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Vivette D D'Agati

Publications and source records attributed to Vivette D D'Agati.

At least 19 recordsLinked to original sources
PubMed2026

Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant.

IMPORTANCE: The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). However, the utility of knowing an individual's M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored. OBJECTIVE: To test 2 hypotheses: (1) in patients with APOL1 high-risk (HR) genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 CKD from non-APOL1 CKD; (2) in people with APOL1 low-risk (LR) genotypes, M1 is independently associated with protection against FSGS and CKD. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-control study using data from 2 tertiary care hospitals (Columbia University Irving Medical Center and Mass General Brigham Biobank) and population-based data (the UK Biobank [UKB], Electronic Medical Records and Genomics [eMERGE-III], and All of Us [AoU]). Participants were individuals with a diagnosis of FSGS or steroid-resistant nephrotic syndrome (SRNS), individuals with CKD, and controls. EXPOSURES: Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry. MAIN OUTCOME AND MEASURE: The main outcome was the presence or absence of kidney disease, defined as FSGS or non-FSGS CKD, compared with non-kidney disease controls. Association between the M1 variant and disease status was assessed using odds ratios (ORs). RESULTS: A total of 107 696 individuals (54 994 [51.1%] female; 8779 [8.2%] with African ancestry, 78 475 [72.9%] with European ancestry, and 16 129 [15.0%] with multiethnic ancestry), including 3460 with FSGS or SRNS, 24 382 with non-FSGS CKD kidney disease, and 79 854 controls were enrolled in the discovery cohort. In the APOL1-HR group (1413 participants), M1 was significantly inversely associated with FSGS or SRNS cases compared with controls without kidney disease (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10-3). Among individuals with CKD with APOL1-HR genotypes, M1 was 4 times more frequent in those whose CKD was not due to FSGS or SRNS. Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases. There was no association between individuals with APOL1-LR genotypes with M1 and protection against CKD or FSGS. CONCLUSIONS AND RELEVANCE: In this case-control study of 107 696 individuals, presence of an APOL1-HR genotype M1 was significantly associated with protection against kidney disease, suggesting that it may have a role as a genetic modifier. Patients with CKD with an APOL1-HR genotype and M1 should be evaluated for an alternative and potentially treatable cause of their CKD.

Humans↗
PubMed2006

Characterization of a large Lebanese family segregating IgA nephropathy.

BACKGROUND: Familial aggregation of IgA nephropathy (IgAN) suggests that genetic factors contribute to the development of this trait. Because clinical manifestations in IgAN families are often limited to episodic haematuria, large kindreds tractable to linkage analysis have been difficult to identify. METHODS: We identified a large Lebanese-Druze kindred ascertained via an index case with biopsy-documented IgAN. We performed systematic screening of 38 family members and tested linkage to reported IgAN loci. RESULTS: Screening of this family identified 16 affected individuals, including 2 individuals with biopsy-documented IgAN and 14 with chronic renal failure or abnormal urinalyses on at least three separate occasions. This kindred spanned five generations and contained five consanguineous unions. Multigenerational inheritance suggested that autosomal dominant inheritance was most likely. Phenotypic manifestations among affected individuals varied from isolated haematuria to advanced renal failure necessitating transplantation; one instance of IgAN recurrence after transplantation was also documented. Older age was associated with greater severity of disease and higher incidence of renal failure. Parametric and non-parametric analyses with 33 microsatellite markers did not reveal any evidence of linkage to reported IgAN loci on chromosomes 6q22-23, 2q36 and 4q22-31. CONCLUSIONS: We describe one of the largest multigenerational IgAN kindreds reported to date. The high incidence of renal failure among older generations suggests a significant risk of progression to renal failure. We found no evidence of linkage to known loci, suggesting that familial IgAN encompasses multiple subtypes that will require distinction based on genetic or biomarker data.

Adolescent↗
PubMed2006

Ischemic preconditioning provides both acute and delayed protection against renal ischemia and reperfusion injury in mice.

Acute as well as delayed ischemic preconditioning (IPC) provides protection against cardiac and neuronal ischemia reperfusion (IR) injury. This study determined whether delayed preconditioning occurs in the kidney and further elucidated the mechanisms of renal IPC in mice. Mice were subjected to IPC (four cycles of 5 min of ischemia and reperfusion) and then to 30 min of renal ischemia either 15 min (acute IPC) or 24 h (delayed IPC) later. Both acute and delayed renal IPC provided powerful protection against renal IR injury. Inhibition of Akt but not extracellular signal-regulated kinase phosphorylation prevented the protection that was afforded by acute IPC. Neither extracellular signal-regulated kinase nor Akt inhibition prevented protection that was afforded by delayed renal IPC. Pretreatment with an antioxidant, N-(2-mercaptopropionyl)-glycine, to scavenge free radicals prevented the protection that was provided by acute but not delayed renal IPC. Inhibition of protein kinase C or pertussis toxin-sensitive G-proteins attenuated protection from both acute and delayed renal IPC. Delayed renal IPC increased inducible nitric oxide synthase (iNOS) as well as heat-shock protein 27 synthesis, and the renal protective effects of delayed preconditioning were attenuated by a selective inhibitor of iNOS (l-N(6)[1-iminoethyl]lysine). Moreover, delayed IPC was not observed in iNOS knockout mice. Both acute and delayed IPC were independent of A(1) adenosine receptors (AR) as a selective A(1)AR antagonist failed to block preconditioning and acute and delayed preconditioning occurred in mice that lacked A(1)AR. Therefore, this study demonstrated that acute or delayed IPC provides renal protection against IR injury in mice but involves distinct signaling pathways.

Animals↗
PubMed2006

An ancestral haplotype defines susceptibility to doxorubicin nephropathy in the laboratory mouse.

Haplotype analysis was used to refine of the DOXNPH locus, which harbors the susceptibility gene for doxorubicin (DOX; Adriamycin) nephropathy, a Mendelian form of selective podocyte injury. Analysis of haplotype structure in three strains with contrasting susceptibility (148 single-nucleotide polymorphisms at 101-kb spacing) was complementary to analysis of recombinants in 176 F2 mice. For example, haplotype analysis but not meiotic mapping could exclude the Abcc1 multidrug transporter, and this was confirmed further by phenotypic evaluation of Abcc1 null mice. Next, comparison of haplotype structure (55 single-nucleotide polymorphisms at 44-kb spacing) with phenotype in 15 inbred strains revealed a risk haplotype that was shared by susceptible strains (P = 0.00017), thereby reducing the DOXNPH region to a 1.3-Mb interval. These data demonstrate that susceptibility to DOX nephropathy represents a founder mutation in the laboratory mouse. Haplotype analysis can be used for identification of the DOXNPH gene and prediction of strain susceptibility pattern.

Animals↗
PubMed2006

Role of ubiquitin-like protein FAT10 in epithelial apoptosis in renal disease.

Dysregulated apoptosis of renal tubular epithelial cells (RTEC) is an important component of the pathogenesis of several renal diseases, including HIV-associated nephropathy (HIVAN), the most common cause of chronic kidney failure in HIV-infected patients. In HIVAN, RTEC become infected by HIV-1 in a focal distribution, and HIV-1 infection has been shown to induce apoptosis in vitro. In microarray studies that used a novel renal tubular epithelial cell line from a patient with HIVAN, it was found that the ubiquitin-like protein FAT10 is one of the most upregulated genes in HIV-infected cells. Previously, FAT10 was shown to induce apoptosis in murine fibroblasts. The expression of FAT10 in HIVAN and the ability of FAT10 to induce apoptosis in human RTEC therefore were studied. This study revealed that FAT10 expression is induced after infection of RTEC by HIV-1 and that expression of FAT10 induces apoptosis in RTEC in vitro. Moreover, it was found that inhibition of endogenous FAT10 expression abrogated HIV-induced apoptosis of RTEC. Immunohistochemical studies demonstrated increased FAT10 expression in a murine model of HIVAN, in HIVAN biopsy samples, and in autosomal dominant polycystic kidney disease, another renal disease that is characterized by cystic tubular enlargement and epithelial apoptosis. These results suggest a novel role for FAT10 in epithelial apoptosis, which is an important component of the pathogenesis of many renal diseases.

AIDS-Associated Nephropathy↗
PubMed2006

Hereditary nephritis mimicking immune complex-mediated glomerulonephritis.

The defining ultrastructural features of hereditary nephritis are "basket weave" lamellation or thinning of glomerular basement membranes. Electron-dense deposits are not seen and immunofluorescence (IF) is generally negative. In this study, we report 5 cases of hereditary nephritis in which substantial amounts of glomerular electron-dense deposits were identified on electron microscopy, with corresponding positive IF staining in 4 cases, suggesting immune complex-mediated glomerulonephritis. However, no case had histological evidence of glomerular endocapillary or extracapillary proliferation or leukocyte infiltration typical of active glomerulonephritis. Four cases were diagnosed at outside institutions simply as forms of glomerulonephritis without considering the possibility of hereditary nephritis and were sent for consultation in contemplation of possible immunosuppressive therapy. All patients had negative serologies and no known underlying infectious or autoimmune disease; 4 patients had family history of hematuria or renal disease. The glomerular electron-dense deposits were predominantly mesangial (4 cases) and intramembranous (4 cases), as well as subepithelial (2 cases) or subendothelial (1 case). Corresponding IF positivity for immune reactants was identified in 4 cases, and IgG was the predominant immunoglobulin deposited. A characteristic feature was the tendency for deposits to form between the complex layers of glomerular basement membrane material, favoring a process of nonspecific entrapment of immune reactants within the thickened, lamellated basement membrane. In all cases, a diagnosis of hereditary nephritis was confirmed by demonstration of the characteristic loss of immunoreactivity for the alpha5 subunit of collagen IV (4 cases) or Goodpasture's antigen (1 case) in renal or epidermal basement membranes. These cases expand the spectrum of unusual pathological findings in hereditary nephritis and emphasize the potential for hereditary nephritis to mimic immune complex glomerulonephritis.

Adolescent↗
PubMed2005

HIV-1 Nef induces dedifferentiation of podocytes in vivo: a characteristic feature of HIVAN.

OBJECTIVE: To determine the specific role of Nef in the pathogenesis of HIV-associated nephropathy. DESIGN: Podocytes are highly differentiated non-dividing cells in the normal glomerulus, however, they undergo dedifferentiation and acquire a proliferative phenotype in HIVAN patients, in HIV-transgenic mice and if infected by HIV-1 in vitro. These changes are accompanied by loss of the maturation markers synaptopodin and WT1, and expression of the proliferation marker Ki-67. Previously, we mapped the gene responsible for these changes in vitro to HIV-1 Nef. To determine the role of Nef in vivo, we developed a transgenic mouse model in which Nef was exclusively expressed in podocytes. METHODS: Transgenic mice were generated using a construct in which Nef expression was blocked by a floxed lacZ intervening gene. When crossed with another transgenic mice expressing Cre under the Podocin promoter (a podocyte specific gene), the intervening lacZ gene was removed activating the expression of Nef in podocytes. The in vivo expression profiles of the Nef, the proliferation marker Ki-67, the differentiation markers synaptopodin and WT1, and phospho-Stat3, were determined by immunohistochemistry. RESULTS: Podocyte-specific expression of Nef induced loss of synaptopodin and WT1, and expression of Ki-67 in podocytes. Furthermore, Nef activated expression of phospho-Stat3, one of the downstream signaling pathways for cell proliferation. CONCLUSIONS: We conclude that Nef induces the early molecular changes in podocytes that are essential for the dedifferentiation and proliferation of podocytes in HIVAN pathogenesis. These data provide the first clear molecular evidence that Nef alters the podocyte phenotype in vivo.

Animals↗
PubMed2005

Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure.

The findings of diffuse tubular injury with abundant tubular calcium phosphate deposits on renal biopsy are referred to as nephrocalcinosis, a condition typically associated with hypercalcemia. During the period from 2000 to 2004, 31 cases of nephrocalcinosis were identified among the 7349 native renal biopsies processed at Columbia University. Among the 31 patients, 21 presented with acute renal failure (ARF), were normocalcemic, and had a history of recent colonoscopy preceded by bowel cleansing with oral sodium phosphate solution (OSPS) or Visicol. Because the precipitant was OSPS rather than hypercalcemia, these cases are best termed acute phosphate nephropathy. The cohort of 21 patients with APhN was predominantly female (81.0%) and white (81.0%), with a mean age of 64.0 yr. Sixteen of the 21 patients had a history of hypertension, 14 (87.5%) of whom were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The mean baseline serum creatinine was 1.0 mg/dl, available within 4 mo of colonoscopy in 19 (90.5%) patients. Patients presented with ARF and a mean creatinine of 3.9 mg/dl at a median of 1 mo after colonoscopy. In a few patients, ARF was discovered within 3 d of colonoscopy, at which time hyperphosphatemia was documented. Patients had minimal proteinuria, normocalcemia, and bland urinary sediment. At follow-up (mean 16.7 mo), four patients had gone on to require permanent hemodialysis. The remaining 17 patients all have developed chronic renal insufficiency (mean serum creatinine, 2.4 mg/dl). Acute phosphate nephropathy is an underrecognized cause of acute and chronic renal failure. Potential etiologic factors include inadequate hydration (while receiving OSPS), increased patient age, a history of hypertension, and concurrent use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

Acute Kidney Injury↗
PubMed2005

NF-kappaB regulates Fas-mediated apoptosis in HIV-associated nephropathy.

Renal parenchymal injury in HIV-associated nephropathy (HIVAN) is characterized by epithelial proliferation, dedifferentiation, and apoptosis along the entire length of the nephron. Although apoptotic cell death in HIVAN has been well documented, the mechanism for HIV-induced apoptosis is poorly understood. Whether the epithelial apoptosis in HIVAN is mediated by NF-kappaB-activated Fas ligand expression was investigated here. In human HIVAN and HIV-1 transgenic mouse kidney specimens, the expression of Fas receptor and ligand proteins were markedly upregulated on epithelium in diseased glomerular and tubulointerstitial compartments when compared with normal. Podocyte cell lines that were derived from HIV-1 transgenic mice showed a similar upregulation of Fas receptor expression and de novo expression of Fas ligand by semiquantitative reverse transcription-PCR and Western blotting. In cultured podocytes, cross-linking of the Fas receptor to mimic ligand binding induced caspase 8 activity and apoptosis in both normal and HIVAN podocytes. Because constitutive NF-kappaB activity has been demonstrated in HIVAN epithelia, evidence for transcriptional control of the Fas ligand expression by NF-kappaB was sought. With the use of cultured podocytes, expression of a Fas ligand promoter reporter plasmid was higher in HIVAN podocytes, indicating increased transcriptional activity. In addition, chromatin immunoprecipitation assays were performed to demonstrate that p65-containing (RelA) complexes bound the Fas ligand promoter and that suppression of activated NF-kappaB with a peptide inhibitor could reduce the expression of Fas ligand mRNA in HIVAN podocytes. These results suggest that NF-kappaB may regulate Fas-mediated apoptosis in HIVAN by controlling the expression of Fas ligand in renal epithelium.

AIDS-Associated Nephropathy↗
PubMed2005

Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis.

BACKGROUND: Treatment of rheumatoid arthritis with anti-tumour necrosis factor alpha (TNFalpha) agents may lead to autoantibody formation and flares of vasculitis, but renal complications are rare. METHODS: We report the clinical and pathologic findings in five patients with longstanding rheumatoid arthritis (duration of rheumatoid arthritis, 10-30 years; mean, 23 years) who developed new onset of glomerular disease after commencing therapy with anti-TNFalpha agents (duration of therapy, 3-30 months; median, 6 months). RESULTS: At presentation, three patients were receiving etanercept, one adalimumab and one infliximab. Two subjects presented with acute renal insufficiency, haematuria, nephrotic-range proteinuria, positive lupus serologies, and hypocomplementemia, and renal biopsies showed proliferative lupus nephritis. Two individuals presented with new onset renal insufficiency, haematuria and proteinuria, and renal biopsies showed pauci-immune necrotizing and crescentic glomerulonephritis. One of these subjects, who had anti-myeloperoxidase autoantibodies, also developed pulmonary vasculitis. The fifth patient presented with nephrotic syndrome and renal biopsy findings of membranous glomerulonephritis, associated with immune complex renal vasculitis. A pathogenic role for anti-TNFalpha therapy is suggested by the close temporal relationship with development of glomerular disease, and by the improvement in clinical and laboratory abnormalities after drug withdrawal and initiation of immunosuppressive therapy in most cases. CONCLUSIONS: Rheumatoid arthritis patients receiving anti-TNFalpha agents may develop glomerulonephritis via the induction of rheumatoid arthritis-related nephropathy or de novo autoimmune disorders.

Adalimumab↗
PubMed2005

A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse.

The development of kidney disease is influenced by both genetic and environmental factors. Searching for models of glomerulopathy that display strong gene-environment interaction, we examined the determinants of anthracycline-induced nephropathy, a classic, strain-dependent experimental model applied to rodents in the past four decades. We produced three crosses derived from mice with contrasting susceptibility to doxorubicin (DOX) nephropathy and, surprisingly, we found that this widely studied model segregates as a single-gene defect with recessive inheritance. By genome-wide analysis of linkage, we mapped the trait locus to chromosome 16A1-B1 (DOXNPH locus) in all three crosses [peak logarithm of odds (lod) score of 92.7, P = 1 x 10(-65)]; this interval represents a susceptibility locus for nephropathy. Gene expression analysis indicated that susceptibility alleles at the DOXNPH locus are associated with blunted expression of protein arginine methyltransferase 7 (Prmt7) on chromosome 8, a protein previously implicated in cellular sensitivity to chemotherapeutic agents (lod = 12.4, P = 0.0001). Therefore, Prmt7 expression serves as a molecular marker for susceptibility to DOX nephropathy. Finally, increased variation in the severity of kidney disease among affected mice motivated a second genome-wide search, identifying a locus on chromosome 9 that influences the severity and progression of nephropathy (DOXmod, peak lod score 4.3, P = 0.0018). These data provide genetic and molecular characterization of a previously unrecognized Mendelian trait. Elucidation of DOX nephropathy may simultaneously provide insight into the pathogenesis of renal failure and mechanisms of cytotoxicity induced by chemotherapeutic agents.

Alleles↗
PubMed2005

Pathology of thin basement membrane nephropathy.

Thin basement membrane nephropathy (TBMN) is a glomerular disorder characterized clinically by isolated hematuria and pathologically by diffuse thinning of the glomerular basement membrane (GBM) on ultrastructural examination. The pathologic diagnosis of TBMN is problematic, in part because of the wide range of GBM thicknesses in the normal population. GBM thickness varies with age, sex, and the different methods of tissue preparation and measurement. In addition, there are no standardized diagnostic criteria defining the degree or extent of GBM thinning required for the diagnosis of TBMN. GBM thinning is often seen in other glomerulopathies, where it may represent an overlap with TBMN or may be secondary to GBM damage and remodeling. Importantly, TBMN must be differentiated from the GBM thinning seen in some renal biopsy specimens from boys and female heterozygotes with X-linked Alport syndrome because of the very different prognoses of these two conditions.

Basement Membrane↗
PubMed2004

Porphyromonas gingivalis induces its uptake by human macrophages and promotes foam cell formation in vitro.

Porphyromonas gingivalis is an etiologic agent of periodontal disease in humans, which has been linked to an increased risk for atherosclerosis-related events. In this study, we examined the effect of P. gingivalis infection on human macrophages with respect to foam cell formation, the hallmark of early atherogenesis, and the potential of P. gingivalis to induce its uptake by these cells. Human monocyte-derived macrophages were incubated with low density lipoprotein and infected with P. gingivalis FDC381 or its fimbriae deficient mutant, DPG3. Consistent with a role for fimbriae in this process, strain 381 significantly increased foam cell formation as compared to DPG3. Recovery of viable P. gingivalis in antibiotic protection experiments was significantly higher for strain 381 than for DPG3. By transmission electron microscopy, the wild-type strain was shown to adhere to and enter THP-1 cells. These results suggest that properties of P. gingivalis which render it capable of adhering to/invading other cell types may also be operative in macrophages and play an important role in its atherogenic potential.

Cells, Cultured↗