Faculty Bibliography

INTRODUCTION/BACKGROUND:Congestive heart failure (CHF) is an important cause of hospital admissions and is associated with an increased risk for development of acute renal failure (ARF). The purpose of this study was to describe the incidence of ARF, to ascertain risk factors for its development, and to determine whether ARF impacts hospital outcomes. METHODS:Review was conducted of 509 hospital medical records of patients hospitalized with a principal diagnosis of CHF during 2004. ARF was defined as an increase in serum creatinine of 0.5 mg/dl compared to the admission value. Multivariable analysis was used to identify independent predictors of ARF. RESULTS:Most patients had reduced renal function at the time of admission with mean serum creatinine of 1.45 +/- 0.72 and calculated creatinine clearance of 43.1 ml/min. ARF developed during the hospitalization in 21% of patients, with a peak increase in serum creatinine of 0.5-3.3 mg/dl. Most cases occurred on hospital days 4-6 (69.5% of cases). ARF was associated with increased risk for in-hospital mortality and increased length of hospital stay. Risk factors for ARF included diabetes, elevated admission serum creatinine and reduced serum sodium and echocardiographic demonstration of diastolic dysfunction. Neither diuretic nor ACEI/ARB treatment was associated with increased risk. CONCLUSION/CONCLUSIONS:ARF is a common complication among patients hospitalized for CHF, and is associated with increased risk for adverse outcomes. Certain clinical characteristics present at the time of admission help identify patients at increased risk.

Hemodialysis is associated with various complications, the most common being intradialytic hypotension (IDH). In the majority of cases, IDH is easily corrected and does not represent a life-threatening condition. We present a patient in whom IDH was unresponsive to various corrective strategies. A new mitral valve regurgitant lesion was diagnosed that eventually led to the patient's demise. Unusual etiologies of IDH need to be considered, particularly in instances where routine therapeutic measures are ineffective.

Foxa1 is a member of the winged helix family of transcription factors and is expressed in the collecting ducts of the kidney. We investigated its potential contribution to renal physiology in Foxa1-deficient mice on a defined genetic background. Foxa1(-/-) mice are dehydrated and exhibit electrolyte imbalance as evidenced by elevated hematocrit and plasma urea levels, hypernatremia, and hyperkalemia. This phenotype is the consequence of decreased urine osmolality secondary to renal vasopressin resistance. Mutations of the human genes encoding the vasopressin 2 receptor and aquaporin 2 cause nephrogenic diabetes insipidus; however, expression of these genes is maintained or increased, respectively, in Foxa1(-/-) mice. Likewise, expression of the genes encoding the Na-K-2Cl cotransporter (NKCC2), the potassium channel ROMK, the chloride channel CLCNKB, barttin (BSND), and the calcium-sensing receptor (CASR), each of which is important in sodium reabsorption in the loop of Henle, is maintained or even increased in Foxa1-deficient mice. Thus, we have shown that Foxa1(-/-) mice represent a new model of nephrogenic diabetes insipidus with unique molecular etiology, and we have identified the first transcription factor whose mutation leads to a defect in renal water homeostasis in vivo.

High urinary flow rates stimulate K secretion in the fully differentiated but not neonatal or weanling rabbit cortical collecting duct (CCD). Both small-conductance secretory K and high-conductance Ca2+/stretch-activated maxi-K channels have been identified in the apical membrane of the mature CCD by patch-clamp analysis. We reported that flow-stimulated net K secretion in the adult rabbit CCD is 1) blocked by TEA and charybdotoxin, inhibitors of intermediate- and high-conductance (maxi-K) Ca2+-activated K channels, and 2) associated with increases in net Na absorption and intracellular Ca2+ concentration ([Ca2+]i). The present study examined whether the absence of flow-stimulated K secretion early in life is due to a 1) limited flow-induced rise in net Na absorption and/or [Ca2+]i and/or 2) paucity of apical maxi-K channels. An approximately sixfold increase in tubular fluid flow rate in CCDs isolated from 4-wk-old rabbits and microperfused in vitro led to an increase in net Na absorption and [Ca2+]i, similar in magnitude to the response observed in 6-wk-old tubules, but it failed to generate an increase in net K secretion. By 5 wk of age, there was a small, but significant, flow-stimulated rise in net K secretion that increased further by 6 wk of life. Luminal perfusion with iberiotoxin blocked the flow stimulation of net K secretion in the adult CCD, confirming the identity of the maxi-K channel in this response. Maxi-K channel alpha-subunit message was consistently detected in single CCDs from animals >/=4 wk of age by RT-PCR. Indirect immunofluorescence microscopy using antibodies directed against the alpha-subunit revealed apical labeling of intercalated cells in cryosections from animals >/=5 wk of age; principal cell labeling was generally intracellular and punctate. We speculate that the postnatal appearance of flow-dependent K secretion is determined by the transcriptional/translational regulation of expression of maxi-K channels. Furthermore, our studies suggest a novel function for intercalated cells in mediating flow-stimulated K secretion.