence of the reduction of proteinuria was not significantly different ( P  = 0.76). No patient reached the secondary endpoint during the 25 months of treatment. Conclusions Both therapeutic regimens significantly reduced the levels of proteinuria. We could not find the additional effect of MZR in combination with steroid-pulses in this small-scale controlled trial. Steroid-pulse therapy with a 25-month course of oral steroids seems to be effective for progressive IgAN.

IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.

Background Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. Methods We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. Results A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p  < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p  < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m 2 , p  < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p  < 0.0001) in children than in adults. S1 (62% vs. 28%, p  < 0.0001) and T1–2 (34% vs. 8%, p  < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p  < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16–3.02, p  = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. Conclusions Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information

IgA nephropathy (IgAN) accounts for a far higher proportion of end-stage renal disease (ESRD) in Asia compared with North America. It is not known whether this is entirely because of differences in disease prevalence or a higher risk of disease progression. The lack of a racially diverse population cohort followed longitudinally has previously precluded the ability to address this question. To determine whether Asians in North America with IgAN are at higher risk for ESRD, we analyzed a cohort of 202 patients of self-reported Pacific Asian origin and 467 of other origin from the Toronto GN Registry followed up for a median of 46.4 months. The primary outcome of ESRD (dialysis, transplantation, or eGFR below 15) was analyzed using Cox regression analysis. Baseline eGFR was 59.6ml/min/1.73m2, and median proteinuria was 1.8g/day. ESRD occurred in 213 patients. By univariable analysis, the risk of ESRD was similar between the two groups (hazard ratio 0.98, 95% CI 0.73, 1.31); however, after adjusting for age, gender, eGFR, medication use, blood pressure, and proteinuria, the risk of ESRD was significantly higher in Pacific Asian individuals (hazard ratio 1.56, 95% CI 1.10, 2.22). This was supported by a significant 1.62ml/min/1.73m2/year faster rate of eGFR decline (95% CI –3.19, –0.5) and an increased risk of a reduction in eGFR by half (hazard ratio 1.81, 95% CI 1.25, 2.62). Thus, in a large multiracial cohort of patients with IgAN, individuals of Pacific Asian origin have a higher risk of progression to ESRD.