Urinary Plasmin(ogen) as a Prognostic Factor for Hypertension.

INTRODUCTION: Plasmin and its precursor, plasminogen, are detectable in urine from patients with glomerular disease. Urinary plasmin(ogen) levels correlate with blood pressure (BP) and may contribute to renal Na+ retention by activating the epithelial Na+ channel (ENaC). In a longitudinal nested-cohort study, we asked whether urinary plasmin(ogen) levels predict subsequent increase in BP, incident hypertension, or mortality in subjects with type I diabetes, who often develop proteinuria. METHODS: The Pittsburgh Epidemiology of Diabetes Complications (EDC) study followed up type I diabetic subjects for 25 years. Urine specimens from 70 subjects with a spectrum of baseline urinary albumin levels were examined. Outcomes included increased BP after 2 years (≥1 SD over baseline systolic or diastolic BP, examined via logistic regression), 25-year incident hypertension (≥140/90 mm Hg or initiating BP-lowering medications), and all-cause or cardiovascular mortality, examined using Cox regression. RESULTS: Subjects experiencing a 2-year increase in BP had higher baseline urinary plasmin(ogen)/creatinine levels (uPl/Cr) than other subjects (P = 0.04); the difference in baseline urinary albumin/creatinine levels (uAlb/Cr) was similar (P = 0.07). Baseline uPl/Cr was associated with increased 25-year hypertension incidence (hazard ratio = 2.05, P = 0.001), all-cause mortality (HR = 2.05, P = 0.01) and cardiovascular mortality (HR = 3.30, P = 0.005), although not independent of uAlb/Cr. CONCLUSION: This is the first long-term prospective study addressing clinical outcomes associated with increased urinary plasmin(ogen). Findings are consistent with a role for plasmin(ogen) in promoting increased BP, but also demonstrate the difficulty in distinguishing effects due to plasmin(ogen) from those of albuminuria.

Trial of Amiloride in Type 2 Diabetes with Proteinuria.

INTRODUCTION: Renal Na+ retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome, which occurs even in the absence of activation of hormones that stimulate renal Na+ transporters. Plasmin-dependent activation of the epithelial Na+ channel (ENaC) has been proposed to have a role in renal Na+ retention in the setting of nephrotic syndrome. We hypothesized that the ENaC inhibitor amiloride would be an effective therapeutic agent in inducing a natriuresis and lowering blood pressure in individuals with macroscopic proteinuria. METHODS: We conducted a pilot double-blind randomized cross-over study comparing the effects of daily administration of either oral amiloride or hydrochlorothiazide (HCTZ) to patients with type 2 diabetes and macroscopic proteinuria. Safety and efficacy were assessed by monitoring systolic blood pressure (SBP), kidney function, adherence, weight, urinary Na+ excretion and serum electrolytes. Nine subjects were enrolled in the trial. RESULTS: No significant difference in SBP or weight was seen between HCTZ and amiloride (p≥0.15). Amiloride induced differences in serum K+ (p<0.001), with a 0.88±0.30 mmol/L greater acute increase observed. Two subjects developed acute kidney injury and hyperkalemia when treated with amiloride. Four subjects had readily detectable levels of urinary plasminogen plus plasmin (uPl), and five did not. Changes in SBP in response to amiloride did not differ between individuals with vs. those without detectable uPl. CONCLUSION: In summary, among patients with type 2 diabetes, normal renal function and proteinuria, there were reductions in SBP in groups treated with HCTZ or amiloride. Acute kidney injury and severe hyperkalemia were safety concerns with amiloride.

Vitamin D deficiency and cardiovascular disease in postmenopausal women: contributions from human and nonhuman primate studies.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death among American postmenopausal women and all adult Americans. The medical community and the lay community have recently become intrigued with vitamin D and its potential role in reducing the risk of CVD. Research findings from multiple retrospective studies, few prospective studies, and recent nonhuman primate studies have been inconsistent and conflicting. The objective of this study is to review what is known about the topic, what questions remain unanswered, and where the research community should be focusing. METHODS: A literature search was conducted through PubMed and Google Scholar up to August 1, 2014. One hundred six articles, including 18 double-blind, placebo-controlled, randomized clinical trials, relevant to the study topic were identified. All studies were stratified based on study design and primary outcome. The effects of vitamin D on CVD were reviewed and summarized. RESULTS: Although there is an abundance of observational studies suggesting an association with CVD protection, the most well-controlled randomized human trial data available show no benefit of vitamin D on CVD. However, highly controlled nonhuman primate studies indicate a beneficial relationship. CONCLUSIONS: Well-designed research, with CVD as primary outcome, is needed to help bridge the gap in our knowledge on this topic. In the meantime, caution should be applied to avoid overdiagnosis and overtreatment of vitamin D deficiency.