Diabetic Kidney Disease: Challenges, Progress, and Possibilities.

Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.

Top Differential Diagnosis Should Be Microscopic Polyangiitis in ANCA-Positive Patient with Diffuse Pulmonary Hemorrhage and Hemosiderosis.

A rat model of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides reveals crescentic glomerulonephritis as seen in human renal biopsies and diffuse lung hemorrhage that is not well documented in human lung biopsies. A 64-year-old male, with shortness of breath and mild elevation of serum creatinine, was found to have a positive serum test for ANCA, but negative antiglomerular basement membrane antibody. A renal biopsy showed pauci-immune type of crescentic glomerulonephritis and focal arteritis. The prior lung wedge biopsy was retrospectively reviewed to show diffuse hemorrhage and hemosiderosis with focal giant cells. In addition, small arteries revealed subtle neutrophil aggregation, and margination along vascular endothelium, but no definitive vasculitis. The pathology of ANCA associated vasculitides results from activated neutrophils by ANCA and subsequent activation of the alternative complement cascade with endothelial injury, neutrophil aggregation and margination. Our findings, after the correlation between lung biopsy and renal biopsy, imply that the top differential diagnosis in the lung biopsy should be microscopic polyangiitis when diffuse pulmonary hemorrhage and hemosiderosis are present in this ANCA-positive patient.

Contribution of polyclonal free light chain deposition to tubular injury.

INTRODUCTION: Excretion of monoclonal free light chains (MFLC) beyond the renal threshold can cause kidney injury, but evidence for polyclonal free light chains (PFLC)-mediated injury is limited. We aimed to study the degree of PFLC deposition in the proximal tubules of chronic kidney disease (CKD) and hypothesized that excess deposition may contribute to tubular injury. METHODS: In this retrospective study, immunohistochemical staining to assess the degree of FLC deposition, periodic acid-Schiff staining for the degree of tubular brush border injury and trichrome staining for interstitial fibrosis were evaluated. Normal renal parenchyma from tumor nephrectomy specimens (control group I, n = 39), minimal change disease controls (group II, n = 13), renal biopsies from CKD and proteinuria (polyclonal study group III, n = 33) and monoclonal light chain nephropathy (group IV, n = 37) were studied. The results of the study including serum creatinine were compared between groups. RESULTS: Both polyclonal and monoclonal groups (groups III and IV) had significantly higher light chain deposition and brush border injury by periodic acid-Schiff scores compared to control groups (groups I and II). When the first three polyclonal groups (groups I-III) were analyzed together, polyclonal light chain deposition was significantly correlated with serum creatinine levels, brush border injury and interstitial fibrosis. CONCLUSION: The results of our study suggest that in CKD patients with proteinuria, excess PFLC deposition in the proximal tubules may cause acute tubular injury akin to monoclonal gammopathy and lead to renal chronicity.

Adjuvant role of p53 immunostaining in detecting BK viral infection in renal allograft biopsies.

BK virus infection is a significant threat to renal transplant outcome. Detecting viral infection in renal transplant biopsies using SV40 staining is less than ideal. SV40 antibody reacts with the large T-antigen of BK virus only at the early phases of infection and can miss cells in later stages of infection. As p53 is upregulated during both early and late phases of infection, this study set out to determine whether p53 staining could improve detection of BK virus infection in renal transplant patients. The control group consisted of 16 renal allograft biopsies without histologic evidence of BK virus infection, while the BK group consisted of 15 renal allograft biopsies with histologic evidence of BK virus infection. The biopsies from both groups were immunohistochemically stained with both SV40 and p53 antibodies. Dual staining with both markers was also performed to identify their nuclear co-localization. In the BK group, the percent of p53 staining (16.6 ± 4.8 %) was significantly higher than the percent of SV40 staining (5.4 ± 2.7%). BK virus infected cells revealed a unique p53 immunostaining pattern (strong nuclear staining with a central halo). Co-localization of SV40 and p53 was identified in cells that had characteristic nuclear features of BK virus infection by histology. The sensitivity and specificity for using p53 staining to identify BK infected cells was 92% and 86 %, respectively. In conclusion, p53 staining detects a higher percentage of BK virus infected cells than SV40 staining alone. Thus, for diagnosis of BK virus infection in renal allograft biopsies, p53 staining is a sensitive and specific method when used along with SV40 staining.

The predictive value of neuroendocrine markers and p53 for response to chemotherapy and survival in patients with advanced non-small cell lung cancer.

BACKGROUND: A minority of patients (30-40%) with advanced non-small cell lung cancer (NSCLC) have objective responses to chemotherapy. Therefore, defining molecular features that determine resistance or response to chemotherapy would have important implications in this disease. Several studies have suggested that patients whose tumors have neuroendocrine features may be more responsive to chemotherapy. In addition, increased expression of p53 may play a role in chemotherapy resistance in patients with NSCLC. METHODS: The objective of this study was to analyze retrospectively, the correlation between marker expression and response to chemotherapy and survival using immunohistochemistry for neuroendocrine markers and p53. Ninety patients with unresectable stage III or IV NSCLC, treated with platinum based combination chemotherapy were evaluated. The pathological specimens were obtained prior to chemotherapy. RESULTS: There was no statistically significant correlation between any individual marker and response to chemotherapy. However, patients with tumors with increased expression of p53 were more likely to have progressive disease following chemotherapy (P=0.02). Similarly, patients with tumors lacking neuroendocrine expression and with increased expression of p53 were more likely to have progressive disease when compared to patients with tumors with normal p53 expression and neuroendocrine differentiation (P=0.03). Normal expression of p53 along with the presence of neuroendocrine differentiation was a favorable factor for both survival (P=0.05) and time to disease progression (P=0.04) in the multivariate analysis. CONCLUSION: The presence of neuroendocrine markers alone was not predictive of response to chemotherapy and did not impact on the survival of this group of patients with advanced stage NSCLC. The normal expression of p53 together with neuroendocrine differentiation seems to impact favorably on overall survival time and time to disease progression without significant improvement in response to chemotherapy.