[Correlation between TGF-B gene promoter-509C/T polymorphism and IgA nephropathy in core families in Guangxi Zhuang Autonomous Region and the therapeutic effect of dendrobium].

OBJECTIVE: To investigate the correlation between transformation growth factor (TGF- B) polymorphisms and IgA nephropathy and the therapeutic effect of dendrobium on IgA nephropathy. METHODS: Polymerase chain reaction- restriction fragment length polymorphism (PCR- RFLP) and direct sequencing were used for analysis of 118 patients with IgA nephropathy from core families in Guangxi Zhuang Autonomous Region. The imbalanced transfer of TGF iso1-509 C/T in the affected offsprings was observed by transfer imbalance test and HRR analysis. The TGF-B genotype of the patients and the core family members were detected. The therapeutic effects of Dendrobium candidum combined with hormone and ACEI/ARB treatments were evaluated by observing the patient's urine protein (24 hUpr), serum albumin (ALB), creatinine (Scr) and urea nitrogen (BUN) levels. RESULTS: In the 118 patients with IgA nephropathy, we identified TGF-B 1 promoter -509C/T genotype CC in 32 (27.1%) cases, CT in 58 (49.2%) cases, and TT in 28 (23.7%) cases. In the core family of the patients, CC genotype was found in 33 (28.0%) cases, CT in 55 (46.6%) cases, and TT in 30 (28.0%) cases. The treatments significantly lowered 24 hUpr, Scr, and BUN levels (P > 0.05) in patients with CC genotype, significantly lowered 24 hUpr and BUN levels in patients with CT genotype (P < 0.05), and significantly lowered 24 hUpr and BUN level and increased (P < 0.05) ALB level (P < 0.01) in patients with TT genotype. CONCLUSIONS: There is no significant correlation between TGF-B promoter - 509C/T polymorphism and IgA nephropathy. The patients with CC genotype are sensitive to the treatments with hormone and ACEI/ ARB and show a stronger response to combined treatments with dendrobium.

Randomized controlled trial of mycophenolate mofetil in children, adolescents, and adults with IgA nephropathy.

BACKGROUND: Previous randomized controlled trials evaluating the efficacy of mycophenolate mofetil (MMF) in patients with immunoglobulin A nephropathy (IgAN) have produced varying results. STUDY DESIGN: Double-blind placebo-controlled randomized controlled trial. SETTING & PARTICIPANTS: 52 children, adolescents, and adults with biopsy-proven IgAN in 30 centers in the United States and Canada. Entry criteria: age older than 7 to younger than 70 years; urine protein-creatinine ratio (UPCR), ≥0.6g/g (males) or ≥0.8g/g (females); and estimated glomerular filtration rate ≥ 50mL/min/1.73m(2) (≥40mL/min/1.73m(2) if receiving angiotensin-converting enzyme inhibitor). Mean age, 32±12 (SD) years; 62% men; and 73% white. INTERVENTION: Lisinopril (or losartan) plus a highly purified omega-3 fatty acid (Omacor [Pronova Biocare]) was given to 94 patients for 3 months; 52 of the patients with persistent UPCR≥0.6g/g (males) and ≥0.8g/g (females) were randomly assigned to MMF or placebo (target dose, 25-36mg/kg/d) in addition to lisinopril/losartan plus Omacor. OUTCOMES: Change in UPCR after 6 and 12 months treatment with MMF/placebo and 12 months after the end of treatment. MEASUREMENTS: UPCR measured on 24-hour urine samples. Glomerular filtration rate estimated with the Schwartz (age < 18 years) or Cockcroft-Gault (age ≥ 18 years) formula. RESULTS: 44 patients completed 6 months of treatment with MMF (n=22) or placebo (n=22). The trial was terminated early at the recommendation of the Data Monitoring Committee because of the lack of benefit. No patient achieved a complete remission (UPCR<0.2g/g). Mean UPCRs at randomization and after 6 months were 1.45 (95% CI, 1.16-1.75) and 1.40 (95% CI, 1.09-1.70) for MMF and 1.41 (95% CI, 1.17-1.65) and 1.58 (95% CI, 1.13-2.04) for placebo, respectively. The mean difference in UPCR change between these groups (MMF minus placebo) was -0.22 (95% CI, -0.75 to 0.31; P=0.4). Adverse events were rare apart from nausea (MMF, 8.7%; placebo, 3.7%); one of these MMF patients withdrew. LIMITATIONS: Low patient enrollment and short follow-up. CONCLUSIONS: MMF did not reduce proteinuria significantly in patients with IgAN who had persistent proteinuria after lisinopril/losartan plus Omacor.

Advanced IgA nephropathy with impaired renal function benefits from losartan treatment in rats.

BACKGROUND: Treatment with angiotensin receptor blockers (ARBs) is successful in mitigating IgA nephropathy (IgAN), independent of blood pressure changes, but the therapeutic role of ARB in advanced IgAN with impaired renal function is to be ascertained. The present study was performed to investigate the effect of losartan on advanced IgAN induced by staphylococcal enterotoxin B (SEB) combined with 5/6 nephrectomy in rats. METHODS: Fifty-four male SD rats were randomly divided into three group: Rats in the model group were treated with SEB plus 5/6 nephrectomy, and those in the losartan group were gavaged with losartan (33.3 mg kg(-1 )d(-1)) besides the treatment with SEB plus 5/6 nephrectomy. The urine and blood biochemical changes of rats were tested. IgA, IgG, IgM and C3 depositions were studied dynamically with immunofluorescence. The renal tissue structures were observed under light microscopy. The expressions of TGF-ß1, FN, alpha-SMA and FGF-1 in rat renal tissues were determined with immunohistochemical methods and real-time PCR. RESULTS: At 12 weeks, rats with SEB treatment plus 5/6 nephrectomy showed gradually increased urinary red blood cell (URBC) with a gradual elevation of the 24 h urinary protein, serum BUN and Scr, but losartan treatment lowered the levels of 24 h urinary protein, serum BUN and Scr. A large number of IgA depositions in the mesangial area, glomerulosclerosis and tubulointerstitial fibrosis were found in the model group, and the losartan group showed relieved injury. The expressions of TGF-ß1, FN, alpha-SMA and FGF-1 were significantly elevated in the model. Losartan lessened their expressions. CONCLUSION: Losartan treatment can delay the progression of advanced IgA nephropathy with impaired renal function.

Wormwood (Artemisia absinthium) for poorly responsive early-stage IgA nephropathy: a pilot uncontrolled trial.

BACKGROUND: Inhibition of the renin-angiotensin system is a widely accepted approach to treat immunoglobulin A (IgA) nephropathy, whereas the role of fish oils as a supplement is controversial. Tumor necrosis factor α (TNF-α) is considered to be involved in the pathophysiologic process of this disorder. Recent in vitro and clinical observations that wormwood can decrease TNF-α levels has led us to investigate the effect of wormwood as a supplement in patients with IgA nephropathy. STUDY DESIGN: Pilot uncontrolled trial. SETTING & PARTICIPANTS: 10 patients with biopsy-proven IgA nephropathy, normal kidney function, and a history of at least 3 months of proteinuria with protein excretion > 500 mg/d and < 3,500 mg/d despite ongoing dual renin-angiotensin system blockade. INTERVENTION: The selected patients were given supplements of 1.8 g/d of thujone-free wormwood preparation for 6 months without discontinuing their renin-angiotensin system blockade. OUTCOMES: Proteinuria and blood pressure after intervention compared with baseline values. MEASUREMENTS: Monthly assessment of urine protein-creatinine ratio and blood pressure during the observation period. RESULTS: Urine protein-creatinine ratio decreased significantly from 2,340 ± 530 to 315 ± 200 mg/g at the end of the supplementation period (P < 0.001) and was stable during the supplement-free follow-up of another 6 months. Estimated glomerular filtration rate and endogenous creatinine clearance were unchanged during the entire study period. There was a moderate, but significant, decrease (P < 0.002) in mean arterial blood pressure. LIMITATIONS: Open uncontrolled trial including a small number of patients. CONCLUSIONS: Thujone-free wormwood with its favorable safety profile can be an alternative supplement to manage proteinuria in patients with IgA nephropathy.

Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy.

Renal tubulointerstitial injury plays an important role in the development of IgA nephropathy (IgAN), the most common form of glomerulonephritis. Few currently in use biomarkers can sensitively detect the earliest signs of renal tubular injury, hindering our efforts to launch preventive and therapeutic measures for this disorder in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that is rapidly released from not only neutrophils but also a variety of cell types upon inflammation and tissue injury. Its small molecular size and protease resistance could render it an excellent biomarker of renal injury in IgAN. In this study, we tested this hypothesis by measuring urinary levels of NGAL, creatinine and N-acetyl-beta-D-glucosaminidase (NAG) in 40 healthy individuals and 70 IgAN patients with various disease severities. The urinary NGAL levels and NGAL/creatinine values were significantly upregulated in Lee grade III IgAN patients, in correlation with progressive glomerular mesangial proliferation and tubulointerstitial injury. Compared with urinary NAG levels, the urinary NGAL levels elevated much more drastically and can be readily detected even in Lee grade II IgAN patients when their NAG levels showed almost no change. Our findings suggest the promising use of urinary NGAL as an early biomarker for tubulointerstitial injury of IgA nephropathy and perhaps other types of renal disease in general.

An "evidence-based" survey of therapeutic options for IgA nephropathy: assessment and criticism.

BACKGROUND: Immunoglobulin A (IgA) nephropathy is a worldwide disease that causes end-stage renal failure in 15% to 20% of patients within 10 years of the apparent onset of disease and in 30% to 40% of individuals within 20 years. Severity of renal lesions, serum creatinine level, and severe proteinuria are adverse prognostic indicators. No specific treatment has been established, but several approaches have been experimented. METHODS: We reviewed the literature and evaluated the quality of published randomized trials using standard methods and the quality of their reporting according to the revised version of the Consolidated Standards for Reporting Trials Statement. Meta-analyses of randomized trials on the efficacy of steroid treatment, cytotoxic agents, and fish oils on the outcome of renal function and daily proteinuria in patients with IgA nephropathy were performed. RESULTS: Only 10 randomized trials were available and included in the review. Their quality was very poor, and a limited amount of data was reported. Cytotoxic agents seem beneficial on both renal function (relative risk, 0.38; 95% confidence interval [CI], 0.22 to 0.66) and daily proteinuria (weighted mean difference [WMD], -1.16; 95% CI, -2.18 to -0.14) in patients with moderate to severe renal damage, steroids act mainly on proteinuria (WMD, -0.50; 95% CI, -0.78 to -0.21), and fish oils do not imply a particular benefit. This statement is based on the very limited and poor available published evidence. CONCLUSION: Only a few randomized trials, of low quality and inadequately reported, are available relating to treatment of IgA nephropathy. More properly designed and reported trials are necessary to reach a definitive assessment of this matter.

Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy.

BACKGROUND: Proteinuria (UP) >1.0 g/24 h at diagnosis is a well-known indicator of progressive renal disease in patients with IgA nephropathy (IgAN). To determine if persistent UP is a more sensitive marker for later progression of IgAN, the hypothesis was tested that the prior level and trend (slope) in UP for 1 year was better at predicting later end-stage renal disease (ESRD) (dialysis or transplant) than a current 24-h UP, serum creatinine (SC), SC slope, hypertension, or total glomerular histopathological score on index renal biopsy in an observational study of 154 high-risk patients enrolled in two clinical trials (IgAN 1, IgAN 2). METHODS: Measurements of 24-h UP and SC were made at time 0, 6 weeks, 6 months and 1 year in all patients, who were then followed for an additional 5.76 years and 1.63 years in the two studies, respectively. The Cox proportional hazards model was used to identify predictors of ESRD following the 1-year visit. RESULTS: Adjusting only for randomized treatment, nearly all UP variables (number of high readings, 1-year level, slopes), SC at 1 year, and SC trends (slopes) over the prior year were significantly associated with subsequent ESRD (all P values <0.05) in both studies. However, among the UP variables, the 1-year readings had the strongest association with ESRD in IgAN 1 (hazard ratio (HR), 95% CI, for a 1g increase: 1.5, 1.2,1.9), and the second strongest association (similar to UP trends) in IgAN 2 (1.4, 1.2,1.6). Males had lower rates of ESRD in both studies (IgAN 1 HR: 0.5, 0.2,1.2, P=0.11; IgAN 2 HR: 0.2, 0.1,0.6, P=0.002). In the multivariate analyses that examined all clinical and histological variables, 1-year levels of 24-h UP and SC, and female gender were independently associated with subsequent ESRD. CONCLUSION: In a high-risk patient with IgAN, the current 24-h UP and SC measurements are as good predictors of subsequent ESRD as UP and SC trends and levels over the prior year. Additionally, it appears that females have poorer outcomes than males.

The effect of fish-oil dietary supplement on the progression of mesangial IgA glomerulonephritis.

The effect of fish-oil dietary supplement on the rate of progression of renal failure in 11 patients with IgA nephropathy was investigated by comparing the slope of the plot of reciprocal serum creatinine versus time before and after supplement. After supplement, the slope significantly decreased in two patients, increased in two, and was not significantly altered in the remainder. Before supplement, serum IgA, IgA circulating immune complexes, and in-vitro Ig production were not significantly different from normal controls. After supplement, urinary protein transiently increased, serum IgA circulating immune complexes decreased, and serum triglyceride and in-vitro platelet aggregation tended to decrease. Only the change in serum IgG and spontaneous in-vitro IgG production correlated with the change in the rate of renal functional deterioration. No clinical or biochemical parameters before supplement predicted the subsequent response. In patients with IgA nephropathy, non-immune factors probably contribute to progression of renal failure, and in these patients fish-oil dietary supplement has either no demonstrable or an unpredictable effect.