Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy

Hastings, Margaret; Bursac, Zoran; Julian, Bruce A.; Baca, Emanuel Villa; Featherston, Jennifer; Woodford, Susan Y.; Bailey, Lisa; Wyatt, Robert

doi:10.1016/j.ekir.2017.08.008

Cited by 37 publications

(40 citation statements)

References 17 publications

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“…As indicated in the Biomarkers, EndpointS, and other Tools (BEST) Resource (3), surrogate end points are used in clinical trials as a substitute for a direct measure of how a patient feels, functions, or survives; they do not measure the clinical benefit of primary interest but are expected to predict that clinical benefit. In the United States, validated surrogate end points can be used as a basis for traditional approval of therapies, whereas "reasonably likely" surrogate end points can be used as a basis for accelerated approval of therapies intended to treat a serious or life-threatening condition such as IgAN (4). Just as the name implies, the accelerated approval program enables approval of a therapy earlier in its development pathway than traditional approval.…”

Section: Surrogate End Points and United States Approval Pathwaysmentioning

confidence: 99%

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy

Thompson

Carroll

Inker

et al. 2019

CJASN

173

128

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IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.

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Section: Surrogate End Points and United States Approval Pathwaysmentioning

confidence: 99%

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy

Thompson

Carroll

Inker

et al. 2019

CJASN

173

128

View full text Add to dashboard Cite

show abstract

“…IgAN is a common cause of chronic kidney disease, particularly for patients with proteinuria persistently more than 1 g/day [ 10 , 11 , 12 ]. There is currently no disease-specific therapy and 30–40% of patients progress to kidney failure that reduces life expectancy by about 10 years [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Knoppová

Reily

King

et al. 2021

JCM

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IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.

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“…IgA nephropathy (IgAN), initially described by Berger and Hinglais in 1968 ( 1 ), is the most common primary glomerulopathy in many countries. IgAN causes end-stage renal disease in 20–40% of the patients within 20 years after diagnosis ( 2 ), and reduces life expectancy by 10 years ( 3 ). The diagnosis is based on immunofluorescence- or immunohistochemical-microscopic examination showing IgA as the dominant or co-dominant immunoglobulin in the glomerular immunodeposits ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

The Emerging Role of Complement Proteins as a Target for Therapy of IgA Nephropathy

et al. 2019

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IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and a common cause of end-stage renal disease. Evaluation of a kidney biopsy is necessary for diagnosis, with routine immunofluorescence microscopy revealing dominant or co-dominant IgA immunodeposits usually with complement C3 and sometimes IgG and/or IgM. IgA nephropathy reduces life expectancy by more than 10 years and leads to kidney failure in 20–40% of patients within 20 years of diagnosis. There is accumulating clinical, genetic, and biochemical evidence that complement plays an important role in the pathogenesis of IgA nephropathy. The presence of C3 differentiates the diagnosis of IgA nephropathy from the subclinical deposition of glomerular IgA. Markers for the activation of the alternative and mannan-binding lectin (MBL) pathways in renal-biopsy specimens are associated with disease activity and portend a worse renal outcome. Complement proteins in the circulation have also been evaluated in IgA nephropathy and found to be of prognostic value. Recently, genetic studies have identified IgA nephropathy-associated loci. Within these loci are genes encoding products involved in complement regulation and interaction with immune complexes. Put together, these data identify the complement cascade as a rational treatment target for this chronic kidney disease. Recent case reports on the successful use of humanized anti-C5 monoclonal antibody eculizumab are consistent with this hypothesis, but a better understanding of the role of complement in IgA nephropathy is needed to guide future therapeutic interventions.

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Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy

Cited by 37 publications

References 17 publications

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

The Emerging Role of Complement Proteins as a Target for Therapy of IgA Nephropathy

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