Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage.

Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule-specific Ddah1 knockout (Ddah1(PT-/-)) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1(PT-/-) mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function.

CKD and mortality risk in older people: a community-based population study in the United Kingdom.

BACKGROUND: The prevalence of chronic kidney disease (CKD) increases with age; however, the prognostic significance in older people is uncertain. This study aims to determine the association of CKD with all-cause and cardiovascular mortality in community-dwelling older people 75 years and older. STUDY DESIGN: Cohort study of people 75 years and older recruited in 1994 to 1999 to 1 arm of a trial of multidimensional health assessment with mortality follow-up. SETTING & PARTICIPANTS: 53 general practices in Great Britain. 15,336 (73%) of those eligible participated. 13,177 (86%) had serum creatinine measured at baseline. MAIN FACTOR: Estimated glomerular filtration rate (eGFR). OUTCOMES: All-cause and cardiovascular mortality. MEASUREMENTS: eGFR derived from serum creatinine level using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation in milliliters per minute per 1.73 m(2); dipstick proteinuria. Mortality by linkage to national death registration and death certification. RESULTS: After a median follow-up of 7.3 years (interquartile range, 5.0), 7,633 (58%) had died, 42% of cardiovascular causes. In the first 2 years of follow-up, adjusted hazard ratios for all-cause mortality in eGFR bands of 45 to 59, 30 to 44, and less than 30 compared with eGFR greater than 60 mL/min/1.73 m(2) were 1.13 (95% confidence interval, 0.93 to 1.37), 1.69 (95% confidence interval, 1.26 to 2.28), and 3.87 (95% confidence interval, 2.78 to 5.38) in men and 1.14 (95% confidence interval, 0.93 to 1.40), 1.33 (95% confidence interval, 1.06 to 1.68), and 2.44 (95% confidence interval, 1.68 to 3.56) in women, respectively. Hazard ratios were greater for cardiovascular mortality and lower after 2 years. Dipstick proteinuria was independently associated with all-cause, but not cardiovascular, mortality risk in both sexes. LIMITATIONS: Single serum creatinine measurement, no calibration of serum creatinine, MDRD Study equation not validated in older people. CONCLUSION: As kidney function decreases, there is a graded and independent increase in all-cause and cardiovascular mortality risk in older people 75 years and older, especially in men and those with eGFR less than 45 mL/min/1.73 m(2). Dipstick proteinuria did not add to cardiovascular mortality risk in this elderly population. In older people, identification and management of CKD should prioritize the smaller numbers with more severe CKD.