Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

Adenosine is an endogenous nucleoside, a byproduct of ATP metabolism, present in nearly all tissues in the body. In the brain, it acts not as a typical neurotransmitter, but as a neuromodulator. Adenosine exerts two parallel modulatory roles in the CNS: as a homeostatic modulator and a neuromodulator at the synaptic level (Cunha 2001). Adenosine can act pre-or post-synaptically on four different membrane bound G-protein coupled receptor subtypes (Fredholm et al. 2001) that have a wide range of affinities. A 1 (3-30 nM) and A 2A (1-20 nM) receptors are higher affinity while A 2B (5-20 lM) and A 3 (> 1 lM) receptors are lower affinity . The receptors are present in the entire brain, but with different abundance and effects. A 1 receptors are mostly localized in the cerebral cortex and hippocampus and are primarily involved in inhibitory neurotransmission. A 2A receptors modulate excitatory neurotransmission and are most abundant in the caudate-putamen. A 1 and A 2A receptors are thought to be activated under normal physiological conditions, because the basal level of adenosine is in the low nanomolar range (Cunha 2001). Low affinity A 2B and A 3 receptors would presumably be activated only under stressful or pathophysiological conditions such as hypoxia or ischemia. Variations in extracellular concentrations would affect the extent of adenosine receptor activation. Therefore, to understand the function and formation of adenosine, real-time measurements of adenosine concentrations are needed.Adenosine is produced intracellularly and extracellularly, but by different mechanisms (Latini and Pedata 2001). Intracellularly, adenosine is mainly formed by catabolism of AMP and then transported through the membrane via bidirectional equilibrative nucleoside transporters. In the extracellular space, released nucleotides such as ATP are metabolized to adenosine by ecto-5¢-nucleotidase. The time course of extracellular adenosine concentrations is expected to vary with the mechanism of formation, with direct transport after intracellular formation expected to be the fastest.Basal levels and evoked concentrations of adenosine have been studied in vitro (in brain slices) as well in vivo. Microdialysis, coupled to HPLC, is the most common method for measurement of neurochemicals in vivo. It is AbstractAdenosine is an endogenous byproduct of metabolism that regulates cerebral blood flow and modulates neurotransmission. Four receptors, with affinities ranging from nanomolar to micromolar, mediate the effects of adenosine. Real-time measurements are needed to understand the extracellular adenosine concentrations available to activate these receptors. In this study, we measured the subsecond time course of adenosine efflux in the caudate-putamen of anesthetized rats after a 1 s, high-frequency stimulation of dopamine neurons in the substantia nigra. Fast-scan cyclic voltammetry at carbonfiber microelectrodes was used for simultaneous detection of adenosine and dopamine, which have different oxidation potentials. While dopamine was ...

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10−8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

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.

We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.