Acute kidney injury predisposes patients to the development of both chronic kidney disease and end-stage renal failure, but the molecular details underlying this important clinical association remain obscure. We report that kidney injury molecule-1 (KIM-1), an epithelial phosphatidylserine receptor expressed transiently after acute injury and chronically in fibrotic renal disease, promotes kidney fibrosis. Conditional expression of KIM-1 in renal epithelial cells (Kim1 RECtg ) in the absence of an injury stimulus resulted in focal epithelial vacuolization at birth, but otherwise normal tubule histology and kidney function. By 4 weeks of age, Kim1 RECtg mice developed spontaneous and progressive interstitial kidney inflammation with fibrosis, leading to renal failure with anemia, proteinuria, hyperphosphatemia, hypertension, cardiac hypertrophy, and death, analogous to progressive kidney disease in humans. Kim1 RECtg kidneys had elevated expression of proinflammatory monocyte chemotactic protein-1 (MCP-1) at early time points. Heterologous expression of KIM-1 in an immortalized proximal tubule cell line triggered MCP-1 secretion and increased MCP-1-dependent macrophage chemotaxis. In mice expressing a mutant, truncated KIM-1 polypeptide, experimental kidney fibrosis was ameliorated with reduced levels of MCP-1, consistent with a profibrotic role for native KIM-1. Thus, sustained KIM-1 expression promotes kidney fibrosis and provides a link between acute and recurrent injury with progressive chronic kidney disease.

Dialyzer reactions are long-appreciated complications of dialysis. Despite advances in dialysis machines and membranes, these life-threatening reactions still occur. It is imperative to recognize potential dialyzer reactions when assessing adverse dialysis events as reexposure to dialytic treatments could be life threatening. We present the case of a 72-year old woman with dialysis-requiring anuric acute kidney injury who experienced acute hypotension and cardiopulmonary arrest during both continuous renal replacement therapy and a subsequent hemodialysis treatment. We concluded that she had an anaphylactic reaction to an unidentified component of the dialysis equipment. Identification, work up, treatment, and reporting of dialyzer reactions are discussed in the context of this case.

Background: PR3-ANCA vasculitis has a genetic association with HLA-DPB1. We explored immunologic and clinical features related to the interaction of HLA-DPB1*04:01 with a strongly binding PR3 peptide epitope (PR3225-239). Methods: ANCA vasculitis patients with active disease and in remission were followed longitudinally. Peripheral blood mononuclear cells from patients and healthy controls with HLA-DPB1*04:01 were tested for HLA-DPB1*04:01 expression and interaction with a PR3 peptide identified via in silico and in vitro assays. Tetramers (HLA/peptide multimers) identified autoreactive T cells. Results: HLA-DPB1*04:01 genotype was associated with risk of relapse in PR3-ANCA (HR for relapse 2.06 (1.01, 4.20)) but not in the myeloperoxidase (MPO)-ANCA or the combined cohort. In silico predictions of HLA and PR3 peptide interactions demonstrated strong affinity between ATRLFPDFFTRVALY (PR3225-239) and HLADPB1*04:01 that was confirmed by in vitro competitive binding studies. The interaction was tested in ex vivo flow cytometry studies of labeled peptide and HLA-DPB1*04:01-expressing cells. We demonstrated PR3225-239 specific autoreactive T cells using synthetic HLA multimers (tetramers). Patients in long-term remission off therapy had autoantigenic peptide and HLA interaction comparable to that of healthy volunteers. Conclusion: The risk allele HLA-DPB1*04:01 has been associated with PR3-ANCA, but its immunopathologic role was unclear. These studies demonstrate that HLA-DPB1*04:01 and PR3225-239 initiate an immune response. Autoreactive T cells specifically recognized PR3225-239 presented by HLA DPB1*04:01. While larger studied should validate these findings,, the pathobiology may explain the observed increased risk of relapse in our cohort. Moreover, lack of HLA and autoantigen interaction observed during long-term remission signals immunological non-responsiveness.

The Nijmegen Biomedical Study is a population-based cross-sectional study conducted in the eastern part of the Netherlands. As part of the overall study, we provide reference values of estimated glomerular filtration rate (GFR) for this Caucasian population without expressed risk. Age-stratified, randomly selected inhabitants received a postal questionnaire on lifestyle and medical history. In a large subset of the responders, serum creatinine was measured. The GFR was then measured using the abbreviated Modification of Diet in Renal Disease (MDRD) formula. To limit possible bias, serum creatinine was calibrated against measurements performed in the original MDRD laboratory. The study cohort included 2823 male and 3274 female Caucasian persons aged 18-90 years. A reference population of apparently healthy subjects was selected by excluding persons with known hypertension, diabetes, cardiovascular-or renal diseases. This healthy study cohort included 1660 male subjects and 2072 female subjects, of which 869 of both genders were 65 years or older. The median GFR was 85 ml/min/1.73 m 2 in 30-to 34-year-old men and 83 ml/min/1.73 m 2 in similar aged women. In these healthy persons, GFR declined approximately 0.4 ml/min/year. Our study provides age-and gender-specific reference values of GFR in a population of Caucasian persons without identifiable risk.

The biology that explains the association of APOL1 variants with nondiabetic kidney diseases in black patients remains controversial.Many, but not all, studies suggest that APOL1 variant-dependent cytotoxicity is associated with kidney diseases (also reviewed in Ref.[1-4]). Furthermore, animal models have linked changes in podocyte number with APOL1 genotype. We previously demonstrated podocyte depletion in transgenic mice constitutively expressing the G2 variant of APOL1 in podocytes under the Nephrin promoter (Nphs1. APOL1-G2), but not in wild type or APOL1-G0 expressing (Nphs1. APOL1-G0) mice, despite normal biochemical and histologic kidney phenotypes. 5 Mice with HIV-associated nephropathy (HIVAN) and transgenic for Nphs1.APOL-G0 had preserved podocyte numbers and densities; whereas, HIVAN mice with Nphs1.APOL1-G2 had podocyte numbers and density similar to HIVAN only mice. 6 The podocyte depletion hypothesis proposes that the progressive podocyte loss occurs with physiological stress of aging but only results