Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial

Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function.     

Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study

BACKGROUND: 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). METHODS: A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2 g per day (N= 21) or placebo (N= 13). After 36 months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis. RESULTS: 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 3 years. 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. CONCLUSION: In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results.     

Role of proteinuria reduction in the progression of IgA nephropathy

Proteinuria has been shown to play a causal role in the progression towards ESRD of IgA nephropathy (IgAN). We demonstrated that steroids are effective in reducing proteinuria and preserving renal function. AIM: to evaluate the long-term effect of steroids in IgAN patients (6th year evaluation) and better clarify the role of proteinuria reduction in slowing down the progression. METHODS: multicenter randomized controlled trial of 86 adult IgAN patients with serum creatinine < or = 1.5 mg/ dL and moderate proteinuria. They received either supportive therapy or methylprednisolone 1-g i.v. for three days at months 1, 3, and 5, plus oral prednisone (0.5 mg/kg every other day for six months). RESULTS: Proteinuria significantly decreased in the treated patients (from 2.0+/-0.60 g/24 h at baseline to 1.0+/-0.68 g/24 h at six months) and remained stable till the 6th year (0.67+/-0.5 g/24 h), it slightly decreased in the control group. Six-year renal survival was significantly better in the steroid than in the control group: 9 patient (20.9%) in the steroid group and 15 (34.8%) in the control group reached the primary end-point of a 50% increase in serum creatinine from baseline. Five controls and none of the steroid-treated patients started dialysis. Steroid-treated patients did not experience any major side effects during follow-up. CONCLUSIONS: Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN patients. Early reduction of proteinuria could also be marker of a persistent reduction in its levels over time and of a better outcome in the long term.     

ROLE OF PROTEINURIA REDUCTION IN THE PROGRESSION OF IgA NEPHROPATHY

Proteinuria has been shown to play a causal role in the progression towards ESRD of IgA nephropathy (IgAN). We demonstrated that steroids are effective in reducing proteinuria and preserving renal function. Aim: to evaluate the long-term effect of steroids in IgAN patients (6th year evaluation) and better clarify the role of proteinuria reduction in slowing down the progression. Methods: multicenter randomized controlled trial of 86 adult IgAN patients with serum creatinine ≤1.5 mg/dL and moderate proteinuria. They received either supportive therapy or methylprednisolone 1-gi.v. for three days at months 1, 3, and 5, plus oral prednisone (0.5 mg/kg every other day for six months). Results: Proteinuria significantly decreased in the treated patients (from 2.0 ± 0.60 g/24 h at baseline to 1.0 ± 0.68 g/24 h at six months) and remained stable till the 6th year (0.67 ± 0.5 g/24 h); it slightly decreased in the control group. Six-year renal survival was significantly better in the steroid than in the control group: 9 patient (20.9%) in the steroid group and 15 (34.8%) in the control group reached the primary end point of a 50% increase in serum creatinine from baseline. Five controls and none of the steroid-treated patients started dialysis. Steroid-treated patients did not experience any major side effects during follow- up. Conclusions: Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN patients. Early reduction of proteinuria could also be marker of a persistent reduction in its levels over time and of a better outcome in the long term.     

Conversion from mycophenolate mofetil to azathioprine in high-risk renal allograft recipients on cyclosporine-based immunosuppression

OBJECTIVE: In a randomized control trial of mycophenolate mofetil (MMF) versus azathioprine (AZA) with cyclosporine and steroids, we demonstrated that MMF reduced acute rejection (AR) among renal allograft recipients (RTX) who were of low to moderate risk. However, 10% had AR when converted from MMF to AZA at 6 months, postrenal transplantation (RT). Two clinical markers, abnormal serum creatinine (SCr) and proteinuria at 6 months, post-RT, were associated with AR postconversion. The present study examined the safety of such conversion in selected high-risk RTX at 1 year of MMF therapy. METHODS: Thirteen high-risk RTX receiving MMF for either high panel reactive antibody (n = 9) or following AR (n = 4), with normal SCr and no proteinuria at 1 year, were selected for conversion. The incidence of AR, adverse events, and renal parameters (SCr, creatinine clearance, proteinuria) at 6 months postconversion was evaluated. Eight high-risk RTX who did not meet these selection criteria were retrospectively reviewed and used as controls. RESULTS: Renal parameters (SCr 123 +/- 26 vs 129 +/- 27 mumol/L; pre- vs postconversion) were not significantly different; no episodes of AR or proteinuria were documented. Azathioprine was discontinued in two patients due to leukopenia. In the control group, one patient had graft loss from chronic rejection, whereas one developed posttransplant lymphoproliferative disease necessitating MMF withdrawal. CONCLUSION: These results suggest that selective conversion from MMF to AZA after 1 year is safe, even in high-risk RTX. Normal SCr and absence of proteinuria are good screening parameters to identify patients at low risk for AR following such conversion.     

"Point of no return (PNR)" in progressive IgA nephropathy: significance of blood pressure and proteinuria management up to PNR

BACKGROUND: Based on observations of the clinical course in patients with IgA nephropathy (IgAN), D'Amico et al proposed the concept of the "point of no return (PNR)", after which progression to end-stage renal disease (ESRD) becomes inevitable. They reported that the approximate PNR is serum creatinine (sCr) 3.0 mg/dL. METHODS: To confirm the PNR and to clarify the factors affecting renal function deterioration in IgAN patients, we analyzed the sequential data of those with 1.2 or= 102 mmHg and/or urinary protein (UP) score >or= 2.0 with sCr up to 2.0 mg/dL was significantly poor. Multivariate analysis using the Cox's proportional hazards model, identified only MBP and UP during the course until sCr reached 2.0 mg/dl as independent prognostic factors for ESRD, having hazard ratios of 2.56 (per 10 mmHg; 95% confidence interval (95% CI) 1.08-6.05) and 4.37 (per 0.5 point; 95% CI 1.36-14.1), respectively. CONCLUSIONS: We confirmed PNR as a sCr level of 2.0 mg/dL (equivalent to estimated glomerular filtration rate (GFR) of 30-35 mL/min/1.73m2) during the course of IgAN in Japan. Proper management of both BP and UP until sCr has reached PNR is essential to arrest the progression to ESRD in IgAN.     

Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy

BACKGROUND: Mycophenolate mofetil (MMF) is increasingly used to treat primary glomerulopathies. Its effectiveness in IgA nephropathy (IgAN) remains unclear. METHODS: Forty IgAN patients with persistent proteinuria (>1 g/24 hours) despite conventional treatment with blockers of the renin-angiotensin system were randomized to receive MMF for 24 weeks (group 1) or continue conventional therapy (group 2), and followed for 72 weeks. The primary end point was reduction of proteinuria by 50% or more over entry level. RESULTS: Sixteen patients (80%) in group 1 versus six patients (30%) in group 2 reached the primary end point (P= 0.0019). Time-averaged change in proteinuria showed a significant decline in group 1, while control subjects displayed a modest rise (P= 0.003). By 72 weeks, the mean proteinuria was 62.0 +/- 7.7% (P= 0.003) and 120.5 +/- 14.1% (P= 0.351) that of the corresponding baseline value in group 1 and group 2, respectively. There was concomitant increase in serum albumin and decrease in serum IgA levels in group 1 but not group 2 patients. Baseline histologic grades, blood pressure control, and the rates of change in serum creatinine and creatinine clearance were not different between the two groups. Normalization in binding of polymeric IgA to cultured mesangial cells and serum interleukin-6 (IL-6) levels, which sustained to study end, was observed in group 1 but not group 2 subjects. CONCLUSION: In selected patients with IgAN, MMF is effective in lowering proteinuria and ameliorating some of the putative pathogenetic abnormalities.     

Validation of some pathophysiological mechanisms of the CKD progression theory and outcome prediction in IgA nephropathy

Background: The "remnant kidney" chronic kidney disease (CKD) progression theory based on hemodynamic, proteinuric and inflammatory mechanisms consequent to nephron loss has not been confirmed in a human disease. The aim of this study was to evaluate whether some of these mechanisms are present in IgA nephropathy (IgAN) and predict functional outcome. Methods: In 132 IgAN patients (68 untreated, 64 angiotensin-converting enzyme inhibitor [ACEi]-treated) fractional excretion of IgG (FEIgG) and alpha1-microglobulin, proteinuria/day and beta-NAG excretion were divided by percentage of nonglobally sclerotic glomeruli ("surviving glomeruli" [SG]) to assess the effective glomerular loss and tubular load of proteins in surviving nephrons. Proteinuric markers were compared between 4 SG groups: group 1: <=50%; group 2: >50% and <80%; group 3: >=80% and <100%; and group 4: 100%. The outcome prediction (estimated glomerular filtration rate [eGFR] improvement and stability, progression) was assessed comparing low- and high-risk groups for each marker. Results: Proteinuric markers showed increasing values in parallel with reduction of percentages of SG (p<0.0001). FEIgG/SG, 40-fold higher in patients with SG <=50% vs. SG=100% (0.00040 ± 0.00039 vs. 0.00001 ± 0.00002, p<0.0001), was the most powerful outcome predictor: in ACEi-untreated patients, FEIgG/SG less or greater than 0.00010 predicted eGFR improvement and stability (88% vs. 12%, p<0.0001) and end-stage renal disease (ESRD) + eGFR reduction >=50% (2% vs. 87.5%, p<0.0001); ACEi treatment reduced ESRD+eGFR reduction >=50%: 36% vs. 87.5% (p=0.002). In patients with FEIgG/SG <0.00010 the eGFR increase is significantly higher in ACEi-treated for >=70 months versus ACEi-untreated with follow up >=70 months (+35% ± 23% vs. +13% ± 8%, p=0.004). Conclusions: In IgAN, progressive nephron loss is associated with an increase of proteinuric markers of glomerular and tubular damage. FEIgG/SG is the best outcome predictor. These data represent the first validation in a human disease of some pathophysiological mechanisms of CKD progression theory.     

Prospective study on renal outcome of IgA nephropathy superimposed on diabetic glomerulosclerosis in type 2 diabetic patients.

BACKGROUND AND METHODS: In order to examine the clinical outcome of IgA nephropathy (IgAN) superimposed on diabetic glomerulosclerosis in type 2 patients we studied 36 Chinese patients (26 men, 10 women), who were recruited for renal biopsy when they had proteinuria of more than 1 g/day. Twenty-seven had isolated diabetic glomerulosclerosis and nine had IgAN superimposed on diabetic glomerulosclerosis (combined). Renal function was assessed by serial serum creatinine, 24-h urine protein and creatinine measurements. Patient survival rate, incidence of end-stage renal disease (ESRD), blood pressure, and glycaemic control status were determined. RESULTS: The age at the time of renal biopsy was younger for the combined group when compared with the diabetic glomerulosclerosis group (44+/-3.6 vs 58+/-2.1 years, P=0.006). The duration of diabetes was, however, similar for the two groups (8.0+/-2.3 vs 6.7+/-1.2 years, P=NS). After a mean follow-up of 31.6+/-15.3 months, 15 patients (one in the combined group and 14 in the diabetic glomerulosclerosis group) developed ESRD. Nine patients (all in the diabetic glomerulosclerosis group) died during follow-up. With similar glycaemic and blood pressure control, the two groups had comparable rate of decline of creatinine clearance (CrCl) (-0.73+/-0.26 vs -0.73+/- 0.18 ml/min/1.73 m(2)/month, P=NS), final serum creatinine (363+/-134 vs 426+/-52 micromol/l, P=NS) and proteinuria levels (4.3+/-0.9 vs 4.4+/-0.6 g/day, P=NS), as well as CrCl (44.1+/-19.0 vs 33.4+/-6.9 ml/min/ 1.73 m(2), P=NS). CONCLUSION: It is concluded that the superimposed IgAN does not significantly alter the medium-term clinical outcome of patients with diabetic glomerulosclerosis.     

Long-term outcome of adding mycophenolate mofetil to tacrolimus for nephrotoxicity following liver transplantation

Mycophenolate mofetil (MMF) has no known nephrotoxicity. This report examines the outcome in patients who received MMF for renal impairment on tacrolimus-based immunosuppression. From 1995 to 1996, twelve liver transplantation (LTx) patients (mean age 54.6 years) with serum creatinine >1.8 mg/dl were included in the study. MMF was introduced and tacrolimus dose was reduced by 30-50%. Each patient was followed for 6 years. Renal function showed improvement in seven patients, deterioration in four, and no change in one patient. Overall mean serum creatinine decreased from 2.5 to 1.9 mg/dl at 6 months but increased to 2.2 mg/dl at 18 to 24 months. After that, renal function remained stable for 72 months. Iothalamate clearance showed 18.5% improvement at 1 year. Three patients developed renal failure. Six patients died in the follow-up period. Addition of MMF with reduced tacrolimus dose resulted in sustained improvement in renal function in 58% of patients.     

Angiotensin-converting enzyme genotype and outcome in pediatric IgA nephropathy

Angiotensin-converting enzyme (ACE) I/D polymorphism has been implicated as a genetic marker for progression of glomerular disease. Studies of ACE genotypes in adults with IgA nephropathy (IgAN) have yielded conflicting results. We performed ACE genotyping on 79 patients with IgAN diagnosed prior to age 18 years who had either progressed to end-stage renal disease (ESRD) or are now more than 5 years post biopsy. Mean follow-up was 14.8 years for those with normal renal function. Forty-three (54.4%) subjects had normal renal function and a normal urinalysis at last evaluation. Sixteen (20%) progressed to ESRD and 1 has chronic renal insufficiency. Kaplan-Meier survival curves for progression to ESRD did not differ significantly for the ACE DD, ID, and II genotype groups (P=0.095, log-rank test). By univariate analysis, presence of hypertension and degree of proteinuria at diagnosis, and unfavorable histology but not ACE genotype, was significantly associated with progression to ESRD. In the Cox proportional hazards model that included grade of proteinuria, the ACE D allele was a significant independent predictor of outcome with a hazard ratio of 2.37 (P=0.031). Our data, while inconclusive, suggest that the ACE D allele may associate with poor outcome in pediatric IgAN.     

Mycophenolate mofetil monotherapy in liver transplant recipients

Kriss M, Sotil EU, Abecassis M, Welti M, Levitsky J. Mycophenolate mofetil monotherapy in liver transplant recipients.
Clin Transplant 2011: 25: E639–E646. © 2011 John Wiley & Sons A/S. Abstract:  Introduction: Complete conversion of calcineurin inhibitor (CNI) immunosuppressant therapy to non‐nephrotoxic agents such as mycophenolate mofetil (MMF) is controversial, but may be safe in selected patients, although appropriate protocols and long‐term benefits of conversion are not well reported. Methods: We analyzed all liver transplant (LT) recipients at our institution who were converted from CNI‐based therapy to MMF monotherapy because of renal dysfunction (n = 23) and compared them with patients remaining on CNI‐based therapy (n = 23). Renal function, rejection episodes, and markers of CNI‐related comorbidities (lipid profile, blood pressure, and glycosylated hemoglobin) were noted. Results: Overall, serum creatinine (SCr) and calculated glomerular filtration rate improved on MMF monotherapy. This improvement was significant when compared with patients who remained on CNI‐based therapy. Improvement was most pronounced in patients with milder renal dysfunction (SCr <2.2 mg/dL prior to conversion) (n = 14) with decrease in SCr from 1.63 ± 0.29 to 1.34 ± 0.26 mg/dL (p = 0.02) at last follow‐up. Five patients on MMF monotherapy (21.7%) progressed to end‐stage renal disease (ESRD), while only two (8.7%) had rejection episodes following conversion. Clinical markers of CNI‐related comorbidities also improved. MMF monotherapy was well tolerated. Conclusion: In summary, our data support the safety and efficacy of CNI to MMF monotherapy conversion.     

15-Deoxyspergualin and cyclophosphamide, but not mycophenolate mofetil, prolong survival and attenuate renal disease in a murine model of ANCA-associated crescentic nephritis.

BACKGROUND: Here we compare the efficacy of cyclophosphamide (CYC) for treatment of crescentic nephritis (CGN) with the newer immunosuppressants 15-deoxyspergualin (DSG) and mycophenolate mofetil (MMF) in SCG/Kj mice, an inbred mouse strain that spontaneously develops CGN, systemic necrotizing vasculitis and antineutrophil cytoplasmic antibodies (ANCAs). METHODS: Mice were randomly assigned to intraperitoneal treatment with either DSG (2 mg/kg/day), CYC (50 mg/kg/week), MMF (60 or 100 mg/kg/day) or vehicle (VEH, dextrose 5% 0.3 ml/day) beginning at the 10th week of life. ANCA, blood urea nitrogen (BUN) and proteinuria were determined in all animals regularly, and survival was calculated. Renal histology was obtained in the 18th week of life in the MMF- or VEH-treated groups and in the 24th week in DSG- or CYC-treated animals. RESULTS: Mean survival in VEH-treated animals was 123 days. At that point, survival was 100% in the CYC- or DSG-treated animals (P<0.001). Survival in the MMF group (pooled data) was not significantly different from the VEH-treated animals [MMF, 117 days (95% CI 108-127)]. BUN (18th week, CYC 43+/-9 mg/dl and DSG 36+/-6 mg/dl vs VEH 73+/-28 mg/dl, P<0.001, MMF 66+/-26 mg/dl), 24 h proteinuria (18th week, CYC 0.4+/-0.2 mg and DSG 0.7+/-0.6 mg vs VEH 2.7+/-3 mg, P<0.001, MMF 2.2+/-3 mg) crescent formation (18th week, VEH 42+/-9%, MMF 39+/-11%; CYC 5+/-2% and DSG 22+/-7% vs VEH, P<0.05), glomerular immune complex deposition, and ANCA formation were significantly improved in CYC- and DSG- but not in MMF-treated animals when compared with controls. CONCLUSION: DSG and CYC, but not MMF, prolong life, limit renal damage and prevent autoantibody formation in SCG/Kj mice.     

Clinicopathologic study on prognostic markers in IgA nephropathy

BACKGROUND/AIM: Few prognostic markers have found general acceptance in IgA nephropathy (IgAN). The aim of the present study was to search for significant predictor(s) at the time of biopsy. METHODS: Fifty-five patients with IgAN undergoing evaluation and treatment at our institution were examined regarding clinicopathologic features at the time of renal biopsy and, if possible, at follow-up. Factors predictive of outcome were evaluated. Renal histopathology was quantified using a glomerulosclerosis index (GSI), a tubulointerstitial index (TII), and a crescent index (CI). RESULTS: The serum creatinine concentration (S-Cr) showed positive correlations with proteinuria and serum total cholesterol concentration, as well as with histopathologic findings. Heavy proteinuria (> or =3.0g/24 h) was associated with higher S-Cr and greater severity of pathologic abnormalities than with milder proteinuria. At follow-up, 6 patients progressed to chronic renal insufficiency, in whom the S-Cr increased by at least 50% to reach or exceed 1.5 mg/dl (132.6 micromol/l). By univariate analysis, elevated GSI, TII, and S-Cr, presence of nephrotic syndrome, elevated CI, and elevated total cholesterol were found to be negative predictors, in descending order of odds ratio. In multivariate analysis, however, only TII independently predicted unfavorable outcome. Conclusion: Renal biopsy in IgAN may be the most powerful predictor for renal outcome; an advanced tubulointerstitial lesion is unfavorable.     

Outcome of relapse in lupus nephritis: roles of reversal of renal fibrosis and response of inflammation to therapy

BACKGROUND: Renal relapse in lupus nephritis has been shown to have ominous prognostic significance with the majority of patients progressing to doubling of serum creatinine (CRX2). However, not all patients do so. This report explores the roles of response of inflammation to therapy and of glomerular scarring and interstitial fibrosis and their potential reversal to outcome of renal relapse. METHODS: Renal biopsies from 71 patients with lupus nephritis with an initial biopsy (Bx1) and systematic control biopsy (Bx2) after six months of therapy, as well as subsequent biopsies for clinical indications, were studied. The relationships of morphologic factors to renal relapse and its outcome as well as to CRX2 and end-stage renal disease (ESRD) were analyzed. Cox proportional hazards modeling was used to assess association of morphologic variables with outcomes. RESULTS: Renal interstitial fibrosis and glomerular segmental scarring were partially reversible in 17 and 11 patients, respectively. This decline was associated with an excellent prognosis, with only one patient in each group (5.9% and 9.1% respectively) progressing to CRX2. All 18 patients who progressed to CRX2 either failed to respond to therapy (7 patients) as defined by normalization of serum creatinine (SCr) and reduction of proteinuria to < or =1 g/day, or relapsed after initial response (11 patients), as defined by recent rise of SCr > 50% and/or proteinuria > 3.5 g/day. However, relapse also occurred in 11 of 47 other patients without progression to CRX2. These patients showed a greater initial response of inflammation and deposits to therapy and fibrous lesions partially reversed in the period prior to relapse, so that active lesions were superimposed on a lower level of chronic lesions. By contrast, chronic lesions mounted steadily in those who progressed to CRX2. Cox proportional hazards modeling indicated a strong association of inflammatory variables with renal relapse, CRX2 and ESRD. However, the extent of immunoglobulin deposits was not significantly associated with any outcome. Finally, we found that failure of disease to remit also is associated with a high rate of CRX2 (64.8% vs. 13.0%, P = 0.00034). CONCLUSIONS: Interstitial fibrosis and glomerular scarring in systemic lupus erythematosus are partially reversible, and this reversal is attended by an excellent outcome. The outcome of renal relapse is determined by the initial response of inflammatory and chronicity elements to therapy, those with prior partial reversal of interstitial and glomerular scarring having a good outcome, and those in whom fibrotic lesions have continued to increase and have a poor outcome. Inflammatory variables appear to be more important in determining outcome than immunoglobulin deposits.     

Progression to end-stage renal disease in children with posterior urethral valves

Diagnostic and therapeutic strategies in boys with congenital posterior urethral valves (PUV) have much improved in past decades, but the impact of these changes on the progression to end-stage renal disease (ESRD) has rarely been investigated. We followed renal function in 20 boys with PUV from diagnosis to ESRD. From the first observation period (1969–1978) to the second period (1979–1992) we found a marked drop in age at diagnosis, at valve resection, at first increase of serum creatinine (SCr), and at onset of ESRD. The progression was analyzed by calculating the slope of 1/SCr and the probability of renal survival. In all patients combined, renal survival at the age of 10 years was 35%. In children undergoing valve resection in the 1st year of life, renal survival was worse than in those undergoing later surgery (15% vs. 65% after 10 years, P=0.006). Patients with a SCr>1.2 mg/dl before the age of 12 months progressed more rapidly to ESRD than those attaining this level later. The lower the minimum level of SCr observed after initial surgery, the older the patient at the onset of ESRD. The presence of renal dysplasia or hypoplasia, but not of vesicoureteric reflux, was associated with a more rapid progression. Mean body height at ESRD was −2.3±1.3 standard deviation score compared with controls, and was lower if PUV was diagnosed before the age of 6 months. Received August 10, 1997; received in revised form December 29, 1997; accepted January 2, 1998     

Does angiotensin blockade influence graft outcome in renal transplant recipients with IgA nephropathy?

BACKGROUND: IgA nephropathy (IgAN) is a frequent cause of end-stage renal disease (ESRD) and recurrent disease causes deterioration and graft loss in transplant recipients. No definitive management is known to reduce the risk or severity of recurrent IgAN, and the evidence to support the use of renin-angiotensin system blockade in such patients is limited. METHODS: All 1137 renal transplants performed at the Belfast City Hospital over a 27-year period were reviewed. A total of 75 patients with ESRD due to biopsy-proven IgAN were identified; 39 of them had been prescribed an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-II type I receptor blocker (ARB). RESULTS: The two groups were well-matched in terms of demographic details, immunosuppressive regimens and duration of follow-up (median 65 months, range 18-261 months). The 5- and 10-year graft survivals were higher in those prescribed ACEi/ARB therapy compared with those who were not, although these differences did not reach statistical significance (92.9 vs 86.5%; P = 0.34 and 81.6 vs 72.7%; P = 0.32, respectively). These results were similar when censored for death with a functioning graft. In the group where an ACEi/ARB was not prescribed, all four with biopsy-proven recurrent IgAN progressed to ESRD, compared with three out of nine in the group treated with an ACEi/ARB. CONCLUSIONS: In transplant recipients with ESRD due to biopsy-proven IgAN, a trend towards improved 5-year and 10-year graft survival was seen in those prescribed ACEi/ARBs. All with recurrent IgAN in their grafts who were not treated with ACEi/ARB therapy progressed again to ESRD.     

Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy

This study examines the clinical features, pathologic findings, and outcome of 24 patients with biopsy-proven lithium toxicity. The patient population was 50% male, 87.5% Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). Mean duration of lithium therapy for bipolar disorder was 13.6 yr (range, 2 to 25). All patients were biopsied for renal insufficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), with associated proteinuria >1.0 g/d in 41.7%. Nephrotic proteinuria (>3.0 g/d) was present in 25%. Other features included nephrogenic diabetes insipidus in 87% and hypertension in 33.3%. Renal biopsy revealed a chronic tubulointerstitial nephropathy in 100%, with associated cortical and medullary tubular cysts (62.5%) or dilatation (33.3%). All of the renal cysts stained for epithelial membrane antigen, while 51.4% stained with lectin Arachis hypogaea, and only 3.8% stained with Tetragonolobus purpureas, indicating they originated from distal and collecting tubules. The degree of tubular atrophy and interstitial fibrosis was graded as severe in 58.3%, moderate in 37.5%, and mild in 4.2% of cases. There was a surprisingly high prevalence of focal segmental glomerulosclerosis (50%) and global glomerulosclerosis (100%), sometimes of equivalent severity to the chronic tubulointerstitial disease. The significant degree of foot process effacement (mean 34%, five of 14 cases with >50%) suggests a potential direct glomerular toxicity. Focal segmental glomerulosclerosis correlated with proteinuria >1.0 g/d (P = 0.0014, Fisher exact test). Despite discontinuation of lithium, seven of nine patients with initial serum creatinine values >2.5 mg/dl progressed to end-stage renal disease (ESRD). Only three patients, all with initial serum creatinine <2.1 mg/dl, had subsequent improvement in renal function. By Kaplan-Meier survival analysis, the only significant predictor of progression to ESRD was serum creatinine >2.5 mg/dl at biopsy (P = 0. 008). In conclusion, lithium nephrotoxicity primarily targets distal and collecting tubules, with a higher incidence of proteinuria and associated glomerular pathology than recognized previously. Renal dysfunction is often irreversible despite lithium withdrawal, and early detection is essential to prevent progression to ESRD.     

Rapamycin at six years can exhibit normal renal function without proteinuria or neoplasia after renal transplantation. A single-center experience

Currently, long-term experience with Rapamune (RAPA) after renal transplantation is scarce. We present our experience with RAPA in patients who were included in clinical trials. Between 1996 and 1999, 27 renal transplant patients received RAPA alone or in combination with cyclosporine (CyA). We study 15 of them (9 males, 6 females; mean age 36 years) who are currently functioning with a mean follow-up of 6 years (range, 5.2-8 years). The presence of delayed graft function was 40% and acute rejection 26.6%, all of them controlled with steroids. Notably, no patients experienced an acute rejection episode after the first year. Among 15 patients, 12 received steroids, RAPA and CyA; and 3 received steroids, RAPA, azathioprine (AZA) or mycophenolate mofetil (MMF) for immunosuppression. At the end of follow-up, the situation was the opposite: 12 patients received steroids (2.5-5 mg/d) and RAPA associated with or without AZA/MMF, and 3 were maintained with steroids, RAPA and CyA. Renal function was excellent in the entire group: mean SCr 1.1 mg/dL (range, 0.7-1.8) with mean RAPA blood levels (HPLC) of 11 ng/dL (range 8-16). Hyperlipidemia was universal with all patients (100%) receiving statins maintaining acceptable levels of cholesterol (mean 209 +/- 28 mg/dL) and tryglycerides (mean 154 +/- 76 mg/dL). Arterial hypertension present in 12 of 15 (80%) patients was controlled with a mean of 1.5 drugs. Notably, no patient presented with proteinuria, neoplasia, posttransplant diabetes, or cardiovascular events. In conclusion, these single-center results suggest that Rapamune may be useful in the long-run after renal transplantation. The presence of normal renal function and the absence of proteinuria and neoplasia in these renal transplant patients may have important clinical implications.     

Presentation, prognosis and outcome of IgA nephropathy in Indian adults

BACKGROUND: IgA nephropathy (IgAN) is not well characterized in India. This retrospective study of 478 patients with IgAN was performed to clarify the presenting features, prognostic factors and the renal survival rates of the disease. METHODS: Three hundred and forty-seven patients who had been followed on average for 27 months after diagnosis were divided into two groups based on renal function at diagnosis. In group 1 (229 patients), the creatinine clearance estimated by the Modification of Diet in Renal Disease formula was <85 mL/min and in group 2 (118 patients) it was >/=85 mL/min. RESULTS: The predominant modes of presentation were nephrotic syndrome, hypertension and renal failure. Twenty-nine percent of patients had more than a 20% decline in renal function at the last follow up. Multivariate analyses with stepwise logistic regression identified hypertension (odds ratio (OR) 3.5), nephrotic range proteinuria (OR 3.4) and sclerosed glomeruli on biopsy (OR 4.1) to be independently associated with progression in group 1 and hypertension (OR 2.3) in group 2. Seventeen percent of patients progressed to end-stage renal disease (ESRD). Using multivariate analysis by the Cox model, four risk factors for developing ESRD were identified: hypertension (hazard ratio (HR) 3.1); nephrotic proteinuria (HR 1.9); interstitial fibrosis (HR 2.5); and sclerosed glomeruli (HR 1.8). The renal survival rates at 1, 5 and 10 years were 84, 55 and 33%, respectively, with a median renal survival of 61 months from the time of biopsy. CONCLUSION: The relatively rapid rate of progression of IgAN in India is suggestive towards a 'malignant' nature of the disease in this country.