Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy.

Renal toxicity constitutes a dose-limiting side effect of anticancer therapies targeting vascular endothelial growth factor (VEGF). In order to study this further, we followed up 29 patients receiving this treatment, who experienced proteinuria, hypertension, and/or renal insufficiency. Eight developed minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and 13 developed thrombotic microangiopathy (TMA). Patients receiving receptor tyrosine kinase inhibitors (RTKIs) mainly developed MCN/FSG-like lesions, whereas TMA complicated anti-VEGF therapy. There were no mutations in factor H, factor I, or membrane cofactor protein of the complement alternative pathway, while plasma ADAMTS13 activity persisted and anti-ADAMTS13 antibodies were undetectable in patients with TMA. Glomerular VEGF expression was undetectable in TMA and decreased in MCN/FSG. Glomeruli from patients with TMA displayed a high abundance of RelA in endothelial cells and in the podocyte nuclei, but c-mip was not detected. Conversely, MCN/FSG-like lesions exhibited a high abundance of c-mip, whereas RelA was scarcely detected. RelA binds in vivo to the c-mip promoter and prevents its transcriptional activation, whereas RelA knockdown releases c-mip activation. The RTKI sorafenib inhibited RelA activity, which then promoted c-mip expression. Thus, our results suggest that c-mip and RelA define two distinct types of renal damage associated with VEGF-targeted therapies.

Rapidly progressive lupus nephritis and concomitant thrombotic microangiopathy.

Although uncommon, thrombotic microangiopathy (TMA) is one of the most serious complications in patients with systemic lupus erythematosus. A 30-year-old black woman admitted to our hospital because of fever, fatigue, 'dark' urine and rapidly progressive renal failure was found to have systemic lupus erythematous and atypical hemolytic uremic syndrome. Kidney biopsy showed WHO class IV lupus nephritis with crescents and TMA. Hemodialysis was initiated for worsening renal failure. The patient was treated with corticosteroids, monthly pulse intravenous Cyclophosphamide, plasmapheresis and Rituximab on a weekly basis for 4 weeks. The patient's blood pressure was aggressively controlled using antihypertensive agents. Despite this extensive therapy, she remained dialysis dependent although hematological parameters returned to normal values.

Kidney diseases in HIV/HCV-co-infected patients.

BACKGROUND: Hepatitis C virus (HCV) co-infection occurs in 25% of HIV-infected persons. The impact of HIV/HCV coinfection on renal and patient outcomes is unclear. METHODS: The main objective of the study is the comparison of outcomes (progression to advanced renal failure, initiation of dialysis, and death) in patients with HIV (n = 40), HCV (n = 30) or coinfection (n = 30) during the period between January 1999 and December 2007. RESULTS: Patients were predominantly white men with a mean creatinine clearance of 50.6 +/- 32.2 ml per min per 1.73 m. Membranoproliferative glomerulonephritis (MPGN) and HIV-associated nephropathy were found in 34 and 9%, respectively. Seventeen patients needed transitory or definitive hemodialysis after 2, 2.5, and 12 months in HIV/HCV (n = 5), HIV (n = 6) and HCV (n = 6) infections, respectively. In multivariate analysis, variables found to independently predict outcome in HIV/HCV coinfected patients were younger age, a longer delay to kidney biopsy, cryoglobulinemia and MPGN. Twenty-one patients died, mostly in the HCV (n = 8) and/or HIV/HCV coinfected (n = 12) groups. The relative risk of death for HIV/HCV co-infected patients was 2.1 times more than for HCV-infected patients and 7.5 times more than for HIV-infected patients. HIV/HCV co-infection [odds ratio (OR), = 4; 95% confidence interval (CI), 1.3-12.9; P = 0.015] and MPGN (OR, 6; 95% CI, 2-18.8; P = 0.0018) were independently associated with death. CONCLUSION: Kidney disease is a relatively frequent complication in HIV or HCV monoinfected individuals. The impact of kidney disease on survival of HIV/HCV coinfected patients seems deleterious but remains largely unknown.

Immunoglobulin M 'Flare' after rituximab-associated acute tubular necrosis in Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma characterized by a circulating monoclonal IgM. Renal involvement in classical cases of WM is rare, and the pathological hallmark finding in the renal biopsy specimen is a thrombotic microangiopathy. We report the case of a 69-year-old man with the diagnosis of WM for 3 months before he presented with acute renal failure (ARF). A renal biopsy performed suggested the diagnosis of acute tubular necrosis. The diagnosis of ARF related to IgM flare after Rituximab therapy was made.

A case of acute renal failure associated with diffuse infiltrative lymphocytosis syndrome.

BACKGROUND: A 58-year-old African American man with an uncontrolled HIV infection presented to hospital with nephrotic syndrome and diffuse lymphadenopathy. The patient had been taking highly active antiretroviral therapy (HAART; lamivudine, abacavir, fosamprenavir and ritonavir) for 10 years. A renal biopsy showed acute granulomatous interstitial nephritis. Despite a negative tuberculin skin test, he was treated with antituberculosis drugs for 12 months without improvement of his renal profile. Two months after antituberculosis treatment was discontinued, the patient was readmitted to hospital because of acute renal failure. Corticosteroid therapy (prednisone) was started and resulted in a marked improvement in renal function. However, 18 months after steroids were discontinued, renal function declined dramatically. Furthermore, the patient had CD8+ lymphocytosis as well as interstitial tissue infiltration by CD8+ T lymphocytes. INVESTIGATIONS: Physical examination, plasma HIV viral load, lymphocyte counts, urinalysis, tuberculin skin test, liver function tests, renal ultrasonography, human leukocyte antigen (HLA) typing, renal and minor salivary gland biopsies, ophthalmological examination, chest radiography and culture of bronchoalveolar lavage fluid. DIAGNOSIS: Acute granulomatous interstitial nephritis secondary to diffuse infiltrative lymphocytosis syndrome. MANAGEMENT: HAART and prednisone.

Loss of podocyte dysferlin expression is associated with minimal change nephropathy.

We report a case of limb-girdle muscular dystrophy type 2B (LGMD2B) associated with minimal change disease. Immunohistochemical examination of quadriceps muscle showed a deficiency in dysferlin in sarcolemma, and dysferlin gene analysis showed 3370 G missense mutation, leading us to the diagnosis of LGMD2B. The patient also developed glomerular proteinuria. We also explored urinary protein levels in 3 other patients with dysferlinopathy and found microalbuminuria with albumin excretion of 0.14 to 0.18 g/d in 2 patients. Renal abnormalities during LGMD2B and kidney dysferlin expression have never been reported. Renal biopsy showed a lack of glomerular dysferlin expression compared with a positive immunohistochemical marking in patients with idiopathic minimal change nephropathy and healthy controls. We therefore suggest that dysferlin is present in glomeruli and may be associated with glomerular permeability.

Drug-induced glomerulopathies.

Normal renal function depends upon an intact glomerular apparatus. Many drugs and chemicals are capable of damaging the glomerulus, causing its increased permeability to large molecules. Glomerular lesions are usually responsible for proteinuria and the nephrotic syndrome. This also holds true for the drug-induced glomerulopathies, of which membranous glomerulo-nephritis is the most frequent type of lesion encountered. Apart from this, several cases of different glomerular changes such as focal segmental glomerulosclerosis and crescentic glomerulonephritis have also been reported. The drug-induced glomerulopathies are probably immune mediated. This is, for instance, reflected in the fact that patients with drug-induced nephritic syndrome frequently have the HLA-B8 and DR3 antigens. In depth information is provided for the previously mentioned disorders.

Drug-induced diabetes mellitus.

AIMS: To review the medications that influence glucose metabolism with a focus on hypertensive, transplant and HIV-infected patient populations. METHODS: Literature obtained from a MEDLINE search from 1970 to present, including studies published in the English language. The search strategy linked drugs, hyperglycaemia and diabetes mellitus, HIV, transplantation, hypertension and psychiatric patients. RESULTS: Many common therapeutic agents influence glucose metabolism. Multiple mechanisms of action on glucose metabolism exist through pancreatic, hepatic and peripheral effects. The prevalence of hyperglycaemia was higher with the use of thiazide diuretic, beta-blocker, calcineurin, protease inhibitors and atypical antipsychotic drugs. CONCLUSIONS: Patients treated with those drugs appear to be at increased risk for developing diabetes. It is prudent to monitor plasma glucose values when it is not possible to avoid prescription of medication with known effects on carbohydrate metabolism.