Deletion of Nedd4-2 results in progressive kidney disease in mice

NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na⁺ channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na⁺Cl⁻ cotransporter expression, increased Na⁺ reabsorption, hypertension and markedly reduced levels of aldosterone. The observed nephropathy is characterized by fibrosis, tubule epithelial cell apoptosis, dilated/cystic tubules, elevated expression of kidney injury markers and immune cell infiltration, characteristics reminiscent of human chronic kidney disease. Importantly, we demonstrate that the extent of kidney injury can be partially therapeutically ameliorated in mice with nephron-specific deletions of Nedd4-2 by blocking ENaC with amiloride. These results suggest that increased Na⁺ reabsorption via ENaC causes kidney injury and establish a novel role of NEDD4-2 in preventing Na⁺-induced nephropathy. Contrary to some recent reports, our data also indicate that ENaC is the primary in vivo target of NEDD4-2 and that Nedd4-2 deletion is associated with hypertension on a normal Na⁺ diet. These findings provide further insight into the critical function of NEDD4-2 in renal pathophysiology.Tanya L Henshall, Jantina A Manning, Omri S Alfassy, Pranay Goel, Natasha A Boase, Hiroshi Kawabe and Sharad Kuma

Prevention of acute kidney injury and protection of renal function in the intensive care unit

Acute renal failure on the intensive care unit is associated with significant mortality and morbidity. To determine recommendations for the prevention of acute kidney injury (AKI), focusing on the role of potential preventative maneuvers including volume expansion, diuretics, use of inotropes, vasopressors/vasodilators, hormonal interventions, nutrition, and extracorporeal techniques. A systematic search of the literature was performed for studies using these potential protective agents in adult patients at risk for acute renal failure/kidney injury between 1966 and 2009. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, and use of potentially nephrotoxic drugs and radiocontrast media. Where possible the following endpoints were extracted: creatinine clearance, glomerular filtration rate, increase in serum creatinine, urine output, and markers of tubular injury. Clinical endpoints included the need for renal replacement therapy, length of stay, and mortality. Studies are graded according to the international Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) group system Several measures are recommended, though none carries grade 1A. We recommend prompt resuscitation of the circulation with special attention to providing adequate hydration whilst avoiding high-molecular-weight hydroxy-ethyl starch (HES) preparations, maintaining adequate blood pressure using vasopressors in vasodilatory shock. We suggest using vasopressors in vasodilatory hypotension, specific vasodilators under strict hemodynamic control, sodium bicarbonate for emergency procedures administering contrast media, and periprocedural hemofiltration in severe chronic renal insufficiency undergoing coronary intervention

Acute kidney injury caused by intravascular hemolysis after mechanical thrombectomy.

A 43-year-old African-American female (gravida 5 para 0) with an 8-week intrauterine pregnancy presented to the emergency room with crampy abdominal pain, shortness of breath, and shoulder pain. She had normal renal function on admission. CT angiography of the chest revealed bilateral pulmonary emboli; therefore, the AngioJet (Possis Medical, Inc., Minneapolis, MN) device was used to perform mechanical thrombolysis. The patient subsequently developed hyperkalemia, red urine and anuria.Physical examination, measurement of serum creatinine level and electrolytes, dipstick urinalysis and centrifugation of urine and blood.Acute kidney injury due to hemoglobinuria as a result of non-immune-mediated intravascular hemolysis following the use of a percutaneous mechanical thrombectomy device (AngioJet).Hydration, alkalinization of urine and initiation of hemodialysis (temporarily switched to continuous venovenous hemodiafiltration). Urine output improved after the 20th day of hospitalization, at which point dialysis was discontinued. The patient's renal function completely recovered by day 25