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There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

The arteriovenous fistula is the preferred type of hemodialysis vascular access for patients with end-stage renal disease, but a high proportion of newly created fistulas fail to mature for use. Stenosis caused by neointimal hyperplasia often is present in fistulas with maturation failure, suggesting that local mechanisms controlling vascular smooth muscle cell (SMC) migration and proliferation are important contributors to maturation failure. SMCs cultured from explants of vein tissue obtained at the time of fistula creation from 19 patients with end-stage renal disease were studied to determine whether smooth muscle responsiveness to nitric oxide is associated with fistula maturation outcomes. Nitric oxide–induced inhibition of smooth muscle cell migration, but not proliferation, was greater in cells from patients with subsequent fistula maturation success than from patients with subsequent fistula maturation failure (mean inhibition percentage, 17 versus 5.7, respectively; P = 0.035). Impaired nitric oxide responsiveness was associated with oxidation of the calcium regulatory protein, sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), and was reversed by overexpressing SERCA (1.8-fold increase in inhibition, P = 0.0128) or down-regulating Nox4-based NADPH oxidase (2.3-fold increase in inhibition; P = 0.005). Our data suggest that the nitric oxide responsiveness of SMC migration is associated with fistula maturation success and raises the possibility that therapeutic restoration of nitric oxide responsiveness through manipulation of local mediators may prevent fistula maturation failure.

Background and objectives CKD is associated with increased cardiovascular risk not fully attributable to traditional risk factors. We compared endothelium-dependent and -independent vascular function among individuals with advanced CKD with function in those with vascular disease but preserved kidney function. Design, setting, participants, & measurements Matched cohort analysis randomly selected from 1259 participants at a single center with measurements of brachial artery flow–mediated dilation, an endothelium-dependent process, and nitroglycerin-mediated dilation, an endothelium-independent process. Patients with advanced CKD (n=70) were matched 1:1 to controls with preserved kidney function and (1) no overt vascular disease, (2) hypertension, and (3) coronary artery disease. Results The trend toward lower flow-mediated dilation (mean±SEM) in advanced CKD (5.4%±0.5%) compared with no overt vascular disease (7.3%±0.6%), hypertension (6.2%±0.5%), and coronary artery disease (5.8%±0.5%) did not reach statistical significance in adjusted analyses (P=0.05). Nitroglycerin-mediated dilation was lower in advanced CKD compared with in the other groups (adjusted nitroglycerin-mediated dilation: 6.9%±0.8%, 11.8%±0.9%, 11.0%±0.7%, and 10.5%±0.7% in advanced CKD, no overt vascular disease, hypertension, and coronary artery disease groups, respectively; P Conclusions Impairment in endothelium-dependent vascular function is present in patients with CKD and those with clinically evident vascular disease but preserved kidney function. In contrast, substantial reduction in endothelium-independent function was observed only in the CKD group, suggesting differences in severity and pathophysiology of vascular dysfunction between CKD and other disease states.

Arginine vasopressin (AVP) is being used increasingly to treat vasodilatory hypotension, although its effects on hepatosplanchnic perfusion have been debated.Prospective study in a university-based experimental research laboratory.We compared the effect of AVP on systemic, gut, and liver blood flow in anesthetized and ventilated rabbits given either saline or endotoxin. Incremental i.v. boluses of AVP ranging from 1 to 1,000[Symbol: see text]ng were administered 90[Symbol: see text]min post-endotoxin or saline.Endotoxin induced a shock state with a transient decrease of mesenteric artery blood flow velocity (pulsed Doppler, in centimeters per second, V(mes)) but had no effect on liver surface microcirculation (laser Doppler in TPU, MicroFl(liver)). Gut microcirculatory (MicroFl(gut)) changes became independent of mean arterial pressure (MAP) after endotoxin. In control rabbits (n = 5), increasing doses of AVP elevated MAP but reduced aortic blood flow (pulsed Doppler, VAo), V(mes), and MicroFl(gut) (p0.05). In endotoxic animals (n = 6), AVP produced a similar rise in MAP (p0.05), while V(mes) and MicroFl(gut) only decreased for AVP doses above 100[Symbol: see text]ng (p0.05). Liver microcirculation was only minimally affected by AVP, although significantly, both in control and endotoxin animals.Preservation of mesenteric blood flow as well as gut and liver microcirculation, with therapeutic doses of AVP during endotoxemia, supports its use as a hemodynamic agent during septic shock.