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Introduction: Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ETA receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD. Methods: The treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks. Results: The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance – all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. Conclusion: These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.

Blockade of the renin-angiotensin system (RAS), the standard treatment for chronic proteinuric nephropathy, slows but may not halt progression of the disease, particularly when therapy is started late. Because vasopressin may also play a role in the progression of renal disease, we measured the effect of a dual V(1a) and V(2) vasopressin receptor antagonist (RWJ-676070) alone or combined with angiotensin-converting enzyme inhibition or angiotensin II type 1 receptor blockade on proteinuria and renal disease progression during overt nephropathy. Twenty-one days after renal mass reduction, a time of established injury, rats were given vehicle, RWJ-676070, enalapril, losartan, RWJ-676070 plus enalapril, or losartan in drinking water for an additional 39 days. RWJ-676070 returned the blood pressure to pre-treatment levels, which were significantly lower than those in vehicle-treated rats. Enalapril, losartan, and the combined therapies reduced blood pressure to a greater extent. RWJ-676070 afforded a partial antiproteinuric effect, which was enhanced by the addition of enalapril or losartan. Renal functional impairment, and glomerular and tubular changes were partially ameliorated by RWJ-676070; parameters significantly improved with either enalapril or losartan alone and improved to a greater extent with the combined therapies. Our findings suggest that vasopressin receptor antagonists could be of additional therapeutic value in the treatment of chronic proteinuric nephropathy.

Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vascular superoxide.BackgroundNitric oxide inactivation by superoxide impairs endothelium-dependent vasodilation and plays a role in various forms of hypertension. Almost no data exist regarding hypertension secondary to chronic renal failure. Previous studies have shown that endothelium-related relaxations, secondary to decreased nitric oxide bioactivity, are impaired in resistance vessels from rats 3 to 10 days after renal mass reduction (RMR).MethodsThe membrane-permeable superoxide dismutase (SOD)-mimetic (tempol) was administered IP (1.5 mmol/kg/day for 10 days) to RMR rats and sham-operated controls (SN). Systolic blood pressure (SBP) was measured by tail cuff manometry at days 0, 3, 6 and 10. The increase of flow induced by acetylcholine (10-6 mol/L) was measured in isolated perfused mesenteric arteries from RMR and SN rats pre-contracted with noradrenaline (1 to 5 μmol/L), with or without exogenous SOD. Plasma levels of advanced oxidative protein products (AOPPs; chloramine-T equivalents) were measured in SN and RMR rats.ResultsTempol prevented the increase of SBP: 118 ± 2.2mm Hg at baseline and 122 ± 1.6mm Hg at 10 days in tempol-treated vs 118.14 ± 1.65mm Hg at baseline and 145 ± 7.69mm Hg at 10 days in untreated RMR rats (P < 0.01). Responsiveness to acetylcholine was reduced in RMR rats (peak flow increase: 139 ± 7.8% vs. 176 ± 11% in SN, P = 0.028 at 3 days and 140 ± 6.4% vs. 187 ± 16.9% in SN at 10 days, P = 0.007). In arteries pre-incubated with SOD (200 U/mL) the peak flows were 175 ± 9.4% at 3 days and 157 ± 5.8% at 10 days (P = 0.007 and P = 0.051, respectively, vs. control RMR vessels). AOPP values were significantly increased in plasma from RMR rats 3 days after 5/6 nephrectomy (747 ± 107 vs. 481 ± 77 μmol/L, P < 0.05) but returned to normal by day 10. AOPP levels were not significantly reduced by tempol.ConclusionsIncreased vascular superoxide production plays a central role in the development of vascular endothelial dysfunction and hypertension early after 5/6 nephrectomy.

Blunted response to vitamin D in uremia. It has been demonstrated that many chains in the vitamin D pathway are affected by uremia. Uremic solute retention is responsible for changes in calcitriol production, resulting in a net decrease of blood calcitriol levels. This effect contributes to the calcitriol deficiency currently observed in renal failure. Next to the altered production and metabolization of calcitriol, altered expression of the vitamin D receptor (VDR) and altered binding properties of the hormone receptor complex to the DNA could also contribute to the relative status of calcitriol resistance in renal failure. These alterations could finally result in an impairment of the end biological action of calcitriol.

ACE (angiotensin-converting enzyme) 2 is expressed in the heart and kidney and metabolizes Ang (angiotensin) II to Ang-(1–7) a peptide that acts via the Ang-(1–7) or mas receptor. The aim of the present study was to assess the effect of Ang-(1–7) on blood pressure and cardiac remodelling in a rat model of renal mass ablation. Male SD (Sprague–Dawley) rats underwent STNx (subtotal nephrectomy) and were treated for 10 days with vehicle, the ACE inhibitor ramipril (oral 1 mg·kg−1 of body weight·day−1) or Ang-(1–7) (subcutaneous 24 μg·kg−1 of body weight·h−1) (all n = 15 per group). A control group ( n = 10) of sham-operated rats were also studied. STNx rats were hypertensive ( P

Factors influencing the appearance and progression of renal damage in patients with unilateral renal agenesis and remnant kidney. Background Although some studies have shown that the risk to develop proteinuria and renal insufficiency is increased in patients with a remnant kidney (RK) or unilateral renal agenesis (URA), other patients maintain normal renal function and negative proteinuria, and the reasons to explain these different outcomes are not known. Methods We performed a retrospective study of 54 patients with a severe reduction in renal mass (33 patients with URA and 21 with RK). Follow-up was 100 ± 72 months. Results Twenty patients (group 1) showed normal renal function at presentation, whereas the 34 remaining (group 2) had proteinuria, and some of them renal insufficiency. Group 2 patients were older and had a higher blood pressure and BMI than group 1 patients. Eleven patients of group 1 remained normal throughout follow-up (group 1A), whereas the remaining 9 developed proteinuria/renal insufficiency (group 1B). BMI at presentation was significantly higher in group 1B: 27 ± 3.6 kg/m 2 versus 21.6 ± 2.6 kg/m 2 , and BMI was the only factor statistically associated with the risk to develop proteinuria/renal insufficiency in group 1. Among group 2 patients, renal function remained stable in 20 (group 2A), and deteriorated (>50% increase of baseline serum creatinine) in the remaining 14 patients (group 2B). BMI at presentation and treatment with ACEI during follow-up were the only factors statistically associated with the risk for renal failure progression among group 2 patients. Conclusion Overweight plays a fundamental role in the appearance of proteinuria and renal damage in patients with severe renal mass reduction.

Influence of obesity on the appearance of proteinuria and renal insufficiency after unilateral nephrectomy.BackgroundSome patients develop proteinuria and progressive renal failure after unilateral nephrectomy, although the majority of patients maintain normal renal function. Reasons to explain this different evolution are not known.MethodsA cross-sectional study was performed in 73 patients who had undergone unilateral nephrectomy 13.6 ± 8.6 years before. Patients with morphologic abnormalities in the remaining kidney, systemic disorders, or abnormal renal function at the time of nephrectomy were excluded. All of the 73 included patients showed normal renal function and negative proteinuria at nephrectomy. The patient's medical records were reviewed, and clinical and analytical data throughout follow-up were obtained.ResultsFifty-three out of the 73 patients (group I) showed a normal renal function and negative proteinuria at the cross-sectional study. The remaining 20 patients (group II) showed proteinuria (3.4 ± 3.1 g/day). The time elapsed between nephrectomy and proteinuria appearance was 10.1 ± 6.1 years. Thirteen patients of group II had developed renal insufficiency (serum creatinine at the cross-sectional study of 3.9 + 3.2 mg/dL) in addition to proteinuria. The time elapsed between proteinuria appearance and the onset of renal insufficiency was 4.1 ± 4.3 years. Renal insufficiency showed a slowly progressive course in most of these patients. There were no significant differences between group I and group II patients in age, gender, renal function, or blood pressure at the time of nephrectomy. In contrast, group II patients showed a body mass index (BMI) that was significantly higher than group I at nephrectomy (31.6 ± 5.6 vs. 24.3 ± 3.7 kg/m2, P < 0.001), at cross-sectional study (33.3 ± 6.6 vs. 25.1 ± 3.5 kg/m2, P < 0.001), and throughout follow-up. Among the 14 obese (BMI > 30 kg/m2) patients at the time of nephrectomy, 13 (92%) developed proteinuria/renal insufficiency. In contrast, among the 59 patients with BMI < 30 kg/m2, only 7 (12%) developed these complications (P < 0.001). Kaplan–Meier estimated probability of negative proteinuria and normal renal function 10 years after nephrectomy was 40 and 70%, respectively, in obese patients at nephrectomy. At 20 years after nephrectomy, these percentages were 8 and 35%, respectively. In contrast, in nonobese patients, the probability of negative proteinuria and normal renal function was 93 and 98%, respectively, at 10 years (P < 0.001) and 77 and 91%, respectively, at 20 years (P < 0.001). Multiple logistic regression analysis showed that the risk of developing renal disease was only statistically correlated with BMI at the time of unilateral nephrectomy (odds ratio 1.34, 1.03 to 1.76 CI).ConclusionsObese patients are at risk for developing proteinuria and chronic renal failure after unilateral nephrectomy. Regular and long-term follow-up are recommended in these patients.

Tight blood pressure control decreases apoptosis during renal damage. Background An excess rate of apoptosis could lead to the gradual loss of renal mass. In this study, we investigated the role of apoptosis in the renal damage secondary to hypertension. Methods Spontaneously hypertensive rats with 5/6 renal mass reduction (subtotal nephrectomy) were distributed to receive no-treatment, 200mg/L quinapril, 360mg/L losartan, or triple therapy (200mg/L hydralazine, 4mg/L reserpine, and 100mg/L hydrochlorothiazide) for 5weeks. Sham-operated spontaneously hypertensive rats served as controls. Age-matched Wistar-Kyoto (WKY) rats, with or without subtotal nephrectomy, were also studied. Results Nontreated spontaneously hypertensive rats + subtotal nephrectomy developed proteinuria, glomerular sclerosis, and tubulointerstitial lesions. In comparison to spontaneously hypertensive rats, an increment in the number of [proliferating cell nuclear antigen (PCNA)]-positive and apoptotic [terminal deoxynucleotidyl transferase (Tdt)-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL)]-positive tubular and glomerular cells was observed. By contrast, WKY + subtotal nephrectomy rats showed less severe morphologic lesions, and only the number of proliferating cells increased. By Western blot, an up-regulation of renal Bax (apoptosis inducer) was noted both in spontaneously hypertensive rats + subtotal nephrectomy and WKY + subtotal nephrectomy rats. By contrast, Bcl-xL (apoptosis protector) was up-regulated in WKY + subtotal nephrectomy rats but not in spontaneously hypertensive rats + subtotal nephrectomy. The administration of appropriate doses of quinapril, losartan, or triple therapy to spontaneously hypertensive rats + subtotal nephrectomy normalized systolic blood pressure, partially prevented proteinuria, renal lesions and apoptosis, and decreased Bax, but no changes were noted in Bcl-xL. The Bax/Bcl-xL index was significantly increased in spontaneously hypertensive rats + subtotal nephrectomy compared to sham-operated spontaneously hypertensive rats and decreased in treated groups. Conclusion The combination of renal mass reduction and hypertension caused severe renal lesions associated to an increment of apoptosis rate, mainly in tubular epithelial cells. Tight blood pressure control decreased the apoptosis rate and morphologic lesions. These studies suggest that changes in the expression of apoptosis-regulatory genes contribute to the progressive damage in hypertensive rats with renal mass reduction.