Blood Kidney Injury Molecule-1 Is a Biomarker of Acute and Chronic Kidney Injury and Predicts Progression to ESRD in Type I Diabetes

Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5–15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.     

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury

Open in a separate window     

Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis

The effectiveness of cisplatin, a mainstay in the treatment of many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes AKI in 30% of patients. Patients who do not develop AKI by clinical standards during treatment are still at risk for long-term decline in kidney function and the development of CKD. The connection between AKI and CKD has become increasingly studied, with renal fibrosis a hallmark of CKD development. To prevent both the short- and long-term effects of cisplatin, researchers must use models that reflect both types of pathology. Although a lot is known about cisplatin-induced AKI, very little is known about the mechanisms by which repeated low levels of cisplatin lead to fibrosis development. In this review, strategies used in various rodent models to prevent kidney injury, its progression to fibrosis, or both, are examined to gain mechanistic insights and identify potential therapeutic targets for cisplatin-induced kidney pathologies. Reviewing the results from these models highlights the diverse and highly complex role of cell death, cell senescence, endoplasmic reticulum stress, autophagy, and immune cell activation in acute and chronic kidney injuries. The use of several models of kidney injury is needed for development of agents that will prevent all aspects of cisplatin-induced kidney injury.     

Vascular-Resident CD169-Positive Monocytes and Macrophages Control Neutrophil Accumulation in the Kidney with Ischemia-Reperfusion Injury

Monocytes and kidney-resident macrophages are considered to be involved in the pathogenesis of renal ischemia-reperfusion injury (IRI). Several subsets of monocytes and macrophages are localized in the injured tissue, but the pathologic roles of these cells are not fully understood. Here, we show that CD169⁺ monocytes and macrophages have a critical role in preventing excessive inflammation in IRI by downregulating intercellular adhesion molecule-1 (ICAM-1) expression on vascular endothelial cells. Mice depleted of CD169⁺ cells showed enhanced endothelial ICAM-1 expression and developed irreversible renal damage associated with infiltration of a large number of neutrophils. The perivascular localization of CD169⁺ monocytes and macrophages indicated direct interaction with blood vessels, and coculture experiments showed that the direct interaction of CD169⁺ cell-depleted peripheral blood leukocytes augments the expression levels of ICAM-1 on endothelial cells. Notably, the transfer of Ly6C^lo monocytes into CD169⁺ cell-depleted mice rescued the mice from lethal renal injury and normalized renal ICAM-1 expression levels, indicating that the Ly6C^lo subset of CD169⁺ monocytes has a major role in the regulation of inflammation. Our findings highlight the previously unknown role of CD169⁺ monocytes and macrophages in the maintenance of vascular homeostasis and provide new approaches to the treatment of renal IRI.     

The efficacy and safety of B-type natriuretic peptide (nesiritide) in patients with renal insufficiency and acutely decompensated congestive heart failure.

BACKGROUND: Nesiritide (B-type natriuretic peptide) reduces preload and afterload, and causes natriuresis, diuresis and suppression of norepinephrine, endothelin-1 and aldosterone. In this study, we sought to explore the safety and efficacy of nesiritide in patients with acute congestive heart failure (CHF) and renal insufficiency (RI). METHODS: We studied the effects of nesiritide in patients with RI in the VMAC trial database, a multi-centre, randomized controlled trial (n = 489) of patients with acute decompensated CHF. RESULTS: The mean serum creatinine (SCr) in nesiritide-treated patients with RI (SCr > or = 2.0 mg/dl, n = 60, range 2.0-11.1 mg/dl) and without RI (SCr < 2.0 mg/dl, n = 209) was 3.0+/-1.51 and 1.2+/-0.34 mg/dl, respectively. Pulmonary capillary wedge pressure (PCWP) was reduced significantly and similarly in both RI and no RI groups starting at 15 min into nesiritide infusion from a baseline of 29.9+/-8.1 and 26.6+/-6.0 mmHg, respectively. Addition of placebo to standard therapies yielded no further improvement in PCWP in patients with RI; in contrast, nesiritide significantly reduced PCWP at every time point during 24 h. The effects of nitroglycerin were less robust than those of nesiritide, and PCWP was not significantly reduced by nitroglycerin at the 3 h primary end-point. At 24 h, 83% of the RI patients and 91% of patients without RI treated with nesiritide reported improvements in dyspnoea. Nesiritide was well tolerated in patients with RI and no RI, and renal function was preserved in both groups. CONCLUSIONS: In patients with RI, nesiritide was safe and improved haemodynamics and dyspnoea.