Shaoshan Liang

Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population

BACKGROUND We sought to identify the long-term renal survival rate and related risk factors of progression to renal failure in Chinese adult patients with IgA nephropathy (IgAN) and to quantify the effects of proteinuria during the follow-up on outcome in patients with IgAN. METHODS Patients with biopsy-proven primary IgAN in the Nanjing Glomerulonephritis Registry were studied. Renal survival and the relationships between clinical parameters and renal outcomes were assessed. RESULTS One thousand one hundred and fifty-five patients were enrolled in this study. The 10-, 15- and 20-year cumulative renal survival rates, calculated by Kaplan-Meier method, were 83, 74 and 64%, respectively. At the time of biopsy, proteinuria>1.0 g/day [hazard ratio (HR) 3.2, P<0.001], estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 (HR 2.6, P<0.001), hypertension (HR 1.9, P<0.001), hypoproteinemia (HR 2.0, P<0.001) and hyperuricemia (HR 2.1, P<0.001) were the independent risk factors. Multivariate Cox analysis showed the time-average proteinuria (TA-P) during follow-up was the most important risk factor of renal failure. Patients with TA-P>1.0 g/day were associated with a 9.4-fold risk than patients with TA-P<1.0 g/day (P<0.001) and 46.5-fold risk than those with TA-P<0.5 g/day (P<0.001). Moreover, patients who achieved TA-P<0.5 g/day benefit much more than those with TA-P between 0.5 and 1.0 g/day (HR 13.1, P<0.001). CONCLUSIONS Thirty-six percent of Chinese adult patients with IgAN progress to end stage renal disease within 20 years. Five clinical features-higher proteinuria, hypertension, impaired renal function, hypoproteinemia and hyperuricemia-are independent predictors of an unfavorable renal outcome. The basic goal of anti-proteinuric therapy for Chinese patients is to lower proteinuria<1.0 g/day and the optimal goal is to lower proteinuria to <0.5 g/day.

A multicenter application and evaluation of the oxford classification of IgA nephropathy in adult chinese patients.

BACKGROUND The Oxford classification of immunoglobulin A (IgA) nephropathy (IgAN) provides a histopathologic grading system that is associated with kidney disease outcomes independent of clinical features. We evaluated the Oxford IgAN classification in a large cohort of patients from China. STUDY DESIGN Retrospective study. SETTING & PARTICIPANTS 1,026 adults with IgAN from 18 referral centers in China. Inclusion criteria and statistical analysis were similar to the Oxford study. PREDICTORS Histologic findings of mesangial hypercellularity score, endocapillary proliferation, segmental sclerosis or adhesion, crescents, necrosis, and tubular atrophy/interstitial fibrosis. Clinical features, blood pressure, estimated glomerular filtration rate (eGFR), proteinuria, and treatment modalities. OUTCOMES Time to a 50% reduction in eGFR or end-stage renal disease (the combined event); the rate of eGFR decline (slope of eGFR); proteinuria during follow-up. RESULTS Compared with the Oxford cohort, the Chinese cohort had a lower proportion of patients with mesangial hypercellularity (43%) and endocapillary proliferation (11%), higher proportion with segmental sclerosis or adhesion (83%) and necrosis (15%), and similar proportion with crescents (48%) and tubular atrophy/interstitial fibrosis (moderate, 24%; severe, 3.3%). During a median follow-up of 53 (25th-75th percentile, 36-67) months, 159 (15.5%) patients reached the combined event. Our study showed that patients with a mesangial hypercellularity score higher than 0.5 were associated with a 2.0-fold (95% CI, 1.5-2.8; P<0.001) higher risk of the combined event than patients with a score of 0.5 or lower. Patients with tubular atrophy/interstitial fibrosis of 25%-50% and >50% versus <25% were associated with a 3.7-fold (95% CI, 2.6-5.1; P<0.001) and 15.1-fold (95% CI, 9.5-24.2; P<0.001) higher risk of the combined event, respectively. Endocapillary proliferation, glomerular crescents, and necrosis were not significant. LIMITATIONS Retrospective study; the therapeutic interventions were miscellaneous. CONCLUSIONS We confirmed the associations of mesangial hypercellularity and tubular atrophy/interstitial fibrosis with kidney disease outcomes.

Validation of the Oxford classification of IgA nephropathy for pediatric patients from China

BackgroundThe Oxford classification of IgA nephropathy (IgAN) provides a useful tool for prediction of renal prognosis. However, the application of this classification in children with IgAN needs validation in different patient populations.MethodsA total of 218 children with IgAN from 7 renal centers in China were enrolled. The inclusion criteria was similar to the original Oxford study.ResultsThere were 98 patients (45%) with mesangial proliferation (M1), 51 patients (23%) with endocapillary proliferation (E1), 136 patients (62%) with segmental sclerosis/adhesion lesion (S1), 13 patients (6%) with moderate tubulointerstitial fibrosis (T1 26-50% of cortex scarred), and only 2 patients (1%) with severe tubulointerstitial fibrosis (T2, >50% of cortex scarred). During a median follow-up duration of 56 months, 24 children (12.4%) developed ESRD or 50% decline in renal function. In univariate COX analysis, we found that tubular atrophy/interstitial fibrosis (HR 4.3, 95%CI 1.8-10.5, P < 0.001) and segmental glomerulosclerosis (HR 9.2 1.2-68.6, P = 0.03) were significant predictors of renal outcome. However, mesangial hypercellularity, endocapillary proliferation, crescents, and necrosis were not associated with renal prognosis. In the multivariate COX regression model, none of these pathologic lesions were shown to be independent risk factors of unfavorable renal outcome except for tubular atrophy/interstitial fibrosis (HR 2.9, 95%CI 1.0-7.9 P = 0.04).ConclusionsWe confirmed tubular atrophy/interstitial fibrosis was the only feature independently associated with renal outcomes in Chinese children with IgAN.

The spectrum of biopsy-proven kidney diseases in elderly Chinese patients

BACKGROUND Studies on biopsy-proven renal disease in the elderly (age ≥65 years) are extremely limited in China. The aim of this study was to examine the spectrum of renal diseases and their clinical presentations in elderly patients undergoing renal biopsy. METHODS All native renal biopsies (n = 851) performed in patients aged ≥65 years from January 2003 to December 2012 were retrospectively analyzed. The results were compared with a control group of 28 574 patients aged 18-64 years undergoing renal biopsy over the same period. RESULTS These 851 patients included 549 males and 302 females. Primary glomerular diseases (53.94%) occurred more frequently than secondary glomerular diseases (36.49%). The clinical manifestations were nephrotic syndrome (NS) in 29.49% of the patients, chronic renal failure in 24.68%, proteinuria and hematuria in 13.28%, proteinuria in 10.93%, acute kidney injury (AKI) in 10.81% and AKI and NS in 8.93%. Membranous nephropathy (MN) was the most frequent diagnosis (28.79%), followed by diabetic nephropathy (DN, 9.75%), IgA nephropathy (IgAN, 9.64%) and vasculitis (6.82%). When compared with the control group, the results showed that MN (P < 0.0001), DN (P < 0.0001), vasculitis (P < 0.0001) and amyloidosis (P < 0.0001) occurred more frequently and IgAN (P < 0.0001), lupus nephritis (P < 0.0001) and minimal change disease (P < 0.0001) occurred less frequently in the elderly. CONCLUSION This study is the first and largest renal biopsy series to analyze patients aged ≥65 years in China, and the results obtained from this study may increase the knowledge of renal diseases in elderly patients.

Role of Myeloid-Derived Suppressor Cells in Glucocorticoid-Mediated Amelioration of FSGS

The mechanism by which glucocorticoids alleviate renal inflammatory disorders remains incompletely understood. Here, we report that the efficacy of glucocorticoids in ameliorating FSGS depends on the capacity to expand myeloid-derived suppressor cells (MDSCs). After glucocorticoid treatment, the frequency of CD11b(+)HLA-DR(-)CD14(-)CD15(+) MDSCs in peripheral blood rapidly increased in patients with glucocorticoid-sensitive FSGS but remained unchanged in patients with glucocorticoid-resistant FSGS. The frequency of CD11b(+)Gr-1(+) MDSCs in mouse peripheral blood, bone marrow, spleen, kidney-draining lymph nodes (KDLNs), and kidney also increased after glucocorticoid treatment. The induced MDSCs from glucocorticoid-treated mice strongly suppressed T cells, dendritic cells, and macrophages but induced regulatory T cells in spleen, KDLNs, and kidney. Moreover, glucocorticoid treatment suppressed doxorubicin-induced T cell proliferation, dendritic cell and macrophage infiltration, and proinflammatory cytokine production, whereas this protective effect was largely abolished by depleting MDSCs using anti-Gr-1 antibody. Finally, the adoptive transfer of induced MDSCs into the doxorubicin-treated mice not only confirmed the protective role of MDSCs in doxorubicin-induced renal injury but also showed that the transferred MDSCs rapidly migrated into the lymphocyte-accumulating organs, such as the spleen and KDLNs, where they suppressed T cell proliferation. Taken together, these results demonstrate that glucocorticoid treatment ameliorates FSGS by expanding functional MDSCs and that this rapid elevation of MDSCs in peripheral blood may serve as an indicator for predicting the efficacy of glucocorticoid treatment.

HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-Related Membranous Nephropathy

Idiopathic membranous nephropathy (MN) is associated with HLA; however, the HLA allele involved remains unknown. To identify the HLA risk alleles associated with phospholipase A2 receptor (PLA2R)-related MN in the Chinese population, we sequenced the entire MHC region in DNA samples from 99 patients with PLA2R-related MN, 50 patients with PLA2R-unrelated MN, and 100 healthy subjects. Two HLA risk alleles, HLA-DRB1*15:01 and HLA-DRB3*02:02, independently and strongly associated with an increased risk of PLA2R-related MN. After adjusting for HLA-DRB1*15:01 and HLA-DRB3*02:02, no other alleles showed significant association with PLA2R-related MN. A replication study in an independent cohort of 293 participants with PLA2R-related MN and 285 healthy controls validated these findings. In a joint analysis, a multivariate logistic regression model confirmed that HLA-DRB1*15:01 (odds ratio [OR], 24.9; 95% confidence interval [95% CI], 15.3 to 42.6; P=2.3×10-35) and HLA-DRB3*02:02 (OR, 17.7; 95% CI, 11.0 to 30.3; P=8.0×10-29) independently and strongly associated with PLA2R-related MN. As many as 98.7% of patients with PLA2R-related MN, compared with 43.9% of control subjects, carried at least one HLA risk allele. Subjects with either risk allele had higher odds of developing PLA2R-related MN than those without a risk allele (OR, 98.9; 95% CI, 44.4 to 281.7; P=2.5×10-23). These HLA risk alleles also associated with the age at disease onset in patients with PLA2R-related MN. In conclusion, our findings provide clear evidence that the HLA-DRB1*15:01 and HLA-DRB3*02:02 alleles independently and strongly associate with PLA2R-related MN in the Chinese population.

Long-Term Outcome of IgA Nephropathy Patients with Recurrent Macroscopic Hematuria

Background/Aims: The long-term renal outcomes of patients with IgA nephropathy (IgAN) who present with recurrent macroscopic hematuria (RMH) have not been described in previous studies. Methods: Patients with biopsy-proven primary IgAN in Jinling Hospital were divided into three groups according to different patterns of macroscopic hematuria (MH): RMH, isolated MH (IMH), and those without a history of MH (NMH). Results: A total of 1,155 patients were enrolled in the study (158 in the RMH group, 256 in the IMH group, and 741 in the NMH group). At biopsy, patients with RMH were younger, had lower median proteinuria, a lower incidence of hypertension, and a higher estimated glomerular filtration rate than those in the NMH group. Pathologically, patients with RMH had a lower level of mesangial hypercellularity and segmental glomerulosclerosis as well as less tubular atrophy than those with NMH. The demographic and clinical features of patients with IMH fell between patients with RMH and those with NMH. During a median follow-up of 7.9 years, the 5-, 10- and 20-year cumulative renal survival after biopsy, as calculated by K-M methods, were 98, 91, and 91% in the RMH group, 95, 89, and 64% in the IMH group, and 95, 79, and 57% in the NMH group. The renal survival in patients with RMH was significantly better than patients with NMH or IMH. Conclusions: The long-term prognosis of patients who present with RMH is significantly better than patients with NMH or IMH.

Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome.

Background: Genetic defects in complement proteins reportedly contribute to the atypical hemolytic uremic syndrome (aHUS). Numerous genetic studies have been published in recent years, but limited data have been gathered from Asian countries. Methods: Genetic variants of 11 complement genes were analyzed in 23 Chinese patients with aHUS by high-throughput sequencing. The genotype-phenotype relationship in the Han population was evaluated and compared with the relationship that existed in other ethnicities. Results: We identified 20 causative mutations in complement genes, including 19 missense mutations and 1 splicing mutation. Six previously reported mutations, 6 mutations detected for the first time, and 8 rare polymorphisms were noted. Twelve out of 23 patients harbored complement mutations. Among the patients, one was a homozygote (Arg142Cys in CFHR3), and 4 carried combined mutations. Chinese patients have a similar prevalence of complement mutations as European, Japanese, and American patients. Complement factor H (CFH) mutations were common in aHUS in different ethnicities, but Chinese patients exhibited a higher percentage of complement factor B mutations than were found in European patients and a lower percentage of component 3 (C3) mutations than in Japanese patients. Compared with non-carriers, the aHUS patients carrying mutations had reduced C3 levels. In particular, patients with CFH mutations had a worse renal function than those with membrane cofactor protein mutations, a higher level of serum creatinine at the disease onset and a higher percentage of renal insufficiency during follow-up. Conclusions: Because complement genetic dysfunction has clinical significance in aHUS, a comprehensive assessment of variants is necessary for the proper management of aHUS patients in China.

Identification of G8969>A in mitochondrial ATP6 gene that severely compromises ATP synthase function in a patient with IgA nephropathy

Here we elucidated the pathogenesis of a 14-year-old Chinese female who initially developed an isolated nephropathy followed by a complex clinical presentation with brain and muscle problems, which indicated that the disease process was possibly due to a mitochondrial dysfunction. Careful evaluation of renal biopsy samples revealed a decreased staining of cells induced by COX and NADH dehydrogenase activities, and a strong fragmentation of the mitochondrial network. These anomalies were due to the presence of a mutation in the mitochondrial ATP6 gene, G8969>A. This mutation leads to replacement of a highly conserved serine residue at position 148 of the a-subunit of ATP synthase. Increasing the mutation load in cybrid cell lines was paralleled by the appearance of abnormal mitochondrial morphologies, diminished respiration and enhanced production of reactive oxygen species. An equivalent of the G8969>A mutation in yeast had dramatic consequences on ATP synthase, with a block in proton translocation. The mutation was particularly abundant (89%) in the kidney compared to blood and urine, which is likely the reason why this organ was affected first. Based on these findings, we suggest that nephrologists should pay more attention to the possibility of a mitochondrial dysfunction when evaluating patients suffering from kidney problems.

Comparison between patients with IgA nephropathy with minimal change disease and patients with minimal change disease

OBJECTIVE To compare the clinicopathological characteristics, treatment response, and prognosis between patients with IgAN nephropathy with minimal change disease (MCD-IgAN) and patients with minimal change disease (MCD). METHODS 77 patients with biopsy-proven MCD-IgAN from the Jinling Hospital IgAN Registry and 77 patients with MCD followed up for ≥ 3 years were retrospectively reviewed. RESULTS MCD-IgAN and MCD patients had similar clinical presentations, both were predominantly young males, the disease mainly manifested as nephrotic syndrome, and the patients rarely presented with microscopic hematuria. Compared with the MCD group, patients with MCD-IgAN had lower levels of baseline serum albumin (p < 0.01) and eGFR (p < 0.05), a higher level of urine n-acetylglucosaminidase (p < 0.01), higher proportion of mesangial hypercellularity (M1), and more severe acute tubulointerstitial lesions in renal pathology (p < 0.01, p < 0.01, respectively). After 8 weeks of corticosteroid therapy, no significant differences were observed in the rate of complete remission, partial remission, and no remission between MCDIgAN and MCD patients (88.3% vs. 90.9%, 10.4% vs. 5.2%, 1.3% vs. 3.9%, p > 0.05). The median time to achieve remission was 4 weeks (range 1 - 24 weeks) and 4 weeks (range 1 - 28 weeks), respectively. No significant difference existed in the efficacy of corticosteroid between the two groups. During 3.96 years (range 3.0 - 8.5 years) of follow-up, no patients in the two groups entered end-stage renal disease (ESRD), only 2 patients (2.6%) with MCD-IgAN had > 50% reduction of eGFR. CONCLUSIONS MCD-IgAN may be controlled well achieving a comparable clinical outcome as MCD but more frequently necessitates additional immunosuppressive medication.