Endothelial dysfunction and oxidative stress in polycystic kidney disease.

Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD2, and PGE2, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD2 and PGF2α were associated with reduced eGFR, whereas 8-isoprostane and again PGF2α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.

Pathogenesis of hypercalciuric nephrolithiasis.

The major contribution of hypercalciuria in raising urinary state of saturation with respect to calcium salts and subsequent risk of nephrolithiasis is appreciated. Derangements in the physiological mechanisms that regulate calcium homeostasis and contribute to hypercalciuria have also been identified. New avenues of research are beginning to explore the specific defects that may contribute to hypercalciuria. From such studies, an understanding of the role of certain dietary excesses as contributors to the development of hypercalciuria and, in some cases, attendant bone loss, is beginning. The contribution of genetics to hypercalciuria has provided a powerful means of identifying genes that contribute to the hypercalciuric phenotype in a number of hypercalciuric conditions. Such studies have disclosed that hypercalciuria is probably polygenic in nature and will require a concerted effort to better understand the defects while attempting to develop gene-specific countermeasures.