Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1.

Ischemic acute kidney injury (AKI) triggers expression of adaptive (protective) and maladaptive genes. Agents that increase expression of protective genes should provide a therapeutic benefit. We now report that bardoxolone methyl (BARD) ameliorates ischemic murine AKI as assessed by both renal function and pathology. BARD may exert its beneficial effect by increasing expression of genes previously shown to protect against ischemic AKI, NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ), and heme oxygenase 1 (HO-1). Although we found that BARD alone or ischemia-reperfusion alone increased expression of these genes, the greatest increase occurred after the combination of both ischemia-reperfusion and BARD. BARD had a different mode of action than other agents that regulate PPARγ and Nrf2. Thus we report that BARD regulates PPARγ, not by acting as a ligand but by increasing the amount of PPARγ mRNA and protein. This should increase ligand-independent effects of PPARγ. Similarly, BARD increased Nrf2 mRNA; this increased Nrf2 protein by mechanisms in addition to the prolongation of Nrf2 protein half-life previously reported. Finally, we localized expression of these protective genes after ischemia and BARD treatment. Using double-immunofluorescence staining for CD31 and Nrf2 or PPARγ, we found increased Nrf2 and PPARγ on glomerular endothelia in the cortex; Nrf2 was also present on cortical peritubular capillaries. In contrast, HO-1 was localized to different cells, i.e., tubules and interstitial leukocytes. Although Nrf2-dependent increases in HO-1 have been described, our data suggest that BARD's effects on tubular and leukocyte HO-1 during ischemic AKI may be Nrf2 independent. We also found that BARD ameliorated cisplatin nephrotoxicity.

Successful renal re-transplantation in the presence of pre-existing anti-DQ5 antibodies when there was zero mismatch at class I human leukocyte antigen A, B, & C: a case report.

INTRODUCTION: Hyperacute rejection may be prevented by avoiding the transplantation of kidneys into patients with pre-existing anti-donor Class I human leukocyte antigen antibodies. However, the role of anti-donor-Class II-human leukocyte antigen-DQ antibodies is not established. The question is ever more relevant as more sensitive cross-matching techniques detect many additional antibodies during the final crossmatch. We now report successful renal transplantation of a patient who had pre-existing antibodies against his donor's human leukocyte antigen-DQ5. CASE PRESENTATION: Our patient, a Caucasian man, was 34 years of age when he received his first deceased donor renal transplant. After 8 years, his first transplant failed from chronic allograft dysfunction and an earlier bout of Banff 1A cellular rejection. The second deceased donor kidney transplant was initially allocated to the patient due to a 0 out of 6 mismatch. The B cell crossmatch was mildly positive, while the T Cell crossmatch was negative. Subsequent assays showed that the patient had preformed antibodies for human leukocyte antigen DQ5 against his second donor. Despite having preformed antibodies against the donor, the patient continues to have excellent allograft function two years after his second renal transplant. CONCLUSION: The presence of pre-existing antibodies against human leukocyte antigen DQ5 does not preclude transplantation. The relevance of having other antibodies against class II human leukocyte antigens prior to transplantation remains to be studied.

The inflammatory response to ischemic acute kidney injury: a result of the 'right stuff' in the 'wrong place'?

PURPOSE OF REVIEW: Ischemic acute kidney injury may be exacerbated by an inflammatory response. How injury elicits inflammation remains a major question in understanding acute kidney injury. The present review examines the hypothesis that molecules released by injured cells elicit inflammation. RECENT FINDINGS: After necrotic death, intracellular molecules find their way into the extracellular space. These molecules include heat shock proteins and HMGB1. Receptors for these proteins include TLR4, TLR2, CD91 and RAGE. These proinflammatory mechanisms may be so useful that nature has evolved mechanisms for programming necrotic death via poly(ADP-ribose) polymerase and cyclophilin D. In addition, apoptosis may also elicit inflammation. SUMMARY: The concepts discussed in this review are important for clinical medicine. Drugs and genetic manipulation may ameliorate ischemic kidney injury by regulating the inflammatory response to cell injury.

An update on renovascular hypertension.

Renovascular hypertension (RVH) represents a secondary and potentially remediable form of hypertension. Elevated blood pressure is only one of a broad array of pathophysiologic consequences that are associated with decreased renal perfusion. Our ability to accurately and noninvasively detect stenotic lesions within the renal artery is growing. However, functional assessment of renal parenchyma and hemodynamic significance of renal artery lesions is still limited. Advances in endovascular techniques spurred interest in the concept of ischemic nephropathy and the effect of renal artery revascularization on renal function. Despite the relative frequency of atherosclerotic renal artery stenosis (ARAS), there currently is no consensus on the most appropriate therapy. In this article, we focus on the two most common causes of RVH, ARAS and fibromuscular dysplasia. We discuss the therapeutic strategies, disease mechanisms, clinical findings, evolving trends, and developments.

Inaccuracy of Tl-201 brain SPECT in distinguishing cerebral infections from lymphoma in patients with AIDS.

PURPOSE: Studies have suggested using Tl-201 brain SPECT to differentiate lymphoma from infectious processes and to determine the timing for biopsy or empirical therapy for patients with AIDS-related brain lesions. This study prospectively investigated the utility of Tl-201 SPECT in distinguishing central nervous system lymphoma from non-neoplastic disease in patients with AIDS. MATERIALS AND METHODS: Fourteen patients with AIDS and focal abnormalities on computed tomography or magnetic resonance imaging underwent brain SPECT before diagnosis (12 by biopsy, 2 by clinical course and response to therapy). A an uptake ratio (UR) was obtained by drawing a region of interest around the lesion, measuring average counts per pixel, and dividing this value by the value of a non-lesion-containing contralateral region of interest. The UR cutoff producing the highest accuracy (TP+TN/TP+TN+FP+FN) in discriminating lymphoma from another condition was determined from URs generated from these 14 patients. RESULTS: Five patients had lymphoma, five had toxoplasmosis, one had Herpes simplex virus encephalitis, two had progressive multifocal leukoencephalopathy, and one had gliosis (UR, 0.8). Patients were separated into categories of lymphoma or nonlymphoma. The mean UR was 2.2 +/- 1.6 (range, 1.0 to 3.85) for lymphoma and 1.7 +/- 0.8 (range, 0.7 to 3.2) for nonlymphoma. Only a UR of 1.63 resulted in sensitivity and specificity better than 50% (60% and 55%, respectively), with an accuracy of 57%, positive predictive value of 43%, and negative predictive value of 71%. CONCLUSIONS: Tl-201 brain SPECT appears unreliable for differentiating primary lymphoma from nonmalignant brain lesions in patients with AIDS. Early brain biopsy is necessary to establish a definitive diagnosis when appropriate.