Renal involvement in Waldenström's macroglobulinemia: case report and review of literature.

Waldenström's macroglobulinemia (WM) is a rare lymphoid neoplasia, accounting for 2% of all hematological malignancies. Renal complications occur rather rarely compared to multiple myeloma. The most common renal manifestations are mild proteinuria and microhematuria. We describe a case of MW presenting with acute renal failure and NS. A 67-year-old man was referred to our hospital for sudden onset nephrotic syndrome. Electrophoresis revealed a monoclonal component in the gamma region, which was classified as an IgM k. During hospitalization, acute kidney injury developed, with creatinine up to 5 mg/dL, despite adequate hydration and alkalinization. A kidney biopsy was performed, showing minimal change disease (MCD) with interstitial and capsular lymphoid infiltrates of B-Lymphocytes CD20+. B-lymphocytes infiltration suggested the possibility of renal localization of lymphoproliferative disorder. So, bone marrow histology was performed, revealing lymphoplasmacytic lymphoma (WM). The patient was treated with bortezomib, desamethasone, and rituximab, with partial recovery of renal function (creatinine 1.5 mg/dL) and complete remission of proteinuria after 8-month follow-up. The remission of NS in our patient with rituximab seems to emphasize the pathogenetic role of B cells in MCD, although a coincident effect of immunosuppression on both the underlying renal disease and the hematologic disease cannot be excluded.

An uncommon presentation of an uncommon nephropathy: the karyomegalic interstitial nephritis.

Karyomegalic interstitial nephritis (KIN) is a rare and certainly underdiagnosed nephropathy. It is characterized by a peculiar histological picture of interstitial nephritis associated with the presence of hyperchromatic, abnormally enlarged nuclei of tubular epithelial cells. KIN has an uncertain etiology, but should be suspected in young patients in the second or third decade of life presenting with progressive renal failure, proteinuria and/or hematuria and a history of recurrent respiratory infections. In these cases, the diagnosis should be suspected and confirmed by a renal biopsy. Herein, we report a case of KIN with atypical clinical presentation in a young patient with progressive kidney failure without proteinuria or hematuria or history of recurrent respiratory infections.

Prognostic value of glomerular collagen IV immunofluorescence studies in male patients with X-linked Alport syndrome.

BACKGROUND AND OBJECTIVES: X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV α5 chain (α5[COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of α1, α3, and α5(COLIV) chains was assessed by immunofluorescence microscopy. RESULTS: GBM distribution of the α5(COLIV) chain was diffuse in 1 and segmental or absent in 21 of the 22 patients; the expression of the α3(COLIV) chain was diffuse in 5 of 22 patients and segmental or absent in 17 of 22 patients. Patients with diffuse staining for the α3(COLIV) chain presented with proteinuria significantly later (median age, 16.9 versus 6.1 years; P=0.02) and reached an estimated GFR < 90 ml/min per 1.73 m(2) at an older age (median age, 27.0 versus 14.9 years; P=0.01) compared with patients with segmental or absent staining. Two thirds of patients with abnormal α3(COLIV) expression by immunofluorescence studies had null or truncating COL4A5 mutations, as opposed to none of the 4 tested patients with diffuse α3(COLIV) chain glomerular distribution. CONCLUSIONS: These results indicate that maintained expression of the α3(COLIV) chain is an early positive prognostic marker in patients with X-linked Alport symdrome.

Human TTRV30M localization within podocytes in a transgenic mouse model of transthyretin related amyloidosis: does the environment play a role?

Transthyretin related amyloidosis is a nosological entity that leads to disability, diminished quality of life, all stages of chronic kidney disease and eventually death. Podocytes are polarized, highly differentiated epithelial cells important for proper nephron function. In the present study we investigated whether deposited TTRVal30Met (TTRV30M) molecules could be localized within podocytes in situ under the effect of different housing conditions (i.e. specific pathogen free [SPF] vs. non-SPF). Murine renal glomeruli from human TTRV30M (hTTRV30M) transgenic mice were examined via direct and indirect immunofluorescence techniques for the presence of hTTRV30M, murine serum amyloid P, activated caspase-3 and NPHS1. Association strength and amount of colocalization for NPHS1-hTTRV30M, NPHS1-activated caspase-3, hTTRV30M-murine serum amyloid P were estimated. Localization of hTTRV30M in podocytes was demonstrated by immuno-electron microscopy. Renal hTTRV30M gene and NPHS1 gene expression levels were estimated. Non-SPF transgenic mice showed increased glomerular hTTRV30M deposition compared to their SPF counterparts. Furthermore increased podocytic localization of hTTRV30M was noticed in non-SPF mice. Glomerular caspase-3 activation was increased only in the non SPF housing conditions. Podocytic caspase-3 activation was increased in SPF and in non-SPF transgenic mice when compared to non transgenic controls. Environmental conditions influence glomerular deposition and podocytic localization of hTTRV30M. In this context increased caspase-3 activation occurred.

The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin.

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, has been shown to inhibit the progression of murine lupus nephritis by virtue of its potent immunosuppressive properties. The phosphoinositol-3-kinase (PI3K)/Akt pathway is a major upstream activator of mTOR and has been implicated in the propagation of cancer and autoimmunity. However, the activation status of the PI3K/Akt/mTOR pathway in lupus nephritis has not been studied so far. METHODS: In NZBW/F1 female mice, we examined the glomerular expression of Akt and mTOR by immunofluorescence and western blot. We also searched for specific phosphorylations of these kinases known to ensue during activation of the PI3K/Akt/mTOR pathway. In parallel, we examined the therapeutic role of rapamycin either before or after the development of overt lupus nephritis. RESULTS: We found that in untreated mice, as opposed to healthy controls, Akt and mTOR were over-expressed and phosphorylated at key activating residues. Rapamycin prolonged survival, maintained normal renal function, normalized proteinuria, restored nephrin and podocin levels, reduced anti-dsDNA titres, ameliorated histological lesions, and reduced Akt and mTOR glomerular expression activation. CONCLUSIONS: These results suggest that: (i) the PI3K/Akt/mTOR pathway is upregulated in murine lupus nephritis, thus justifying treatment with rapamycin; (ii) rapamycin not only blocks mTOR but also negatively regulates the PI3K/Akt/mTOR pathway; and (iii) rapamycin is an effective treatment of murine lupus nephritis. Examination of the PI3K/Akt/mTOR pathway may offer new insights into the pathogenesis of lupus nephritis in humans and may lead to more individualized and less toxic treatment.

Cyclosporine A treatment in patients with Alport syndrome: a single-center experience.

Limited and discordant data are available on cyclosporine A (CsA) treatment for proteinuria in Alport syndrome (AS). To address this lack of consistent data, we have studied 15 AS patients (14 males; mean age 15.3 +/- 6.0 years) treated with CsA. Patient selection criteria included a urinary protein/creatinine ratio > or =1 mg/mg and a creatinine clearance >40 ml/min/1.73 m(2). CsA treatment was started at an initial dose of 5 mg/kg/day and subsequently adjusted to reach target C2 levels of 500 ng/ml. Renal function, proteinuria, and blood pressure were monitored. Blood pressure was treated to avoid the administration of angiotensin converting enzyme or angiotensin receptor blockers for the first 2 years of therapy. The average follow-up was 3.5 years. Five patients had chronic renal failure at the beginning of treatment, of whom three and one reached end-stage renal failure within 1 and 3 years, respectively. In the remaining 11 patients, the glomerular filtration rate declined by 11 +/- 6% within 6 months, but remained stable thereafter. Proteinuria decreased by 63 +/- 21% from baseline, but returned nearly to baseline after 2.5 years of follow-up. Based on these results, we suggest that CsA is effective in reducing proteinuria in patients with Alport syndrome but that this effect is temporary. Our data do not support the use of CsA therapy for proteinuric patients with AS, particularly if they have chronic renal failure.