Lei-Shi Li

Successful Treatment of Class V+IV Lupus Nephritis with Multitarget Therapy

Treatment of class V+IV lupus nephritis remains unsatisfactory despite the progress made in the treatment of diffuse proliferative lupus nephritis. In this prospective study, 40 patients with class V+IV lupus nephritis were randomly assigned to induction therapy with mycophenolate mofetil, tacrolimus, and steroids (multitarget therapy) or intravenous cyclophosphamide (IVCY). Patients were treated for 6 mo unless complete remission was not achieved, in which case treatment was extended to 9 mo. An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy at both 6 and 9 mo (50 and 65%, respectively) than with IVCY (5 and 15%, respectively). At 6 mo, eight (40%) patients in each group experienced partial remission, and at 9 mo, six (30%) patients receiving multitarget therapy and eight (40%) patients receiving IVCY experienced partial remission. There were no deaths during this study. Most adverse events were less frequent in the multitarget therapy group. Calcineurin inhibitor nephrotoxicity was not observed, but three patients developed new-onset hypertension with multitarget therapy. In conclusion, multitarget therapy is superior to IVCY for inducing complete remission of class V+IV lupus nephritis and is well tolerated.

Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation

Abstract:  Objective:  Tacrolimus is an immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Cytochrome P450 (CYP) 3A and P‐glycoprotein (P‐gp, encoded by MDR1) play an important role in the absorption and metabolism of tacrolimus. The objective of this study was to evaluate whether or not CYP3A5*1/*3 or MDR1 C3435T polymorphisms are associated with the tacrolimus concentration per dose.

Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen Aα-Chain Amyloidosis

Mutations in the fibrinogen A alpha-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A alpha-chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0-12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.

Triptolide protects podocytes from puromycin aminonucleoside induced injury in vivo and in vitro

Extracts of Tripterygium wilfordii Hook F have been used to treat glomerulonephritis for more than 30 years in China with dramatic antiproteinuric effects. Triptolide, a diterpene triepoxide, is one of the major active components of these extracts. To clarify its antiproteinuric effects we induced podocyte injury by puromycin aminonucleoside. Triptolide effectively reduced the proteinuria induced by puromycin in nephrotic rats without reducing the glomerular filtration rate. The antiproteinuric effect was associated with improvement in the foot process effacement, a decrease in the podocyte injury marker desmin as well as the restoration of nephrin and podocin expression and distribution. In cultured mouse podocytes triptolide pretreatment prevented the puromycin-induced disruption of the actin cytoskeleton and microfilament-associated synaptopodin while protecting nephrin and podocin expression. Triptolide suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase activation while restoring RhoA signaling activity. These results show that triptolide ameliorates puromycin aminonucleoside-mediated podocyte injury in vivo and in vitro.

Obesity-Related Glomerulopathy in China: A Case Series of 90 Patients

BACKGROUND The epidemic of obesity has been paralleled by an increase in the incidence of chronic kidney disease. However, epidemiological data for obesity-related glomerulopathy (ORG) from developing countries, including China, are very limited. STUDY DESIGN Case series. ORG defined as body mass index (BMI) of 28.0 kg/m(2) or greater; urinary protein excretion of 0.4 g/24 h or greater, and glomerulomegaly (glomerular volume > 3.27 x 10(6) microm(3)) with or without focal segmental glomerulosclerosis (FSGS). SETTING & PARTICIPANTS 10,093 renal biopsy samples from patients obtained from February 2002 to November 2006 at the Research Institute of Nephrology, Nanjing University School of Medicine, China. PREDICTOR Obesity defined as a BMI of 28.0 kg/m(2) or greater. Subjects were divided into 3 groups: mild-obesity group with BMI of 28.0 to less than 30 kg/m(2), moderate-obesity group with BMI of 30 to less than 35 kg/m(2), and severe-obesity group with BMI of 35 kg/m(2) or greater. OUTCOMES & MEASUREMENTS Clinicoepidemiological and histopathologic characteristics of patients with ORG at the time of biopsy were described separately. RESULTS ORG was observed in 90 biopsy specimens (0.89%); frequency increased from 0.62% to 1.0% during the last 5 years (P = 0.02). Mean age was 37.5 +/- 9.3 (SD) years, 67% were men, mean BMI was 31.2 +/- 3.3 kg/m(2), waist circumference was 103 cm (range, 89.4 to 124 cm) in men and 96.5 cm (range, 88.5 to 113 cm) in women, waist-hip ratio was 0.95 +/- 0.07, and 100% had visceral obesity. Of the total, 49%, 37%, and 14% had mild, moderate, and severe obesity, respectively. Mean urinary protein excretion of subjects was 1.48 +/- 1.2 g/24 h; 51%, 39%, and 10% had proteinuria with protein of 0.4 to 1.0, 1.0 to 3.5, and greater than 3.5 g/d, respectively. Mean measured creatinine clearance (Ccr) was 109 +/- 32.2 mL/min/1.73 m(2), with 42%, 36%, and 22% with a Ccr greater than 120, 90 to 120, and less than 90 mL/min/1.73 m(2), respectively. Glucose dysmetabolism, insulin resistance, dyslipidemia, and hypertension were observed in 77%, 88%, 76%, and 63% of patients, respectively. FSGS was observed in 70%. Mean foot-process width was 534 +/- 176 nm. Foot-process fusion was seen in 36% of patients. Greater BMI was associated with greater proteinuria (P < 0.02), greater Ccr (P < 0.03), and greater foot-process width (P < 0.04). LIMITATIONS Inability to compute prevalence or incidence from case series. BMI was calculated at time of renal biopsy. CONCLUSIONS Most patients with ORG had mild obesity, visceral obesity, minor proteinuria, preserved Ccr, and FSGS.

Rhein Improves Renal Lesion and Ameliorates Dyslipidemia in db/db Mice with Diabetic Nephropathy

Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is purified from rhubarb (Rheum officinale), a widely used traditional Chinese herb. In our previous studies, rhein was shown to be effective in ameliorating diabetic renal pathological changes and attenuating hyperlipidemia. Statins have also been proven to ameliorate renal pathological changes associated with diabetic nephropathy (DN) through lipid-dependent and -independent mechanisms. We here study the protective and regulatory effects of rhein on renal injury and dyslipidemia in db/db mice with DN, using simvastatin as the control, and provide information on the mechanisms by which rhein protects against renal damage from DN. The results indicated that urinary albumin excretion (UAE) was reduced after 8 weeks of treatment in the rhein group, and 12 weeks in the simvastatin group. The morphometric analysis revealed that levels of extracellular matrix (ECM) significantly decreased in the rhein group after the full treatment course, but not in the simvastatin group. The more powerful effects of rhein on decreasing transforming growth factor-beta1 (TGF-beta1) and fibronectin immunohistochemistry expression in renal tissue were also observed. And the plasma levels of cholesterol (Chol), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and ApoE all decreased in both the rhein and the simvastatin groups. Together, our data suggested that both rhein and simvastatin regulate dyslipidemia. The powerful effect of rhein in renal protection is due to its widespread effects. Rhein is a new drug that can decrease lipid levels and protect against DN progression in a different fashion with simvastatin.

Mercury-Induced Membranous Nephropathy: Clinical and Pathological Features

BACKGROUND AND OBJECTIVES Long-term contact with mercury may induce membranous nephropathy (MN); however, the clinical pathologic features and pathogenesis of mercury-induced MN have not been investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The present study retrospectively evaluated 11 cases of mercury-induced MN to analyze its causes and its clinical and pathologic features. RESULTS A total of 10 women and 1 man ages 15 to 45 years were enrolled in the present study. Mercury exposure was caused by mercury-containing pills (five patients), skin lightening cream (four patients), hair-dyeing agents (one patient), and mercury vapor (one patient). The duration of contact with mercury ranged from 2 to 60 months, and the urinary mercury concentrations were 1.5 to 50 times higher than reference values. All patients presented with proteinuria and normal renal function; three had nephrotic syndrome. Light microscopy revealed thickened glomerular basement membrane and mildly proliferative mesangial cells. Acute tubulointerstitial injury occurred in three patients. The immunofluorescence findings showed granular deposits of IgG and C3 along the glomerular capillary wall, mostly accompanied by deposits of C4 and C1q. IgG1 and IgG4 (predominantly IgG1) deposits were observed along the glomerular capillary loops. Nine patients reached complete remission in follow-up after withdrawal from mercury exposure. CONCLUSIONS Deposits of IgG1 subclasses in renal tissues indicated that the pathogenesis of mercury-induced MN differs from that of idiopathic MN. It is important that clinicians are aware that mercury exposure should be considered a possible cause of membranous nephropathy.

Triptolide reduces proteinuria in experimental membranous nephropathy and protects against C5b-9-induced podocyte injury in vitro

Membranous nephropathy is a major cause of nephrotic syndrome in adults where podocyte injuries were found to mediate the development of proteinuria. Triptolide, a major active component of Tripterygium wilfordii Hook F, has potent immunosuppressive, anti-inflammatory and antiproteinuric effects. To study its antiproteinuric properties, we established an experimental rat model of passive Heymann nephritis and a C5b-9 injury model of podocytes in vitro. Treatment or pretreatment with triptolide markedly reduced established proteinuria as well as the titer of circulating rat anti-rabbit IgG antibodies in these nephritic rats, accompanied by a reduction in glomerular C5b-9 deposits. Expression of desmin, a marker of podocyte injury, diminished after triptolide treatment, whereas quantitative analysis of mean foot process width showed that effacement of foot processes was substantially reversed. In in vitro studies we found that triptolide deactivated NADPH oxidase, suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase, and restored RhoA signaling activity. Triptolide did not interfere with the formation of C5b-9 on the membrane of podocytes. Thus, triptolide reduces established heavy proteinuria and podocyte injuries in rats with passive Heymann nephritis, and protects podocytes from C5b-9-mediated injury.

Sex Differences in Estrogen Receptor Gene Polymorphism and Its Association with Lupus Nephritis in Chinese

Background/Aims: Lupus nephritis (LN) is a clinical heterogeneous autoimmune disease and genetic factors contribute to the development of LN. One of the most striking characteristics in LN is the high prevalence among childbearing women, as well as that its clinical manifestation differs in women and men, suggesting the role of sex hormones in its pathogenesis. Methods: ThePvuII and XbaI restriction fragment length polymorphism (RFLP) of estrogen receptor (ER) gene were analyzed in 245 biopsy-proven LN patients (58 males and 187 females) and 172 normal controls (101 males and 71 females) by PCR-RFLP. The clinical and pathological features of 49 male and 152 female LN patients with different genotypes were analyzed. Results: It was found that genotype PpXx, ppxx and Ppxx were three major genotypes of ER gene in both of lupus patients and control groups. The distribution of ER gene polymorphism was quite different in lupus patients of different genders. The frequency of the PpXx genotype in male LN patients was significantly higher than both the gender matched normal controls (p < 0.05) and the female LN patients (p < 0.05), while no difference was shown in the frequency of PpXx genotype between female LN patients and gender matched controls. Interestingly, skin rashes and arthritis were found more common in the patients with PpXx genotype. The frequency of hematological abnormalities and hypertension were higher in patients with ppxx genotype (p < 0.05), while capillary thrombi and glomerular sclerosis were more frequently complicated in the patients with ppxx genotype. In addition, the renal vasculitis and interstitial injury were more frequent in those with Ppxx genotype (p < 0.01). Conclusion: The distribution of ER gene polymorphism in LN patients is distinct with different gender. The PpXxgenotype of ER gene may be associated with the susceptibility of SLE in male. ER gene polymorphism is probably one of the genetic factors contributing to the development of clinical heterogeneity and sexually dimorphic manifestations of LN.

Obesity-Related Glomerulopathy: Body Mass Index and Proteinuria

BACKGROUND AND OBJECTIVES Obesity-related glomerulopathy (ORG) is an increasing cause of end-stage renal disease, but evidence concerning the effects of treatments is rather limited. This study was aimed at exploring the renoprotective effects of weight loss on patients with ORG. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 63 patients with renal biopsy-proven ORG had food and exercise intervention in the physician-supervised weight loss program and were divided into three groups on the basis of the percentage of weight change from baseline to follow-up: significant weight loss (>3% reduction in body mass index [BMI]), stable weight, or significant weight gain (>3% increase). Metabolic parameters and renal lesions were evaluated regularly for 2 years. RESULTS After 6 months, 27 patients lost weight by 8.29 +/- 4.00%, with a mean decrease in proteinuria of 35.3%, whereas 24 months later, 27 patients achieved a 9.20 +/- 3.78% reduction in BMI and a 51.33% reduction in urine protein secretion. The levels of serum triglyceride, serum uric acid, and BP were also decreased. Contrarily, in patients with increased BMI, urine protein was increased by 28.78%. Correlation analysis showed proteinuria was associated with BMI, serum triglyceride, and uric acid, and multivariate regression analysis indicated the changes in BMI were the only predictor of proteinuria (P < 0.01). CONCLUSIONS Weight loss intervention benefited remission of proteinuria in patients with ORG, whose function could not be replaced by conventional pharmacotherapy.