Salt, but not protein intake, is associated with accelerated disease progression in autosomal dominant polycystic kidney disease

Abstract

In autosomal dominant polycystic kidney disease (ADPKD), there are only scarce data on the effect of salt and protein intake on disease progression. Here we studied association of these dietary factors with the rate of disease progression in ADPKD and what the mediating factors are by analyzing an observational cohort of 589 patients with ADPKD. Salt and protein intake were estimated from 24-hour urine samples and the plasma copeptin concentration measured as a surrogate for vasopressin. The association of dietary intake with annual change in the estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) growth was analyzed with mixed models. In case of significant associations, mediation analyses were performed to elucidate potential mechanisms. These patients (59% female) had a mean baseline age of 47, eGFR 64 mL/min/1.73m2 and the median htTKV was 880 mL. The mean estimated salt intake was 9.1 g/day and protein intake 84 g/day. During a median follow-up of 4.0 years, eGFR was assessed a median of six times and 24-hour urine was collected a median of five times. Salt intake was significantly associated with annual change in eGFR of −0.11 (95% confidence interval 0.20 – −0.02] mL/min/1.73m2) per gram of salt, whereas protein intake was not (−0.00001 [−0.01 – 0.01] mL/min/1.73m2) per gram of protein). The effect of salt intake on eGFR slope was significantly mediated by plasma copeptin (crude analysis: 77% mediation, and, adjusted analysis: 45% mediation), but not by systolic blood pressure. Thus, higher salt, but not higher protein intake may be detrimental in ADPKD. The substantial mediation by plasma copeptin suggests that this effect is primarily a consequence of a salt-induced rise in vasopressin. In autosomal dominant polycystic kidney disease (ADPKD), there are only scarce data on the effect of salt and protein intake on disease progression. Here we studied association of these dietary factors with the rate of disease progression in ADPKD and what the mediating factors are by analyzing an observational cohort of 589 patients with ADPKD. Salt and protein intake were estimated from 24-hour urine samples and the plasma copeptin concentration measured as a surrogate for vasopressin. The association of dietary intake with annual change in the estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) growth was analyzed with mixed models. In case of significant associations, mediation analyses were performed to elucidate potential mechanisms. These patients (59% female) had a mean baseline age of 47, eGFR 64 mL/min/1.73m2 and the median htTKV was 880 mL. The mean estimated salt intake was 9.1 g/day and protein intake 84 g/day. During a median follow-up of 4.0 years, eGFR was assessed a median of six times and 24-hour urine was collected a median of five times. Salt intake was significantly associated with annual change in eGFR of −0.11 (95% confidence interval 0.20 – −0.02] mL/min/1.73m2) per gram of salt, whereas protein intake was not (−0.00001 [−0.01 – 0.01] mL/min/1.73m2) per gram of protein). The effect of salt intake on eGFR slope was significantly mediated by plasma copeptin (crude analysis: 77% mediation, and, adjusted analysis: 45% mediation), but not by systolic blood pressure. Thus, higher salt, but not higher protein intake may be detrimental in ADPKD. The substantial mediation by plasma copeptin suggests that this effect is primarily a consequence of a salt-induced rise in vasopressin. see commentary on page 831 see commentary on page 831 In chronic kidney disease (CKD), salt restriction is advocated to slow disease progression.1Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1579) Google Scholar Salt restriction lowers blood pressure and potentiates renoprotective effects of renin-angiotensin-aldosterone system (RAAS) blockade.2Humalda J.K. Navis G. Dietary sodium restriction: a neglected therapeutic opportunity in chronic kidney disease.Curr Opin Nephrol Hypertens. 2014; 23: 533-540Crossref PubMed Scopus (57) Google Scholar The role of dietary protein restriction in slowing progression of CKD is more controversial, although several meta-analyses indicate a beneficial, albeit small effect.3Kasiske B.L. Lakatua J.D. Ma J.Z. Louis T.A. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function.Am J Kidney Dis. 1998; 31: 954-961Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar,4Yan B. Su X. Xu B. et al.Effect of diet protein restriction on progression of chronic kidney disease: a systematic review and meta-analysis.PLoS One. 2018; 13e0206134Crossref PubMed Scopus (40) Google Scholar In autosomal dominant polycystic kidney disease (ADPKD) specifically, there are only scarce data on the renal effects of salt and protein intake. In the Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) cohort, an observational study in 241 patients with ADPKD with early stage disease, higher urinary sodium excretion (indicating higher salt intake) was associated with more rapid kidney volume growth. In a post hoc analysis of the HALT Progression of Polycystic Kidney Disease (HALT-PKD) study, a randomized controlled trial in 1044 patients with later-stage ADPKD, sodium excretion was associated with steeper estimated glomerular filtration rate (eGFR) decline in patients with later-stage ADPKD but not in patients with early-stage ADPKD.5Torres V.E. Grantham J.J. 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