Osmoregulation Performance and Kidney Transplant Outcome

Abstract

Background: Kidney transplant recipients have an impaired ability to dilute urine but seldom develop baseline hyponatremia before ESRD. Although hyponatremia is a risk factor for adverse events in CKD and in kidney transplant recipients, it remains unclear whether subtler alterations in osmoregulation performance are associated with outcome.

Methods: We studied a single-center prospective cohort of 1258 kidney transplant recipients who underwent a water-loading test 3 months after transplant to determine osmoregulation performance. Measured GFR (mGFR) was performed at the same visit. A group of 164 healthy candidates for kidney donation served as controls. We further evaluated the association of osmoregulation performance with transplantation outcomes and subsequent kidney function.

Results: Unlike controls, most kidney transplant recipients failed to maintain plasma sodium during water loading (plasma sodium slope of -0.6±0.4 mmol/L per hour in transplant recipients versus -0.12±0.3 mmol/L per hour in controls; P<0.001). Steeper plasma sodium reduction during the test independently associated with the composite outcome of all-cause mortality and allograft loss (hazard ratio [HR], 1.73 per 1 mmol/L per hour decrease in plasma sodium; 95% confidence interval [95% CI], 1.23 to 2.45; P=0.002) and allograft loss alone (HR, 2.04 per 1 mmol/L per hour decrease in plasma sodium; 95% CI, 1.19 to 3.51; P=0.01). The association remained significant in a prespecified sensitivity analysis excluding patients with hyperglycemia. In addition, a steeper plasma sodium slope 3 months after transplantation independently correlated with lower mGFR at 12 months (β=1.93; 95% CI, 0.46 to 3.41; P=0.01).

Conclusions: Reduced osmoregulation performance occurs frequently in kidney transplant recipients and is an independent predictor of renal outcome.

Keywords: Sodium; kidney transplantation; osmoregulation.

Graphical abstract

Figure 1.

Kidney transplant recipients have altered osmoregulatory response to water loading: variation of mean P_Na, urine flow rate, urine osmolality, and renal free water clearance during water loading in KTRs (red) and healthy candidates to kidney donation (controls in blue). Bars indicate 95% confidence intervals. t test: *P<0.05, **P<0.01, ****P<0.001.

Figure 2.

P_Na slope is an indicator of osmoregulation performance. (A) Examples of P_Na variations in four patients with normal or low initial P_Na and normal (gray lines) or altered osmoregulation kinetics (green lines). The solid lines represent observed P_Na variations. The dashed lines represent the linear regression of P_Na concentration and time. The slopes of the regression lines are indicated on the right. (B) Distribution of P_Na slopes in KTRs and control patients. (C and D) Linear regression of P_Na slopes and the minimal urine osmolality observed during the test (C) or the mean urine flow rate observed throughout the test (D).

Figure 3.

Steeper P_Na slopes associate with greater incidence of mortality and allograft loss in KTRs. (A–C) Cumulative incidence plots of P_Na slope tertiles and the composite outcome of all-cause mortality and allograft loss (A), all-cause mortality (B), and allograft loss (C).