Background

Previous studies in HIV-infected individuals have demonstrated serum albumin to be strongly associated with kidney function decline, independent of urine albumin and inflammatory markers. Lower serum albumin concentrations may be an under-appreciated risk factor for kidney function decline in elders.

Methods

We performed a cohort analysis in the Health Aging and Body Composition Study, a cohort of well-functioning, bi-racial, community-dwelling elders between the age of 70 and 79 years. We examined the associations of serum albumin concentration with longitudinal kidney function decline by estimated glomerular filtration rate (eGFR). Outcomes included linear eGFR decline, rapid kidney function decline defined as >30% decrease in eGFR, defined as a final eGFR <60 mL/min/1.73 m2 in those with an eGFR >60 mL/min/1.73 m2 at baseline. Cystatin C-based eGFR was calculated at baseline, Year 3 and Year 10.

Results

Mean age was 74 years, and mean eGFR was 73 mL/min/1.73 m2 at baseline. The mean rate of eGFR change was 1.81 mL/min/1.73 m2 per year. After multivariate adjustment, lower serum albumin concentrations were strongly and independently associated with kidney function decline (-0.11 mL/min/1.73 m2 per year for each standard deviation decrease serum albumin; -0.01 to - 0.20) with no attenuation after adjustment for urine albumin and inflammatory markers (-0.12, -0.03 to - 0.22). When divided into quartiles, serum albumin levels ≤3.80 g/dL were associated with increased odds of rapid kidney function decline (odds ratio 1.59; 1.12-2.26) and increased risk of incident chronic kidney disease (incident rate ratio 1.29; 1.03-1.62) relative to levels >4.21g/dL. Urine albumin to creatinine ratio (ACR) was also significantly and independently associated with kidney function decline (-0.08 mL/min/1.73 m2 per year for urine ACR >30 mg/g; -0.82 to - 0.13).

Conclusions

Lower serum albumin levels are strongly and independently associated with kidney function decline in elders, independent of clinical risk factors, urine albumin and measured inflammatory markers.

Introduction

APOL1 G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of APOL1 and elucidate potential mechanisms in APOL1-nephropathy.

Methods

A global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed.

Results

APOL1 genotypes did not alter APOL1 expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to BAK1 was a trans eQTL for APOL1 and a cis eQTL for BAK1; APOL1 and BAK1 were co-expressed in cells. BAK1 knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on APOL1 expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various APOL1 genotypes. Mitochondria in APOL1 wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing APOL1 G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2.

Conclusion

Results suggest the mitochondrial fusion/fission pathway may be a therapeutic target in APOL1-nephropathy.