Changes In Proteinuria Research Articles

Retinoids and Phototherapy for Psoriasis

Retinoids are the most widely used agents for systemic treatment of psoriasis; as structural and functional analogs of vitamin A, they are involved in the regulation of several biologic functions. Acitretin is the oral retinoid currently used, alone or in combination with other treatments, for plaque type, erythrodermic, and pustular psoriasis. Due to its high teratogenic effect, therapeutic contraception is required for women taking the drug. Narrowband ultraviolet B (nbUVB, 311 +/- 2 nm) is effective for guttate and plaque-type psoriasis. At the molecular level, UV light acts (1) directly (type I reaction) inducing the formation of pyrimidine dimers that, in turn, cause a transient cellular growth arrest; and (2) indirectly (type II reaction) through the generation of reactive oxygen species that act on key molecules such as lipids (in particular lipid membranes), proteins, and nucleic acids. Several studies show that UV rays can cause a transient decrease in DNA, RNA, and protein synthesis. These events are accompanied by a temporary normalization of cell kinetics of psoriatic keratinocytes. Phototherapy is carried out 3 times a week alone or in combination with topical treatments and/or acitretin. Several studies have confirmed that oral retinoids together with nbUVB (ReUVB) reduce the recovery time and also the doses of both acitretin and nbUVB. The regimen is carried out treating the patient with acitretin alone (0.5 mg/kg bw) for 2 weeks, then the dose of acitretin is reduced to 0.3 mg/kg bw, and the nbUVB is added 3 times a week until complete resolution of disease. As retinoids exert an anticarcinogenic effect, the ReUVB regimen could lower skin cancer risk resulting from longterm UVB therapy.

Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria

OBJECTIVEWe investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination.RESEARCH DESIGN AND METHODSThis was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR).RESULTSPlacebo geometric mean albuminuria was 258 mg/day (range 84–2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m2. Aliskiren treatment reduced albuminuria by 48% (95% CI 27–62) compared with placebo (P < 0.001), not significantly different from the 58% (42–79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59–79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3–8.8) ml/min per 1.73 m2 by aliskiren, 8.0 (3.6–12.3) ml/min per 1.73 m2 by irbesartan, and 11.7 (7.4–15.9) ml/min per 1.73 m2 by the combination.CONCLUSIONSThe combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Effect of Candesartan on Microalbuminuria and Albumin Excretion Rate in Diabetes

Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preventive therapies are therefore a clinical priority. To determine whether the angiotensin-receptor blocker candesartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes. 3 randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program. 309 secondary care centers. 3326 and 1905 patients with type 1 and type 2 diabetes, respectively. Most were normotensive, and all had normoalbuminuria (median urinary albumin excretion rate, 5.0 microg/min). Candesartan, 16 mg/d increasing to 32 mg/d, versus placebo. Assignment was done centrally using an interactive voice-response system. Patients, caregivers, and researchers were blinded to treatment assignment. During a median follow-up of 4.7 years, 793 patients discontinued therapy and 63 were lost to follow-up. Urinary albumin excretion rate, assessed annually by 2 overnight collections; if it was 20 microg/min or greater, then 2 further collections were done. The primary end point was new microalbuminuria (3 or 4 collections of urinary albumin excretion rate >or=20 microg/min). The secondary end point was rate of change in albuminuria. Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; P = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; P = 0.024) with candesartan than with placebo. Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria. Studies were powered for retinal and not renal end points. Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.

Intrarenal Hemodynamics in Primary Aldosteronism before and after Treatment

Elevated urinary albumin excretion has been reported in primary aldosteronism and might partially reflect reversible abnormalities initiated by glomerular hyperfiltration. The aim of the study was to examine the outcome of renal function and intrarenal Doppler velocimetric indices in primary aldosteronism. We conducted a prospective study of patients with primary aldosteronism who were reevaluated 1 yr after either adrenalectomy or treatment with spironolactone. The study was conducted at a university referral center. Fifty-four patients with tumoral or idiopathic aldosteronism were followed after either surgical (n = 24) or medical (n = 30) treatment. Patients with primary aldosteronism were compared with 100 patients with primary hypertension and comparable severity and duration of disease. Changes in renal function and intrarenal echo-Doppler indices were measured. Patients with primary aldosteronism had greater creatinine clearance and urinary albumin excretion than patients with primary hypertension. Patients with primary aldosteronism and creatinine clearance above the median (105 ml/min per 1.73 m(2)) had significantly lower resistance and pulsatility index than patients with creatinine clearance below the median, independent of disease subtype. After 1 yr, creatinine clearance and albuminuria declined, and resistance and pulsatility index increased to the same extent in patients with primary aldosteronism treated with either adrenalectomy or spironolactone. Changes in glomerular filtration and albuminuria were inversely related with baseline values of the resistance index. In primary hypertension, echo-Doppler velocimetric indices did not change during follow-up. In primary aldosteronism, sonographic evidence of decreased intrarenal vascular resistance is associated with glomerular hyperfiltration. Both adrenalectomy and spironolactone revert the intrarenal hemodynamic pattern and decrease urinary protein losses.

Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin-angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. This paper discusses the design and key methodological issues that arose during the planning of the study.

Effect of Spironolactone Therapy on Albuminuria in Patients with Type 2 Diabetes Treated with Angiotensin-Converting Enzyme Inhibitors

To investigate whether the addition of spironolactone to angiotensin-converting enzyme (ACE) inhibitors further decreases albuminuria in patients with type 2 diabetes mellitus (DM). We conducted a prospective open-label trial in patients recruited at the Cleveland Clinic between February 2004 and November 2006. Patients with type 2 DM were eligible if they were older than 18 years of age, had been treated with any ACE inhibitor for longer than 1 month, and had a random urinary albumin to creatinine ratio (ACR) greater than 100 mg/g within 1 month of study entry. Based on screening ACR, patients were assigned to a microalbuminuria group (ACR 100-300 mg/g) or a macroalbuminuria group (ACR >300 mg/g). Patients were followed up for 12 weeks, with 4 clinic visits, 4 weeks apart. At visit 2, spironolactone, 25 mg once daily, was initiated and continued for 4 weeks. At visit 3, spironolactone was discontinued. Clinical information was obtained at each visit as were serum chemistries and 24-hour urinary albumin excretion. Twenty-four patients with type 2 DM and albuminuria completed the study. Eleven patients had microalbuminuria and 13 had macroalbuminuria. Following treatment with spironolactone, urinary albumin excretion dropped from a mean +/- SD of 404.6 +/- 60.9 mg/d to 302.7 +/- 52.7 mg/d (25.7% decrease, P<.001). In the microalbuminuria and macroalbuminuria groups, the urinary albumin excretion dropped 27.2% (P = .05) and 24.3% (P = .02), respectively. Despite a significant decrease in systolic blood pressure between visits 2 and 3 (141.2 +/- 3.5 to 132.5 +/- 3.6 mm Hg; P = .002), this change did not correlate to the change in albuminuria (r(2) = 0.02; P = .23). There were no withdrawals due to hyperkalemia. Spironolactone is effective in further decreasing albuminuria in patients with type 2 DM who are already treated with ACE inhibitors.

Relation between degree of weight loss after bariatric surgery and reduction in albuminuria and C-reactive protein

Background Bariatric surgery achieves long-term weight loss in obese adults with amelioration of diabetes and hypertension. Improvement in albuminuria and high-sensitivity C-reactive protein (hs-CRP) has also been reported. We investigated, at a weight control center in a community hospital setting, the relation between degree of surgical weight loss and reduction in the cardiovascular risk markers, albuminuria and hs-CRP. Methods We performed a retrospective study of 62 obese adults who had undergone Roux-en- Y gastric bypass surgery and had a median follow-up of 15 months. Results The baseline (preoperative) mean age was 46 years, 82% were women, 26 had a blood pressure of ≥140/90 mm Hg, and 25 had type 2 diabetes. During follow-up (postoperative), a decrease occurred in the body mass index (mean ± standard deviation 49.2 ± 8.7 kg/m 2 to 34.1 ± 8.1 kg/m 2; P <.0001), excess body weight (mean ± SD 76.1 ± 23.6 kg to 34.9 ± 21.7 kg; P <.0001), hemoglobin A1c (mean ± SD 6.5% ± 1.3% to 5.6% ± 0.8%; P <.0001), systolic blood pressure (mean ± SD 133.7 ± 14.3 mm Hg to 112.9 ± 14.6 mm Hg; P < .0001), urine albumin creatinine ratio (from a median of 8.0 mg/g [interquartile range 5.0–29.3] to a median of 6.0 mg/g [interquartile range 3.3–11.5]; P <.0001), and hs-CRP (mean ± SD 11.2 ± 9.8 mg/L to 4.7 ± 5.9 mg/L; P <.0001). The study sample was divided into tertiles of the percentage of excess body weight loss; the mean percentage of excess body weight loss was −37.1% ± 5.5% in the first tertile, −54.3% ± 6.8% in the second tertile, and −75.8% ± 10.9% in the third tertile. The median percentage of change in albuminuria was greatest (median −52.8%, interquartile range −79.1% to −17.5%) in the third tertile, intermediate (median −45.5%, interquartile range −72.4% to 0%) in the second tertile, and lowest (−42.6%, interquartile range −80.5% to 16.7%) in the first tertile ( P = .953). The mean percentage of change in hs-CRP was greatest (−72.4% ± 30.4%) in the third tertile, intermediate (−55.4% ± 31.9%) in the second tertile, and lowest (−44.8% ± 30.6%) in the first tertile ( P = .037). Conclusion The results of our study have shown that obese adults experience a reduction in albuminuria and hs-CRP after bariatric surgery, with a greater reduction in hs-CRP observed with more surgical weight loss.

Antiproteinuric effects of angiotensin receptor blockers: telmisartan versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathy

Renin-angiotensin system blockade reduces proteinuria and prevents nephropathy progression in patients with type 2 diabetes mellitus (T2D). Experimental evidence demonstrates that angiotensin receptor blockers (ARBs) possess anti-inflammatory potential, which might contribute to reducing proteinuria and providing renoprotection. We conducted a multicentre, double-blind, prospective, parallel-group non-inferiority study of 885 hypertensive [systolic blood pressure/diastolic blood pressure (SBP/DBP) >130/80 mmHg] patients with T2D, proteinuria (> or =900 mg/24 h) and serum creatinine (< or =3.0 mg/dl) who were randomized to once-daily telmisartan 80 mg or valsartan 160 mg; additional antihypertensive therapy was permitted. The primary endpoint was the change from baseline in the 24-h proteinuria after 12 months. Secondary endpoints included changes in 24-h albuminuria, estimated glomerular filtration rate (eGFR) and inflammatory parameters asymmetrical dimethylarginine (ADMA), high-sensitivity C-reactive protein (CRP) and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)). Telmisartan and valsartan produced comparable reductions in 24-h urinary protein excretion rates: geometric mean reduction (95% confidence interval) [telmisartan, 33% (27-39%); valsartan, 33% (27-38%)]. No significant differences between treatments were seen in changes from baseline in 24-h urinary albumin excretion rate and eGFR at 12 months. With both treatments, greater renoprotection was seen among patients with better blood pressure control. No significant changes in ADMA or CRP were noted in either group after 12 months, but urinary 8-iso-PGF(2alpha) levels decreased by 14% with telmisartan and by 7% with valsartan (P = 0.040). In patients with T2D, hypertension and overt nephropathy, the renoprotection afforded by telmisartan and valsartan appears similar, and the study was unable to show any effect beyond that due to blood pressure control. At doses used to treat hypertension, there is no evidence of inflammatory parameters being modified by ARBs in patients with more advanced kidney disease due to T2D.

The Effects of Spironolactone on Nephron Function in Patients with Diabetic Nephropathy

Increasing evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular diseases. We sought to evaluate the effects of a three-month treatment with 25 mg spironolactone, an aldosterone receptor antagonist, on nephron function in 20 type II diabetic patients with persistent microalbuminuria, despite at least six months' use of an ACEi or ARB (combination group), and in eleven type II diabetic patients with persistent microalbuminuria who have never used an ACEi or an ARB (spironolactone group). In the combination group, urinary protein excretion (UPE, p = 0.015), urinary albumin excretion (UAE, p = 0.010), and the urinary albumin to creatinine ratio (ACR, p = 0.007) decreased, and serum potassium (sK+, p = 0.004) was significantly elevated. ACR (p = 0.016) decreased significantly in the spironolactone group. In 31 patients given spironolactone (all patients group), UPE (p = 0.019), UAE (p = 0.002), and ACR (p = 0.011) decreased, and serum creatinine (sCr, p = 0.025) and sK+ (p = 0.002) were significantly elevated. Changes in albuminuria showed a positive correlation with changes in GFR (p = 0.002) and a negative correlation with changes in sCr (p = 0.007), and changes in ACR showed a negative correlation with changes in sCr (p = 0.004) in all patient groups. In our study, we observed that spironolactone, both alone and in combination with ACEi/ARB treatment, was well tolerated, and that it slowed down the progression of diabetic nephropathy with a marked antialbuminuric effect. Our results showed that the antialbuminuric effect developed by the decrease of intraglomerular pressure, particularly in patients with persistent microalbuminuria despite long-term ACEi/ARB treatment; adding aldosterone blockers to treatment was beneficial.

Change in Albuminuria Is Predictive of Cardiovascular Outcome in Normotensive Patients With Type 2 Diabetes and Microalbuminuria

Microalbuminuria is associated with cardiovascular complications and all-cause mortality in patients with diabetes (1–3). Inhibitors of the renin-angiotensin system (RAS) protect renal and cardiac function in these patients, at least partly independent of the associated blood pressure reduction (4–9). Recently, a few studies showed that reduction in albuminuria in hypertensive diabetic patients reduces the risk of subsequent cardiovascular events (10–12). The question remains whether this risk reduction is explained by the reduction of high blood pressure. No data are available for normotensive diabetic patients. Therefore, we investigated whether sustained change in albuminuria independently predicts cardiovascular outcome in patients with type 2 diabetes and microalbuminuria but without hypertension. The present study is a prospective follow-up study of 67 normotensive patients (baseline blood pressure ≤140/90 mmHg without antihypertensive treatment) with type 2 diabetes and microalbuminuria (urinary albumin excretion 20–200 mg/l), who participated in a previously published, larger, randomized, double-blind, placebo-controlled, multicenter trial investigating the short-term effects of the angiotensin-receptor antagonist losartan on microalbuminuria (7). Exclusion criteria included a history of macrovascular complications and a baseline serum creatinine level >150 μmol/l. After the original 20-week study period, a cohort of 67 patients from that study was prospectively followed during mean ± SEM 4.7 ± 0.1 years. They were recruited on the basis of their address and received standard medical care. Data were collected on current and past health, medication use, blood pressure, renal function, and albuminuria, which was annually assessed …

Albuminuria Is a Target for Renoprotective Therapy Independent from Blood Pressure in Patients with Type 2 Diabetic Nephropathy

Albuminuria reduction could be renoprotective in hypertensive patients with diabetic nephropathy. However, the current use of renin-angiotensin-system intervention is targeted to BP only. Therefore, this study investigated the adequacy of this approach in 1428 patients with hypertension and diabetic nephropathy from the placebo-controlled Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Investigated were the extent of discordance in treatment effects on systolic BP (SBP) and albuminuria and its association with renal outcome in a multivariate Cox model. Among patients with a reduced SBP during treatment, a lack of albuminuria reduction was observed in 37, 26, and 51% (total, losartan, and placebo, respectively) at month 6. SBP or albuminuria reduction was associated with a lower risk for ESRD, whereas combined SBP and albuminuria reduction was associated with the lowest risk for events. Across all categories of SBP change, a progressively lower ESRD hazard ratio was observed with a larger albuminuria reduction. A lower residual level of albuminuria was also associated with lower ESRD risk. In conclusion, changes in albuminuria are not concordant in a substantial proportion of patients when titrated for BP. Meanwhile, the ESRD risk showed a clear dependence on albuminuria reduction. The ESRD risk also showed dependence on the residual level of albuminuria, even in patients who reached the current SBP target. Antihypertensive treatment that is aimed at improving renal outcomes in patients with diabetic nephropathy may therefore require a dual strategy, targeting both SBP and albuminuria reduction.

Sex Differences in the Renal Changes Elicited by Angiotensin II Blockade During the Nephrogenic Period

The renin-angiotensin system plays an important role in renal development. However, it is unknown whether reduction in angiotensin II effects during the nephrogenic period leads to different renal alterations in males and females during the adult age. The aim of this study was to evaluate whether the role of angiotensin II on renal development is sex dependent and whether there are sex differences in blood pressure, renal hemodynamics, and severity of renal damage during adult life when nephrogenesis is altered by blocking angiotensin II effects. Newborn Sprague-Dawley rats were treated with an angiotensin II type 1 receptor antagonist (L-158.809; 7 mg/kg per day) during the first 2 weeks of life. At 3 months of age, changes in blood pressure, albuminuria, and renal hemodynamics were assessed, and stereological and histopathologic studies were performed. Blood pressure increased (127+/-0.5 versus 115+/-0.7 mm Hg in control rats; P<0.05) and nephron number decreased (37%; P<0.05) similarly in treated males and females. However, only males had an elevation in albuminuria (5.92+/-1.65 versus 0.33+/-0.09 mg per day in control rats; P<0.05), a fall in glomerular filtration rate (12.6%; P<0.05), and a significant decrease in papillary volume (42%; P<0.05). Mean glomerular volume, glomerulosclerosis, arteriolar hypertrophy, and tubulointerstitial damage in cortex and medulla were also higher (P<0.05) in angiotensin II type 1 receptor antagonist-treated males than in treated females. The results of this study suggest that females seem to be more protected than males to the renal consequences of reducing angiotensin II effects during renal development.

Impact of weight change on albuminuria in the general population

Increased levels of albuminuria have been recognized as a feature of obesity and the metabolic syndrome, and to be associated with an increased risk for cardiovascular and renal disease. The impact of weight change on albuminuria and its possible mechanism has not been studied yet in the general population. We investigated this issue in a cohort of the Northern European population. A total of 6894 participants of the Prevention of Renal and Vascular Endstage Disease (PREVEND) study were evaluated from baseline to a mean period of follow-up of 4.2 years for weight change (gain/loss), and its impact on albuminuria, renal function and cardiovascular risk factors. Participants were categorized into three groups based on absolute change in weight from baseline to follow-up: significant weight loss (>10 kg reduction in weight), stable weight, or significant weight gain (>10 kg increase). Multivariate regression analysis was used to evaluate the effect of baseline characteristics and time-dependent changes in these characteristics on the relationship of weight change with urine albumin excretion (UAE). At follow-up 101 subjects experienced significant weight loss (mean change = -14.2 kg), 348 had significant weight gain (mean change = +13.4 kg) and the remaining were defined stable in weight (mean change = +1.4 kg). Weight loss was associated with significant improvement in systolic blood pressure (-11 +/- 15 mmHg), diastolic blood pressure (-5 +/- 8 mmHg), and cholesterol (-0.7 +/- 1.3 mmol/l), even after adjustment for the use of medications (P < 0.001). These parameters worsened significantly in those who substantially gained weight (P < 0.001). Similarly, weight loss was significantly associated with a reduction in UAE (mean -2.2 +/- 1.1 mg/24 h), whereas weight gain was associated with a rise in UAE (mean +0.42 +/- 2.0 mg/24 h). Notably, no changes were observed in GFR (assessed as 24 h urinary creatinine clearance) in subjects with weight loss or weight gain. Multivariate regression modelling with changes in UAE as dependent variable-correcting for factors that might explain the association-showed that only part of the relationship between weight changes and changes in UAE was explained by effect of weight change on blood pressure and cholesterol, whereas the association disappeared with changes in CRP in the model (P = 0.50). This is the first population-based longitudinal study to show that changes in weight are associated with parallel changes in albuminuria. This relationship cannot be fully explained by the association between weight and classical cardiovascular risk factors and renal function. Based on our data we hypothesize that weight-induced changes in vascular inflammation may cause changes in albuminuria.

Anti-albuminuric effect of losartan versus amlodipine in hypertensive Japanese patients with type 2 diabetes mellitus: A prospective, open-label, randomized, comparative study

Abstract. The antiproteinuric effect of the angiotensin II receptor-antagonist losartan has been observed in patients with type 2 diabetes mellitus (T2DM). Proteinuria is considered to be a predictor of the progression of kidney disease. The aims of the present study were to compare and examine the ability of losartan and amlodipine to ameliorate albuminuria in hypertensive Japanese patients (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) with T2DM and whether the change in albuminuria was associated with a change in glomerular filtration rate (GFR). This prospective, open-label, randomized, comparative study was conducted over 3 months at the Kinki University School of Medicine, Osaka-Sayama, Japan. Hypertensive patients with T2DM were enrolled and randomly assigned to 1 of 2 study groups receiving either losartan (25-100 mg/d) or the calcium channel-blocker amlodipine (2.5-5 mg/d). Urinary albumin excretion (UAE), creatinine clearance, and GFR were recorded at study initiation (baseline) and study end (month 3). The GFR was measured from the fractional renal accumulation of (99m)Tc-diethylenetriaminepentaacetic acid. Adverse events (AEs) were monitored by a clinical research nurse during the examination. Fifty patients were asked to enroll and 38 returned the informed written consent. Thirty-five Japanese patients were included in the final study analysis. Seventeen patients were assigned to the losartan group (male sex, 10 [58.8%]; mean [SD] age, 58.1 [8.2] years) and 18 were assigned to the amlodipine group (male sex, 10 [55.6%]; mean [SD] age, 57.4 [8.9] years); no significant between-group difference in demographics was observed. A significant decrease from baseline to month 3 of mean (SD) UAE was observed in the losartan group (352.5 [556.6] mg/d vs 275.7 [466.1] mg/d; P = 0.048). No significant difference in mean (SD) UAE was observed in the amlodipine group for the same time period (298.2 [416.6] mg/d vs 322.7 [415.4] mg/d). There was a statistically significant difference found in the mean (SD) percent change of UAE from baseline to month 3 in the losartan group compared with the amlodipine group (-23.52 [28.42] vs +27.90 [63.51]; P = 0.004). Neither group was associated with a significant change in GFR during the course of the study. No patient discontinued the study due to AEs that were considered, by the investigator, to be possibly or probably associated with study treatment. Treatment with losartan, but not amlodipine, was associated with a reduction in albuminuria in these hypertensive Japanese patients with T2DM within a period as short as 3 months. Neither drug was associated with a significant change in GFR. Therefore, the reduction of UAE was independent of a change in the GFR.

Enalapril/amlodipine combination in cyclosporine‐treated renal transplant recipients: a prospective randomized trial

Most hypertensive renal transplant recipients require two or more antihypertensive medications to achieve blood pressure control. However, which medications must be combined is still a matter of debate. A prospective randomized open-label blinded evaluation trial comparing the six-month effects of the amlodipine-enalapril combination (n = 32) vs. enalapril alone (n = 33) and vs. amlodipine alone (n = 34) on arterial pressure, renal function, albuminuria and tolerability. At six months, diastolic arterial pressure was more adequately controlled (i.e., <90 mmHg) in the combination group than in the amlodipine and enalapril groups (100% vs. 82.4% and 84.8%, respectively, p = 0.038). The same trend was observed for systolic arterial pressure (65.6% vs. 58.8% and 51.5%, NS). The six-month change in albuminuria was similar in the combination group and in the enalapril group (-64.7% vs. -59.5%); however, patients in the combination group exhibited a greater reduction in albuminuria than in the amlodipine group (-64.7% vs. -29.0%, p = 0.002). As compared with baseline values, serum creatinine and potassium remained unchanged in the combination group, whereas they increased by 9 +/- 12 micromol/L (p = 0.01) and by 0.2 +/- 0.4 mmol/L (p < 0.01), respectively, in the enalapril group. The cyclosporine trough levels remained unchanged in the combination group, but increased in the amlodipine group. Angiotensin-converting enzyme inhibitor (ACEI)-calcium-channel blocker (CCB) combination controls arterial pressure more adequately than ACEI alone or CCB alone, reduces albuminuria and may prevent the ACEI-induced initial rise in serum creatinine.

Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function

To study the effects of addition of spironolactone to angiotensin-converting enzyme (ACE) inhibition or angiotensin II (AngII) receptor antagonism on proteinuria, blood pressure (BP) and renal function in overt type 2 diabetic nephropathy. A placebo-controlled, double-blind, parallel-group trial in patients from two outpatient clinics with a follow-up of 1 year. Type 2 diabetic patients with macroalbuminuria, despite long-term use of an ACE inhibitor or AngII receptor blocker were allocated to spironolactone, 25-50 mg once daily (n = 29) or placebo (n = 30). Urinary albumin to creatinine ratio, BP and biochemical parameters were measured at regular intervals. Five patients of the spironolactone and one of the placebo group developed hyperkalemia and had to be excluded. Compared to other patients their baseline serum creatinine [161 (123-248) versus 88 (72-170) micromol/l] and potassium concentrations (4.7 +/- 0.3 versus 4.2 +/- 0.2 mmol/l) were elevated (P < 0.001). Albuminuria decreased by 40.6% [95% confidence interval (CI) 23.4-57.8%] and BP by 7 mmHg (2-12 mmHg)/3 mmHg (1-6 mmHg) with spironolactone, but did not change with placebo. Estimated glomerular filtration rate (eGFR) during the 1-year follow-up declined on average by 12.9 ml/min per 1.73 m (9.5-16.5 ml/min per 1.73 m) in the spironolactone and by 4.9 ml/min per 1.73 m (0.8-8.9 ml/min per 1.73 m) in the placebo group (P = 0.004). This decline was progressive in the placebo but leveled off in the spironolactone group. In the spironolactone group changes in albuminuria and GFR were correlated (r = 0.48, P = 0.007). Addition of spironolactone to an ACE inhibitor or AngII receptor blocker is associated with a marked and sustained antiproteinuric effect, which in part relates to the more pronounced reduction in GFR.

Differential Effects of β-Blockers on Albuminuria in Patients With Type 2 Diabetes

Increases in the cardiovascular risk marker microalbuminuria are attenuated by blood pressure reduction using blockers of the renin-angiotensin system. Such changes in microalbuminuria have not been observed when beta-blockers are used. A prespecified secondary end point of the Glycemic Effects in Diabetes Mellitus Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial was to examine the effects of different beta-blockers on changes in albuminuria in the presence of renin-angiotensin system blockade. Participants with hypertension and type 2 diabetes were randomized to either metoprolol tartrate (n=737) or carvedilol (n=498) in blinded fashion after a washout period of all antihypertensive agents except for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Blinded medication was titrated to achieve target blood pressure, with a-5 month follow-up period. The current analysis examined microalbuminuria, using spot urine albumin:creatinine, in participants who had values at screening and trial end. A greater reduction in microalbuminuria was observed for those randomized to carvedilol (-16.2%Delta; 95% confidence interval, -25.3, -5.9; P=0.003). Of those with normoalbuminuria at baseline, fewer progressed to microalbuminuria on carvedilol versus metoprolol (20 of 302 [6.6%] versus 48 of 431 [11.1%], respectively; P=0.03). Microalbuminuria development was not related to differences in blood pressure or achievement of blood pressure goal (68% carvedilol versus 67%, metoprolol). Presence of metabolic syndrome at baseline was the only independent predictor of worsening albuminuria throughout the study (P=0.004). Beta-blockers have differential effects on microalbuminuria in the presence of renin-angiotensin system blockade. These differences cannot be explained by effects on blood pressure or alpha1-antagonism but may relate to antioxidant properties of carvedilol.

Néphropathie diabétique et traitement antihypertenseur : quelles sont les leçons des essais cliniques ?

Diabetic nephropathy is the most serious problem among current issues in nephrology, as 40 % of the cases of end-stage renal disease are due to this entity. The close relationship between type 2 diabetes and hypertension makes the problem even more severe. The knowledge of the intrarenal effects of angiotensin II and the greater effect of angiotensin converting enzyme inhibitors (ACEI) on reducing albuminuria suggested in the past a trend toward preferable use of these drugs in diabetic nephropathy. The first relevant clinical trials yielded rather poor conclusions because of lack of blind randomization and short duration. Subsequent double-blind studies with adequate numbers of patients and sufficient duration underlined the importance of blood pressure (BP) control as well as the rather poor response of diabetic nephropathy to any treatment. In most of these studies, the changes in albuminuria or microalbuminuria were a substitute end point for the renal function. Three clinical trials using angiotensin II receptor blockers (ARB), planned specifically to monitor the progression of renal damage, have been recently published. They showed better renal protection by ARB, as compared with placebo or calcium channel blockers (CCB), beyond or independently of the BP reduction. Nevertheless, these recent trials, like the previous ones with similar results, invariably demonstrate slightly better control of BP in the groups of the active drug. Another issue is that the vast majority of the patients need so many nonstudy drugs to keep their pressure under control, that the isolation of advantageous effects of certain drugs seems unrealistic.

Reducing Microalbuminuria-Does It Lower Cardiovascular Risk?: Reduction in Albuminuria Translates to Reduction in Cardiovascular Events in Hypertensive Patients: Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension 45: 198-202, 2005.

Reducing Microalbuminuria-Does It Lower Cardiovascular Risk?: Reduction in Albuminuria Translates to Reduction in Cardiovascular Events in Hypertensive Patients: Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension 45: 198-202, 2005.

Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria

The purpose of this study was to evaluate the renoprotective effect as reflected by short-term changes in albuminuria of ultrahigh doses of irbesartan in type 2 diabetic patients with microalbuminuria. This double-masked randomized crossover trial included 52 (41 males) hypertensive type 2 diabetic patients with microalbuminuria on ongoing antihypertensive medication. At inclusion, previous antihypertensive treatment was discontinued and replaced with bendroflumethiazide, 5 mg once daily, for the entire study. Following 2 months wash-out (baseline), patients were treated randomly with irbesartan 300, 600, and 900 mg once daily, each dose for 2 months. End points evaluated at the end of each study period included urinary albumin excretion rate (UAE) (mean of three 24-hour collections), 24-hour ambulatory blood pressure, and glomerular filtration rate (GFR) [chromium 51 ethylenediaminetetraacetic acid (51Cr-EDTA)]. Baseline values were: 24-hour UAE [geometric mean (95% CI)] 134 (103 to 170) mg/24 hours, ambulatory blood pressure [mean (SD)] 140 (10)/77 (7) mm Hg, and GFR 103 (19) mL/min/1.73 m2. All doses of irbesartan significantly reduced UAE, ambulatory blood pressure, and GFR from baseline. Reductions in UAE from baseline were 52% (46% to 57%), 49% (43% to 54%), and 59% (54% to 63%) with increasing doses of irbesartan (P < 0.01). UAE was reduced significantly more by irbesartan 900 mg compared with lower doses with an additional reduction in UAE of 15% (2% to 26%) by irbesartan 900 mg compared with 300 mg (P = 0.02). The greater reduction in albuminuria by irbesartan 900 vs. 300 mg was more pronounced in patients with UAE during irbesartan 300 mg above vs. below the median [31% (18% to 42%) vs. -9% (-25% to 6%), respectively (P < 0.05)]. With increasing doses systolic ambulatory blood pressure was reduced from baseline by 8 (4 to 12), 9 (5 to 13), and 9 (5 to13) mm Hg, and diastolic ambulatory blood pressure by 6 (4 to 7), 7 (6 to 9), and 7 (6 to 9) mm Hg (NS between doses). Ultrahigh dosing of irbesartan (900 mg once daily) is generally safe and offers additional renoprotection independent of changes in systemic blood pressure and GFR in comparison to the currently recommended dose of 300 mg.