Volume overload and adverse outcomes in chronic kidney disease: clinical observational and animal studies

Abstract

Background: Volume overload is frequently encountered and is associated with cardiovascular risk factors in patients with chronic kidney disease (CKD). However, the relationship between volume overload and adverse outcomes in CKD is not fully understood.

Methods and results: A prospective cohort of 338 patients with stage 3 to 5 CKD was followed for a median of 2.1 years. The study participants were stratified by the presence or absence of volume overload, defined as an overhydration index assessed by bioimpedance spectroscopy exceeding 7%, the 90th percentile for the healthy population. The primary outcome was the composite of estimated glomerular filtration rate decline ≥50% or end-stage renal disease. The secondary outcome included a composite of morbidity and mortality from cardiovascular causes. Animal models were used to simulate fluid retention observed in human CKD. We found that patients with volume overload were at a higher risk of the primary and secondary end points in the adjusted Cox models. Furthermore, overhydration appears to be more important than hypertension in predicting an elevated risk. In rats subjected to unilateral nephrectomy and a high-salt diet, the extracellular water significantly increased. This fluid retention was associated with an increase in blood pressure, proteinuria, renal inflammation with macrophage infiltration and tumor necrosis factor-α overexpression, glomerular sclerosis, and cardiac fibrosis. Diuretic treatment with indapamide attenuated these changes, suggesting that fluid retention might play a role in the development of adverse outcomes.

Conclusions: Volume overload contributes to CKD progression and cardiovascular diseases. Further research is warranted to clarify whether the correction of volume overload would improve outcomes for CKD patients.

Keywords: bioimpedance; cardiovascular disease; chronic kidney disease; hypertension; overhydration; volume overload.

Figure 1

Relationship between relative overhydration (OH) and systolic blood pressure (SBP). The patients were classified into 4 groups according to the baseline SBP (<140 or ≥140 mm Hg) and OH (<7 or ≥7%).

Figure 2

Kaplan–Meier survival curve for renal (A) and cardiovascular (B) outcomes. The patients were classified into 4 groups according to the baseline systolic blood pressure (SBP; <140 or ≥140 mm Hg) and overhydration (OH; <7 or ≥7%). The patients with volume overload demonstrated a substantially increased risk compared with those without volume overload.

Figure 3

Metabolic caging studies in the rats at baseline and after 4 weeks on normal- or high-salt diets. A, Changes in water intake, (B) urine volume, (C) urine sodium, (D) the ratio of extracellular water to the total body water (ECW/TBW), (E) systolic blood pressure (SBP), and (F) urine protein–creatinine ratio (UPCR). N=8 in each group. ^‡P<0.001 vs Sham+NS and UNX+NS; *P<0.001 vs Sham+NS and UNX+NS (A and B). ^‡P<0.001 vs Sham+NS, UNX+NS, and UNX+HS; *P<0.001 vs Sham+NS, Sham+HS, and UNX+NS; ^†P<0.001 vs Sham+NS, UNX+NS, and UNX+HS (C). *P<0.001 vs Sham+NS, Sham+HS, and UNX+NS; ^†P<0.001 vs UNX+HS (D through F) (2-way ANOVA with Bonferroni’s post-hoc tests). IDP indicates indapamide; Sham+HS, sham-operated rats raised with high salt diet; Sham+NS, sham-operated rats raised with a normal diet; UNX+HS, uninephrectomized rats raised with high salt diet; UNX+NS, uninephrectomized rats raised with a normal diet.

Figure 4

Systemic and renal inflammation in the rats after 4 weeks on normal- or high-salt diets. A, Tumor necrosis factor-α (TNF-α) level in the serum. N=8 in each group. *P<0.01 vs Sham+NS, Sham+HS, and UNX+NS; ^†P<0.01 vs UNX+HS. B, TNF-α level in the kidney homogenate. N=8 in each group. *P<0.05 vs Sham+NS and UNX+NS; ^†P<0.05 vs UNX+HS (1-way ANOVA with Tukey’s post-hoc tests). ANOVA indicates analysis of variance; IDP, indapamide; Sham+HS, sham-operated rats raised with high salt diet; Sham+NS, sham-operated rats raised with a normal diet; UNX+HS, uninephrectomized rats raised with high salt diet; UNX+NS, uninephrectomized rats raised with a normal diet.

Figure 5

Renal and cardiac histology in the rats after 4 weeks on normal- or high-salt diets. A, Representative microphotographs of immunohistochemistry for ED1 in the renal cortex. B, Quantitative ED1-positive macrophage infiltration (number of positive cells per high power field). Significantly greater macrophage infiltrations were elicited in the UNX+HS rats. C, Representative microphotographs of PAS staining in the renal cortex. D, Quantitative analysis of collagen deposition (% stained area in the glomeruli). Significantly greater glomerular damage was elicited in the UNX+HS rats. E, Representative microphotographs of Masson staining in the heart. F, Quantitative analysis of collagen deposition (% stained area in the cardiac tissue). Significantly greater cardiac interstitial fibrosis was elicited in the UNX+HS rats. *P<0.05 vs Sham+NS, Sham+HS, and UNX+NS; ^†P<0.05 vs UNX+HS (1-way ANOVA with Tukey’s post-hoc tests). Magnification ×400. ANOVA indicates analysis of variance; IDP, indapamide; PAS, periodic acid-Schiff; Sham+HS, sham-operated rats raised with high salt diet; Sham+NS, sham-operated rats raised with a normal diet; UNX+HS, uninephrectomized rats raised with high salt diet; UNX+NS, uninephrectomized rats raised with a normal diet.