Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis

Inker, Lesley A.; Mondal, Hasi; Greene, Tom; Masaschi, Taylor; Locatelli, Francesco; Schena, Francesco Paolo; Katafuchi, Ritsuko; Appel, Gerald B.; Maes, Bart; Li, Philip K.; Praga, Manuel; Vecchio, Lucia Del; Andrulli, Simeone; Manno, Carlo; Gutiérrez, Eduardo; Mercer, Alex; Carroll, Kevin; Schmid, Christopher H.; Levey, Andrew S.

doi:10.1053/j.ajkd.2016.02.042

Cited by 101 publications

(81 citation statements)

References 55 publications

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“…As evidence of this CQ, albuminuria/proteinuria at baseline and at the end of the study was measured, and six RCT articles [42][43][44][51][52][53] and four meta-analysis articles [45,46,54,55] using ESRD as the endpoint were adopted.…”

Section: Discussionmentioning

confidence: 99%

“…These randomized controlled trials and post hoc analysis results confirmed a relationship between the decrease in albuminuria/proteinuria as a result of treatment using RA inhibitors for diabetic nephropathy and prevention of progression to ESRD. On the other hand, there are four papers reporting systematic review/ meta-analysis reviewing the usefulness of decrease in albuminuria/proteinuria as a surrogate endpoint [45,46,54,55]. In a meta-analysis of 32 randomized controlled trials (9008 subjects) evaluating five treatment interventions (RA inhibitor, Ca antagonist, intensive depressor therapy, low protein diet, and immunosuppressive drug) with renal disease progression as an outcome, the relationships between changes in albuminuria 2.5-13 months later and composite endpoints (doubling of serum creatinine level, ESRD, death) were investigated [45].…”

Section: Discussionmentioning

confidence: 99%

“…Here, the changes in proteinuria of RA inhibitors and corticosteroids matched the course of treatment effects for composite endpoints. It has also been reported that when using RA inhibitors and corticosteroids for IgA nephropathy, the early decrease in proteinuria is a useful surrogate endpoint [54]. Furthermore, in a meta-analysis of 27 randomized controlled trials (97,458 subjects) with ESRD as the outcome, the validity of the two surrogate endpoints, changes in proteinuria and doubling of serum creatinine levels, was verified using the index, treatment effect ratio (TER).…”

Section: Discussionmentioning

confidence: 99%

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“…The patients enrolled had a very limited renal function decline of –1.6 mL/min/year, rendering it difficult to prove the benefits of any additional treatment after a relatively short follow-up [26]. The STOP-IgAN trial was primarily powered to detect a difference in clinical remission, which it did in favor of immunosuppression [27], showing a reduction in proteinuria which has been validated by a recent meta-analysis [28]. The trial was too short and underpowered to detect the changes in renal function which have been validated as surrogate markers of ESRD such as a 50% decline in eGFR.…”

Section: Indications For Corticosteroid Therapy For Igan In Europe Dementioning

confidence: 99%

“…Addition of corticosteroids to supportive care induces reduction in proteinuria and possible reno-protective effects on the long term with increase in adverse events but mostly in cases with impaired renal function [8, 28, 33]. …”

Section: Conclusion From Recent European Studies On Corticosteroid Trmentioning

confidence: 99%

IgA Nephropathy: A European Perspective in the Corticosteroid Treatment

Coppo

2018

Kidney Dis

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Background: IgA nephropathy (IgAN) is detected in Europe in 22% of glomerular diseases diagnosed by biopsy. The frequency of IgAN as cause of ESRD in Europe has increased in the last decades, accounting for 35% of young and adult transplanted patients. These data justify the interest for risk factors and a possible therapeutic approach. Summary: Insight into a European perspective of IgAN was allowed by the multicenter study VALIGA, on 1,147 patients, almost all Caucasians, with follow-up of 4.7 years. The predictive value of mesangial hypercellularity (M), segmental sclerosis (S), tubular atrophy interstitial fibrosis (T) as independent biomarkers of progression was validated. Endocapillary hypercellularity was predictive of increased follow-up proteinuria. Two groups of patients selected by a propensity score to perfectly match for histologic features (MEST) and clinical data treated with renin-angiotensin system blockers (RASBs) and corticosteroids, or RASBs alone were compared and a beneficial effect of corticosteroids in addition to RASB was found in patients with proteinuria > 1 g/day, with an initial eGFR < 50 mL/min/1.73 m². On the contrary, the STOP-IgAN RCT found that immunosuppressive therapy in addition to optimal supportive care did not provide substantial kidney-related benefits in European patients with IgAN, because there was no difference in the rate of decrease in eGFR, although corticosteroid/immunosuppressive therapy induced complete remission of proteinuria more frequently than supportive care alone. The NEFIGAN trial evaluated a targeted release formulation of budesonide (TRF budesonide) delivering the drug in the distal ileum. TRF budesonide, additionally to optimized RAS blockade, reduced proteinuria and maintained eGFR in IgAN patients, suggesting a reduced risk of future progression to ESRD. Key Messages: In Europe, there is a reasoned search of a balanced approach to corticosteroid therapy for patients with IgAN, with particular attention to selecting the patients at risk of progression while limiting the unwanted systemic adverse events.

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