Legend:

RCT with >= 2000 patients

RCT with 1000-1999 patients

RCT with 500-999 patients

RCT with < 500 patients

Pathophysiology

Disease Outcomes and Trajectory

Biomarkers

Date:  2007

Abbreviation: IgACE Trial 

Placebo controlled randomized trial of angiotensin  converting enzyme inhibitors in children and young people with IgAN and proteinuria 

Description: Multicentric , randomized controlled trial performed in Europ in which ACE inhibitor (benazepril 0.2 mg/kg/d) versus placebo were tested in 66 patients with  IgA nephropathy between age group of 9 – 35 years of age  with  proteinuria (1-3.5 g/d/proteinuria) and CrCl > 50 ml/min. Primary outcome was progression of kidney disease (>30% decrease of CrCl). Secondary outcomes were composite outcomes of > 30 percent decrease in creatinine clearance or worsening of proteinuria > 3.5 g/day. The other secondary outcome was partial (< 0.5 gm / day ) or complete remission of proteinuria (< 160mg / day ). Progression of renal failure tends to be slower in ACE inhibitors although not statistically significant with respect to the primary end point . Treatment with ACE inhibitor was an independent predictor of  good prognosis and survival to the combined secondary end point.

Date: 2015

Abbreviation: STOP IgA 

Intensive supportive care plus immunosuppression in IgA nephropathy

Description: Prospective multicentric open-label randomized controlled trial  done in Germany in which supportive care alone versus supportive care with immunosuppressive therapy were studied in 309 patients between age group of 18 to 70 years with IgA nephropathy with a proteinuria of 0.75 g/day ,GFR < 90  or both after optimal run in phase of 6 months of supportive therapy.The immunosuppressive regimen consisted of glucocorticoids in patient with GFR > 60 and a combination of steroids and cyclophosphamide followed by azathioprine in patients with GFR between 30 and 59  with  two hierarchical primary end points which  were i) full clinical remission at the end of the trial (UPCR <0.2 and stable renal function with decrease in eGFR of <5 ml/min  from baseline at the end of 3 years)  and  decrease in eGFR of at least 15 ml/min from baseline.There was a significantly higher degree of  remission of proteinuria in the immunosuppressive group but with no significant differences in the GFR between two groups. More episodes of severe and non severe infections were found in the immunosuppressive groups as compared to non immunosuppressive groups

Date:  2017

Abbreviation: High dose TESTING trial 

Effect of Oral Methylprednisolone on clinical outcomes in patients with IgA Nephropathy: the TESTING Randomized Clinical Trial

Description: Multicentric double blinded randomized controlled trial in 100 centers from China, Australia, India, Canada, and Malaysia in which 0.6 to 0.8 mg/kg/d of oral methylprednisolone for 2 months, with a slow taper over 4 to 6 months was intended to be studied against placebo in 262 participants with IgAN with >1 g/day proteinuria & eGFR between 20 and 120 after a 3 month optimal blood pressure control with renin angiotensin blockade.  Primary outcome was a composite of 40% decrease in eGFR, the development of ESRD (defined as a need for maintenance dialysis or kidney transplantation), or death due to kidney disease. The hazard ratio for the  primary outcome was 0.37 (0.17-0.85) favoring steroids. The study had to be terminated owing to an excess of SAEs (mostly infections) in the corticosteroid group

Date: 2019

Abbreviation: International IgA nephropathy risk prediction tool

Evaluating a New International Risk-Prediction Tool in IgA Nephropathy

Description: The purpose of the study was to derive and externally validate a prediction model for progression of IgAN. It consisted of 3927 patients from cohorts from Europe (VALIGA, n = 1406), Asia and North and South America (Oxford validation, n = 187), China (Beijing, n = 410, Nanjing, n= 1026) and Japan (Fukoka, n=702) were included and consisted of patients with biopsy proven IgAN with MEST scores and long term follow up. It analyzed the risk of 50% decline in eGFR for ESRD. Three prediction models were created: one which was clinical (eGFR, BP, proteinuria at biopsy) and 2 full models (including MEST score, age, medication use, and with or without  racial/ethnic characteristics). External  validation was performed in a cohort of  1146 patients. The 2 full prediction models were accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multiethnic cohorts

Date: 2019

Abbreviation: Galactose-deficient IgA1 autoantibodies

Glomerular Immunodeposits of Patients with IgA Nephropathy Are Enriched for IgG Autoantibodies Specific for Galactose-Deficient

Description: This single center study was done to define the precise specificities and molecular properties of IgG antibodies in IgAN. Investigators EBV immortalized IgG secreting lymphocytes from remnant frozen kidney-biopsy specimens from 34 patients with IgAN and found that the secreted IgG formed immune complexes with galactose deficient IgA1 in a glycan  dependent manner. They also developed a dot blot assay for the glycan specific IgG that differentiated patient with IgAN from healthy and disease controls 88% specificity and 95% sensitivity and found that elevated levels of this antibody in the sera of patients with IgAN correlated with proteinuria.

Date: 2021

Abbreviation: DAPA CKD trial

A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy

Description: A multicenter, double-blinded RCT study (386 study sites in 21 countries), that included 270 IgAN patients (254 [94%] confirmed by renal biopsy) with eGFR between 25-75mL/min, and urinary albumin-to-creatinine ratio between 200-5000mg/g. Patients were randomized to receive either dapagliflozin 10mg daily (n=137) or placebo (n=133) as adjunct to standard of care. The primary composite endpoint was sustained decline of eGFR more than or equal to 50%, ESKD, or death due to renal disease- related/cardiovascular cause. The primary outcome was seen in 6 (4%) patients on dapagliflozin and 20 (15%) patients on placebo. Mean rate of eGFR decline was -3.5 and -4.7 mL/min/year with dapagliflozin and placebo respectively. Dapagliflozin reduced uACR was 26% relative to placebo. There were fewer severe adverse events with dapagliflozin. Hence, dapagliflozin reduced the risk of CKD progression in patients with IgANephropathy with good safety profile. 

Date: 2022

Abbreviation: Low dose testing trial

Effect of Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial

Description: An international, double-blind, randomized clinical trial in 67 centers from Australia, Canada, China, India and Malaysia. 503 participants with IgA nephropathy, proteinuria ≥1 g per day, and eGFR of 20 to 120 mL/min after at least 3 months of optimized background care were enrolled and randomized to oral methylprednisolone 0.4 mg/kg/d (with a maximum dose of 32 mg/d, weaning by 4 mg/d/mo) or placebo. Antibiotic prophylaxis for pneumocystis pneumonia was given for both groups. Mean follow up period was 4.2 years. Primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. Treatment with steroids reduced the risk of  composite renal outcome compared to placebo. However, there was an increase incidence of serious adverse events with high dose steroid therapy. 

Date: 2022

Abbreviation: NefigArd trial

Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy

Description: A multi-center, double-blinded, randomized controlled trial involving 199 biopsy-proven, proteinuric (>0.8g/g) IgAN patients between 23-73 years old and eGFR between 35-90 on optimized ACE who were randomized to either oral budesonide 16mg daily or placebo. The primary endpoint was 24 hour urine protein-to-creatinine ratio (UPCR) after 9 months. The secondary endpoint was decline in eGFR at 9 months and 12 months and change in proteinuria at 12 months. The study found that treatment patients had 27% lower proteinuria than control at 9 months as well as preservation of eGFR with an average of 3.8mL/min. Adverse events in the treatment group were characterized mild-moderate and included hypertension, peripheral edema, spasms, and acne. 

Date: 2023

Abbreviation: MAIN trial

Effectiveness of Mycophenolate Mofetil Among Patients With Progressive IgA Nephropathy: A Randomized Clinical Trial

Description: A single-center, randomized controlled trial involving 170 proteinuric IgAN (90% were biopsy proven) with mean age of 36.6 years and eGFR between 30-60 on maximal ACE were randomized to MMF or standard of care. Primary endpoints included doubling of serum creatinine, ESKD requiring dialysis, death due to renal or cardiovascular cause and progression of CKD. The MMF group had a 77% reduction in reaching primary endpoints versus standard of care, with a median follow up time of 60 months and without significant adverse events

Date: 2023

Abbreviation: PROTECT trial

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Description: International, randomized, double-blind, active-controlled study (134 sites, 18 countries) which examined sparsentan (400 mg daily) vs irbesartan (300 mg daily) in adults (≥18 years) with biopsy proven IgAN and proteinuria (1 gm/day or higher) despite maximized RAS inhibitor treatment for at least 12 weeks. 404 participants (202 sparsentan and 202 irbesartan) were stratified by eGFR (30 to < 60mL/min or >= 60mL/min) and urine protein excretion (≤ 1.75g/day and > 1.75g/day). Primary endpoint was the change from baseline to week 36 in the urine protein-creatinine ratio based on a 24-hour urine sample. At week 36, there was a statistically significant change from baseline in urine protein-creatinine ratio in the sparsentan group (-49.8%) compared to the irbesartan group (-15.1%); there was a between-group relative reduction of 41%. Treatment-emergent adverse events and safety were similar between irbesartan and sparsentan; once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. A two-year double blind period and its analyses will demonstrate whether or not these effects result in long-term nephroprotective potential of sparsentan.