Minlin Zhou

Renal histologic changes and the outcome in patients with diabetic nephropathy

BACKGROUND The progression of diabetic nephropathy (DN) is frequently determined by clinical parameters; however, the predictive value of histologic lesions remains largely unknown. Our aim was to evaluate the relationship between histologic changes and renal outcome in patients with type 2 diabetes mellitus (T2DM). METHODS A total of 396 patients with T2DM and biopsy-proven DN who received follow-up for at least 1 year were recruited. The severity of different histologic lesions was assessed using the pathologic classification established by the Renal Pathology Society. Renal outcomes were defined by progression to end-stage renal disease and doubling of serum creatinine. The influence of histologic findings on renal outcomes was assessed using univariate and multivariate Cox regression. RESULTS A univariate Cox regression showed that the severity of glomerular and interstitial lesions had a significant impact on renal outcomes (P < 0.001). Scores of vascular lesions demonstrated no association with renal outcomes (P > 0.05). A multivariate COX analysis demonstrated that the glomerular classes and scores of interstitial fibrosis and tubular atrophy were significantly associated with renal outcomes when adjusting for baseline proteinuria, mean arterial pressure and estimated glomerular filtration rate (P < 0.05). The glomerular and interstitial lesions correlated significantly among each other. However, in several patients, the severity of interstitial lesions did not correlate with glomerular lesions. CONCLUSION These findings indicated that the severity of glomerular and interstitial lesions were significantly associated with renal outcomes in patients with DN, whereas the vascular indexes did not have any impact on renal outcomes.

Long-term renal outcomes in a cohort of 1814 Chinese patients with biopsy-proven lupus nephritis.

In the present study, we observed the renal outcomes in a cohort of 1814 Chinese patients with biopsy-proven lupus nephritis (LN) and evaluated the risk factors associated with poor renal prognosis. The 5 -, 10 -, 15 - and 20-year renal survival rates were 93.1%, 87.9%, 81.0% and 68.3%, respectively. Gender, LN duration, mean arterial pressure (MAP), proteinuria, serum creatinine, haemoglobin and pathological classification at the time of biopsy were independent risk factors for end-stage renal disease (ESRD). The long-term renal outcomes of patients with class II LN were unfavorable as opposed to those with class V. Additionally, the time-average proteinuria (TA-Pro) and the time-average mean arterial pressure (TA-MAP) during the follow-up were important risk factors for ESRD, with better predictive values than the baseline proteinuria and MAP. The results underscore the need for proteinuria and blood pressure control during follow-up in patients with LN; proteinuria levels should be controlled at least to < 1.0 g/24 h, and optimally to < 0.5 g/24 h; MAP should not exceed 96.5 mmHg. More attention should be paid to class II LN and emphasis should be placed on recurrence prevention of class II LN.

Relationship between Serum Soluble Urokinase Plasminogen Activator Receptor Level and Steroid Responsiveness in FSGS

BACKGROUND AND OBJECTIVES Soluble urokinase plasminogen activator receptor (suPAR) was initially proposed as a pathogenic and predictive biomarker of primary FSGS, but the findings were controversial. This study aimed to clarify the clinical implications of suPAR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The study enrolled 109 patients with biopsy-proven primary FSGS who were administered prednisone between January 2011 and May 2013 and followed up for 6-24 months (median duration of follow-up, 12 months). Ninety-six healthy volunteers, 20 patients with minimal-change disease (MCD), and 22 patients with membranous nephropathy (MN) served as controls. Serum suPAR levels were measured using ELISA. RESULTS suPAR levels in patients with FSGS (median, 3512 [interquartile range (IQR), 2232-4231] pg/ml) were significantly higher than in healthy controls (median, 1823 [IQR, 1563-2212] pg/ml; P<0.001), patients with MCD (median, 1678 [IQR, 1476-2182] pg/ml; P<0.001), and patients with MN (median, 1668 [IQR, 1327-2127] pg/ml; P<0.001). With 3000 pg/ml used as a threshold, suPAR levels were elevated in 48.6% of patients with FSGS, in contrast to 5% of patients with MCD and 4.5% of those with MN. suPAR levels were independently associated with steroid response in patients with FSGS (odds ratio, 85.02; P=0.001). Patients who were sensitive to steroids had significantly higher suPAR levels than nonsensitive patients (median, 3426 [IQR, 2670-5655] pg/ml versus 2523 [IQR, 1977-3460] pg/ml; P=0.001). A suPAR level of 3400 pg/ml was chosen as the optimal cutoff value for steroid response. At the 6-month follow-up in 84 patients with FSGS, suPAR levels were significantly decreased in those with suPAR level ≥ 3400 pg/ml (median, 4553 [IQR, 3771-6120] pg/ml versus 3149 [IQR, 2278-3953]; P=0.002) but were unchanged in patients with suPAR level <3400 pg/ml (median, 2359 [IQR, 2023-2842] pg/ml versus 2490 [IQR, 1916-3623] pg/ml; P=0.09). CONCLUSIONS suPAR is specifically elevated in some patients with FSGS, which differs from the finding in patients with MCD and MN. A suPAR assay may help predict steroid response in patients with primary FSGS.

Endothelial injury in transplant glomerulopathy is correlated with transcription factor T-bet expression

Transplant glomerulopathy is an important cause of late graft loss. Inflammatory lesions including glomerulitis and peritubular capillaritis, suggestive of endothelial injury, are prominent in this condition but the mechanism underlying this inflammation remains unclear. Here we measured the expression of T-bet (a member of the T-box family of transcription factors regulating Th1 lineage commitment) and its relationship with inflammation in 70 patients with transplant glomerulopathy. Within this cohort, 32 patients were diagnosed with transplant glomerulopathy, 23 with interstitial fibrosis/tubular atrophy, and 15 with stable grafts. There was a significant increase in T-bet expression in both glomerular and peritubular capillaries of the transplant glomerulopathy group. This expression was strongly correlated with CD4(+), CD8(+), and CD68(+) cell infiltration within glomerular and peritubular capillaries. The expression of GATA3, a Th2 regulator, was rarely found in the transplant glomerulopathy group. Transplant glomerulopathy was associated with diffuse peritubular capillary dilation without reduced capillary density. Moreover, the degree of capillary dilation was significantly correlated with the number of infiltrating CD68(+) cells. Since endothelial injury is a typical lesion that follows alloantibody reactivity, our results suggest that T-bet is involved in the pathogenesis of this glomerulopathy.

Multitarget Therapy for Maintenance Treatment of Lupus Nephritis

Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2-3 mg/d; mycophenolate mofetil, 0.50-0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; P=0.74), and serum creatinine levels and eGFR remained stable in both groups. The azathioprine group had more adverse events (44.4% versus 16.4% for multitarget therapy; P<0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; P=0.02). In conclusion, multitarget therapy as a maintenance treatment for lupus nephritis resulted in a low renal relapse rate and fewer adverse events, suggesting that multitarget therapy is an effective and safe maintenance treatment for patients with lupus nephritis.

Transcriptomic analysis uncovers novel synergistic mechanisms in combination therapy for lupus nephritis

A recent clinical study showed that combination therapy consisting of mycophenolate mofetil, tacrolimus and steroids was shown to be more effective in achieving complete remission in patients with severe forms of lupus nephritis than conventional therapy consisting of intravenous cyclophosphamide and steroids. To explore the underlying molecular and cellular mechanisms of increased efficacy of the combination therapy regimen, we employed a mouse model of lupus nephritis, MRL/lpr mice, and treated them with monotherapies of prednisone, mycophenolate mofetil, or tacrolimus, or with their combination. Consistent with previous clinical findings, combination therapy markedly improved renal outcome compared to the monotherapies in mice with lupus nephritis. Transcriptomic analysis of their kidneys revealed distinct molecular pathways that were differentially regulated in combination therapy versus monotherapies. Combination therapy not only provided additive immunosuppressive effects, but also induced gene expression and molecular pathways to confer enhanced renoprotection. Specifically, combination therapy inhibited TLR7 expression in the kidneys of mice with lupus nephritis; combination of tacrolimus and mycophenolate mofetil led to better stabilization of the podocyte actin cytoskeleton through the reciprocal regulation of RhoA and Rac1 activities. Combination therapy strongly suppressed the IL-6/Stat3 pathway. These findings were further validated in renal biopsy samples from patients with lupus nephritis before and after treatments with mycophenolate mofetil, tacrolimus or combination therapy. Thus, our study further supports the earlier clinical finding and further provides insights into the molecular basis for increased efficacy of combination therapy.

The short-term efficacy of bortezomib combined with glucocorticoids for the treatment of refractory lupus nephritis

Objective The treatment of refractory lupus nephritis (LN) remains challenging for clinicians because these patients either do not respond to conventional therapy or relapse during the maintenance treatment period. The aim of this study was to investigate the efficacy and safety of bortezomib combined with glucocorticoids in refractory lupus patients. Methodology Five refractory LN patients aged 21 to 43 years (four females and one male) with biopsy-proven diagnosis (four with type IV and one with type V+IV) were recruited. These patients received bortezomib therapy for four cycles (1.3 mg per square meter of body surface area as an intravenous bolus on days 1, 4, 8, and 11 of 21-day cycles) and glucocorticoids (methylprednisolone 0.5 g/d intravenously for three days, followed by prednisone 0.6 mg/kg/d orally for four weeks, with gradual tapering to 10 mg/d). Proteinuria, serum albumin and creatinine, and immunological parameters were assessed, and adverse effects were also evaluated. Results After two to four bortezomib treatment cycles, four patients achieved partial remission with decreases in SLE disease activity index scores from the range of 12–16 to that of 4–8. The patients also exhibited a decline in proteinuria and an elevation of albumin level after treatment. SCr level was decreased in three of five patients with elevated SCr at baseline. The anti-autoantibodies and complements were also improved. Adverse events were of grades 1–2 and included transient thrombocytopenia, gastrointestinal symptoms and acroesthesia. During a 6- to 24-month follow-up period, three patients achieved complete remission, and one had partial remission. However, one patient received renal replacement therapy. Conclusion Bortezomib combined with glucocorticoids reduces proteinuria, improves renal function and decreases anti-autoantibodies, with good tolerance and mild adverse events, thus representing an alternative therapy for refractory LN and warranting further study.

Urinary Fibrinogen as a Predictor of Progression of CKD

BACKGROUND AND OBJECTIVES Fibrinogen has been reported to be involved in kidney tubulointerstitial fibrosis and podocyte injury in mouse models. However, the relationship between urinary fibrinogen and kidney outcomes has not been clarified in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We evaluated 402 patients with CKD and kidney biopsies, including 101 with diabetic nephropathy, 94 with idiopathic membranous nephropathy, 55 with idiopathic FSGS, and 152 with IgA nephropathy. We quantified urinary fibrinogen by ELISA and tested associations with kidney histology and progression to ESRD. RESULTS Median (interquartile range) urinary fibrinogen-to-creatinine ratio was 536 (191-1461) ng/mg for patients with CKD, significantly higher than 2 (2-3) ng/mg for healthy controls (P<0.001). Urinary fibrinogen was positively correlated with urine protein (r=0.64; P<0.001) and interstitial fibrosis and tubular atrophy (r=0.10; P=0.04), and it was negatively correlated with eGFR (r=-0.20; P<0.001). Over a median follow-up period of 35 months (interquartile range, 24-78 months), 68 of 402 patients (17%) developed ESRD. Higher urinary fibrinogen level was associated with increased risk of ESRD (hazard ratio, 2.12; 95% confidence interval, 1.31 to 3.26) per log10 higher urinary fibrinogen-to-creatinine ratio (P=0.003) adjusting for age, sex, BP, urine protein, disease type, eGFR, and interstitial fibrosis and tubular atrophy. For prediction of ESRD, the addition of urinary fibrinogen to eGFR, urine protein, and BP increased the area under the receiver operating curve from 0.73 to 0.76, and the Akaike information criterion improved from 333.6 to 327.0. CONCLUSIONS Urinary fibrinogen correlated with interstitial fibrosis and tubular atrophy and was an independent risk factor for progression of CKD to ESRD.

Comparing the GFR estimation equations using both creatinine and cystatin c to predict the long-term renal outcome in type 2 diabetic nephropathy patients

AIMS This study aimed to determine whether eGFRcre-cys and its slope could improve the prediction of the long-term renal outcome in patients with type 2 diabetic nephropathy (DN). METHODS The cross-sectional and longitudinal analyses included 501 type 2DN patients from 2003 to 2009. GFR was estimated using either eGFRcre-cys or the serum creatinine-based equation (eGFRcre) or the cystatin C-based equation (eGFRcys), and was classified into 3 categories (≥90, 60-90, ≤60ml/min per 1.73m2). The proportion of patients was evaluated in each creatinine-calculated eGFR category for which the category was reclassified based on either cystatin C or the combined measurement. Long-term changes in eGFRcre-cys, eGFRcys and eGFRcre were estimated using linear mixed effect models. The receiver operating characteristic (ROC) curves was applied to study the sensitivity and specificity of different eGFR slopes for predicting the renal endpoint. RESULTS In the cross-sectional analyses, eGFRcre was overestimated compared to eGFRcre-cys [median bias -8.5 (95% CI: -25.01, 1.21)]. The reclassification of eGFRcre to a higher value was associated with an increased risk of ESRD [OR: 4.01 (95% CI: 2.36 to 6.82)]. In the longitudinal analyses for predicting end-stage renal disease (ERSD), the ROC curves for eGFRcre-cys (AUC=0.86±0.03) over 24months were increased compared with the ROC curves for eGFRcre and eGFRcys (p<0.05). CONCLUSIONS The study suggests that the eGFRcre-cys equation may be more precise and sensitive for predicting the renal outcome in T2DN patients. Tracking renal decline using eGFRcre-cys may be used as a surrogate for determining the renal endpoint in a clinical setting.

Phosphorus is an independent risk factorfor the progression of diabetic nephropathy

BACKGROUND Serum phosphorus is thought to be an important risk factor for the progression of chronic kidney disease (CKD). However, the association of serum phosphorus with disease progression in patients with different causes of kidney diseases remains to be elucidated. OBJECTIVES The aim of this study was to estimate the effect of serum phosphorus on disease progression in 2 cohorts of CKD with different causes. MATERIAL AND METHODS A total of 591 patients with diabetic nephropathy and 957 patients with IgA nephropathy from the National Clinical Research Center of Kidney Diseases, Nanjing, China, with biopsy-proven kidney disease, stage 1-4 CKD and a follow-up of at least 1 year were recruited. We evaluated the relationship between the baseline phosphorus category and the disease progression in the 2 cohorts. RESULTS Multivariate Cox regression analyses indicated that the risk of the endpoint event was 1.68-fold higher (95% confidence interval (CI): 0.95-2.91) in IgA nephropathy patients and 2.88-fold higher (95% CI: 1.12-5.04) in diabetic nephropathy patients with the highest quartile of serum phosphorus compared with the risk of those with the lowest quartile. CONCLUSIONS The association of serum phosphorus with the progression of CKD may vary in specific CKD patient subgroups. Serum phosphorus is independently associated with the progression of kidney disease in patients with diabetic nephropathy.