Identifying Clinical and Genomic Features Associated With Chronic Kidney Disease

We apply a pattern-based classification method to identify clinical and genomic features associated with the progression of Chronic Kidney disease (CKD). We analyze the African-American Study of Chronic Kidney disease with Hypertension dataset and construct a decision-tree classification model, consisting 15 combinatorial patterns of clinical features and single nucleotide polymorphisms (SNPs), seven of which are associated with slow progression and eight with rapid progression of renal disease among African-American Study of Chronic Kidney patients. We identify four clinical features and two SNPs that can accurately predict CKD progression. Clinical and genomic features identified in our experiments may be used in a future study to develop new therapeutic interventions for CKD patients.

Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK)

Oxidative stress is acknowledged to play a role in kidney disease progression. Genetic variants that affect the capacity to handle oxidative stress may therefore influence the outcome of kidney disease. We examined whether genetic variants of the GSTM1 gene, a member of a superfamily of glutathione S-transferases, influence the course of kidney disease progression in participants of the African American Study of Kidney Disease (AASK) trial. Groups with and without the common GSTM1 null allele, GSTM1(0), differed significantly in the time to a glomerular filtration rate (GFR) event or dialysis ( P = 0.04) and in the time to GFR event, dialysis, or death ( P = 0.02). The hazard ratios (HR) for the time to a GFR event or dialysis in those with two or one null allele relative to those possessing none were 1.88 [95% confidence interval (CI), 1.07 to 3.30, P = 0.03] and 1.68 (95% CI, 1.00 to 2.84, P < 0.05), respectively. For the time to GFR event, dialysis, or death, the HR for two null alleles was 2.06 (95% CI, 1.20 to 3.55, P = 0.01) and for one null allele 1.70 (95% CI, 1.02 to 2.81, P = 0.04). We demonstrated that GSTM1 directly regulates intracellular levels of 4-hydroxynonenal (4-HNE) in vascular smooth muscle cells. Furthermore, we showed that renal 4-HNE levels and GSTM1 are both increased after reduction of renal mass (RRM) in the mouse. We conclude that GSTM1 is normally upregulated in chronic kidney disease (CKD) in a protective response to increased oxidative stress. A genetic variant that results in loss of GSTM1 activity may be deleterious in CKD.