Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy

Marras, Daniele; Bruggeman, Leslie A.; Gao, Feng; Tanji, Nozomu; Mansukhani, Mahesh; Cara, Andrea; Ross, Michael D.; Gusella, G. Luca; Benson, Gary; D’Agati, Vivette D.; Hahn, Beatrice H.; Klotman, Mary E.; Klotman, Paul E.

doi:10.1038/nm0502-522

Cited by 283 publications

(219 citation statements)

References 25 publications

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“…HIV-1 is strongly associated with FSGS, particularly the collapsing glomerulopathy variant, although other variants are also seen (79). The mechanisms likely involve direct infection of podocytes (80). A similar renal syndrome can be reproduced in transgenic mice bearing HIV-1 Nef (81) or Vpr (82) accessory proteins, suggesting possible mechanisms.…”

Section: Virus-associated Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

414

366

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Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies arenow recognized asdrivers of FSGS: high-penetrance geneticFSGSdue to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g., glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g., to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

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Section: Virus-associated Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

414

366

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“…The pathologic variants and percentage of sclerotic glomeruli were also comparable between the two groups. These findings indicated that IgM deposition is not likely the initiation of FSGS lesion, which has been identified as several genes mutations or variants (9-13), circulating permeability factors (14)(15)(16), and others (17)(18)(19)(20)(21)(22)(23). However, IgM and complement-mediated injury may be secondary phenomena that occur after the primary renal insult.…”

Section: Discussionmentioning

confidence: 97%

Clinical Significance of IgM and C3 Glomerular Deposition in Primary Focal Segmental Glomerulosclerosis

Zhang

Huang

et al. 2016

CJASN

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Background and objectives Glomerular IgM deposition is commonly shown in primary FSGS and sometimes accompanied by C3 deposition. Clinical presentation and treatment outcomes of these patients are not investigated in detail.Design, setting, participants, &measurements One hundred six consecutive patients with biopsy-proven primary FSGS from 2004 to 2014 were enrolled retrospectively. Clinical features and treatment outcomes were compared between patients with and without IgM/C3 deposition.Results Fifty-eight (54.7%) patients presented with IgM glomerular deposition on sclerotic segments. C3 and C1q depositions were shown exclusively in patients with IgM deposition (34.5% versus 0.0%; P,0.001 and 8.6% versus 0.0%; P=0.04, respectively). Patients with IgM deposition were younger (median; range: 24.5; 18.8-39.0 versus 46.5; 26.0-64.0 years old; P=0.001), had higher level of serum IgM (142.5;.0 versus 107.0; 71.0-140.0 mg/dl; P=0.01), and had higher level of eGFR (median; range 97.7; 48.0-135.8 versus 62.1; 33.7-93.9 ml/min per 1.73 m 2 ; P=0.01) at the time of kidney biopsy. The percentage of sclerosis lesions was significantly higher in patients with C3 deposition (median; range: 21.7%; 15.3%-31.1% versus 9.2%; 6.6%-20.0%; P=0.002). Although patients received comparable immunosuppressive treatments during 58.9 (29.5-81.1) months of follow-up, a significantly higher prevalence of refractory cases (no response or steroid dependent) occurred in patients with combined IgM and C3 deposition compared with patients with IgM deposition alone or without IgM deposition (58.8% versus 22.2% versus 15.6%, respectively; P=0.004). Multivariate analysis identified combined IgM and C3 deposition (odds ratio, 11.32; 95% confidence interval, 2.26 to 56.65; P=0.003) as an independent risk factor for refractory patients; 19 of 98 patients developed renal dysfunction when their serum creatinine levels increased .30% from baseline and reached .1.5 mg/dl. Combined IgM and C3 deposition (hazard ratio, 5.67; 95% confidence interval, 1.34 to 23.84; P=0.02) was identified as an independent risk factor for renal dysfunction.Conclusions Patients with primary FSGS and IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes, which indicate that IgM and C3 deposition might involve disease progression via complement activation.

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“…These findings have then been confirmed by detection of HIV-1 in tubular cells as well as glomerular visceral and parietal epithelial cells by PCR amplification and RNA in situ hybridization (50). It seems that the virus is even capable of active replication and evolution within the renal epithelium (51). These findings suggest that kidney cells not only are infected with HIV-1 but also might constitute a viral reservoir, allowing the virus to undergo slow but productive replication.…”

Section: Genetic Susceptibility and Hivanmentioning

confidence: 96%

Genetic Susceptibility, HIV Infection, and the Kidney

Kiryluk

Martino

Gharavi

2007

Clinical Journal of the American Society of Nephrology

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In recent years, the sequencing of mammalian and microbial genomes has provided the opportunity to study how genetic variation in the host and pathogen influence the course of infectious disease. In the case of HIV-1 infection, such studies have led to identification of key viral proteins that determine pathogenicity, immune evasion, or drug resistance. In addition, candidate gene association studies have uncovered a large number of host genetic variants that influence the outcome of infection and some organ-specific complications. HIV-associated nephropathy (HIVAN) is a pathologically distinct complication of HIV infection. Interindividual variability in incidence, skewed ethnic distribution, and familial aggregation of HIVAN with other forms of ESRD have suggested genetic susceptibility as a major contributing factor. This article reviews the host genetic factors that influence the course of HIV-1 infection and discusses murine models that have increased the understanding of HIVAN pathogenesis and demonstrated the role of genetic background on determination of disease.

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Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy

Cited by 283 publications

References 25 publications

Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis

Clinical Significance of IgM and C3 Glomerular Deposition in Primary Focal Segmental Glomerulosclerosis

Genetic Susceptibility, HIV Infection, and the Kidney

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