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There is little data availableon the nephrotoxicity of pemetrexed, a new generation antifolate agent that is increasingly used in the treatment of numerous malignant tumors. We report the observation of two patients suffering from non-small cell lung cancer who developed acute kidney injury (AKI) after administration of pemetrexed. In one case, pemetrexed was used as a single agent treatment. In the other, pemetrexed was first co-administered with cisplatin, then alone, with AKI worsening 2 months after the discontinuation of cisplatin. The two patients concomitantly developed edema of the face, which is a rare adverse side effect of pemetrexed. Renal biopsies showed acute tubular necrosis and interstitial fibrosis. In both cases, chronic kidney disease (CKD) persisted despite drug discontinuation. Herein, we discuss renal presentation, risk factors, and prognosis of pemetrexed-induced nephrotoxicity.

Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome., (Copyright © 2014 by the American Society of Nephrology.)

Few studies have examined the occurrence of minimal change nephrotic syndrome (MCNS) in patients with non-Hodgkin lymphoma (NHL). We report here a series of 18 patients with MCNS occurring among 13,992 new cases of NHL. We analyzed the clinical and pathologic characteristics of this association, along with the response of patients to treatment, to determine if this association relies on a particular disorder. The most frequent NHLs associated with MCNS were Waldenström macroglobulinemia (33.3%), marginal zone B-cell lymphoma (27.8%), and chronic lymphocytic leukemia (22.2%). Other lymphoproliferative disorders included multiple myeloma, mantle cell lymphoma, and peripheral T-cell lymphoma. In 4 patients MCNS occurred before NHL (mean delay, 15 mo), in 10 patients the disorders occurred simultaneously, and in 4 patients MCNS was diagnosed after NHL (mean delay, 25 mo). Circulating monoclonal immunoglobulins were present in 11 patients. A nontumoral interstitial infiltrate was present in renal biopsy specimens from 3 patients without significant renal impairment. Acute kidney injury resulting from tubular lesions or renal hypoperfusion was present in 6 patients. MCNS relapse occurred more frequently in patients treated exclusively by steroid therapy (77.8%) than in those receiving steroids associated with chemotherapy (25%). In conclusion, MCNS occurs preferentially in NHL originating from B cells and requires an aggressive therapeutic approach to reduce the risk of MCNS relapse.

Objective: Although in most patients induction therapy leads to complete or partial remission, relapses in patients with non-infectious mixed cryoglobulinemia vasculitis (CryoVas) remain a major problem. We aimed to identify predictors of early relapses occurring within the first 12months of treatment in such patients., Methods: Patients included in the French CryoVas survey exhibiting complete/partial clinical remission and followed-up for at least 12months after induction therapy (n=145) were analyzed for predictors of early relapses., Results: Forty out of 145 patients (28%) experienced early relapse. Relapses occurred after a median time of 9.5months after induction therapy (3-12) and involved skin (75%), joints and peripheral nerve (28% each), kidneys (25%) and gastrointestinal tract (5%). Baseline factors associated with an early relapse were purpura [HR 3.35 (1.02-10.97), P=0.046], cutaneous necrosis [HR 4.46 (1.58-12.57), P=0.005] and articular involvement [HR 2.20 (1.00-4.78), P=0.048]. The only factor negatively associated with an early relapse during follow-up was the achievement of complete immunological response [HR 0.07 (0.01-0.51), P=0.009]. The use of corticosteroids plus rituximab or cyclophosphamide tended to be associated negatively with early relapse [HR 0.43 (0.17-1.08), P=0.07]., Conclusion: In patients with non-infectious CryoVas, main predictors of early relapses after initial remission are purpura, articular involvement, and cutaneous necrosis. The absence of complete immunological response during follow-up was associated with early relapse. These findings may help in adapting future treatment strategies., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background and Objectives: The therapy and outcome of HIV infection have dramatically changed over the last 15 years, resulting in a change in renal complications. This study analyzed the characteristics of HIV-infected patients and biopsy-proven tubulointerstitial nephropathies to define disease patterns and therapeutic implications., Design, Setting, Participants, & Measurements: A clinico-pathologic retrospective study of 59 consecutive renal biopsies showing predominant tubular and/or interstitial lesions in HIV-infected patients referred to the nephrology department between 1995 and 2011 was performed. HIV-associated nephropathy and vascular diseases were excluded from the study., Results: Tubulointerstitial nephropathies accounted for 26.6% of 222 native renal biopsies performed in HIV-infected patients. Two pathologic groups were analyzed, tubulopathy and interstitial nephritis, which represented 49% and 51% of tubulointerstitial nephropathies, respectively. Most patients presented with AKI (76.3%) and high-grade proteinuria (57.7%). Drug-related nephrotoxicity was the leading cause (52.5%). Alternative etiologies included infections (15.2%), dysimmune disorders (8.5%), malignancies (3.4%), and chronic (10.2%) and acute (10.2%) tubulointerstitial nephropathies of undetermined origin. Tubulopathy was strongly associated with antiretroviral drug toxicity (75.9%) and mostly caused by tenofovir (55.2%), which was associated with proximal tubular dysfunction (87.5%), overt Fanconi's syndrome (37.5%), and nephrogenic diabetes insipidus (12.5%). Interstitial nephritis was associated with a broader spectrum of pathologic lesions and etiologies., Conclusions: In this series, tubulointerstitial nephropathies accounted for 26.6% of renal diseases in HIV-infected patients. Considering the therapeutic implications of diagnoses of drug toxicity, infection, and dysimmune syndromes, this study underscores the importance of monitoring renal parameters in HIV-infected patients and points to the relevance of kidney biopsy to allow an accurate diagnosis.

Hepatitis C virus (HCV) may instigate mixed cryoglobulinemia; the most significant accompanying kidney lesion is type I membranoproliferative glomerulonephritis, usually occurring in the context of type II mixed cryoglobulinemia. Additionally, recent data support a link between HCV infection and proteinuria in population-based studies, raising the possibility that kidney diseases associated with HCV may be more common than previously thought. A number of strategies have been used to treat HCV-related glomerulonephritis, including antiviral agents, immunosuppressive therapies such as corticosteroids and cytotoxic agents, and plasma exchange. Limited but encouraging data about the utility of antiviral treatment in the setting of HCV-associated glomerulonephritis exist, with one pooled analysis noting a sustained viral response of 42%, albeit with significant heterogeneity. Immunosuppressive therapy may be most useful for cryoglobulinemic kidney disease, with individualized approaches considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis based on the level of proteinuria and kidney failure. Of note, rituximab, a chimeric monoclonal antibody that blocks CD20 receptors on B cells, has been reported to be effective for the treatment of mixed cryoglobulinemia symptoms, including glomerulonephritis., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Type I cryoglobulinemia vasculitis (CryoVas) is considered a life-threatening condition; however, data on the characteristics and outcome are scarce. To analyze the presentation, prognosis, and efficacy and safety of treatments of type I CryoVas, we conducted a French nationwide survey that included 64 patients with type I CryoVas between January 1995 and July 2010: 28 patients with monoclonal gammopathy of unknown significance (MGUS) and 36 with hematologic malignancy.Type I monoclonal CryoVas was characterized by severe cutaneous involvement (necrosis and ulcers) in almost half the patients and high serum cryoglobulin levels, contrasting with a lower frequency of glomerulonephritis than expected. The 1-, 3-, 5-, and 10-year survival rates were 97%, 94%, 94%, and 87%, respectively. Compared to MGUS, type I CryoVas related to hematologic malignancy tended to be associated with a poorer prognosis. Therapeutic regimens based on alkylating agents, rituximab, thalidomide or lenalinomide, and bortezomib showed similar efficacy on vasculitis manifestations, with clinical response rates from 80% to 86%.Data from the CryoVas survey show that the prognosis of type I CryoVas does not seem to be as poor as previously suggested. Besides alkylating agents, the use of regimens based on rituximab, thalidomide or lenalinomide, and bortezomib are interesting alternative options, although the exact role of each strategy remains to be defined.

Background: Data on the prognosis of non-infectious mixed cryoglobulinaemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking., Methods: The French multicentre and retrospective CryoVas survey included 242 patients with non-infectious mixed CryoVas. Causes of death and prognostic factors of survival were assessed and a prognostic score was determined to predict survival at 5 years., Results: After a median follow-up of 35 months, 42 patients (17%) died. Causes of death were mainly serious infections (50%) and vasculitis flare (19%). One-, 2-, 5- and 10-year overall survival rates were 91%, 89%, 79% and 65%, respectively. A prognostic score, the CryoVas score (CVS), for the prediction of survival at 5 years was devised. Pulmonary and gastrointestinal involvement, glomerular filtration rate <60 ml/min and age >65 years were independently associated with death. At 5 years the death rates were 2.6%, 13.1%, 29.6% and 38.5% for a CVS of 0, 1, 2 and ≥3, respectively. At 1 year the death rates were 0%, 3.2%, 18.5% and 30.8% for a CVS of 0, 1, 2 and ≥3, respectively. The CVS was strongly correlated with the Five Factor Score (FFS) 2009, another prognostic score validated in primary necrotising vasculitis (r=0.82; p<0.0001). The area under the curve for the CVS was 0.74 compared with 0.67 for the FFS, indicating a better performance of the CVS (p=0.052)., Conclusions: In patients with non-infectious mixed CryoVas, the main prognostic factors are age >65 years, pulmonary and gastrointestinal involvement and renal failure. A score including these variables is significantly associated with the prognosis.

Takayasu arteritis (TA) is a rare large vessels vasculitis. Conventional therapy consists of glucocorticoids which may be associated with other immunosuppressive drugs. However, some patients fail to achieve remission with conventional treatment. The use of anti-tumor necrosis factor-α (TNF-α) in patients with difficult to treat TA could be useful. We report here the main characteristics, treatment and outcome of 84 patients (5 personal cases and 79 patients from the literature) with refractory Takayasu arteritis treated with anti TNF-α. The mean age was 28.5years [median 26.0years, range 7-61years], with 74/83 (89%) of female. All patients, except one, were inadequately controlled with other immunosuppressive regimens before anti TNF-α therapy. First line of anti-TNF-α included infliximab (IFX) in 81% (68/84) and etanercept (ETA) in 19% (16/84). Most patients received IFX at 5mg/kg associated to methotrexate or azathioprine. Thirty one out of 84 (37%) patients achieved a complete remission, and 45 (53.5%) were partial responders. There were 8 (9.5%) non responders at all. Twenty seven out of 84 (32%) patients needed to increase the dose of anti TNF-α because of uncontrolled disease and 15 (18%) needed to change of anti TNF-α. Glucocorticoids have been tapered in 41/79 (52%) [from 20mg (13.1-60) to 2.5mg (0-10) daily, at baseline and after anti-TNF, respectively, p<0.0001] and discontinued in 31/77 (40%). After a median follow-up of 10months [range 3-82], 17 (20%) side effects were recorded leading to discontinuation of anti TNF-α in 8 cases. They included mainly infections, and hypersensitivity reactions. In conclusion, anti-TNF-α are an efficient therapy in refractory TA patients although side effects are observed in 20% of cases. Further studies are warranted to assess the long term efficacy and safety of anti-TNF in TA and to better define if they should be prescribed earlier in the course of TA., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.

Screening of chronic kidney disease (CKD) that includes estimation of the glomerular filtration rate (GFR) and evaluation proteinuria should be performed in all HIV-infected patients and these parameters have to be monitored annually in patients at higher risk for CKD. Black patients have a genetic predisposition to develop HIV-associated nephropathy. Suppression of HIV viral replication with antiretroviral therapy prevents the development of HIV-associated nephropathy or halts its progression. Kidney biopsy remains the most informative diagnosis test to differentiate various forms of kidney diseases in HIV-infected patients. Dosing antiretroviral agents with kidney metabolism should be adjusted when eGFR is bellow 50 mL/min/1.73 m(2). eGFR and serum phosphorus at baseline and during treatment should be carefully assessed in patients receiving tenofovir. Proximal renal tubular toxicity must be further evaluated in the presence of eGFR decrease and/or hypophosphatemia under tenofovir therapy., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Background and Objectives: Several different entities have recently been described among glomerular diseases associated with monoclonal IgG deposits. The aim of this study was to describe the distribution of the different pathologic subtypes of IgG-associated glomerulopathy and to evaluate the IgG isotype involved in these diseases., Design, Setting, Participants, & Measurements: This was a retrospective study including all patients with glomerular deposits of monoclonal IgG referred to three nephrology departments between 1980 and 2008., Results: Twenty-six patients were included. Nephrotic syndrome was almost constantly associated with a renal dysfunction in 14 of 26 patients. The presence of M-spike was detected in only 30% of the patients, and an overt hematologic malignancy (myeloma, lymphoma) was identified in 9 of 26 patients. Patients were almost equally divided into two distinct histologic patterns: membranous nephropathy (MN) or membranoproliferative glomerulonephritis (MPGN). IgG3 deposits were identified in 80% of patients with MPGN, whereas IgG1 deposits were present in 64% of patients with MN. Ultrastructural study showed that immune deposits were nonorganized in most patients. Seven patients were treated with rituximab with excellent results: five of seven had a complete remission of the nephrotic syndrome and two of seven had a partial response. After a mean 24-month follow-up, only one patient experienced relapse of the nephropathy., Conclusions: GN with monoclonal Ig deposits can be associated with MPGN or MN, which are correlated with IgG3 and IgG1 isotypes, respectively. Rituximab appears to have a very favorable benefit-to-risk ratio for patients with no overt hematologic malignancy.

Light, light and heavy, and heavy chain deposition diseases (LCDD, LHCDD and HCDD, respectively) belong to a family of diseases featuring deposition in the kidney of a monoclonal immunoglobulin (Ig) or its isolated subunits, which also includes light chain amyloidosis, non-amyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis. In clinical and pathologic terms, LCDD, LHCDD and HCDD display essentially similar characteristics, such as involvement of multiple organs, prominent renal involvement with severe renal failure, diabetes-like nodular glomerulosclerosis, marked thickening of tubular basement membranes, and monotypic deposits of Ig light chains (mostly κ) and/or heavy chains (mostly γ) that feature a non-organized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma, although in a fair proportion of cases there is no (clinically) patent hematological disease. Recent progress has been made in understanding the molecular mechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathophysiological mechanism may help unraveling the pathomechanisms of kidney fibrosis and renal disease progression., (Copyright © 2011 S. Karger AG, Basel.)

The development of well-tolerated and effective therapies that target the pathogenesis of membranous nephropathy (MN) would be useful. Our objective was to evaluate the efficacy of rituximab in MN. We analyzed the outcome of 28 patients treated with rituximab for idiopathic MN. Anti-PLA(2)R antibodies in serum and PLA(2)R antigen in kidney biopsy were assessed in 10 and 9 patients, respectively. Proteinuria was significantly decreased by 56, 62 and 87% at 3, 6 and 12 months, respectively. At 6 months, 2 patients achieved complete remission (CR) and 12 partial remission (PR; overall renal response, 50%). At 12 months (n = 23), CR was achieved in 6 patients and PR in 13 patients (overall renal response, 82.6%). Three patients suffered a relapse of nephrotic proteinuria 27-50 months after treatment. Univariate analysis suggested that the degree of renal failure (MDRD estimated glomerular filtration rate <45/ml/min/1.73 m(2)) is an independent factor that predicts lack of response to rituximab. Anti-PLA(2)R antibodies were detected in the serum of 10 patients, and PLA(2)R antigen in immune deposits in 8 of 9 patients. Antibodies became negative in all 5 responsive patients with available follow-up sera. In this retrospective study, a high rate of remission was achieved 12 months after treatment.

Ig-related renal diseases occurring in lymphoplasmacytic disorders (LPD) cover a wide spectrum of renal lesions. Except for cast nephropathy, which is almost specific for multiple myeloma, similar renal lesions caused by deposition or precipitation of monoclonal Ig-related material may occur in the various types of LPD. Because the secreted Ig provides the link between the LPD and the kidney disease, the renal outcome is linked to efficacy of chemotherapy. In the past 10 years, considerable advances have occurred in chemotherapy regimens with the advent of new classes of drugs, which already result in markedly improved renal and vital survival., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The COL4A1 gene encodes the α1-chain of type IV collagen, which is ubiquitously expressed in basement membranes. Mutations in COL4A1 have been reported in autosomal-dominant porencephaly and in patients with symptomatic small vessel brain disease, inconstantly associated with eye defects. We have previously reported three COL4A1 mutations associated with a systemic phenotype that we called HANAC (Hereditary Angiopathy, Nephropathy, Aneurysms, and Cramps). We carried out a clinical and genetic study of three families presenting with characteristic features of HANAC syndrome. Common systemic signs included arterial retinal tortuosity and muscle cramps, with a variable combination of small vessel brain disease, Raynaud phenomena, and kidney defects. Three novel COL4A1 missense substitutions are described, which affect highly conserved glycine residues within the collagenous domain of the protein. All six known mutations associated with the HANAC phenotype are localized within the CB3[IV] fragment of COL4A1, which encompasses major integrin-binding sites. Our results confirm that HANAC syndrome is a distinct clinical entity within the COL4A1-related disorders, which is characterized by systemic involvement and usually asymptomatic brain disease. The restricted distribution of COL4A1 mutations within the CB3[IV] region is a characteristic of the reports of patients with HANAC, which suggests that abnormal cell-type IV collagen interactions may underlie the systemic defects observed in this syndrome., (Copyright © 2010 Wiley-Liss, Inc.)

Objective: To report on the long-term followup of a cohort of patients with hepatitis C virus (HCV)-related vasculitis treated with rituximab with or without PEGylated interferon alfa-2b (PEG-IFN alfa-2b) plus ribavirin., Methods: The study group comprised 32 HCV RNA-positive patients with HCV-related vasculitis: 20 patients were treated with rituximab and PEG-IFN alfa-2b (9 of whom had not previously received antiviral treatment and 11 of whom had experienced disease resistance to or relapse with antiviral treatment), and 12 antiviral-intolerant patients were treated with rituximab alone., Results: Treatment with rituximab and PEG-IFN alfa-2b plus ribavirin induced a complete clinical response and a partial clinical response in 80% and 15% of patients, respectively, a complete immunologic response and a partial immunologic response in 67% and 33% of patients, respectively, and a sustained virologic response in 55% of patients. Treatment with rituximab alone induced a complete clinical response and a partial clinical response in 58% and 9% of patients, respectively, and a complete immunologic response and a partial immunologic response in 46% and 36% of patients, respectively. B cell depletion was achieved in 96% of patients, and B cell recovery began after a median delay of 12 months. After a mean+/-SD followup period of 23+/-12 months, 22% of patients experienced a clinical relapse, and 34% of patients experienced an immunologic relapse. All relapses were associated with the absence of virologic control, and 78% of relapses were associated with B cell recovery. Six patients were re-treated with rituximab. All 6 of these patients had a complete clinical response, 50% had a complete immunologic response, and 50% had a partial immunologic response. Rituximab was well tolerated overall., Conclusion: Rituximab is an effective treatment of severe and/or refractory HCV-related vasculitis. Relapses were consistently associated with the absence of virologic control. The clinical and immunologic efficacy of rituximab after repeated infusion appeared to be the same as that observed after induction therapy.

Since 2005, several neurological diseases, including porencephaly, leukoencephalopathy and intracerebral hemorrhage without hypertension, and retinal arteriolar tortuosity have been linked to mutations in the COL4A1 gene, which encodes the alpha1 chain of type IV collagen, the main constituent of basement membranes. In three families, we observed a new syndrome that we called HANAC, for hereditary angiopathy with nephropathy, aneurysms and muscle cramps, which is associated with morphological alterations of cutaneous and renal basement membranes. This novel "basalopathy" is caused by glycine mutations in COL4A1 exons 24 and 25. We discuss phenotype-genotype correlations and the implications of the HANAC syndrome for the diagnosis of autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.

Light-, light- and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light- and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly kappa, and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression.

Background: A 30-year-old HIV-infected woman presented with fever and abdominal pain 4 days after initiation of highly active antiretroviral therapy (HAART), and 1 month after initiation of antimicrobial therapy for Mycobacterium tuberculosis infection. A diagnosis of immune restoration inflammatory syndrome (IRIS) was considered, and corticosteroids were started. Steroid therapy doses were progressively tapered, during which time the patient developed renal failure with enlarged kidneys. A renal biopsy showed acute interstitial nephritis. Extensive investigations failed to detect active infection. The efficacy of HAART was attested by increased CD4+ cell counts and undetectable viral replication., Investigations: Physical examination, plasma viral load and CD4+ cell count, abdominal and renal ultrasound, renal and peritoneal biopsies, renal and liver function, chest X-ray, and bronchoalveolar lavage culture., Diagnosis: Acute renal failure secondary to IRIS., Management: Prednisone therapy.

Introduction: Autosomal dominant syndrome of retinal arterial tortuosity is a rare condition, often discovered after a benign macular hemorrhage., Case Report: We report here the case of a 52-year-old man who was refereed to our center for an abrupt decrease in vision after an effort. The initial visual acuity was 2/10 for distance and Parinaud 6 for near vision. The biomicroscopic examination showed a small foveal hemorrhage associated with loops and bilateral vascular tortuosities limited to the arterioles. The aspect evoked inherited retinal arteriolar tortuosity. Questioning the patient revealed an antecedent of macular hemorrhage in the patient's sister that had spontaneously resolved. After a few months, redfree photographs were obtained from the two asymptomatic daughters of the patient, which showed a dominant arterial tortuosity in one of the two daughters, confirming the familial aspect of the disease., Conclusion: The case described here illustrates the advantage of biomicroscopy in establishing the diagnosis and the usefulness of questioning the patient further to disclose family history. Imagery studies complement the examination to eliminate other causes for the decrease in vision. Some recently published data suggest an advantage to including at least the search for a microscopic or macroscopic hematuria during the assessment.

The myelin protein 0 (MPZ or P0) is a transmembrane glycoprotein that represents the most abundant myelin component. Mutations in the P0 gene are associated with one form of autosomal dominant demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 1B (CMT1B). Because CMT1 may be associated with renal involvement, mostly focal segmental glomerulosclerosis, we hypothesized that P0 could be expressed in the kidney. P0 mRNA was detected by reverse transcriptase-PCR in the human and mouse renal cortex. P0 transcripts were identified by in situ hybridization at different stages of the mouse kidney development, especially in embryonic structures that give rise to the glomerulus. P0 protein was also detected by Western blot in human and rat glomerular extracts and in a human podocyte cell line using a monoclonal anti-P0 antibody. Immunofluorescence studies on human kidney sections showed that the podocytes were intensely labeled. Immunogold electron microscopy disclosed a predominant staining of the membranes of intracellular vesicles in podocytes. P0 was also detected in the podocyte cell membrane, including at the foot processes. P0(-/-) mice exhibited mild growth retardation and demyelinating neuropathy similar to the one observed in patients with CMT1B. They also presented mild albuminuria, without significant ultrastructural change of the glomerular basement membrane or the podocytes. These results demonstrate that P0, the major myelin protein, is also expressed during nephrogenesis and in mature kidney, mostly in podocytes. They suggest that P0 gene mutations might be involved in renal diseases.

Background: Autosomal-dominant forms of hematuria have been mostly related to mutations in the COL4A3/COL4A4 genes. Patients with thin basement membrane (BM) disease do not have extrarenal manifestations, while those with Alport syndrome often present with hearing loss, anterior lenticonus, and dot-and-fleck retinopathy., Methods: We performed a phenotypic study and a candidate gene approach in a four-generation family presenting with autosomal-dominant hematuria associated with extrarenal manifestations. Renal biopsy was analyzed for determination of BM thickness and expression of chains of type IV collagen. Linkage to 18 candidate genes/loci was investigated using polymorphic microsatellite markers., Results: In all affected patients, hematuria without proteinuria was associated with muscular contractures and retinal arterial tortuosities responsible for retinal hemorrhages. Cardiac arrhythmia, Raynaud phenomena, and brain MRI abnormalities were also observed. Despite the presence of red cells in tubule sections, no glomerular abnormalities were found by electron microscopy. Expression of type IV collagen chains and glomerular BM thickness was normal. We searched for a molecular defect affecting either BM or angiogenesis. Linkage analyses of genes encoding BM components (COL4A3/COL4A4, COL6A1, COL6A2, COL6A3, FBLN1), and angiogenic factors or their receptors (VHL, ANPT1, ANPT2, TIE, TEK, NOTCH2, NOTCH3, NOTCH4, DLL4, JAG1, JAG2) and of the facio-sapulo-humeral dystrophy and 3q21 loci failed to show segregation of the disease with those gene loci., Conclusion: We have identified a new inherited hematuria syndrome associated with retinal vessel tortuosities and contractures. We recommend performing a fundus examination in patients with familial hematuria and episodes of visual impairment, as well as a urinary analysis in patients with retinal arterial tortuosity or congenital muscular contractures.

HOX genes encode highly conserved transcription factors responsible for developmental patterning and postnatal tissue homeostasis. Previous studies have shown that a 1.4-kb segment of the Hoxb-7 proximal promoter drives renal expression of reporter genes specifically in the ureteric bud and collecting ducts. In this study using stably transfected renal tubule cell lines, we have identified three short cis-acting sequences within this promoter segment that cooperate to induce high-level expression specifically in collecting duct cells. In addition to an inverted CCAAT box (-71/-67) that acts as an ubiquitous enhancer and binds the transcription factor CBF/NF-Y, two different cis-acting sequences, named CDSE-1 and CDSE-2 (for Collecting Duct Specific Element 1 and 2), allow collecting duct cell-specific promoter activation. CDSE-1 (-56/-34) is composed of two E-boxes separated by a 9-bp GC-rich sequence. Only the latter sequence enhances reporter gene expression specifically in collecting duct cells. CDSE-2 (-34/-13) contains sequence bears high homology with a segment of the Pax-2 promoter. CDSE-2 also conveys cell specificity but has no enhancer activity by itself.

Background: The influence of hepatitis C virus (HCV) treatment on the course of HCV cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) is controversial., Methods: Twenty-five patients with nephrotic-range proteinuria, mixed cryoglobulinemia, MPGN proved by renal biopsy, and HCV infection were studied for their response to antiviral treatment., Results: After first-line treatment with prednisone, furosemide, or plasmapheresis, antiviral therapy with standard or pegylated interferon alfa and ribavirin was introduced in 18 patients. These patients were compared with 7 patients who did not receive antiviral treatment. Mean duration of antiviral treatment was 18 +/- 10 months, with a follow-up of at least 6 months after treatment withdrawal. HCV RNA clearance (sustained virological response) was achieved in 12 of 18 patients. Compared with values before antiviral therapy, a decrease in proteinuria was observed in sustained virological responders at the end of combination therapy, as well as at the end of follow-up (mean, 2.85 +/- 2.2 [SD] versus 1 +/- 1.4 and 0.4 +/- 0.8 g/d, respectively; P < 0.05). In sustained virological responders, cryoglobulin levels at the end of treatment (0.29 +/- 0.4 g/L) and end of follow-up (0.25 +/- 0.4 g/L) were decreased (P < 0.05) compared with pretreatment values (1.38 +/- 2.2 g/L). Conversely, no changes in serum cryoglobulinemia levels were observed in nonresponders or controls. Serum creatinine levels remained stable in the 18 patients with antiviral therapy, regardless of response to treatment., Conclusion: Anti-HCV treatment improved HCV-associated cryoglobulinemic glomerulonephritis.

Background: Anti-glomerular basement membrane (GBM) nephritis is a rare disease induced by antibodies directed against alpha3(IV)NC1, the Goodpasture antigen. We report a patient with Crohn's disease who developed anti-GBM nephritis and the skin blistering disorder bullous pemphigoid, owing to distinct autoantibodies., Methods: Frozen sections of skin and kidney biopsies were incubated with antisera specific for human IgG, IgA, IgM, fibrin, and C3. Reactivity of the patient's serum with GBM antigens was studied by Western blot using bovine solubilized type IV collagen and by enzyme-linked immunosorbent assays using alpha1(IV), alpha3(IV), and alpha5(IV)NC1 recombinant proteins. Reactivity studies against skin antigens were done by Western blot using human keratinocyte and dermal extracts and three recombinant forms of the bullous pemphigoid antigen180 (BP180, also called BPAG2 or type XVII collagen). The patient's serum was affinity fractionated on a (IV)NC1 column, and the bound and unbound fractions were analyzed for their reactivity against GBM and skin antigens., Results: The patient had deposits of IgG along the GBM and the epidermal basement membrane zone. Circulating IgG antibodies against alpha3(IV)NC1 were detected. The patient's autoantibodies immunoblotted the intracellular domain but not the extracellular domain of BP180. Reactivity of the patient's IgG with BP180 was found only in the unbound fraction of the serum., Conclusion: The simultaneous development of a rare renal and skin autoimmune disorder, resulting from non-cross-reactive autoantibodies, suggests that a common triggering event could be responsible for the autoimmune injury., (Copyright 2002 by the National Kidney Foundation, Inc.)