Abnormal urinary excretion of NKCC2 and AQP2 in response to hypertonic saline in chronic kidney disease: an intervention study in patients with chronic kidney disease and healthy controls

BACKGROUND: Renal handling of sodium and water is abnormal in chronic kidney disease (CKD). The aim of this study was to test the hypothesis that abnormal activity of the aquaporin-2 water channels (AQP2), the sodium-potassium-2chloride transporter (NKCC2) and/or the epithelial sodium channels (ENaC) contribute to this phenomenon. METHODS: 23 patients with CKD and 24 healthy controls at baseline and after 3% saline infusion were compared. The following measurements were performed: urinary concentrations of AQP2 (u-AQP2), NKCC2 (u-NKCC2), ENaC (u-ENaCγ), glomerular filtration rate (GFR) estimated by (51)Cr-EDTA clearance, free water clearance (C(H2O)), urinary output (UO), fractional excretion of sodium (FE(Na)), plasma concentrations of AVP, renin (PRC), Angiotensin II (ANG II), Aldosterone (Aldo) and body fluid volumes. RESULTS: At baseline, GFR was 34 ml/min in CKD patients and 89 ml/ml in controls. There were no significant differences in u-AQP2, u-NKCC2 or u-ENaCγ, but FE(Na), p-Aldo and p-AVP were higher in CKD patients than controls. In response to hypertonic saline, patients with CKD had an attenuated decrease in C(H2O) and UO. A greater increase in U-AQP2 was observed in CKD patients compared to controls. Furthermore, u-NKCC2 increased in CKD patients, whereas u-NKCC2 decreased in controls. Body fluid volumes did not significantly differ. CONCLUSIONS: In response to hypertonic saline, u-NKCC2 increased, suggesting an increased sodium reabsorption via NKCC2 in patients with CKD. U-AQP2 increased more in CKD patients, despite an attenuated decrease in C(H2O). Thus, though high levels of p-AVP and p-Aldo, the kidneys can only partly compensate and counteract acute volume expansion due to a defective tubular response. TRIAL REGISTRATION: Clinical trial no: NCT01623661. Date of trial registration: 18.06.2012

Increased renal sodium absorption by inhibition of prostaglandin synthesis during fasting in healthy man. A possible role of the epithelial sodium channels

<p>Abstract</p> <p>Background</p> <p>Treatment with prostaglandin inhibitors can reduce renal function and impair renal water and sodium excretion. We tested the hypotheses that a reduction in prostaglandin synthesis by ibuprofen treatment during fasting decreased renal water and sodium excretion by increased absorption of water and sodium via the aquaporin2 water channels and the epithelial sodium channels.</p> <p>Methods</p> <p>The effect of ibuprofen, 600 mg thrice daily, was measured during fasting in a randomized, placebo-controlled, double-blinded crossover study of 17 healthy humans. The subjects received a standardized diet on day 1, fasted at day 2, and received an IV infusion of 3% NaCl on day 3. The effect variables were urinary excretions of aquaporin2 (u-AQP2), the beta-fraction of the epithelial sodium channel (u-ENaCbeta), cyclic-AMP (u-cAMP), prostaglandin E2 (u-PGE2). Free water clearance (CH2O), fractional excretion of sodium (FENa), and plasma concentrations of vasopressin, angiotensin II, aldosterone, atrial-, and brain natriuretic peptide.</p> <p>Results</p> <p>Ibuprofen decreased u-AQP2, u-PGE2, and FENa at all parts of the study. During the same time, ibuprofen significantly increased u-ENaCbeta. Ibuprofen did not change the response in p-AVP, u-c-AMP, urinary output, and free water clearance during any of these periods. Atrial-and brain natriuretic peptide were higher.</p> <p>Conclusion</p> <p>During inhibition of prostaglandin synthesis, urinary sodium excretion decreased in parallel with an increase in sodium absorption and increase in u-ENaCbeta. U-AQP2 decreased indicating that water transport via AQP2 fell. The vasopressin-c-AMP-axis did not mediate this effect, but it may be a consequence of the changes in the natriuretic peptide system and/or the angiotensin-aldosterone system</p> <p>Trial Registration</p> <p>Clinical Trials Identifier: NCT00281762</p

Comparing CKD populations with T1D and T2D: a perspective based on the FINE-ONE and FIDELITY populations

Chronic kidney disease (CKD) is a common comorbidity of both type 1 diabetes (T1D) and type 2 diabetes (T2D) and is associated with increased mortality, end-stage kidney disease, and cardiovascular disease risk. Despite standard-of-care treatment with renin–angiotensin system inhibitors added to blood pressure and glycaemic control, people with CKD and T1D have a residual risk of CKD progression. Advances in therapeutic management have been limited over the past three decades, especially compared with CKD in T2D, for which new treatment options have emerged in the last 5 years. In this review article, we discuss similarities and differences between T1D and T2D populations with CKD, including epidemiology, pathophysiology, and clinical findings. Additionally, we explore the use of albuminuria as a potential bridging biomarker to extrapolate clinical evidence from one population to the other. This concept could offer a promising strategy to narrow the gap in treatment availability between these populations and address the unmet therapeutic need in people with CKD and T1D. The FINE-ONE trial is investigating the non-steroidal mineralocorticoid receptor antagonist finerenone in a population with CKD and T1D using change in urine albumin-to-creatinine ratio from baseline (ratio to baseline) over 6 months as its primary endpoint and bridging biomarker. Similarities between the populations from FINE-ONE and FIDELITY (a pooled dataset of individuals with CKD and T2D included in two large phase 3 clinical trials of finerenone) may inform the translation of clinical evidence on finerenone from people with CKD and T2D to those with CKD and T1D

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

The effect of sodium nitrite infusion on renal function, brachial and central blood pressure during enzyme inhibition by allopurinol, enalapril or acetazolamide in healthy subjects: a randomized, double-blinded, placebo-controlled, crossover study

Abstract Background Sodium nitrite (NaNO2) causes vasodilation, presumably by enzymatic conversion to nitric oxide (NO). Several enzymes with nitrite reducing capabilities have been discovered in vitro, but their relative importance in vivo has not been investigated. We aimed to examine the effects of NaNO2 on blood pressure, fractional sodium excretion (FENa), free water clearance (CH2O) and GFR, after pre-inhibition of xanthine oxidase, carbonic anhydrase, and angiotensin-converting enzyme. The latter as an approach to upregulate endothelial NO synthase activity. Methods In a double-blinded, placebo-controlled, crossover study, 16 healthy subjects were treated, in a randomized order, with placebo, allopurinol 150 mg twice daily (TD), enalapril 5 mg TD, or acetazolamide 250 mg TD. After 4 days of treatment and standardized diet, the subjects were examined at our lab. During intravenous infusion of 240 μg NaNO2/kg/hour for 2 h, we measured changes in brachial and central blood pressure (BP), plasma cyclic guanosine monophosphate (P-cGMP), plasma and urine osmolality, GFR by 51Cr-EDTA clearance, FENa and urinary excretion rate of cGMP (U-cGMP) and nitrite and nitrate (U-NOx). Subjects were supine and orally water-loaded throughout the examination day. Results Irrespective of pretreatment, we observed an increase in FENa, heart rate, U-NOx, and a decrease in CH2O and brachial systolic BP during NaNO2 infusion. P-cGMP and U-cGMP did not change during infusion. We observed a consistent trend towards a reduction in central systolic BP, which was only significant after allopurinol. Conclusion This study showed a robust BP lowering, natriuretic and anti-aquaretic effect of intravenous NaNO2 regardless of preceding enzyme inhibition. None of the three enzyme inhibitors used convincingly modified the pharmacological effects of NaNO2. The steady cGMP indicates little or no conversion of nitrite to NO. Thus the effect of NaNO2 may not be mediated by NO generation. Trial registration EU Clinical Trials Register, 2013-003404-39. Registered December 3 2013

Prednisolone treatment in acute interstitial nephritis (PRAISE) – protocol for the randomized controlled trial

Abstract Background Acute interstitial nephritis (AIN) is an important and common cause of acute renal failure. There are no generally accepted guidelines for the treatment of AIN, due to the lack of prospective randomized trials. Since AIN is characterized by an enhanced immune response, immunosuppressive treatment could potentially improve prognosis by attenuating inflammation and subsequent fibrosis. Despite the limited evidence of effects of steroids and potential adverse effects, prednisolone is frequently used in the treatment of AIN and there is a strong need for clinical trials on the effects of immunosuppression, including steroids, in the treatment of AIN. We aimed to evaluate the effectiveness of prednisolone treatment in AIN, and hypothesized a positive effect of prednisolone treatment on renal function in AIN. Methods The study is a randomized, controlled, prospective, open label multicenter study, including incident adult patients with biopsy proven AIN. Patients will be randomized 1:1 to one of 2 treatment regimens: No prednisolone treatment (control group) and B) Oral prednisolone treatment staring with 60 mg daily tapered over 8 weeks. One hundred ten patients (55 in each group) are planned to be included and followed for 1 year. Primary outcome is renal function estimated by eGFR 3 months after inclusion. Secondary outcomes are renal function after 12 months and need for renal replacement therapy and quality of life after 3 and 12 months. In addition, with-in prednisolone group analysis are performed to estimate the importance of treatment delay. Exploratory analyses include analysis of biomarkers in urine and plasma and the evaluation of these biomarkers in relation to renal prognosis and re-evaluation of renal biopsies to identify possible renal prognostic factors. Discussion Strengths and possible limitations in the design are evaluated. The study will provide important information on the effects of prednisolone treatment in AIN and as well as prognostic information relevant for future use of biomarkers and histology. Ultimately, this would lead to improved and evidence based clinical guidelines for the treatment of AIN. Trial registration ClinicalTrials.gov identifier NCT04376216 (Retrospectively registered on May 6, 2020). </jats:sec