Dietary sodium restriction:a neglected therapeutic opportunity in chronic kidney disease

PURPOSE OF REVIEW: Restriction of dietary sodium is recommended at a population level as well as for groups at high cardiovascular risk, and chronic kidney disease (CKD). This review addresses recent evidence for the protective effect of dietary sodium restriction in CKD patients specifically. RECENT FINDINGS: Sodium intake in CKD populations is generally high, and often above population average. Recent data demonstrated that moderately lower sodium intake in CKD patients is associated with substantially better long-term outcome of renin–angiotensin–aldosterone system (RAAS)-blockade, in diabetic and nondiabetic CKD, related to better effects of RAAS-blockade on proteinuria, independent of blood pressure. This is in line with better short-term efficacy of RAAS-blockade during moderate sodium restriction in diabetic and nondiabetic CKD. This effect of sodium restriction is likely mediated by its effects on volume status. Sustainable sodium restriction can be achieved by approaches on the basis of behavioral sciences. SUMMARY: Moderate restriction of dietary sodium can substantially improve the protective effects of RAAS-blockade in CKD, by specific renal effects apparent from proteinuria reduction. The latter precludes straightforward extrapolation of data from nonrenal populations to CKD. Concerns regarding the adverse effects of a very low sodium intake should not distract from the protective effects of moderate sodium restriction. Prospective studies should assess the efficacy and sustainability of different strategies to target high sodium intake in CKD, along with measures at population level. VIDEO ABSTRACT: http://links.lww.com/CONH/A1

Vitamin D analogues to target residual proteinuria:potential impact on cardiorenal outcomes

Residual proteinuria, the amount of proteinuria that remains during optimally dosed renin-angiotensin-aldosterone system (RAAS) blockade, is an independent risk factor for progressive renal function loss and cardiovascular complications in chronic kidney disease (CKD) patients. Dual RAAS blockade may reduce residual proteinuria but without translating into improved cardiorenal outcomes at least in diabetic nephropathy; rather, dual RAAS blockade may increase the risk of adverse events. These findings have challenged the concept of residual proteinuria as an absolute treatment target. Therefore, new strategies must be explored to address whether by further reduction of residual proteinuria using interventions not primarily targeting the RAAS benefit in terms of cardiorenal risk reduction would accrue. Both clinical and experimental intervention studies have demonstrated that vitamin D can reduce residual proteinuria through both RAAS-dependent and RAAS-independent pathways. Future research should prospectively explore vitamin D treatment as an adjunct to RAAS blockade in an interventional trial exploring clinically relevant cardiorenal end points

Fibroblast Growth Factor 23 and Cardiovascular Mortality after Kidney Transplantation

<p>Background and objectivesCirculating fibroblast growth factor 23 (FGF23) is associated with adverse cardiovascular outcomes in CKD. Whether FGF23 predicts cardiovascular mortality after kidney transplantation, independent of measures of mineral metabolism and cardiovascular risk factors, is unknown.Design, setting, participants, & measurementsThe association between plasma C-terminal FGF23 and cardiovascular mortality was analyzed in a single-center prospective cohort of 593 stable kidney transplant recipients (mean age SD, 5212 years; 54% male; estimated GFR, 47 +/- 16 ml/min per 1.73 m(2)), at a median of 6.1 (interquartile range, 2.7-11.7) years after transplantation. Multivariate Cox regression models were built, adjusting for measures of renal function and mineral metabolism; Framingham risk factors; the left ventricular wall strain markers midregional fragment of pro-A-type natriuretic peptide (MR-proANP) and N-terminal-pro brain natriuretic peptide (NT-proBNP); and copeptin, the stable C-terminal portion of the precursor of vasopressin.ResultsIn multivariate linear regression analysis, MR-proANP (=0.20, P</p>

Response of fibroblast growth factor 23 to volume interventions in arterial hypertension and diabetic nephropathy

Fibroblast growth factor 23 (FGF-23) rises progressively in chronic kidney disease and is associated with adverse cardiovascular outcomes. FGF-23 putatively induces volume retention by upregulating the sodium-chloride cotransporter (NCC). We studied whether, conversely, interventions in volume status affect FGF-23 concentrations. We performed a post hoc analysis of 1) a prospective saline infusion study with 12 patients with arterial hypertension who received 2L of isotonic saline over 4 hours, and 2) a randomized controlled trial with 45 diabetic nephropathy (DN) patients on background angiotensin-converting enzyme -inhibition (ACEi), who underwent 4 6-week treatment periods with add-on hydrochlorothiazide (HCT) or placebo, combined with regular sodium (RS) or low sodium (LS) diet in a cross-over design. Plasma C-terminal FGF-23 was measured by ELISA (Immutopics) after each treatment period in DN and before and after saline infusion in hypertensives. The patients with arterial hypertension were 45 +/- 13 (mean +/- SD) years old with an estimated glomerular filtration rate (eGFR) of 101 +/- 18mL/min/1.73m(2). Isotonic saline infusion did not affect FGF-23 (before infusion: 68 median [first to third quartile: 58-97] relative unit (RU)/mL, after infusion: 67 [57-77] RU/mL, P=0.37). DN patients were 65 +/- 9 years old. During ACEi+ RS treatment, eGFR was 65 +/- 25mL/min/1.73m(2) and albuminuria 649mg/d (230-2008mg/d). FGF23 level was 94 (73-141) RU/mL during ACEi therapy. FGF-23 did not change significantly by add-on HCT (99 [74-148] RU/mL), LS diet (99 [75-135] RU/mL), or their combination (111 [81-160] RU/mL, P= 0.15). Acute and chronic changes in volume status did not materially change FGF-23 in hypertensive patients and DN, respectively. Our data do not support a direct feedback loop between volume status and FGF-23 in hypertension or DN

Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

Background: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. Study Design: Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition. Setting & Participants: 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50 +/- 13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). Predictor: Plasma carboxy-terminal FGF-23 levels. Outcomes: Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. Results: Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized beta = -0.46; P = 0.001; model R-2 = 0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized beta = 0.27; P = 0.003) in linear regression analysis adjusted for baseline proteinuria (model R-2 = 0.71). There was no interaction with creatinine clearance (P interaction = 0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment. Limitations: Observational study, limited sample size. Conclusions: FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-232-lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction. (C) 2015 by the National Kidney Foundation, Inc

Fibroblast growth factor 23 correlates with volume status in haemodialysis patients and is not reduced by haemodialysis

Recent data suggest a role for fibroblast growth factor 23 (FGF-23) in volume regulation. In haemodialysis patients, a large ultrafiltration volume (UFV) reflects poor volume control, and both FGF-23 and a large UFV are risk factors for mortality in this population. We studied the association between FGF-23 and markers of volume status including UFV, as well as the intradialytic course of FGF-23, in a cohort of haemodialysis patients. We carried out observational, post hoc analysis of 109 prevalent haemodialysis patients who underwent a standardized, low-flux, haemodialysis session with constant ultrafiltration rate. We measured UFV, plasma copeptin and echocardiographic parameters including cardiac output, end-diastolic volume and left ventricular mass index at the onset of the haemodialysis session. We measured the intradialytic course of plasma C-terminal FGF-23 (corrected for haemoconcentration) and serum phosphate levels at 0, 1, 3 and 4 h after onset of haemodialysis and analysed changes with linear mixed effect model. Results. Median age was 66 (interquartile range: 51-75) years, 65% were male with a weekly Kt/V 4.3 +/- 0.7 and dialysis vintage of 25.4 (8.5-52.5) months. In univariable analysis, pre-dialysis plasma FGF-23 was associated with UFV, end-diastolic volume, cardiac output, early diastolic velocity e0 and plasma copeptin. In multivariable regression analysis, UFV correlated with FGF-23 (standardized : 0.373, P <0.001, model R2: 57%), independent of serum calcium and phosphate. The association between FGF-23 and echocardiographic volume markers was lost for all but cardiac output upon adjustment for UFV. Overall, FGF-23 levels did not change during dialysis [7627 (330013 514) to 7503 (3109-14 433) RU/mL; P = 0.98], whereas phosphate decreased (1.71 +/- 0.50 to 0.88 +/- 0.26 mmol/L; P <0.001). FGF-23 was associated with volume status in haemodialysis patients. The strong association with UFV suggests that optimization of volume status, for example by more intensive haemodialysis regimens, may also benefit mineral homeostasis. A single dialysis session did not lower FGF-23 levels