Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Up to 40% progress to end-stage renal disease (ESRD) over 10-20 years. Currently, treatment is limited. We studied the use of mycophenolate mofetil (MMF) vs placebo in a group of North American IgAN patients at high risk for progressive disease. METHODS: Included were 32 patients aged 18-75 years from multiple centres who had their biopsies read at Columbia and who had at least 1 g of proteinuria per day plus at least two of the following risk factors: (i) male sex; (ii) hypertension >150/90 mmHg or requiring antihypertensive medications; (iii) creatinine clearance, measured by 24 h urine collection, <80 and >20 ml/min at time of enrolment; and (iv) presence of glomerulosclerosis or tubulointerstitial atrophy and fibrosis on renal biopsy. Patients were randomized to either 1 year of MMF, titrated up to a dose of 1000 mg bid, or placebo. Total follow-up was 2 years. All patients received angiotensin inhibition medication. The primary outcome was a 50% increase in baseline serum creatinine (SCr). Secondary outcomes were an increase of 0.5 mg/dl SCr, ESRD and a 50% reduction in proteinuria. RESULTS: The mean baseline SCr was 2.4 mg/dl. No statistically significant differences were observed for any outcome. Five of 17 who received MMF vs two of 15 patients in the placebo group reached a 50% increase in SCr (P = 0.4). In both groups, all patients who reached the primary outcome also reached ESRD. Ten who received MMF vs seven who received placebo had a 0.5 mg/dl increase in SCr (P = 0.7) Only three MMF and two placebo patients had a 50% reduction in 24 h proteinuria. No serious adverse events occurred in either group. CONCLUSION: No benefit was seen in patients who received MMF in this high risk group, probably reflecting the relatively advanced stage of disease of our population. We conclude that MMF is probably not effective in patients with IgAN who already have moderate renal insufficiency.     

Angiotensin-converting enzyme insertion/deletion polymorphism and prognosis of IgA nephropathy

BACKGROUND/AIM: Well-known factors for a poor prognosis in IgA nephropathy (IgAN) are hypertension, proteinuria, and renal insufficiency at the time of diagnosis. Also hypertriglyceridemia and hyperuricemia seem to play a role in the progression of IgAN. Angiotensin-converting enzyme (ACE) gene I/D polymorphism has been associated with cardiovascular diseases and with progression of IgAN. We, therefore, investigated the contribution of ACE gene I/D polymorphism in the prognosis of IgAN and its association with the other risk factors affecting the prognosis. METHODS: A total of 168 patients with IgAN were followed up for 6-17 (median 11) years from renal biopsy with respect to progression of renal disease defined as elevation of serum creatinine above 125 microM (1.4 mg/dl) in men or 105 microM (1.2 mg/dl) in women and over 20% from the baseline level. In addition to serum creatinine, the urinary protein excretion was evaluated at the time of renal biopsy and at the assessment visit at the end of the follow-up period. RESULTS: During the follow-up period, 26 (15%) patients showed progression of renal disease. Patients with ACE genotype II had a more favorable course than those with genotypes ID or DD. Although there were no significant differences among the ACE genotypes with respect to proteinuria > or =1 g/24 h at the time of renal biopsy, proteinuria > or =1 g/24 h was more frequent in patients with genotypes ID or DD than in those with genotype II at the end of the follow-up period. No associations were found between hypertension, serum lipids or serum urate, and ACE genotypes. CONCLUSIONS: Our results show that patients with ACE genotype II have a more favorable prognosis than those with genotypes ID/DD. Secondly, proteinuria (> or =1 g/24 h) found in patients with genotype II at diagnosis may improve, while in patients with genotypes ID/DD it is a more constant feature.     

Angiotensinogen gene variation and renoprotective efficacy of renin-angiotensin system blockade in IgA nephropathy

BACKGROUND: Blockade of the renin-angiotensin system (RAS) is well documented to be renoprotective; however, not all patients with glomerulonephritis respond well to this therapy. The interindividual variation in response to the RAS blockade may be in part genetically determined, whereas the results have been controversial. METHODS: We investigated whether the therapeutic efficacy of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blocker on renal prognosis is modified by the angiotensinogen gene (AGT) polymorphism in immunoglobulin A nephropathy (IgAN). In total, 259 patients with histologically proven IgAN were analyzed for clinical manifestations, renal survival, and their associations with AGT A(-20)C and M235T. RESULTS: The renal prognosis of 110 patients, who received ACE inhibitors/angiotensin receptor blocker during their clinical course, was significantly better than those without ACE inhibitors/angiotensin receptor blockers despite higher blood pressures and heavier proteinuria. The Cox proportional hazards regression model showed an increased hazard ratio (HR) for urinary protein (more than 1.0 g/day) of 3.346 (P = 0.0001), hypertension of 1.949 (P = 0.01), deteriorated renal function of 3.040 (P < 0.0001), no ACE inhibitor/angiotensin receptor blocker administration of 2.725 (P = 0.0004), and the T235 and C(-20) haplotype of 1.608 (P = 0.0322). Only in patients carrying at least one M235 and A(-20) haplotype did the administration of ACE inhibitors/angiotensin receptor blockers have no significant effect on the prognosis of renal function (Kaplan-Meier, log rank test, chi2 = 0.700; P = 0.4028), whereas it was significant in patients who had other haplotypes of AGT (chi2 = 11.805; P = 0.0006). CONCLUSION: This study provides evidence that the M235T and A(-20)C genotype of AGT can influence the therapeutic efficacy of a RAS blockade on the renal survival in IgAN.     

Combined treatment with steroids and azathioprine in IgA nephropathy: design of a prospective randomised multicentre trial

Corticosteroids have had variable success in IgA nephropathy (IgAN). Our previous trial with a six-month course of steroids in IgAN patients showed they were effective in reducing the risk of renal function deterioration and proteinuria, but this effect seemed to decrease in the long term. This new randomised trial was designed to prospectively evaluate whether adding low-dose azathioprine to steroids improves long-term renal survival in adult biopsy-proven IgAN patients with proteinuria > or = 1 g/24 h and plasma creatinine < or = 2.0 mg/dl. The patients will be treated with steroids (methylprednisolone 1 g i.v. for three consecutive days at months 1, 3 and 5, plus oral prednisone 0.5 mg/kg every other day for six months) plus azathioprine 1.5 mg/kg/day for six months or steroids alone with the same schedule. Altogether a minimum of 346 patients should be enrolled within a four-year recruitment period. The planned duration of follow-up is five years.     

Long-term renal survival in HIV-associated nephropathy with angiotensin-converting enzyme inhibition

BACKGROUND: Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is the most common cause of end-stage renal disease (ESRD) in HIV-infected patients. Angiotensin-converting enzyme (ACE) inhibition has previously shown a short-term benefit in HIVAN. This study examines the long-term effects of ACE inhibition on renal survival in HIVAN. METHODS: In this single-center prospective cohort study, 44 patients with biopsy-proven HIVAN were enrolled prior to the onset of severe renal insufficiency (serum creatinine or=two antiviral drugs for >or=30 consecutive days, CD4 lymphocyte count, initial median serum creatinine concentration, or proteinuria. Risk of renal failure was reduced with ACE inhibitors (RR = 0.003, P < 0.0001). Exposure to antiretroviral therapy did not have a significant impact on the risk of renal failure. Of the ACE inhibitor-treated group, 87.5% survived compared with 21.4% of the control group (P < 0.001). CONCLUSION: ACE inhibition initiated prior to severe renal insufficiency may offer long-term renal survival benefits in HIVAN. Diagnosis should be sought early in patients with clinical signs suggestive of HIVAN.     

Vasopeptidase inhibitor restores the balance of vasoactive hormones in progressive nephropathy

BACKGROUND: The mechanism(s) underlying greater renoprotection of combined blockade of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) by vasopeptidase over ACE inhibitors are ill defined. We previously found that progressive renal disease is associated with increased renal synthesis of endothelin-1 (ET-1) in the face of reduced generation of renal nitric oxide (NO) in the remnant kidney model. Here we compared changes in urinary excretion of ET-1 and nitrite/nitrate, markers of renal ET-1, and NO synthesis, respectively, and urinary cGMP, an indirect index of renal atrial natriuretic peptide (ANP) synthesis, after administration of vasopeptidase or ACE inhibitor in rats with renal mass reduction (RMR). METHODS: Twenty-one days after 5/6 nephrectomy, after the onset of hypertension and overt proteinuria, rats were divided in 3 groups (N= 7-8) and given daily by gavage: vehicle, the vasopeptidase inhibitor AVE7688 (3 mg/kg bid), or enalapril (5 mg/kg bid) until day 90. Normal rats (N= 5) served as control rats. RESULTS: Systolic blood pressure in RMR rats was equally controlled by AVE7688 and enalapril. AVE7688 resulted in a significant antiproteinuric effect, with urinary protein levels being reduced on average by 83% in respect to vehicle (88 +/- 28 vs. 518 +/- 27 mg/day, P < 0.0001). Enalapril achieved a 47% reduction in proteinuria (277 +/- 81 mg/day, P < 0.01 vs. vehicle) to levels that remained higher (P < 0.01), however, than those after AVE7688. Renal function impairment and glomerular and tubular changes were significantly (P < 0.05 vs. vehicle) ameliorated by AVE7688, and partially affected by enalapril. AVE7688 reduced the abnormal urinary excretion of ET-1 of RMR animals (98 +/- 8 vs. vehicle: 302 +/- 50 pg/24 h, P < 0.001) more than enalapril (159 +/- 14 pg/24 h, P < 0.05 vs. AVE7688). Consistently, AVE7688 was more effective than enalapril in augmenting renal synthesis of NO (2487 +/- 267 and 1519 +/- 217 vs. vehicle: 678 +/- 71 nmol/15 h; P < 0.001, AVE7688 vs. vehicle, P < 0.01 AVE7688 vs. enalapril). AVE7688 significantly increased urinary cGMP (78 +/- 6 vs. vehicle 45 +/- 9 nmol/24 h; P < 0.01). CONCLUSION: The superior renoprotection achieved by AVE7688 over enalapril in progressive renal injury is due to the correction of the altered balance of vasoconstrictor/vasodilator mediators in the kidney.     

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.     

No effect of enalapril on progression in autosomal dominant polycystic kidney disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are capable of reducing proteinuria and microalbuminuria with preservation of renal function in diabetic and non-diabetic renal disease. We designed a study investigating the effect of enalapril on the protection of renal function in autosomal dominant polycystic kidney disease (ADPKD). METHODS: We studied 61 normotensive and 28 hypertensive ADPKD patients. The normotensive group participated in a randomized double-blind placebo-controlled study, using enalapril. The hypertensive group was randomized for open label treatment with enalapril or the beta-blocker atenolol. The follow-up was 3 years, and renal function was established repetitively by measuring the clearance of inulin. RESULTS: In the normotensive group, renal function at baseline was 112 +/- 3 ml/min and decreased by -8 +/- 2 ml/min (P < 0.001). The loss of renal function in the patients treated with enalapril or placebo was similar (-7 +/- 3 vs -9 +/- 1 ml/min; P = 0.4). Although blood pressure significantly decreased with enalapril treatment, it had no effect on microalbuminuria. In the hypertensive group, renal function at baseline was 89 +/- 2 ml/min. The mean decline in renal function was -12 +/- 2 ml/min (P < 0.001), and was equal in patients treated with enalapril and those treated with atenolol. The patients treated with atenolol required more additional treatment to control blood pressure, but no difference on microalbuminuria was observed between the two treatments. CONCLUSION: This study was unable to detect a beneficial effect of ACE inhibition on loss of renal function in ADPKD patients.     

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.     

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.     

Angiotensin-converting enzyme inhibition attenuates hypercholesterolemia and glomerular injury in hyperlipidemic Imai rats.

Hyperlipidemic Imai rats spontaneously develop hypercholesterolemia, proteinuria and glomerulosclerosis. We investigated the effect of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, on spontaneous hypercholesterolemia and the progressive renal injury in this rat strain. Male Imai rats (n = 7) were treated with enalapril at a dose of 50 mg/l in drinking water starting at 6 weeks of age. Body weight, blood pressure, urinary protein excretion and serum constituents were checked and compared with untreated controls (n = 5) up to 38 weeks of age. Enalapril treatment significantly reduced hypercholesterolemia (247 +/- 41 vs. 102 +/- 13 mg/dl, p < 0.01, at 38 weeks) and proteinuria (766 +/- 290 vs. 206 +/- 119 mg/kg/day, p < 0.01, at 38 weeks). The glomerulosclerosis index (SI) was significantly higher in untreated control rats than in the enalapril-treated group (227 +/- 57 vs. 27 +/- 9, p < 0.01). Although we could not clarify whether hypercholesterolemia is a primary event or secondary to the nephrotic syndrome, these results indicate that the ACE inhibitor has the property to protect remnant glomeruli from glomerulosclerosis in male Imai rats as well as in other animal models in which focal and segmental glomerulosclerosis is believed to represent a common pathologic pattern. This rat strain represents a unique model of a spontaneous proteinuria which can provide an important information on the pathogenesis of human focal and segmental glomerulosclerosis.     

Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial

Proteinuria plays a causal role in the progression of IgA nephropathy (IgAN). A previous controlled trial showed that steroids are effective in reducing proteinuria and preserving renal function in patients with IgAN. The objective of this study was to evaluate the long-term effectiveness of steroids in IgAN, examine the trend of proteinuria during follow-up (starting from the hypothesis that the degree of reduction in proteinuria may influence IgAN outcome), and evaluate how histologic scores can influence steroid response. A secondary analysis of a multicenter, randomized, controlled trial of 86 adult IgAN patients who were receiving supportive therapy or intravenous methylprednisolone plus oral prednisone for 6 mo was conducted. Ten-year renal survival was significantly better in the steroid than in the control group (97% versus 53%; log rank test P = 0.0003). In the 72 patients who did not reach the end point (doubling in baseline serum creatinine), median proteinuria significantly decreased (1.9 g/24 h at baseline, 1.1 g/24 h after 6 mo, and 0.6 g/24 h after a median of 7 yr). In the 14 progressive patients, proteinuria increased from a median of 1.7 g/24 h at baseline to 2.0 g/24 h after 6 mo and 3.3 g/24 h after a median of 5 yr. Steroids were effective in every histologic class. Cox multivariate regression analyses showed that, in addition to steroids, a low baseline histologic score, a reduction in proteinuria after 6 mo, and no increase in proteinuria during follow-up all were independent predictors of a beneficial outcome. Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN. The histologic picture and proteinuria during early and late follow-up improve the prediction of outcome, but considerable variability remains outside the model.     

High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients

Background: The resistence to recombinant human erythropoietin (rHuEpo) therapy in haemodialysis (HD) patients has multifactorial aetiologies; erythropoietin insufficiency, dialysis insufficiency, iron deficiency, and secondary hyperparathyroidism. Angiotensin-converting enzyme (ACE) inhibitors induce anaemia in patients with essential hypertension, congestive heart failure, chronic renal insufficiency, and renal transplants. Data exist suggesting that ACE inhibitors impair erythropoiesis in HD patients. Therefore the aim of this study was to investigate the impact of enalapril on rHuEpo requirement. Methods: In the present prospective non-randomized study of 12 months, we compared the effects of enalapril and nifedipine on rHuEpo requirement in 40 hypertensive patients receiving rHuEpo for more than 6 months on maintenance haemodialysis. Twenty normotensive rHuEpo-dependent patients served as a control group. All patients with severe hyperparathyroidism or iron deficiency were excluded. The mean (±SD) haemoglobin concentration was >10 g/dl in all groups. The mean weekly rHuEpo dose increased in the enalapril group (P<0.0001 vs before) and remained constant in the nifedipine and control groups (P=NS vs before). Statistically, there was no differences with regard to iPTH levels, dialysis parameters, iron status, and underlying renal diseases among all groups. Conclusion: High-dose enalapril increases rHuEpo requirement and should be reserved for dialysis patients with hypertension uncontrollable with other antihypertensive medications or dialysis patients with cardiac failure.     

Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study

Renal impairment is associated with an increased risk of carotid atherosclerosis and stroke, determinants of cognitive dysfunction and dementia. The purpose of this study was to determine whether moderate renal impairment is associated with incident dementia among community-dwelling older adults. Participants in the Cardiovascular Health Cognition Study without prevalent dementia (n = 3349) were included in the analysis. Incident dementia was confirmed through neurologic testing. Renal function at baseline was estimated by the inverse of serum creatinine (1/SCr); moderate renal impairment was defined as SCr > or = 1.3 mg/dl for women and > or = 1.5 mg/dl for men. Cox regression models were used to estimate the association of renal impairment with incident dementia. Because SCr is also a function of muscle mass, the authors determined whether the relationship between SCr and dementia was particularly strong among individuals without severe co-morbidity at baseline, as reflected by self-reported general health status. There were 477 incident dementia cases over a median 6 yr follow-up. After adjustment for potential confounders, moderate renal insufficiency was associated with a 37% increased risk of dementia (95% CI = 1.06 to 1.78). Similarly, a 0.5-unit decrement in 1/SCr (equivalent to an increase in SCr from 1.0 to 2.0 mg/dl) was associated with a 26% increased risk (95% CI = 1.02 to 1.60). These associations were present only among the 84% of older adults who reported good-excellent health. Among those in good-excellent health, higher SCr was associated with vascular-type dementia but not Alzheimer-type dementia. Moderate renal impairment, reflected by a higher SCr, is associated with an excess risk of incident dementia among individuals in good-excellent health. Strategies to prevent or delay the onset of dementia in patients with moderate renal impairment are needed.     

Tolerance to ACE inhibitors after cardiac surgery.

OBJECTIVES: Several studies have shown angiotensin-converting enzyme (ACE) inhibitors to confer significant mortality and morbidity benefits in heart failure. First-dose hypotension may necessitate interruption of such therapy. This is more likely to occur if the ACE inhibitor is administered early after coronary artery bypass grafting (CABG). The purpose of this study was to analyse the haemodynamic tolerance to early post-operative treatment with perindopril and enalapril in patients with impaired renal and ventricular function. METHODS: Eighty one consecutive CABG patients with a previous myocardial infarction, impaired pre-operative left ventricular ejection fraction (LVEF) on ventriculography and moderately impaired renal function (serum creatinine of 115-150 micromol/l) were randomised into three groups to receive oral placebo, perindopril (4 mg) or enalapril (5 mg) once daily. Groups were subdivided into those with mild ventricular dysfunction (LVEF = 35-65%, n = 20) and significant ventricular dysfunction (LVEF < 35%, n = 7). Exclusion criteria included oliguria (<0.5 ml/kg per h) or inotrope dependance at the point of entry on the first post-operative day. Intolerance to ACE inhibitor was defined as hypotension (<95 mmHg systolic blood pressure or a decrease exceeding 25 mmHg in systolic blood pressure) leading to oliguria (<0.5 ml/kg per h) which was unresponsive to intravenous furosemide (20 mg). In such cases ACE inhibitor treatment was discontinued and patients commenced on dopamine. RESULTS: In the groups with mild ventricular dysfunction (LVEF = 35-65%) perindopril was discontinued in 1/20 and enalapril in 4/20 patients (P = n.s). However, in the groups with significant ventricular dysfunction (LVEF < 35%) perindopril was discontinued in 2/7 and enalapril in 7/7 patients (P = 0.02). CONCLUSION: Our results suggest that after CABG, patients with moderately impaired renal function and significant ventricular dysfunction do not tolerate ACE inhibitors well when these were commenced on the first post-operative day. However, perindopril was associated with less haemodynamic deterioration than enalapril and consequently may be advantageous in this setting. rights reserved.     

Histologically advanced IgA nephropathy treated successfully with prednisolone and cyclophosphamide

Background

No definitive therapeutic consensus has been established for progressive immunoglobulin A nephropathy (IgAN).

Methods

We retrospectively investigated 35 patients with histologically advanced IgAN. The patients were divided into two groups: 27 received prednisolone and cyclophosphamide (PSL+CPA group) and 8 received supportive treatment (control group). The initial doses of PSL and CPA were 30?mg/day and 50?mg/day, respectively. PSL was tapered to 2.5?mg/day over 2 years and CPA was discontinued at 6 months.

Results

In the control group, mean follow-up duration was 22.9 months, renal progression rate was ?20.9 × 10<συπ>?3?dl/mg per month, and all patients developed endstage renal disease within 5 years. In the PSL+CPA group, mean follow-up duration was 64.3 months, renal progression rate was ?1.5 × 10<συπ>?3?dl/mg per month, and renal survival at 5 years was 89.8%. Renal prognosis was markedly improved in the PSL+CPA group compared with the control group. The patients in the PSL+CPA group were divided into two subgroups according to baseline serum creatinine (<2?mg/dl or ≥2?mg/dl); renal survival in the two subgroups was similar (84.4% versus 100% at 5 years). Adverse effects of PSL+CPA were minimal and mild.

Conclusions

It is possible that PSL+CPA therapy safely improved the renal prognosis of patients with severe IgAN who would otherwise have required dialysis therapy within 5 years. However, a prospective, multicenter clinical trial is required to prove the effects and safety of this treatment.

     

Association of interleukin-10 gene G-1082A polymorphism with the progression of primary glomerulonephritis

BACKGROUND: Interleukin-10 (IL-10) is a cytokine with immunosuppressive properties. We evaluated the influence of G-1082A polymorphism in the IL-10 gene promoter, which has been associated with modified IL-10 production, on the two most common forms of primary glomerulonephritis: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). METHODS: We studied Caucasian patients (N= 191) with biopsy-proven glomerulonephritis (IgAN: N= 123, FSGS: N= 68) followed-up for 6.5 +/- 5.5 years. Patients were classified according to the slope of reciprocal serum creatinine (>/= or <-0.1 dL(*)mg(-1) (*)year(-1)) into group A (slow progressors, IgAN: N= 75, FSGS: N= 47) and group B (fast progressors, IgAN: N= 48, FSGS: N= 21). One hundred healthy volunteers were analyzed as control patients. G-1082A polymorphism was determined by polymerase chain reaction (PCR) amplification. RESULTS: The allele frequencies were similar in patients and control group (NS). Initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. G-1082A polymorphism was associated with the progression of both IgAN and FSGS: GA/AA genotypes were more frequent in group B (fast progressors) than in group A (slow progressors; P= 0.012 for IgAN, P < 0.05 for FSGS). Patients with the GA/AA genotypes showed a worse outcome in the Kaplan-Meier analysis of renal survival (P < 0.05 for both IgAN and FSGS). The IL-10 polymorphism remained an independent risk factor for progression in multivariate analysis (Cox regression model, P < 0.05 for IgAN and FSGS). CONCLUSION: Our results suggest that IL-10 gene G-1082A polymorphism is an important marker of progression in patients with IgAN and FSGS.     

Conservative versus immunosuppressive treatment of patients with idiopathic membranous nephropathy.

BACKGROUND: Treatment of idiopathic membranous glomerulonephritis (MGN) is a controversial issue. Whereas some authors recommend early immunosuppressive treatment of all patients with nephrotic syndrome, others do not support aggressive therapies, based on the spontaneous long-term favorable outcome of most patients. However, 20 to 50% of untreated patients develop progressive renal insufficiency. METHODS: All of the patients with biopsy-proven MGN who developed renal insufficiency at our Hospital during the period of 1975 to 2000 were studied. Selected patients (N=39) were separated into two groups according to the two different therapeutic policies followed at our department: a conservative approach during the first period, 1975 to 1989 (group I, N=20), and a course of immunosuppressive therapy (oral prednisone for six months and concurrent oral chlorambucil, 0.15 mg/kg/day, during the first 14 weeks) during the second period, 1990 to 2000 (group II, N=19). RESULTS: There were no significant differences between both groups at the time of renal biopsy, nor at the onset of renal function decline. All group I patients showed a progressive renal insufficiency; at the end of the follow-up 13 patients (65%) were on chronic dialysis, 2 (10%) showed advanced renal failure, and 5 (25%) had died. In contrast, most of group II patients showed an improvement or stabilization of serum creatinine (SCr; 2.3 +/- 0.9 mg/dL at onset of treatment, 2 +/- 1.5 mg/dL at the end of follow-up) together with decreased proteinuria (11.2 +/- 3.3 vs. 5.2 +/- 6.7 g/24 h). At the end of the follow-up 58% of group II patients had a SCr value < or =1.5 mg/dL and 36% showed a complete or partial remission, whereas no patient in group I showed remission. After four years of follow-up the probability of renal survival without dialysis was 55% in group I and 90% in group II (P < 0.001), and after seven years the renal survival was 20% and 90%, respectively (P < 0.001). Side effects of immunosuppressive treatment were uncommon but severe, as two patients suffered Pneumocystis carinii pneumonia. CONCLUSION: A course of immunosuppressive treatment administered early at the onset of renal function decline induces a favorable effect in most of patients with MGN and deteriorating renal function. Untreated patients progressed without exception toward advanced renal failure.     

Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy

BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. RESULTS: Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 +/- 2, 8 +/- 2, 6 +/- 3, and 11 +/- 3 mm Hg (mean +/- SEM), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition. CONCLUSION: The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.     

Chronic allograft nephropathy and nephrotic range proteinuria

While the association between post-transplant nephrotic range proteinuria (PTx-NP) and chronic allograft nephropathy (CAN) has been described, the factors that determine graft survival in such patients are unclear. We retrospectively identified 30 patients with biopsy-proven CAN who presented with PTX-NP between 1988 and 2002. Patients were stratified into two groups according to PTX-NP onset: <1 yr vs. >1 yr post-transplantation. Both groups were comparable with respect to the degree of renal dysfunction (serum creatinine 4.3 +/- 2.5 mg/dL vs. 3.4 +/- 1.5 mg/dL) and proteinuria (4.7 +/- 1.6 gm/d vs. 5.8 +/- 3 gm/d). After a mean follow-up of 14 months post-biopsy, 87% of patients had lost their grafts in both groups (89% vs. 83%, p = NS). Overall, patients with serum creatinine 2 mg/dL (75% vs. 4%, Fisher Exact Probability p = 0.0038). Using Kaplan-Meier estimate, the 5-yr graft survival rate was 100% for patients with serum creatinine 2 mg/dL (p = 0.06). The magnitude of proteinuria beyond 3 gm/d did not influence graft survival. One-half of the patients (n = 15) received therapy with angiotensin converting enzyme inhibitors (ACEI). Graft survival, however, was not different between the patients who received ACEI compared with the patients who did not receive ACEI (13% vs. 13%). PTx-NP related to CAN was associated with poor allograft survival, irrespective of the time of onset of presentation, especially when renal function was reduced at the time of biopsy.