https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60242-6.pdf

Renin-angiotensin system and cardiovascular risk

Background
Cardiovascular disease (CVD) is the most frequent cause of death in people with early stages of chronic kidney disease (CKD), for whom the absolute risk of cardiovascular events is similar to people who have existing coronary artery disease. This is an update of a review published in 2009, and includes evidence from 27 new studies (25,068 participants) in addition to the 26 studies (20,324 participants) assessed previously; and excludes three previously included studies (107 participants). This updated review includes 50 studies (45,285 participants); of these 38 (37,274 participants) were meta-analysed.

Objectives
To evaluate the benefits (such as reductions in all-cause and cardiovascular mortality, major cardiovascular events, MI and stroke; and slow progression of CKD to end-stage kidney disease (ESKD)) and harms (muscle and liver dysfunction, withdrawal, and cancer) of statins compared with placebo, no treatment, standard care or another statin in adults with CKD who were not on dialysis.

Search methods
We searched the Cochrane Renal Group's Specialised Register to 5 June 2012 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.

Selection criteria
Randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of statins with placebo, no treatment, standard care, or other statins, on mortality, cardiovascular events, kidney function, toxicity, and lipid levels in adults with CKD not on dialysis were the focus of our literature searches.

Data collection and analysis
Two or more authors independently extracted data and assessed study risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes (lipids, creatinine clearance and proteinuria) and risk ratio (RR) for dichotomous outcomes (major cardiovascular events, all-cause mortality, cardiovascular mortality, fatal or non-fatal myocardial infarction (MI), fatal or non-fatal stroke, ESKD, elevated liver enzymes, rhabdomyolysis, cancer and withdrawal rates) with 95% confidence intervals (CI).

Main results
We included 50 studies (45,285 participants): 47 studies (39,820 participants) compared statins with placebo or no treatment and three studies (5547 participants) compared two different statin regimens in adults with CKD who were not yet on dialysis. We were able to meta-analyse 38 studies (37,274 participants).

The risk of bias in the included studies was high. Seven studies comparing statins with placebo or no treatment had lower risk of bias overall; and were conducted according to published protocols, outcomes were adjudicated by a committee, specified outcomes were reported, and analyses were conducted using intention-to-treat methods. In placebo or no treatment controlled studies, adverse events were reported in 32 studies (68%) and systematically evaluated in 16 studies (34%).

Compared with placebo, statin therapy consistently prevented major cardiovascular events (13 studies, 36,033 participants; RR 0.72, 95% CI 0.66 to 0.79), all-cause mortality (10 studies, 28,276 participants; RR 0.79, 95% CI 0.69 to 0.91), cardiovascular death (7 studies, 19,059 participants; RR 0.77, 95% CI 0.69 to 0.87) and MI (8 studies, 9018 participants; RR 0.55, 95% CI 0.42 to 0.72). Statins had uncertain effects on stroke (5 studies, 8658 participants; RR 0.62, 95% CI 0.35 to 1.12).

Potential harms from statin therapy were limited by lack of systematic reporting and were uncertain in analyses that had few events: elevated creatine kinase (7 studies, 4514 participants; RR 0.84, 95% CI 0.20 to 3.48), liver function abnormalities (7 studies, RR 0.76, 95% CI 0.39 to 1.50), withdrawal due to adverse events (13 studies, 4219 participants; RR 1.16, 95% CI 0.84 to 1.60), and cancer (2 studies, 5581 participants; RR 1.03, 95% CI 0.82 to 130).

Statins had uncertain effects on progression of CKD. Data for relative effects of intensive cholesterol lowering in people with early stages of kidney disease were sparse. Statins clearly reduced risks of death, major cardiovascular events, and MI in people with CKD who did not have CVD at baseline (primary prevention).

Authors' conclusions
Statins consistently lower death and major cardiovascular events by 20% in people with CKD not requiring dialysis. Statin-related effects on stroke and kidney function were found to be uncertain and adverse effects of treatment are incompletely understood. Statins have an important role in primary prevention of cardiovascular events and mortality in people who have CKD.

/pdf/hmg-coa-reductase-inhibitors-statins-for-people-with-chronic-t7xlyphl28.pdf

HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening disease in which lysis of PNH red blood cells frequently manifests with chronic hemolysis, anemia, and thrombosis. Renal damage in PNH is associated with chronic hemosiderosis and/or microvascular thrombosis. We determined the incidence of renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients and evaluated the safety and efficacy of the complement inhibitor eculizumab in altering its progression. Renal dysfunction or damage was observed in 65% of the study population at baseline with 21% of patients with later stage CKD or kidney failure (glomerular filtration rate [GFR] ≤60 ml/min/1.73 m2; Stage 3, 4, or 5). Eculizumab treatment was safe and well-tolerated in patients with renal dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P < 0.001) compared with baseline and to placebo (P = 0.04). Improvement in renal function was more commonly seen in patients with baseline CKD Stages 1–2 (67.1% improvement, P < 0.001) although improvement was also observed in patients with CKD Stages 3–4 (P = 0.05). Improvements occurred quickly and were sustained for at least 18 months of treatment. Patients categorized at CKD Stages 3–5 did not worsen during treatment with eculizumab. Overall, 40 (21%) of 195 patients who demonstrated renal dysfunction or damage at baseline were no longer classified as such after 18 months of treatment. Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement. Am. J. Hematol. 85:553–559, 2010. © 2010 Wiley-Liss, Inc.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.21757

Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria

The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, despite intense research into potential treatments. Targeting the inflammatory response and/or sepsis-induced alterations in the (micro)circulation are two therapeutic strategies. Another approach could involve modulating the downstream mechanisms that are responsible for organ system dysfunction. Activation of inducible nitric oxide (NO) synthase (iNOS) during sepsis leads to elevated NO levels that influence renal hemodynamics and cause peroxynitrite-related tubular injury through the local generation of reactive nitrogen species. In many organs iNOS is not constitutively expressed; however, it is constitutively expressed in the kidney and, in humans, a relationship between the upregulation of renal iNOS and proximal tubular injury during systemic inflammation has been demonstrated. For these reasons, the selective inhibition of renal iNOS might have important implications for the treatment of sepsis-induced AKI. Various animal studies have demonstrated that selective iNOS inhibition-in contrast to nonselective NOS inhibition-attenuates sepsis-induced renal dysfunction and improves survival, a finding that warrants investigation in clinical trials. In this Review, the selective inhibition of iNOS as a potential novel treatment for sepsis-induced AKI is discussed.

Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury

Objective
To assess the effect of vitamin C supplementation on serum uric acid (SUA) by pooling the findings from published randomized, controlled trials (RCTs).

https://onlinelibrary.wiley.com/doi/pdf/10.1002/acr.20519

Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials.

Background. According to experimental data, the afferent glomerular arteriole is particularly under control of nitric oxide (NO). By use of pharmacological manoeuvres, we examined whether this finding holds true in the human renal circulation in vivo. Methods. Seventy-seven volunteers (aged 50±9 years) with mild to moderate essential hypertension (n ¼ 57) or arterial normotension (n ¼ 20) were examined. Basal NO activity in the renal circulation was assessed by the change of renal plasma flow (RPF) through systemic infusion of the NO synthase inhibitor, N G -monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). Hypertensive patients were treated over 8 weeks with either the calcium-channel blocker amlodipine or the AT1-receptor blocker valsartan, primarily dilating the afferent and efferent arteriole, respectively. Subsequently, renal haemodynamics and NO activity in the renal circulation were determined again. Results. L-NMMA reduced RPF in normotensive (by 57±70 ml/min/1.73 m 2 ; P<0.01) and hypertensive subjects (by 46±56 ml/min/1.73 m 2 ; P<0.001) with no significant difference between the two groups. The decrease of RPF through L-NMMA was closely related with the glomerular filtration rate (GFR; r ¼ 0.39, P<0.001). Administration of amlodipine increased GFR by 7.1±12.1 ml/min/1.73 m 2 ;( P<0.01) and in parallel reduced the response of RPF to L-NMMA to 19±48 ml/min/1.73 m 2 ;( P<0.05). In contrast, valsartan maintained GFR and left the response of RPF to L-NMMA unchanged. Conclusions. NO plays an important role in the regulation of human glomerular haemodynamics, probably with a greater contribution to afferent than to efferent arteriolar tone in man.

/pdf/the-role-of-nitric-oxide-in-the-regulation-of-glomerular-42tlftbg6b.pdf

The role of nitric oxide in the regulation of glomerular haemodynamics in humans

Rosuvastatin improves basal nitric oxide activity of the renal vasculature in patients with hypercholesterolemia

https://www.kidney-international.org/article/S0085-2538(15)52080-2/pdf

Impaired basal NO activity in patients with glomerular disease and the influence of oxidative stress

Background Angiotensin II has been found to be a growt stimulating factor for myocardial cells. In humans, angiotensin II infusion causes vasoconstriction in systemic and renal vasculature and leads to aldosterone secretion. Our hypothesis was that hyper-responsiveness to angiotensin II is related to left ventricular mass in human essential hypertension. Methods and results In 30 normotensive individuals and 30 subjects with mild essential hypertension (white men, mean age 26 ± 3 years), the responsiveness to angiotensin II was assessed by measuring changes in mean arterial pressure, renal blood flow, glomerular filtration rate and aldosterone secretion in response to i.v. angiotensin II infusion (0.5 and 3.0 ng/kg per min). The provoked changes to angiotensin II infusion were similar ir the normotensive and hypertensive group with the exception of an exaggerated increase in mean arterial pressure in hypertensives (14 ± 5 versus 10 ± 5 mmHg, P< 0.001 at 3.0 ng/kg per min angiotensin II). The increase in mean arterial pressure was correlated with left ventricular mass in hypertensive subjects (angiotensin II 0.5 ng/kg per min: r= 0.49, P< 0.005; angiotensin II 3.0 ng/kg per min: r= 0.35, P< 0.05); no such correlation was found in the normotensive group. After taking into account baseline mean arterial pressure and body mass index, the increase in mean arterial pressure to angiotensin II 0.5 ng/kg per min was still correlated with left ventricular mass (partial r = 0.50, P< 0.01). Similarly, the change of glomerular filtration rate but not of renal blood flow in response to angiotensin II 0.5 ng/kg per min was correlated with left ventricular mass, (r= 0.42, P<0.02) in the hypertensive group but not in the normotensive one. This relationship remained significant even after taking baseline glomerular filtration rate, mean arterial pressure and body mass index into account (partial r = 0.43, P < 0.05). Conclusion Hyper-responsiveness to angiotensin II is related to an increased left ventricular mass in hypertensive subjects independent of blood pressure.

Hyper-responsiveness to angiotensin II is related to cardiac structural adaptation in hypertensive subjects.

Background It has been proposed that hyperlipidemia contributes to the progression of renal diseases, and conversely, that treatment with statins decreases the progressive decline of renal function. Increased glomerular pressure has been found to cause endothelial dysfunction of glomerular capillaries. However, the potential renoprotective effects of statin treatment have not been fully elucidated and so far no study has analyzed the effects of statin treatment on intrarenal hemodynamics. Methods Forty hypercholesterolemic patients were randomly assigned to receive rosuvastatin or placebo in a double-blind crossover study. Renal plasma flow(RPF) and glomerular filtration rate (GFR) were determined by constant input clearance technique with p-aminohippurate (PAH) and inulin. Glomerular hydrostatic pressure (Pglom) and resistances of the afferent(RA) and efferent arterioles (RE) were calculated according to the model originally established by Gomez. Results RPF and GFR were similar after treatment with rosuvastatin and placebo. Neither Pglom (66.2 +/- 3.9vs. 66.4 +/- 5.1 mm Hg, p=0.861) nor RA (3,200 +/- 1,780 vs.3,188 +/- 1,870 dyn-s-cm-5, p=0.957) or RE (3,620 +/- 1,174vs. 3,490 +/- 1,272 dyn-s-cm-5, p=0.378) were affected by treatment with rosuvastatin, compared with placebo. Conclusions The beneficial effects on renal function by statin treatment seem not to be mediated by changes in intrarenal hemodynamics in patients with hypercholesterolemia.

Tim Schäufele

Papers

The role of nitric oxide in the regulation of glomerular haemodynamics in humans

Rosuvastatin improves basal nitric oxide activity of the renal vasculature in patients with hypercholesterolemia

Impaired basal NO activity in patients with glomerular disease and the influence of oxidative stress

Hyper-responsiveness to angiotensin II is related to cardiac structural adaptation in hypertensive subjects.

Rosuvastatin does not affect intrarenal hemodynamics in patients with hypercholesterolemia.