Liffert Vogt

Effects of Dietary Sodium and Hydrochlorothiazide on the Antiproteinuric Efficacy of Losartan

There is large interindividual variability in the antiproteinuric response to blockade of the renin-angiotensin-aldosterone system (RAAS). A low-sodium diet or addition of diuretics enhances the effects of RAAS blockade on proteinuria and BP, but the efficacy of the combination of these interventions is unknown. Therefore, this randomized, double-blind, placebo-controlled trial to determine the separate and combined effects of a low-sodium diet and hydrochlorothiazide (HCT) on proteinuria and BP was performed. In 34 proteinuric patients without diabetes, mean baseline proteinuria was 3.8 g/d, and this was reduced by 22% by a low-sodium diet alone. Losartan monotherapy reduced proteinuria by 30%, and the addition of a low-sodium diet led to a total reduction by 55% and the addition of HCT to 56%. The combined addition of HCT and a low-sodium diet reduced proteinuria by 70% from baseline (all P < 0.05). Reductions in mean arterial pressure showed a similar pattern (all P < 0.05). In addition, individuals who did not demonstrate an antiproteinuric response to losartan monotherapy did respond when a low-sodium diet or a diuretic was added. In conclusion, a low-sodium diet and HCT are equally efficacious in reducing proteinuria and BP when added to a regimen containing losartan and especially seem to benefit individuals who are resistant to RAAS blockade. Combining these interventions in sodium status is an effective method to maximize the antiproteinuric efficacy of RAAS blockade.

High Absolute Risks and Predictors of Venous and Arterial Thromboembolic Events in Patients With Nephrotic Syndrome Results From a Large Retrospective Cohort Study

Background— No data are available on the absolute risk of either venous thromboembolism (VTE) or arterial thromboembolism (ATE) in patients with nephrotic syndrome. Reported risks are based on multiple case reports and small studies with mostly short-term follow-up. We assessed the absolute risk of VTE and ATE in a large, single-center, retrospective cohort study and attempted to identify predictive factors in these patients. Methods and Results— A total of 298 consecutive patients with nephrotic syndrome (59% men; mean age, 42±18 years) were enrolled. Mean follow-up was 10±9 years. Nephrotic syndrome was defined by proteinuria ≥3.5 g/d, and patients were classified according to underlying histological lesions accounting for nephrotic syndrome. Objectively verified symptomatic thromboembolic events were the primary study outcome. Annual incidences of VTE and ATE were 1.02% (95% confidence interval, 0.68 to 1.46) and 1.48% (95% confidence interval, 1.07 to 1.99), respectively. Over the first 6 months of follow-up, these rates were 9.85% and 5.52%, respectively. Proteinuria and serum albumin levels tended to be related to VTE; however, only the predictive value of the ratio of proteinuria to serum albumin was significant (hazard ratio, 5.6; 95% confidence interval, 1.2 to 26.2; P=0.03). In contrast, neither the degree of proteinuria nor serum albumin levels were related to ATE. Sex, age, hypertension, diabetes, smoking, prior ATE, and estimated glomerular filtration rate predicted ATE (P≤0.02). Conclusions— This study verifies high absolute risks of symptomatic VTE and ATE that were remarkably elevated within the first 6 months. Whereas the ratio of proteinuria to serum albumin predicted VTE, estimated glomerular filtration rate and multiple classic risk factors for atherosclerosis were predictors of ATE.

Effect of Renin-Angiotensin-Aldosterone System Inhibition, Dietary Sodium Restriction, and/or Diuretics on Urinary Kidney Injury Molecule 1 Excretion in Nondiabetic Proteinuric Kidney Disease: A Post Hoc Analysis of a Randomized Controlled Trial

BACKGROUND Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels. STUDY DESIGN Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial. SETTING & PARTICIPANTS 34 proteinuric patients without diabetes from our outpatient renal clinic. INTERVENTION Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet. OUTCOMES & MEASUREMENTS Urinary excretion of KIM-1, total protein, and N-acetyl-beta-d-glucosaminidase (NAG) as a positive control for tubular injury. RESULTS Mean baseline urine protein level was 3.8 +/- 0.4 (SE) g/d, and KIM-1 level was 1,706 +/- 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 +/- 388 ng/d; P = 0.04), losartan/high sodium (1,184 +/- 296 ng/d; P = 0.09), losartan/LS (921 +/- 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 +/- 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 +/- 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P < 0.001), but not blood pressure or creatinine clearance. 16 patients reached target proteinuria with protein less than 1 g/d, whereas KIM-1 levels normalized in only 2 patients. Urinary NAG level was increased at baseline and significantly decreased during the treatment periods of combined losartan plus HCT only. The decrease in urinary NAG levels was not closely related to proteinuria. LIMITATIONS Post hoc analysis. CONCLUSIONS Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with proteinuria by using losartan, sodium restriction, their combination, losartan plus HCT, and the latter plus sodium restriction. These results are consistent with the hypothesis of amelioration of proteinuria-induced tubular damage. Long-term studies are warranted to evaluate whether targeting treatment on KIM-1 can improve outcomes in patients with CKD with proteinuria.

Immune Modulation by Different Types of β2→1-Fructans Is Toll-Like Receptor Dependent

Introduction β2→1-fructans are dietary fibers. Main objectives of this study were 1) to demonstrate direct signalling of β2→1-fructans on immune cells, 2) to study whether this is mediated by the pattern recognition receptors Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain-containing proteins (NODs), and 3) to relate the observed effects to the chain length differences in β2→1-fructans. Methods Four different β2→1-fructan formulations were characterised for their chain length profile. Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with β2→1-fructans, and production of IL-1Ra, IL-1β, IL-6, IL-10, IL-12p70, and TNF-α was analysed. Reporter cells for TLRs and NODs were incubated with β2→1-fructans and analysed for NF-κB/AP-1 activation. Results Cytokine production in human PBMCs was dose- and chain length-dependent. Strikingly, short chain enriched β2→1-fructans induced a regulatory cytokine balance compared to long chain enriched β2→1-fructans as measured by IL-10/IL-12 ratios. Activation of reporter cells showed that signalling was highly dependent on TLRs and their adapter, myeloid differentiation primary response protein 88 (MyD88). In human embryonic kidney reporter cells, TLR2 was prominently activated, while TLR4, 5, 7, 8, and NOD2 were mildly activated. Conclusions β2→1-fructans possess direct signalling capacity on human immune cells. By activating primarily TLR2, and to a lesser extent TLR4, 5, 7, 8, and NOD2, β2→1-fructan stimulation results in NF-κB/AP-1 activation. Chain length of β2→1-fructans is important for the induced activation pattern and IL-10/IL-12 ratios.

Antiproteinuric treatment reduces urinary loss of vitamin D-binding protein but does not affect vitamin D status in patients with chronic kidney disease

Vitamin D deficiency is common in chronic kidney disease (CKD). Increased urinary loss of vitamin D binding protein (VDBP), the main transporter of 25-hydroxyvitamin D(3) in the circulation, has been postulated to contribute to vitamin D deficiency in proteinuria. To test this hypothesis we analyzed urinary and plasma levels of VDBP, 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) from proteinuric patients, before and after antiproteinuric interventions. We performed a post-hoc analysis of a clinical trial in CKD patients (n=13, creatinine clearance median 60 (range 25-177) ml/min) subjected to the following study periods: washout (no antiproteinuric treatment, 4 weeks), lisinopril 40mg QD (ACEi, 6 weeks), or indomethacin 75mg BID (NSAID, 4 weeks) in randomized sequence. Healthy subjects screened for donation (n=10) served as controls. Plasma and urine VDBP levels were measured by ELISA, 25-hydroxyvitamin D(3) levels by LC-MS and 1,25-dihydroxyvitamin D(3) levels by radioimmunoassay. In CKD patients urinary VDBP excretion was strongly increased (median (range) 5413 (155-211,027) μg/24h) as compared to healthy controls (64 (23-111) μg/24h, p<0.001). Both NSAID and ACEi significantly decreased urinary VDBP excretion, in proportion to proteinuria reduction. Plasma VDBP, 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, however, were similar between patients and controls and not affected by antiproteinuric intervention. Urinary VDBP excretion is markedly increased in proteinuria and responds to antiproteinuric treatment. Urinary VDBP loss is not associated with plasma VDBP or vitamin D(3) levels, suggesting that urinary loss of VDBP does not affect vitamin D status.

Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy

The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and <3.0 g, systolic blood pressure >135 and <170 mm Hg, and/or diastolic blood pressure >85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether urotensin receptor antagonism represents a new treatment strategy in this high-risk patient population.

Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis.

Thiazide diuretics are recommended as first-line therapy for hypertension and are among the most commonly prescribed drugs worldwide. According to their molecular structure, thiazide diuretics can be divided in thiazide-type (TT) and thiazide-like (TL) diuretics. TL diuretics have a longer elimination half-life compared with TT diuretics and have been shown to exert additional pharmacological effects, which may differently affect cardiovascular risk. In this meta-analysis, we compared the effects of TT and TL diuretics on cardiovascular events and mortality. Randomized, controlled studies in adult hypertensive patients that compared TT or TL diuretics with placebo or antihypertensive drugs and had ≥1 year follow-up were included. Primary outcome was cardiovascular events; secondary outcomes included coronary events, heart failure, cerebrovascular events, and all-cause mortality. Meta-regression analysis was used to identify confounders and correct for the achieved blood pressure reductions. Twenty-one studies with >480 000 patient-years were included. Outcomes were not affected by heterogeneity in age, sex, and ethnicity among included studies, whereas larger blood pressure reductions were significantly associated with increased risk reductions for all outcomes (P<0.001). Corrected for differences in office blood pressure reductions among trials, TL diuretics resulted in a 12% additional risk reduction for cardiovascular events (P=0.049) and a 21% additional risk reduction for heart failure (P=0.023) when compared with TT diuretics. The incidence of adverse events was comparable among TT, TL diuretics, and other antihypertensive therapy. Our data suggest that the best available evidence seems to favor TL diuretics as the drug of choice when thiazide treatment is considered for hypertension.

Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients: A feasible strategy?

Agents that interfere with the renin-angiotensin system (RAS) reduce proteinuria and afford renal protection. The combination of different measures that serve maximization of RAS blockade is thought to improve the antiproteinuric efficacy. The feasibility and the efficacy of such a combination strategy were studied in nondiabetic patients with residual proteinuria during previous RAS blockade by individual antiproteinuric titration. Previous medication was replaced by irbesartan 300 mg combined with a diuretic. Lisinopril was added in increasing doses until a maximal dose of 40 mg/d. Titration stopped when target proteinuria (< 1 g/d) was reached or further dose titration was not tolerated because of side effects. Residual proteinuria (median, 3.2 g/d; 95% confidence interval, 1.8 to 5.2 g/d) was significantly reduced with 55.6% (95% confidence interval, 16.0 to 73.2%; P < 0.02) on the maximal additional tolerated dose of lisinopril. The maximal dose of lisinopril was 10 mg in two of eight, 20 mg in two of eight, 30 mg in one of eight, and 40 mg in three of eight patients. At this dose, target proteinuria of < 1 g/d was reached in two of eight patients. The number of patients with adverse events during dose titration was five of eight patients: two had cough; two had hyperkalemia (> 5.5 mmol/L), one of whom had > 50% increase of serum creatinine; and one had dizziness. In conclusion, individual titration for maximal RAS blockade, entailing dose titration of angiotensin-converting enzyme inhibitors on top of high-dose angiotensin II antagonists with diuretic, induces further reduction of residual proteinuria. However, this occurs at the expense of adverse events. To further improve renoprotective treatment strategies, it is important to explore other modes of antiproteinuric intervention in patients with residual proteinuria during RAS blockade.

SFlt-1 elevates blood pressure by augmenting endothelin-1-mediated vasoconstriction in mice.

Objective Scavenging of vascular endothelial growth factor (VEGF) elevates blood pressure (BP) in patients receiving anti-angiogenic therapy. Similarly, inhibition of circulation VEGF by its soluble receptor fms-like tyrosine kinase-1 (sFlt-1) underlies BP elevation in pre-eclampsia. Both phenotypes are characterized by augmented production of endothelin-1 (ET-1), suggesting a role for ET-1 in anti-angiogenic hypertension. We aimed to assess the effect of VEGF inhibition on ET-1-induced contractility and downstream ET-1 signaling. Approach and Results Male C57BL/6N mice were treated with either sFlt-1 or vehicle and BP was assessed via tail-cuff. Mean arterial pressure of sFlt-1-treated mice markedly increased compared to vehicle-treated controls (N = 11–12, p<0.05). After sacrifice, carotid and mesenteric arteries were isolated for isometric tension measurements. ET-1-induced contractions were similar in mesenteric arteries of vehicle and sFlt-1-treated mice, but augmented in carotid segments of sFlt-1-treated mice compared to controls (N = 9–10, p<0.05). The increased contraction in carotid segments could be completely abrogated by the cyclooxygenase (COX) inhibitor indomethacin (N = 9–10, p<0.05), indicating heightened prostaglandin-mediated vasoconstriction. This was associated with a shift towards procontractile ETB signaling in sFlt-1-treated mice, possibly explaining the increased ET-1-induced prostaglandin-mediated vasoconstriction. In line with the ex vivo findings, sFlt-1-induced BP elevation could be prevented in vivo by oral treatment with either a high-dose of the COX inhibitor aspirin (N = 7) or with picotamide (N = 9), a dual thromboxane A2 synthase inhibitor and receptor antagonist. Conclusions VEGF inhibition augments the pressor response to ET-1. The cyclooxygenase-thromboxane signaling route downstream of ET-1 might be a possible target to prevent BP elevation during VEGF inhibition.

Statin and the Risk of Renal-Related Serious Adverse Events: Analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and Other Placebo-Controlled Trials

A recent study has shown an association between high-potency statins and risk of acute kidney injury. However, these data are from observational studies, and it is not clear if similar signal is seen from randomized controlled trials. We evaluated the risk of renal-associated serious adverse events (SAEs) using statins versus placebo trials and the high-dose versus low-dose statin trials that were available to us. The outcome of interest was renal-related SAEs. The incidence of adverse events relating to kidney injury was determined through review of the adverse event database. The following outcomes were evaluated: (1) renal-related SAEs within 120 days of randomization (primary outcome), (2) renal-related SAEs after 120 days of randomization (secondary), and (3) drug discontinuation due to renal-related SAEs (secondary). There was no difference in the incidence of renal-related SAEs at 120 days (0.04% vs 0.10%, p = 0.162) between atorvastatin and placebo in the 24 placebo-controlled trials (10,345 patients on atorvastatin (10 to 80 mg/day) versus 8,945 patients on placebo) or in the high-dose versus low-dose statin trials including the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (0.05% vs 0.02%, p = 0.625) or the Treating to New Targets (TNT) trial (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAE (placebo controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]). In conclusion, the results from clinical trials with data from 149,882 patient-years of follow-up fail to show any increase in renal-related SAEs with statins compared with controls.