Non-diabetic Proteinuric Nephropathies Research Articles

The influence of renin-angiotensin system genotypes on the antiproteinuric response to high doses of olmesartan in non-diabetic proteinuric nephropathies.

To assess the antiproteinuric response to multifactorial treatment based on high doses of angiotensin II receptor antagonists (ARBs) (olmesartan) in patients with non-diabetic proteinuric nephropathies, according to three renin-angiotensin system (RAS) polymorphisms: insertion/deletion of the angiotensin converting enzyme (ACE) gene, the angiotensinogen gene M235T and the angiotensin II type 1 receptor (AT1R) A1166C. We studied 53 patients with non-diabetic proteinuric nephropathy with a mean progression time of 84.4±15 months. 41 were males (77.4%); mean age 49.7±3 years, body mass index 30±6kg/m2. All received olmesartan (40mg/12h) associated with a mean of 2.4±1.6 antihypertensive drugs for a median period of 13 months (interquartile range 7-25 months). Systolic blood pressure (BP) decreased from 145±14mmHg to 128±14mmHg (P<.001) and diastolic BP from 85±11mmHg to 79±7mmHg (P<.01). Pulse pressure decreased from 53.5±14mmHg to 48±12mmHg (P<.05). Proteinuria decreased from 2.74±1.6g/24h to 0.9±1g/24h (P<.001), representing a mean decrease of 67.1%. According to RAS polymorphisms, antiproteinuric response was: angiotensinogen gene polymorphism: genotype TT: 76.8%; genotype MM: 67.3%; genotype MT: 65.8%, significantly higher (P<.05) for genotype TT compared to genotypes MM and MT. Polymorphism of the ACE gene: genotype DD: 71.4%; genotype ID: 60.6%, genotype II: 34.8%, significantly higher (P<.05) for genotype DD compared to genotypes ID and II, and also (P<.05) for genotype ID compared to II. AT1R gene polymorphism: genotype AC: 85.2%; genotype CC: 73.7%; genotype AA: 62.7%; significantly higher for genotype AC (P<.05) compared to genotypes AA and CC. The differences between initial and final proteinuria for the follow-up period were significant (P<.01) for genotypic associations DD/AA, DD/MT, DD/MM, DD/TT and DD/AC, although the association with the highest antiproteinuric effect was DD/AC (89.9%, P<.05%). Administering high doses of olmesartan in patients with non-diabetic proteinuric nephropathy results in significant reductions in proteinuria. This decrease was independent of blood pressure control and other confounding factors. RAS polymorphisms may modulate the antiproteinuric response to treatment with ARBs.

Renoprotective efficacy of valsartan in chronic non‐diabetic proteinuric nephropathies with renin–angiotensin system gene polymorphisms

The renoprotective effects of angiotensin receptor blockers vary considerably among individuals. We investigated the renoprotective effects of valsartan according to polymorphisms of the renin-angiotensin system and transforming growth factor-b1 (TGFB1) genes in patients with chronic non-diabetic proteinuric nephropathies. Two hundred and thirty-nine non-diabetic patients with proteinuria of at least 1 g/day were enrolled. Patients received 80 g of valsartan daily, followed by 160 mg/day after 6 weeks. The follow-up period was 18 months. The status of the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T, type 1 angiotensin II receptor (ATR1) A1166C, and TGFB1 C509 and T869C polymorphisms was determined in 162 patients. Valsartan treatment caused a significant reduction in proteinuria from baseline throughout the study in patients with each genotype of the ACE, AGT and TGFB1 genes. However, patients with the ATR1 AC genotype had no significant reduction in proteinuria from baseline throughout the study course. The median reductions in proteinuria after 6 months were 45.7% and 10.8% in the patients with the ATR1 AA and AC genotypes, respectively (P = 0.034). The annual change in the estimated glomerular filtration rate did not differ significantly among the genotypes for each gene. On multiple regression analysis, the change in proteinuria after 6 months of treatment was independently associated with the ATR1 genotype and the change in blood pressure (P = 0.005 and 0.019, respectively). Valsartan treatment significantly reduced the blood pressure and urinary protein excretion of patients with chronic non-diabetic proteinuric nephropathies. Interindividual differences in the anti-proteinuric effect of valsartan may be related partly to the ATR1 A1166C polymorphism.

Angiotensin Converting Enzyme Insertion/Deletion Polymorphism and Renoprotection in Diabetic and Nondiabetic Nephropathies

Despite the huge amount of studies looking for candidate genes, the ACE gene remains the unique, well-characterized locus clearly associated with pathogenesis and progression of chronic kidney disease, and with response to treatment with drugs that directly interfere with the renin angiotensin system (RAS), such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA). The II genotype is protective against development and progression of type I and type II nephropathy and is associated with a slower progression of nondiabetic proteinuric kidney disease. ACE inhibitors are particularly effective at the stage of normoalbuminuria or microalbuminuria in both type I and type II diabetics with the II genotype, whereas the DD genotype is associated with a better response to ARA therapy in overt nephropathy of type II diabetes and to ACE inhibitors in male patients with nondiabetic proteinuric nephropathies. The role of other RAS or non-RAS polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Thus, evaluating the ACE I/D polymorphism is a reliable tool to identify patients at risk and those who may benefit the most of renoprotective therapy with ACE inhibitors or ARA. This may guide pharmacologic therapy in individual patients and help design clinical trials in progressive nephropathies. Moreover, it might help optimize prevention and intervention strategies at population levels, in particular, in countries where resources are extremely limited and 1 million patients continue to die every year of cardiovascular or renal disease.

Renoprotective therapy: is it blood pressure or albuminuria that matters?

In today's Lancet, Piero Ruggenenti and colleagues, for the REIN-2 Study Group, address whether reduction of blood pressure below 140/90 mm Hg offers additional renoprotection. They added the dihydropyridine calcium-channel-blocker felodipine to ramipril, an inhibitor of angiotensin-converting enzyme (ACE) in 335 patients with a baseline glomerular filtration rate of 35 mL/min and overt proteinuria (urinary protein loss 2·9 g a day). Felodipine was not renoprotective. This finding is remarkable given that felodipine lowered systolic and diastolic blood pressures by 4 and 3 mm Hg, respectively. On the basis of their findings, the authors inadvertently challenge the widely accepted view of nephrologists that further reduction of blood pressure should be aimed at to achieve optimum renoprotection. 1 Peterson JC Adler S Burkart JM et al. Blood pressure control, proteinuria, and the progression of renal disease. Ann Intern Med. 1995; 123: 754-762 Crossref PubMed Scopus (1223) Google Scholar , 2 Jafar TH Stark PC Schmid CH et al. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann Intern Med. 2003; 139: 244-252 Crossref PubMed Scopus (951) Google Scholar Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trialIn patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown. Full-Text PDF

Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial

In chronic nephropathies, inhibition of angiotensin-converting enzyme (ACE) is renoprotective, but can further renoprotection be achieved by reduction of blood pressure to lower than usual targets? We aimed to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease. We undertook a multicentre, randomised controlled trial of patients with non-diabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril (2.5-5 mg/day). We randomly assigned participants either conventional (diastolic <90 mm Hg; n=169) or intensified (systolic/diastolic <130/80 mm Hg; n=169) blood-pressure control. To achieve the intensified blood-pressure level, patients received add-on therapy with the dihydropyridine calcium-channel blocker felodipine (5-10 mg/day). The primary outcome measure was time to end-stage renal disease over 36 months' follow-up, and analysis was by intention to treat. Of 338 patients who were randomised, three (two assigned intensified and one allocated conventional blood-pressure control) never took study drugs and they were excluded. Over a median follow-up of 19 months (IQR 12-35), 38/167 (23%) patients assigned to intensified blood-pressure control and 34/168 (20%) allocated conventional control progressed to end-stage renal disease (hazard ratio 1.00 [95% CI 0.61-1.64]; p=0.99). In patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown.

Losartan in diabetic nephropathy

Diabetic nephropathy has become the single most important cause of end-stage renal disease in the USA, Europe and Japan. The earliest marker of incipient diabetic nephropathy is the transition of normoalbuminuria to microalbuminuria at an albumin excretion rate of 20 μg/min. Human studies in patients both with and without diabetic kidney diseases have shown that the severity of baseline proteinuria is an important predictor of the rate of loss of renal function. Moreover, the reduction in protein excretion rate when patients with nephropathies are being treated with antihypertensive agents predicts the efficacy of subsequent renoprotection. Experimental and clinical observations provide the rationale for targeting the renin–angiotensin system as a renoprotective approach in diabetic and nondiabetic proteinuric nephropathies. Losartan (Cozaar®, Merck Sharpe and Dohme) is a potent, orally active and highly specific angiotensin-type 1 receptor blocker. In addition to its antihypertensive efficacy, losartan decreases the left ventricular mass index in patients with hypertension, left ventricular end-diastolic and end-systolic volume in subjects with heart failure and prevents cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction. Short-term studies in Type 1 diabetic patients with overt nephropathy have demonstrated that losartan and angiotensin-converting enzyme inhibitors have similar beneficial effects on albumin excretion rate, blood pressure and renal hemodynamics. Losartan also lowered albumin excretion rate in microalbuminuric patients with Type 2 diabetes mellitus. Moreover, the large multicenter Reduction of End points in Noninsulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial has shown that blockade of angiotensin-type 1 receptor with losartan is superior to conventional antihypertensive therapy in slowing the progression of overt Type 2 diabetic nephropathy. Together, data from clinical trials demonstrate the beneficial effect of angiotensin-type 1 receptor blockers, including losartan, in the primary and secondary prevention of renal disease progression in diabetic patients. Nevertheless, it can be expected that the positive results achieved so far with this class of drugs may be further implemented by including angiotensin-type 1 receptor antagonists as a part of the multidrug approach that may hold more promise for the future of renoprotection in diabetic patients with chronic nephropathy.

The verapamil versus amlodipine in nondiabetic nephropathies treated with trandolapril (VVANNTT) study

Background:We tested whether the combination of verapamil (V) or amlodipine (A) with trandolapril (T) affected proteinuria differently from T alone in patients with nondiabetic nephropathies. Methods:After T, 2 mg, in open conditions for 1 month, 69 patients were randomly assigned to be administered T, 2 mg, combined with V, 180 mg, plus a placebo or T, 2 mg, plus A, 5 mg, once a day in a double-blind fashion. Patients were followed up for 8 months. Results:Proteinuria diminished significantly after T treatment from mean protein excretion of 3,078 ± 244 (SEM) to 2,537 ± 204 mg/24 h (P = 0.018). In the randomized phase, there was a slight reduction in proteinuria in both groups without significant differences within and between treatments (T + V, protein from 2,335 ± 233 to 2,124 ± 247 mg/24 h; T + A, protein from 2,715 ± 325 to 2,671 ± 469 mg/24 h). The selectivity index (SI; calculated as the ratio of immunoglobulin G to albumin clearance) was slightly and not significantly reduced in patients treated with T plus V from a median of 0.20 (interquartile range, 0.13) to 0.16 (interquartile range, 0.15; P = not significant), whereas it significantly increased from 0.20 (interquartile range, 0.14) to 0.30 (interquartile range, 0.14; P = 0.0001) in patients treated with T plus A. Modifications in SI and serum creatinine levels at the end of the study from randomization were significantly directly correlated (r = 0.45; P = 0.001). The number of patients reporting adverse effects was significantly higher in the T plus A than T plus V group (63.8% versus 33.3%; P = 0.016). Conclusion:In patients with nondiabetic proteinuric nephropathies treated with T, the combination of V or A does not significantly increase its antiproteinuric effect.

Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies

Background: Proteinuria is a recognized complication of obesity, but no study has investigated the effect of weight loss in overweight patients with chronic proteinuric nephropathies of different causes. Methods: We randomly assigned (in a 2:1 ratio) 30 overweight patients (body mass index [BMI] > 27 kg/m2) with diabetic and nondiabetic proteinuric nephropathies to either follow a low-calorie normoproteinic diet or maintain their usual dietary intake for 5 months. The primary outcome was change in urinary protein excretion. Secondary outcomes were changes in renal function (serum creatinine level and Cockcroft-Gault creatinine clearance) and lipid profile. Results: Patients in the diet group showed a significant decrease in body weight and BMI, whereas patients in the control group showed a significant increase in body weight and BMI (between-group comparison, P < 0.05). Mean weight loss in the diet group was 4.1% ± 3%, and 14 of 20 patients in this group lost more than 3%. Proteinuria decreased by 31.2% ± 37% in the diet group (from protein of 2.8 ± 1.4 to 1.9 ± 1.4 g/24 h; P < 0.005), whereas it tended to increase in the control group (between-group comparison, P < 0.05). Changes in renal function did not differ significantly between groups, although renal function remained stable in the diet group and showed significant worsening in the control group. Serum triglyceride levels remained stable in the diet group and tended to increase in the control group (between-group comparison, P < 0.05). Conclusion: Moderate weight loss in overweight patients with chronic proteinuric nephropathies induces a significant decrease in proteinuria. Am J Kidney Dis 41:319-327.

Renoprotective therapy in patients with nondiabetic nephropathies.

End-stage renal failure (ESRF) represents a major health problem. Early diagnosis and effective measures to slow or to stop renal damage are essential goals for nephrologists to prevent or delay progression to ESRF. Identifying mechanisms of progressive parenchymal injury is instrumental in developing renoprotective strategies. Protein traffic through the glomerular barrier is an important determinant of progression in chronic nephropathies and proteinuria is the best predictor of renal outcome. At the moment, ACE inhibition is the most effective treatment in patients with chronic nondiabetic proteinuric nephropathies, reducing protein traffic, urinary protein excretion rate and progression to ESRF more effectively than conventional treatment. Low sodium diet and/or diuretic treatment may help to increase the antiproteinuric effect of ACE inhibitors by maximally activating the renin-angiotensin system. Intensified blood pressure control, whatever treatment is employed, also enhances the antiproteinuric response to ACE inhibitors. However, since this is not always sufficient to normalise urinary proteins and fully prevent renal damage, additional treatments may be needed in patients poorly or not responding to ACE inhibitors. These may include angiotensin II receptor antagonists, non-dihydropyridine calcium antagonists and perhaps low doses of nonsteroidal anti-inflammatory drugs. Preliminary data on multidrug treatments including these additional antiproteinuric agents are encouraging, but additional studies in larger patient numbers are needed to better define the risk/benefit profile of this innovative approach.

ACE and alpha-adducin genotypes and renal disease progression.

In the REIN study of non-diabetic proteinuric nephropathies, renal disease progression was independent of the angiotensin-converting enzyme (ACE) and alpha-adducin genotypes. However, the ACE genotype predicted the renoprotective effect of ACE inhibition. Subgroup analysis in patients with Berger disease showed a tendency (NS) for a faster progression in DD homozygotes.

ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies

ACE genotype and ACE induced renoprotection in chronic proteinuric nephropathies. Whether angiotensin-converting enzyme (ACE) gene polymorphism affects disease progression and response to ACE inhibitor therapy in nondiabetic proteinuric nephropathies is not clearly established. The relationship between insertion/deletion (I/D) genotypes and proteinuria, rate of glomerular filtration rate decline (DeltaGFR)-centrally evaluated by repeated measures of iohexol plasma clearance-and incidence of end-stage renal disease (ESRD) was prospectively evaluated in 212 patients with nondiabetic proteinuric chronic nephropathies enrolled in the Ramipril Efficacy in Nephropathy (REIN) trial, where patients were randomly assigned to ramipril or conventional treatment. The DeltaGFR +/- SEM (-0.38 +/- 0.09 vs. -0.50 +/- 0.08 vs. -0.36 +/- 0.06 mL/min/1.73 m2 per month) and incidence of ESRD (19 vs. 22 vs. 25%) in the three subgroups with the II, ID, and DD genotypes, respectively, were comparable. Of note, DeltaGFR (-0.28 +/- 0.07 vs. -0.43 +/- 0.09 mL/min/1.73 m2 per month) and incidence of ESRD [14% vs. 36%, P = 0.04, RR (95% CI), 2.62 (1.02 to 6.71)] were lower in ramipril than in conventionally treated patients in the DD genotype, but not in the II and ID genotype. Either at univariate (P = 0.04) or at multivariate (P = 0.01) analysis, ramipril significantly predicted a lower incidence of events in DD, but not in II and ID patients. At three months, ramipril decreased proteinuria more effectively in DD (-38.2%) than in the II (-26.7%) or ID (-19.2%) genotype. In DD (but not in II or ID) ramipril-treated patients, a short-term reduction in proteinuria correlated with DeltaGFR over the entire follow-up period (P = 0.02, r = -0.41). In nondiabetic proteinuric nephropathies, the ACE I/D polymorphism does not predict disease progression, but is a strong predictor of ACE inhibition-associated renoprotection in that proteinuria, DeltaGFR, and progression to ESRD are effectively reduced in patients with the DD, but not in those with the II or ID genotype.

Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies

We investigated the predictors of the rate of glomerular filtration rate decline (delta GFR) and progression to end-stage renal failure (ESRF) in the 352 patients with proteinuric non-diabetic chronic nephropathies [urinary protein excretion rate (UProt) > or = 1 g/24 hr, creatinine clearance 20 to 70 ml/min/1.73 m2] enrolled in the Ramipril Efficacy In Nephropathy (REIN) study. Overall the GFR declined linearly by 0.46 +/- 0.05 ml/min/1.73 m2/month (mean rate +/- SEM) over a median follow-up of 23 months (range 3 to 64 months), and progression to ESRF was 17.3%. Using multivariate analysis, higher UProt and mean arterial pressure (MAP) independently correlated with a faster delta GFR (P = 0.0001 and P = 0.0002, respectively) and progression to ESRF (P = 0.0001 and P = 0.003, respectively). Mean UProt and systolic blood pressure during follow-up were the only time-dependent covariates that significantly correlated with delta GFR (P = 0.005 and P = 0.003, respectively) and ESRF (P = 0.006 and P = 0.0001, respectively). After stratification for baseline UProt, patients in the lowest tertile (UProt < 1.9 g/24 hr) had the slowest delta GFR (0.16 +/- 0.07 ml/min/1.73 m2/month) and progression to ESRF (4.3%) as compared with patients in the middle tertile (UProt 2.0 to 3.8 g/24hr; delta GFR, 0.55 +/- 0.09 ml/min/1.73 m2/month, P = 0.0002; ESRF, 15.3%, P = 0.0001) and in the highest tertile (UProt 3.9 to 18.8 g/24 hr; delta GFR, 0.70 +/- 0.11 ml/min/1.73 m2/month, P = 0.0001; ESRF, 32.5%, P = 0.0001). Both delta GFR (P = 0.01) and progression to ESRF (P = 0.01) significantly differed even between the middle and the highest tertiles. On the contrary, stratification in tertiles of baseline MAP failed to segregate subgroups of patients into different risk levels. Patients with the highest proteinuria and blood pressure were those with the fastest progression (delta GFR, 0.91 +/- 0.23; ESRF 34.7%). Of interest, at each level of baseline MAP, a higher proteinuria was associated with a faster delta GFR and progression to ESRF. On the other hand, at each level of proteinuria, a faster delta GFR was associated with MAP only in the highest tertile (> 112 mm Hg) and the risk of ESRF was independent of the MAP. Thus, in chronic nephropathies proteinuria is the best independent predictor of both disease progression and ESRF. Arterial hypertension may contribute to the acceleration of renal injury associated with enhanced traffic of plasma proteins. Antihypertensive drugs that most effectively limit protein traffic at comparable levels of blood pressure are those that most effectively slow disease progression and delay or prevent ESRF in proteinuric chronic nephropathies.