25 (OH) vitamin D levels and renal disease progression in patients with type 2 diabetic nephropathy and blockade of the renin-angiotensin system.

BACKGROUND AND OBJECTIVES: Experimental studies show that 25 (OH) vitamin D is a suppressor of renin biosynthesis and that vitamin D deficiency has been associated with CKD progression. Patients with type II diabetes and CKD have an exceptionally high rate of severe 25 (OH) vitamin D deficiency; however, it is not known whether this deficiency is a risk factor for progression of diabetic nephropathy. This study aimed to investigate whether there is an association of 25 (OH) vitamin D deficiency with disease progression in type II diabetic nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 25 (OH) vitamin D levels were measured at baseline and 4 and 12 months in 103 patients included in a multicenter randomized controlled trial to compare the efficacy of combining an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker with the efficacy of each drug in monotherapy to slow progression of established diabetic nephropathy during 2006-2011. The primary composite endpoint was a >50% increase in baseline serum creatinine, ESRD, or death. All study participants were included in the analysis. RESULTS: Fifty-three patients (51.5%) had 25 (OH) vitamin D deficiency (<15 ng/ml). After a median follow-up of 32 months, the endpoint was reached by 23 patients with deficiency (43.4%) and 8 patients without (16%). Multivariate Cox regression analysis adjusted for urinary protein/creatinine ratio, estimated GFR, and baseline aldosterone showed that 25 (OH) vitamin D deficiency was associated with the primary endpoint (hazard ratio, 2.88; 95% confidence interval, 1.84 to 7.67; P=0.04). CONCLUSIONS: These results show that 25 (OH) vitamin D deficiency is independently associated with a higher risk of the composite outcome in patients with type II diabetic nephropathy.

Effect of dual blockade of the renin-angiotensin system on the progression of type 2 diabetic nephropathy: a randomized trial.

BACKGROUND: Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers has been shown to lessen the rate of decrease in glomerular filtration rate in patients with diabetic nephropathy. STUDY DESIGN: A multicenter open-label randomized controlled trial to compare the efficacy of combining the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor blocker irbesartan with that of each drug in monotherapy (at both high and equipotent doses) in slowing the progression of type 2 diabetic nephropathy. SETTING & POPULATION: 133 patients with type 2 diabetic nephropathy (age, 66 ± 8 years; 76% men) from 17 centers in Spain. INTERVENTION: Patients were randomly assigned (1:1:2) to lisinopril (n = 35), irbesartan (n = 28), or the combination of both (n = 70). OUTCOMES: The primary composite outcome was a >50% increase in baseline serum creatinine level, end-stage renal disease, or death. RESULTS: Baseline values for mean estimated glomerular filtration rate and blood pressure were 49 ± 21 mL/min/1.73 m(2) and 153 ± 19/81 ± 11 mm Hg. Mean geometric baseline proteinuria was protein excretion of 1.32 (95% CI, 1.10-1.62) g/g creatinine. After a median follow-up of 32 months, 21 (30%) patients in the combination group, 10 (29%) in the lisinopril group, and 8 (29%) in the irbesartan group reached the primary outcome. HRs were 0.96 (95% CI, 0.44-2.05; P = 0.9) and 0.90 (95% CI, 0.39-2.02; P = 0.8) for the combination versus the lisinopril and irbesartan groups, respectively. There were no significant differences in proteinuria reduction or blood pressure control between groups. The number of adverse events, including hyperkalemia, was similar in all 3 groups. LIMITATIONS: The study was not double blind. The sample size studied was small. CONCLUSIONS: We were unable to show a benefit of the combination of lisinopril and irbesartan compared to either agent alone at optimal high doses on the risk of progression of type 2 diabetic nephropathy.

Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.

Spontaneous remission is a well known characteristic of idiopathic membranous nephropathy, but contemporary studies describing predictors of remission and long-term outcomes are lacking. We conducted a retrospective, multicenter cohort study of 328 patients with nephrotic syndrome resulting from idiopathic membranous nephropathy that initially received conservative therapy. Spontaneous remission occurred in 104 (32%) patients: proteinuria progressively declined after diagnosis until remission of disease at 14.7 +/- 11.4 months. Although spontaneous remission was more frequent with lower levels of baseline proteinuria, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8 to 12 g/24 h and 22% among those with proteinuria >12 g/24 h. Baseline serum creatinine and proteinuria, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and a >50% decline of proteinuria from baseline during the first year of follow-up were significant independent predictors for spontaneous remission. Only six patients (5.7%) experienced a relapse of nephrotic syndrome. The incidence of death and ESRD were significantly lower among patients with spontaneous remission. In conclusion, spontaneous remission is common among patients with nephrotic syndrome resulting from membranous nephropathy and carries a favorable long-term outcome with a low incidence of relapse. A decrease in proteinuria >50% from baseline during the first year predicts spontaneous remission.

Dual blockade of the renin-angiotensin system in the progression of renal disease: the need for more clinical trials.

There is clear evidence that pharmacologic blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) reduces proteinuria and slows the progression of renal disease in diabetic and nondiabetic nephropathies, a beneficial effect that is not related to BP control. Some patients exhibit a significant beneficial response, whereas others do not. The absence of response may be explained by the incomplete blockade of the RAS obtained with ACEI. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, the association of ACEI and ARB might prove useful. ARB produces a complete blockade of the RAS. Several studies have shown a more marked antiproteinuric effect of the dual blockade of the RAS versus ACEI or ARB alone. A recent study also demonstrated that this more marked antiproteinuric effect is associated with less progression of renal disease in primary nondiabetic nephropathies despite a similar effect on BP. Until now, there has not been any reference to a beneficial effect on progression of the dual blockade in type 2 diabetic nephropathy, which is the most frequent cause of ESRD. A multicenter, prospective, open, active-controlled, and parallel-group trial was designed to compare the effects of an ACE inhibitor versus an ARB or its combination on renal disease progression, proteinuria, and cardiovascular events in type 2 diabetic nephropathy.

Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies.

BACKGROUND: Blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or with angiotensin II type 1 (AT1) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies. Additionally, this beneficial effect is not dependent on blood pressure control. METHODS: To assess and compare the effects of lisinopril (up to 40 mg/day), candesartan (up to 32 mg/day) and combination therapy (lisinopril up to 20 mg/day plus candesartan up to 16 mg/day) on urinary protein excretion, 45 patients with primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8+/-2.4 g/g) and normal or slightly reduced renal function (CCr 95+/-33 mL/min) were enrolled in a six month multicenter, prospective, open, randomized, active-controlled and parallel-group trial with 1:1:1 allocation. Blood pressure goal was set at or below 125/75 mm Hg for all patients, with additional antihypertensive medication prescribed if required. RESULTS: Renal function, estimated by creatinine clearance, remained stable throughout the study. Hyperkalemia (K>5.5 mmol/L) was detected in 3.1% of all measurements in follow-up, and was more frequent in patients treated with lisinopril alone or lisinopril plus candesartan (P<0.001) than in those on candesartan alone. No other relevant adverse event was recorded. The blood pressure goal (<125/75 mm Hg) was achieved by week 4 in all treatment groups (P<0.005 when compared to baseline), and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically significant differences between groups. Urinary protein/creatinine ratio (percentage reduction 95% confidence intervals CI) decreased in patients treated with lisinopril alone to -33% (CI -12-56) to -31% (CI 0-68) and to -50% (CI -9-90), in patients treated with candesartan to -28% (CI -12-45), to -41% (CI -30-52) and to -48% (CI -32-63), in patients treated with the combination of both to -60% (CI -44-77) to -54% (CI -38-69) and to -70% (CI -57-83) at two, three, and six months, respectively. All comparisons with baseline achieved statistical significance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with candesartan alone at two and six months (P=0.004 and P=0.023, respectively) and than treatment with lisinopril only at two months (P=0.03). CONCLUSION: Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated.