The kidney protects against sepsis by producing systemic uromodulin.

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. Although electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We have previously demonstrated that systemic Tamm-Horsfall protein (THP; uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we showed that the kidney increases circulating THP by enhancing the basolateral release of THP from medullary thick ascending limb cells. In patients with sepsis, changes in circulating THP were positively associated with a critical illness. THP was also found de novo in injured lungs. Genetic ablation of THP in mice led to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo led macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis, and chemotaxis, and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improved survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function, and systemic THP has therapeutic potential in sepsis.NEW & NOTEWORTHY Specific therapies to improve outcomes in sepsis with kidney injury have been limited by an unclear understanding of how kidney injury increases sepsis mortality. Here, we identified Tamm-Horsfall protein, known to protect in ischemic acute kidney injury, as protective in preclinical sepsis models. Tamm-Horsfall protein also increased in clinical sepsis without severe kidney injury and concentrated in injured organs. Further study could lead to novel sepsis therapeutics.

Kayexalate-induced colonic ulcer.

A 61-year-old male presents to the emergency room with complaints of fatigue, dizziness and bright red blood per rectum (BRBPR) for 2 days. Past medical history was significant for gastroesophageal reflux disease, non-steroidal anti-inflammatory drug (NSAID) induced ulcer, and end-stage renal disease (GFR < 30) status post 2 failed renal grafts. Pertinent medications include pantoprazole and sodium polystyrene sulfonate in sorbitol (Kayexalate 30 g/d orally). On esophagogastroduodenoscopy (EGD) there was a single shallow, flat, non-bleeding gastric ulcer (3 mm) in the pre-pyloric region of the stomach with no stigmata of bleeding. A colonoscopy was performed showing evidence of colitis and localized ulcerations in the cecum which were biopsied. Histopathology revealed basophilic, nonpolarizable, rhomboid-like crystals without evidence of necrosis.

Presence and outcomes of kidney disease in patients with pulmonary hypertension.

BACKGROUND AND OBJECTIVES: Pulmonary hypertension is associated with higher mortality rates. The associations of nondialysis-dependent CKD and all-cause mortality in patients with pulmonary hypertension were studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study population included those patients who underwent right heart catheterization for confirmation of pulmonary hypertension between 1996 and January 2011. Pulmonary hypertension was defined as the presence of mean pulmonary artery pressure ≥ 25 mmHg at rest measured by right heart catheterization. CKD was defined as the presence of two measurements of eGFR<60 ml/min per 1.73 m(2) 90 days apart. The risk factors associated with CKD as well as the association between CKD and death in those patients with pulmonary hypertension using logistic regression and Cox proportional hazard models were examined. RESULTS: Of 1088 patients with pulmonary hypertension, 388 (36%) patients had CKD: 340 patients had stage 3 CKD, and 48 (4%) patients had stage 4 CKD. In the multivariable analysis, older age, higher hemoglobin, and higher mean right atrial pressures were independently associated with CKD. During a median follow-up of 3.2 years (interquartile range=1.5-5.6 years), 559 patients died. After adjusting for relevant covariates, presence of stage 3 CKD (hazard ratio, 1.37; 95% confidence interval, 1.14 to 1.66) and stage 4 CKD (hazard ratio, 2.69; 95% confidence interval, 1.88 to 3.86) was associated with all-cause mortality in those patients with pulmonary hypertension. When eGFR was examined as a continuous measure, a 5 ml/min per 1.73 m(2) lower eGFR was associated with a 5% (95% confidence interval, 1.03 to 1.07) higher hazard for death. This higher risk with CKD was similar irrespective of demographics, left ventricular function, and pulmonary capillary wedge pressure. CONCLUSION: In a clinical population referred for right heart catheterization, presence of CKD was associated with higher all-cause mortality in those patients with pulmonary hypertension. Mechanisms that may underlie these associations warrant additional studies.