Association Between Surrogate Endpoints and Clinical Outcomes in Immunoglobulin A Nephropathy: A Systematic Literature Review

Abstract

Introduction

At least 50% of patients with immunoglobulin A nephropathy (IgAN) reach kidney failure within 12 years of diagnosis. Delayed progression to kidney failure remains the gold standard treatment endpoint in IgAN, but the prolonged time course limits feasibility as a primary endpoint in clinical trials. Earlier measurable endpoints may serve as surrogate endpoints for clinically important long-term kidney outcomes. Regulatory bodies recognize surrogate endpoints like proteinuria reduction. However, other stakeholders, like payers, health technology assessment agencies, and policymakers, may require additional evidence. This literature review assessed data on associations between surrogate endpoints, including proteinuria and estimated glomerular filtration rate (eGFR), and long-term kidney outcomes in IgAN.

Methods

A systematic search of IgAN studies conducted in any country was performed in MEDLINE, Embase, and CENTRAL via Ovid (January 1, 2006–September 1, 2023), supplemented by conference abstracts (2019–2023) and relevant literature reviews and meta-analyses. Eligible studies evaluated the association of surrogate endpoints of kidney disease progression with long-term outcomes in IgAN.

Results

Among 1833 unique citations screened, 23 publications met inclusion criteria. Proteinuria was associated with progression to kidney failure (p < 0.001–0.021; n = 5 studies), reaching a composite kidney event (p < 0.001–0.02; n = 6), doubling of serum creatinine (p = 0.009; n = 1), and long-term eGFR decline (p < 0.001–0.910; n = 5); absolute eGFR at months 3 and 6 was associated with composite kidney events (p ≤ 0.001–0.03; n = 2); and eGFR slope was associated with kidney failure (p < 0.001; n = 1) and doubling of serum creatinine (p < 0.001–0.007; n = 1).

Conclusion

The literature supports associations of proteinuria and eGFR with long-term clinical outcomes in IgAN across multiple studies and geographic regions. Despite regional variability in standard of care, which introduces heterogeneity in the strength of associations, the consistency of findings across regions supports the utility of proteinuria and eGFR as surrogate endpoints for clinically important long-term kidney outcomes.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03331-3.

Key Summary Points

The primary goal of treatment in immunoglobulin A nephropathy (IgAN) is delaying the loss of kidney function, but the time frame required makes assessment of long-term kidney outcomes in clinical trials impractical.

Previous evidence supports the use of estimated glomerular filtration rate (eGFR) and proteinuria as shorter-term surrogate endpoints for treatment efficacy in IgAN, but the utility of all potential biomarkers of response has not been systematically assessed.

We performed a systematic literature review to assess the range of possible surrogate endpoints in IgAN therapy, identifying 23 relevant publications.

The results confirm the predictive value of shorter-term endpoints of eGFR and proteinuria and suggest the utility of other potential surrogate endpoints, including hematuria, blood pressure, and serum creatinine.

Introduction

Immunoglobulin A nephropathy (IgAN) is among the most common forms of primary glomerulonephritis worldwide and is a principal cause of kidney failure [1]. At least 50% of patients with IgAN progress to kidney failure within 12 years of diagnosis [2, 3]. Delaying kidney failure remains the gold standard endpoint for IgAN treatment; however, the time required for disease progression to kidney failure can be long, and thus this endpoint is often impractical to investigate in clinical trials. Historically, this has been a barrier hindering clinical development programs for novel therapies for IgAN [4]. Consequently, regulatory agencies including the US Food and Drug Administration (FDA) have accepted surrogate endpoints—like proteinuria reduction—to support accelerated drug approval based on delayed progression to kidney failure. The accelerated approvals of therapies for IgAN (budesonide targeted-release, sparsentan, iptacopan, and atrasentan) by the FDA for the reduction of proteinuria underscore this regulatory shift [5–8]. Full FDA approvals of budesonide targeted-release and sparsentan were contingent and granted after data also demonstrated benefit in slowing estimated glomerular filtration rate (eGFR) decline [9, 10]. Sparsentan received conditional approval for IgAN in the European Union in April 2024 [11]. Further full approvals of IgAN therapies in the USA and European Union are likely to also require data on eGFR benefit [6, 7, 11]. The increasing acceptance of surrogate endpoints in clinical trials for IgAN is part of a broader shift to their use in interventional trials for many forms of kidney disease, including diabetic nephropathy, polycystic kidney disease, and glomerular diseases other than IgAN, an evolution that has been well documented in the nephrology literature [12–15].

Beyond regulatory considerations, stakeholders like payers, health technology assessment agencies, and policymakers may require robust evidence linking surrogate markers to clinical outcomes [16, 17]. In this context, there is interest in assessing shorter-term surrogate endpoints that reliably predict clinically important long-term kidney outcomes, including progression to kidney failure, death, or time to kidney replacement therapy. These shorter-term predictors should be measurable at baseline/diagnosis and during treatment to enable assessment of treatment effect, and can include both absolute measures (e.g., proteinuria at 3 months after treatment initiation) or measures of change (e.g., mean rate of change of eGFR) [18].

A recent large registry study in the UK (including 2299 adults and 140 children in the cohort) highlighted a significant association of time-averaged (TA) proteinuria with 10-year risk of kidney failure and long-term rate of eGFR loss [3]. However, there is limited information on the validity of other surrogate endpoints in IgAN populations that may be reliable predictors of longer-term kidney outcomes. To address this gap and support outcome selection for future clinical trials in an IgAN population, a systematic literature review was conducted to identify studies reporting associations between surrogate markers of kidney disease progression and long-term clinical outcomes including composite kidney events, kidney failure, doubling of serum creatinine, and decline in eGFR in patients with IgAN. Earlier systematic literature reviews evaluated individual potential surrogate progression markers in IgAN [19–22], but we are not aware of any recent systematic reviews of the range of clinically plausible surrogate endpoints. This review provides a comprehensive overview of the most current evidence on the identification and validation of surrogate endpoints suitable for clinical trials in IgAN to support informed decision-making by stakeholders like payers and policymakers.

Methods

Database searches were run in MEDLINE, Embase, and CENTRAL via Ovid. The initial search (February 2022) and an updated search (September 2023) covered studies published between January 1, 2006 and September 1, 2023. The search strategy incorporated Medical Subject Headings terms, validated filters [23], and free-text words specific to the population, interventions, and study designs of interest (Tables S1–S2 in the Supplementary Material).

Studies were selected using predefined eligibility criteria based on population, intervention, comparison, outcome measures, and study design (Table S3 in the Supplementary Material). Inclusion criteria consisted of interventional trials and observational studies in patients with IgAN that reported on the relationship between a potential surrogate endpoint and at least one of the following disease progression outcomes: kidney failure, mortality, time to kidney replacement therapy, or doubling of serum creatinine. Surrogate endpoints were required to be clinical measures or biomarkers that demonstrated diagnostic and prognostic information in global cohorts (proteinuria, eGFR, blood pressure, and histopathological features) [24]. Oxford classification (MEST-C) score is a known prognostic factor but was excluded, given that it is typically measured only at time of biopsy (baseline) and hence generally is not evaluable for effects of IgAN treatment [25].

Two independent reviewers performed title/abstract and full-text screenings, with a third reviewer resolving discrepancies. Clinical trials were excluded during full-text screening if they did not explicitly mention the potential surrogate outcomes, because searching trials for all potential relevant post hoc analyses was out of scope. Data extraction was completed by one reviewer and validated by a second, independent reviewer. Heterogeneity in surrogate endpoint definitions precluded a meta-analysis. For example, the predictive utility of eGFR as a surrogate endpoint was assessed using eGFR at specified short-term time points (e.g., month 3 or 6), a threshold for eGFR decline (e.g., < 60 mL/min/1.73 m²), or rate of eGFR change over time.

Supplemental searches of conference abstracts (2019–2023) and reference lists of relevant literature reviews and meta-analyses were conducted. Literature searches were not restricted by language, but any studies that were not published in English were excluded during the title/abstract screening.

This article is based on previously conducted studies and does not include any new studies involving human participants or animals performed by the authors.

Results

The searches in MEDLINE, Embase, and CENTRAL via Ovid generated a total of 2592 hits. The removal of duplicates yielded 1833 unique citations, which were screened at the title and abstract level. From these, the full texts of 604 publications were reviewed, and ultimately 23 were deemed eligible for inclusion in the systematic literature review. All of the included publications were full-text articles; no conference abstracts were found to be eligible. Figure 1 presents the flow of literature through the search and screening process.

Fig. 1.

PRISMA diagram showing the flow of literature. PRISMA - Preferred Reporting Items for Systematic reviews and Meta-Analyses

Twenty-one studies identified in the literature review reported a statistically significant (p < 0.05) association between at least one potential surrogate endpoint and a long-term clinical outcome of interest (Table 1). Identified surrogate endpoints included eGFR (e.g., at month 3, at month 6, TA, or slope), hematuria, blood urea nitrogen (BUN), diastolic blood pressure (DBP; e.g., time-updated), mean arterial pressure (MAP), proteinuria (e.g., at month 3 or month 6), systolic blood pressure (SBP; e.g., at month 6), serum albumin, serum creatinine, remission, T lesions, and urinary protein-to-creatinine ratio (uPCR; e.g., at month 3, month 6, or TA).

Table 1.

Studies assessing surrogate endpoints: overview of identified surrogate endpoints and associated outcomes

Surrogate endpoints	Associated clinical outcomes
	Composite kidney events	Decline in eGFR	Doubling of serum creatinine	Kidney failure
eGFR	eGFR at month 3: univariate [35] eGFR at month 6: univariate [30, 35], multivariate [30] TA eGFR: univariate [35] Mean rate of change: univariate [30, 36], multivariate [30]		GFR decline slope: univariate [43], multivariate [43]	eGFR slope: univariate [41]
Hematuria	Hematuria remission: univariate [33], multivariate [33] Time-varying hematuria: multivariate [33] Persistent TA hematuria: univariate, multivariate [38]	Microhematuria during follow-up: multivariate [46]	Persistent TA hematuria [38]	TA hematuria: univariate and multivariate [42]
BUN	BUN at month 3: univariate [35] BUN at month 6: univariate [35] TA BUN: univariate [35]
DBP	Time-updated DBP: univariate, multivariate [39]
MAP	TA MAP: univariate [26]* MAP at month 6: univariate [30]	TA MAP: univariate [27], multivariate [27]
Proteinuria	TA proteinuria: univariate [26]* [32], multivariate [32] Urinary protein at month 3: univariate [30, 35], multivariate [30, 35] Proteinuria at month 6: univariate [27], multivariate [27] Partial remission of proteinuria	TA proteinuria; univariate [28, 32], multivariate [28, 32] Remission of proteinuria: univariate [37, 44], multivariate [37, 44] Protein reduction at 6 months: univariate [20, 45] Heavy proteinuria in period more than 1 year post diagnosis: univariate [29], multivariate [29]		TA proteinuria: univariate [3, 28, 41], multivariate [3, 28, 41] Degree of proteinuria during follow-up**: univariate [29], multivariate [29]
SBP	SBP at month 6: univariate [27], multivariate [27] Time-updated SBP: univariate [39], multivariate [39]			TA SBP: univariate [41], multivariate [41]
Serum albumin	Serum albumin at month 6: univariate [30, 35], multivariate [30, 35] TA serum albumin: univariate [35, 38], multivariate [35, 38]
Serum creatinine	SCr at month 3: univariate [35] SCr at month 6: univariate [35] TA SCr: univariate [35], multivariate [35]
Remission	Total duration of first remission: univariate [31], multivariate [31]	Complete remission after 2 years: univariate [45], multivariate [45]
T lesions	T lesions at second biopsy: univariate [40], multivariate [40]
uPCR			TA uPCR: univariate [43], multivariate [43]

BUN blood urea nitrogen, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate, MAP mean arterial pressure, SBP systolic blood pressure, TA time-averaged, uPCR urinary protein-to-creatinine ratio

*Results not explicitly reported; authors state that results for TA MAP are similar to the significant association of baseline MAP with composite kidney event

**Heavy proteinuria with hypoalbuminemia (> 1.0 g/day/1.73 m²) with serum albumin level < 3.0 g/dL

Regarding the populations evaluated, 11 of 23 studies specified inclusion or exclusion criteria by age. Of those 11 studies, 8 studies specified aged ≥ 18 years or “adult,” while Li 2014 included patients aged ≥ 15 years, Reich 2007 included patients aged ≥ 16 years, and Coppo 2020 included a population with 15% pediatric patients (aged < 18 years) [26–28]. Kamei 2016 included only pediatric patients [29]. All included studies reported on the age distribution of the population assessed; mean/median age ranged from 30 to 47 years in non-pediatric populations (22 of 23 studies). The mean age at diagnosis in the pediatric study (Kamei 2016) was 11.6 years [29].

Surrogate Relationships with Composite Kidney Events

Twelve studies reported significant associations between potential surrogate endpoints and composite kidney events (Table 2). Definitions of composite kidney events differed across studies, but the most common definition (n = 6 studies) included a composite of ≥ 50% decline in eGFR or kidney failure [26, 27, 30–33]. Other definitions included a composite of eGFR decrease ≥ 5 mL/min/1.73 m²/year or doubling of serum creatinine, a composite of a 50% increase in serum creatinine or kidney failure, a composite of a 30% decline in eGFR or kidney failure, and a composite of doubling of serum creatinine or kidney failure. All definitions included components as described in the 2020 International Consensus Definitions of Clinical Trial Outcomes for Kidney Outcomes [34].

Table 2.

Studies assessing surrogate endpoints for composite kidney events

Study	Number	Study design	Follow-up time	Country/region	Study objective	Composite kidney event definition	Surrogate endpoint	Statistical results	Study conclusions
eGFR
Ni 2014 [35]	369	Prospective study	Mean 49 months	China (Shanghai)	To evaluate kidney disease progression and the risk factors for progression in patients with IgAN who achieved remission	Progression: eGFR decreased ≥ 5 mL/min/1.73 m2/year or doubling of SCr	Absolute and TA eGFR	Univariate analysis: eGFR at month 3: HR 0.96 (0.94–0.98), p = 0.004 eGFR at month 6: HR 0.96 (0.93–0.98), p = 0.001 TA eGFR: HR 0.96 (0.93–0.98), p = 0.001	Study confirmed that baseline SCr and eGFR were associated with kidney progression among patients with IgAN
Yu 2017 [36]	37	Observational study	5 years	Korea	To investigate the changes in proteinuria and kidney function after discontinuation of tacrolimus	Increase in SCr of ≥ 50% from baseline or deterioration of kidney function to kidney failure	Mean rate of change of eGFR	Mean rate of change of eGFR was an independent risk factor for the composite outcome
Alexander 2022 [30]	201	Observational study	3 years	India	To report the actual 3-year longitudinal clinical outcomes of the GRACE-IgANI cohort	50% decrease in eGFR from baseline, eGFR < 15 mL/ min/1.73 m2, commencement of kidney replacement therapy, or death	eGFR CKD-Epidemiology Collaboration at 6 months Rate of eGFR decline at 6 months	Univariate Cox PH model: eGFR < 60 mL/min/1.73 m2 at 6 months (HR 5.9, 95% CI 2.3–14.6, p ≤ 0.001) Rate of eGFR decline measured at 6 months of ≥ 5 mL/min/1.73 m2 per year (HR 2.2, 95% CI 1.3–3.6, p = 0.003) Multivariate Cox PH model: eGFR < 60 mL/min/1.73 m2 at 6 months (HR 2.9, 95% CI 1.1–7.6, p = 0.03) Rate of eGFR decline measured at 6 months of ≥ 5 mL/min/1.73 m2 per year (HR 2.7, 95% CI 1.6–4.8, p < 0.001)	Longitudinal clinical parameters measured at 6 months and rate of eGFR decline at 1 year along with MEST-C T2 score (baseline) were independent risk factors for development of the composite outcome at 3 years and performed better than baseline clinical parameters In addition, a ≥ 5 mL/min/1.73 m2 fall in eGFR in the first year after kidney biopsy had 86% sensitivity and 89% specificity for predicting the CO in a 3-year period, and that this measure could in the future be used to better inform patients, plan for KRT, and select patients for clinical trials or direct more intensive immunosuppression
Proteinuria
Mohd 2021 [32]	130	Observational study	Median 7.5 (IQR 4.0–13.0) years	Malaysia	To investigate the clinicopathological characteristics, treatment, and long-term kidney outcomes of patients with IgAN diagnosed in a single center	50% decrease in the eGFR (compared to baseline at kidney biopsy) or kidney failure	TA proteinuria	Univariate analysis: HR 2.41 (1.77–3.30), p < 0.001 ≥ 0.5 g/day HR 2.57 (1.15–5.73), p = 0.021 ≥ 1 g/24 h HR 9.91 (4.39–22.39), p < 0.001 ≥ 3 g/24 h HR 21.88 (6.0–79.81), p < 0.001 Multivariate analysis: HR 2.23 (1.57–3.16), p < 0.001	Average proteinuria during follow-up had a higher predictive value than the degree of proteinuria at diagnosis. Sustained proteinuria reduction (as reflected by lower TA proteinuria in this study) has a more important role than transient proteinuria reduction in preventing CKD progression in IgAN
Li 2014 [27]	703	Observational study	Mean 45 months	China	To evaluate if therapy with RAS inhibitors and sequential addition of steroids or other immunosuppressive agents were associated with proteinuria reduction and BP control. A secondary aim was to investigate kidney disease progression and its risk factors for IgAN under current therapy	50% decrease in the eGFR (compared to baseline at kidney biopsy) or kidney failure	Proteinuria at month 6	Univariate analysis: Proteinuria at month 6 (per g/day) HR 1.85 95% CI 1.64–2.09, p < 0.001 Multivariate analysis: Proteinuria at month 6 (per g/day) HR 1.53 95% CI 1.27–1.84, p < 0.001	Lower proteinuria was associated with lower risk of kidney failure event in patients currently being treated for IgAN
Ni 2014 [35]	369	Prospective study	Mean 49 months	China (Shanghai)	To evaluate kidney disease progression and the risk factors for progression in patients with IgAN who achieved remission	Progression: eGFR decreased ≥ 5 mL/min/1.73 m2/year or doubling of SCr	UPE at month 3 TA UPE	Univariate analysis: UPE (g/day) at month 3: HR 1 (1.00–1.002), p = 0.003 TA UPE (g/day): HR 1 (1.000–1.002), p = 0.01	Study authors were unable to provide clear evidence that baseline UPE was associated with kidney outcomes. However, TA UPE value was used to represent the average level of proteinuria during the follow-up; while TA UPE was a strong predictor of kidney function decline in patients with IgAN according to the univariate analysis, this parameter did not independently contribute to risk of adverse kidney outcomes in the multivariate models
Coppo 2020 [26]	1130	Observational study	Median 7 years (IQR 4.1–10.8) and ranged from 0.08 to 35 years, prolonged by 51% from the median follow-up of 4.7 years (IQR 2.4–7.9) of the original VALIGA study	Europe	To test the relationship of the MEST-C score at diagnosis with kidney outcomes in the VALIGA cohort over an extended follow-up period	50% reduction in eGFR or kidney failure and the rate of kidney function decline (eGFR slope)	TA proteinuria	Results not explicitly reported	Authors state that analysis of TA proteinuria confirmed the association found between proteinuria at baseline and clinical endpoint
Alexander 2022 [30]	201	Observational study	3 years	India	To report the actual 3-year longitudinal clinical outcomes of the GRACE-IgANI cohort	50% reduction in eGFR from baseline, eGFR < 15 mL/min/1.73 m2, commencement of kidney replacement therapy, or death	24-h urine protein at 6 months	Univariate Cox PH model: 24-h urine protein at 6 months ≥ 1 g/day (HR 3.1, 95% CI 1.8–5.4, p < 0.001) Multivariate Cox PH model: 24-h urine protein at 6 months ≥ 1 g/day (HR 2.1, 95% CI 1.1–3.9, p = 0.02)	Longitudinal clinical parameters measured at 6 months and rate of eGFR decline at 1 year along with MEST-C T2 score (baseline) were independent risk factors for development of the composite outcome at 3 years and performed better than baseline clinical parameters
Huang 2023 [37]	684	Retrospective study	Median follow-up: Low-degree hematuria cohort: 44.93 months High-degree hematuria cohort: 48.22 months	China	To analyze the clinicopathologic and prognostic features of IgAN with different degrees of persistent hematuria	30% reduction in eGFR, kidney failure, or death	Remission of proteinuria (i.e., follow-up level ≤ 1.0 g/day)	Remission of urine protein Univariate: HR 0.28, CI 0.18–0.44, p < 0.001 Multivariate: HR 0.28, CI 0.14–0.56, p < 0.001	In patients with IgAN and persistent hematuria, remission of urine protein was an independent protective factor, which was consistent with the previous research conclusions
Hematuria
Yu 2020 [33]	1333	Retrospective study	Median 45 months	China	To evaluate the association of hematuria and progression of IgAN	50% eGFR decline or kidney failure	Hematuria remission at month 6	Hematuria remission during the first 6 months treated as a time-varying covariate significantly reduced the risk for the composite kidney disease progression event (HR 0.46, 95% CI 0.32–0.68, p < 0.001) in patients without proteinuria remission (protein excretion > 1.0 g/day) during the first 6 months	Severity of persistent hematuria during follow-up was significantly associated with kidney disease progression. Hematuria remission was associated with reduced incidence of kidney disease progression events, especially in those without proteinuria remission and was associated with greatly reduced risk for kidney failure
Yu 2020 [33]	1333	Retrospective study	Median 45 months	China	To evaluate the association of hematuria and progression of IgAN	50% eGFR decline or kidney failure	TA hematuria	Hematuria by automated method, per 1 unit greater Unadjusted: HR 1.50, 95% CI 1.23–1.83, p < 0.001 Model 1: HR 1.63, 95% CI 1.33–2.01, p < 0.001 Model 2: HR 1.44, 95% CI 1.13–1.85, p = 0.004 Model 3: HR 1.46, 95% CI 1.13–1.87, p = 0.003 Hematuria by manual method, per 1 unit greater Unadjusted: HR 1.51, 95% CI 1.27–1.80, p < 0.001 Model 1: HR 1.61, 95% CI 1.34–1.93, p < 0.001 Model 2: HR 1.45, 95% CI 1.14–1.84, p = 0.002 Model 3: HR 1.46, 95% CI 1.15–1.86, p = 0.002 Model 1 was adjusted for age and sex; sex was expressed as a dichotomous variable. Model 2 was adjusted for covariates in model 1 plus log-transformed proteinuria and mean arterial pressure, which were time-varying covariates; eGFR; and Oxford classification (MEST-C scores). Model 3 was adjusted for covariates in model 2 plus steroids or other immunosuppressive agents	Authors stated that time-varying covariates in proportional hazard models may create time-varying confounding, and the predictive value of reductions in hematuria was not directly evaluated. Thus, the findings still need further confirmation
Weng 2022 [38]	182	Retrospective study	Mean 58.08 ± 23.51 months	China (Fuzhou)	To investigate the association of TA hematuria with the progression of IgAN	Doubling of SCr or kidney failure	Persistent TA hematuria (mean of > 28 red blood cells/µL) TA hematuria	Persistent hematuria yes vs no: Composite outcome: p = 0.042 Univariate Cox model: TA hematuria: HR 1.002 (1.001–1.003), p < 0.001 Multivariate Cox model: TA hematuria: HR 1.004 (1.001–1.008), p = 0.010	Patients who have IgAN and persistent microscopic hematuria have a substantially higher risk of developing kidney failure or impaired kidney function, especially those who also have persistent proteinuria and persistent hypoalbuminemia. The severity of TA hematuria could be considered an independent predictor for the progression of IgAN, especially in female patients
Other surrogate endpoints
Coppo 2020 [26]	1130	Observational study	Median 7 years (IQR 4.1–10.8), and ranged from 0.08 to 35 years, prolonged by 51% from the median follow-up of 4.7 years (IQR 2.4–7.9) of the original VALIGA study	Europe	To test the relationship of the MEST-C score at diagnosis with kidney outcomes in the VALIGA cohort over an extended follow-up period	50% reduction in eGFR or kidney failure and the rate of kidney function decline (eGFR slope)	TA MAP	Multivariable analysis: Authors state that additional multivariable analyses, including TA values of MAP over the follow-up period rather than the corresponding baseline values, substantially confirmed association with composite endpoint; however, data was not shown
Li 2014 [27]	703	Observational study	Mean 45 months	China	To evaluate kidney disease progression and its risk factors in a Chinese cohort under current therapy	50% decrease in the eGFR (compared to baseline at kidney biopsy) or kidney failure	SBP at month 6	Univariate analysis: SBP at month 6 (per 10 mmHg) HR 1.64, 95% CI 1.38–1.95, p = 0.001 Multivariate analysis: SBP at month 6 (per 10 mmHg): HR 1.36, 95% CI 1.05–1.77, p = 0.02	Lower BP was associated with slower eGFR decline and lower risk of kidney failure events in patients currently being treated for IgAN. However, the risk of kidney failure remained high
Tang 2023 [39]	1530	Observational study	Median 43.5 months	China	To determine the effect of intensive BP control on the progression of IgAN	30% decrease in eGFR from baseline or the development of kidney failure (initiation of sustained dialysis or kidney transplantation, or with an eGFR level < 15 mL/min/1.73 m2)	SBP and DBP, time-updated BP	Marginal structural models HRs (95% CI) Time-updated DBP < 70 mmHg: HR 1.04 (0.68, 1.59), p = 0.845 70–79 mmHg: (Reference) 80–89 mmHg: HR 1.73 (1.05, 2.82), p = 0.029 ≥ 90 mmHg: HR 2.09 (1.23, 3.52), p = 0.006 Time-updated SBP < 110 mmHg: HR 1.48 (1.02, 2.17), p = 0.040 110–119 mmHg: (Reference) 120–129 mmHg: HR 1.13 (0.80, 1.60), p = 0.473 130–139 mmHg: HR 2.21 (1.54, 3.16), p < 0.001 ≥ 140 mmHg: HR 2.91 (1.94, 4.35), p < 0.001 The U-shaped association between time-updated SBP and the composite outcomes was more prominent in patients with proteinuria ≥ 1 g/day and eGFR ≥ 60 mL/min/1.73 m2; a similar trend was not observed when analyzed with time-updated DBP	Adequate BP control during the treatment period may retard the progression of IgAN, but an increased risk of composite kidney outcomes was found in the lowest group of SBP. Aside from intensive BP control strategies, other potential risks of hypotension must be considered in the future. For office BP, SBP < 130 mmHg seems to be an appropriate range. Standardized BP measurements should be promoted to help determine the optimal BP target for patients with CKD
Canney 2021 [31]	3335	Observational study	Median 3.9 years	Europe, Asia, North and South America	To evaluate the association between duration of proteinuria remission and the subsequent risk of disease progression in a large and multiethnic international cohort of adult patients with biopsy-proven IgA nephropathy	First occurrence of either kidney failure (eGFR, 15 mL/min/1.73 m2, dialysis, or transplantation) or a reduction in eGFR to below 50% of the value at the time of remission, which persisted across all subsequent eGFR measurements	Total duration of first remission	Each 3 months during shorter remission, up to a maximum of approximately 4 years: unadjusted HR 0.91 (95% CI 0.89–0.93); adjusted HR 0.92 (0.89 to 0.94), p < 0.001 Each 3 months beyond 4 years: unadjusted HR 0.99 (95% CI 0.96–1.03); adjusted HR 0.97 (0.92 to 1.03), p = 0.13 4 years in remission: 79% (95% CI 68–86%) reduction in the risk of the primary outcome 6 years in remission: 82% (95% CI 73–87%) reduction in the risk of the primary outcome	A nonlinear dose–response relationship was observed between the duration of first proteinuria remission and the risk of disease progression. Each 3 months of additional time in remission was associated with a further 9% reduction in the risk of kidney failure or a 50% decline in eGFR
Ni 2014 [35]	369	Prospective study	Mean 49 months	China (Shanghai)	To evaluate kidney disease progression and the risk factors for progression in patients with IgAN who achieved remission	Progression: eGFR decreased ≥ 5 mL/min/1.73 m2/year or doubling of SCr	Serum ALB level	Univariate analyses: ALB g/L at month 6: HR 0.86 (0.76–0.96), p = 0.01 TA ALB g/L: HR 0.80 (0.70–0.93), p = 0.002 Multivariate analysis: TA ALB g/L: HR 0.86 (0.75–0.98), p = 0.03	Study provides strong support for the predictive value of serum ALB during a long-term follow-up for the assessment of kidney progression risk. The adjusted multivariate Cox analysis model revealed that each 1 g/L drop in the TA ALB level was associated with a 14% increase in the risk of kidney progression
Ni 2014 [35]	369	Prospective study	Mean 49 months	China (Shanghai)	To evaluate kidney disease progression and the risk factors for progression in patients with IgAN who achieved remission	Progression: eGFR decreased ≥ 5 mL/min/1.73 m2/year or doubling of SCr	SCr level	Univariate analyses: SCr μmol/L at month 3: HR 1.03 (1.02–1.05), p < 0.001 SCr μmol/L at month 6: HR 1.03 (1.02–1.04), p < 0.001 TA SCr μmol/L: HR 1.02 (1.01–1.03) p < 0.001 Multivariate analysis: TA SCr μmol/L: HR 1.02 (1.01–1.03), p < 0.0001	Baseline SCr and eGFR were associated with kidney progression among patients with IgAN. The TA SCr value was an important independent risk factor for kidney progression
Ni 2014 [35]	369	Prospective study	Mean 49 months	China (Shanghai)	To evaluate kidney disease progression and the risk factors for progression in patients with IgAN who achieved remission	Progression: eGFR decreased ≥ 5 mL/min/1.73 m2/year or doubling of SCr	BUN	Univariate analyses: BUN mmol/L at month 3: HR 1.35 (1.15–1.59), p < 0.001 BUN mmol/L at month 6: HR 1.36 (1.10–1.69), p = 0.005 TA BUN mmol/L: HR 1.56 (1.25–1.94), p < 0.001
Weng 2022 [38]	182	Retrospective study	Mean 58.08 ± 23.51 months	China (Fuzhou)	To investigate the association of TA hematuria with the progression of IgAN	Doubling of SCr or kidney failure	TA serum ALB	Univariate Cox model: TA serum ALB: HR 0.881 (0.814–0.953), p = 0.002 Multivariate Cox model: TA serum ALB: HR 0.845 (0.716–0.998), p = 0.047	Presence of persistent TA hematuria, persistent proteinuria, and persistent hypoalbuminemia can be used to predict prognosis in patients with IgAN However, additional studies are necessary to validate this approach
Shen 2015 [40]	60	Retrospective study	Median 32 months	China (Nanjing)	To evaluate the reversal of kidney pathological lesions after immunosuppressive treatment and its association with disease outcome in patients with IgAN	Kidney failure or 30% reduction in the eGFR after the second biopsy	Active glomerular lesions, M score, T score at second biopsy	Univariate Cox analyses demonstrated that the kidney outcomes were only associated with lesions M and T. Multivariate Cox regression analyses showed a significant association between lesion T at the second biopsy and kidney outcome, and the association for lesion M did not have statistical significance Univariate model: Active lesions present (vs absent): HR 0.93 (0.33–2.63), p = 0.889 Lesion M > 0.5 (vs ≤ 0.5): HR 4.47 (1.56–12.79), p = 0.005 Lesion T > 25% (vs < 25%): HR 16.36 (2.12–126.16), p = 0.007 Multivariate model A (pathological features + initial GFR, MAP, proteinuria): Lesion M: > 0.5 (vs ≤ 0.5): HR 1.95 (0.58–6.57), p = 0.280 Lesion T: > 50% (vs < 25%): HR 11.60 (1.23–109.71), p = 0.032 Multivariate model B (pathological features + initial GFR, follow-up MAP and proteinuria: Lesion M: > 0.5 (vs ≤ 0.5): HR 1.44 (0.44–4.76), p = 0.550 Lesion T: > 25% (vs < 25%): HR 20.34 (2.01–205.59), p = 0.011	Reversal of the above active glomerular lesions after immunosuppressive treatment was accompanied by a significant improvement in proteinuria and hematuria. Reversal of these lesions during the disease process may explain the lack of significant correlation of such lesions with clinical outcomes in the present study as well as in previous studies. It also adds pathological evidence of the benefit for patients with active glomerular lesions of receiving immunosuppressive therapy The powerful predictive value of tubular atrophy/interstitial fibrosis was confirmed by repeat kidney biopsy in this study. The association of mesangial hypercellularity at the second biopsy with kidney outcome failed to reach statistical significance, partly because of the limited number of patients in this study
Alexander 2022 [30]	201	Observational study	3 years	India	To report the actual 3-year longitudinal clinical outcomes of the GRACE-IgANI cohort	Primary endpoint was CO defined as ≥ 50% fall in eGFR (CKD-Epidemiology Collaboration) from baseline, eGFR (CKD-Epidemiology Collaboration) < 15 mL/ min/1.73 m2, commencement of kidney replacement therapy, or death	MAP at 6 months Hemoglobin at 6 months Serum ALB at 6 months	Univariate Cox PH model: MAP at 6 months, ≥ 102 mmHg: HR 0.9 (0.6–1.6), p = 0.80 Hemoglobin at 6 months ≤ 12 g/dL: HR 2.2 (1.3–3.7), p = 0.002 Serum ALB at 6 months ≤ 4 g/dL: HR 1.8 (1.1–3.0), p = 0.03	Using the data collected during follow-up, the authors identified that longitudinal clinical parameters measured at 6 months and rate of eGFR decline at 1 year along with MEST-C T2 score (baseline) were independent risk factors for development of the composite outcome at 3 years and performed better than baseline clinical parameters In addition, we identified that a ≥ 5 mL/min/1.73 m2 fall in eGFR in the first year after kidney biopsy had 86% sensitivity and 89% specificity for predicting the CO in a 3-year period and that this measure could in the future be used to better inform patients, plan for KRT, and select patients for clinical trials or direct more intensive immunosuppression

ALB albumin, BUN blood urea nitrogen, CI confidence interval, CKD chronic kidney disease, CO composite outcome, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate, HR hazard ratio, KRT kidney replacement therapy, MAP mean arterial pressure, PH proportional hazards, RAS renin–angiotensin system, SBP systolic blood pressure, SCr serum creatinine, TA time-averaged, UPE urinary protein excretion

Three studies, conducted in Asia (China, Korea, and India), evaluated the predictive value of eGFR during follow-up for composite kidney events. Ni 2014 [35] found significant associations of absolute eGFR at month 3 (p = 0.004) and month 6 (p = 0.001) and TA eGFR (p = 0.001) with the composite kidney outcome among patients who had achieved remission, while Yu 2017 found that the mean rate of change of eGFR was an independent risk factor for the composite kidney outcome in a cohort of patients unselected for remission status (p value not reported) [36]. In the South Asian (Glomerular Research And Clinical Experiments-IgA Nephropathy in Indians [GRACE-IgANI]) cohort [30], eGFR < 60 mL/min/1.73 m² at 6 months and rate of change of eGFR decline at 6 months were associated with the risk of a composite event comprising a 50% decrease in eGFR, eGFR < 15 mL/min/1.73 m², kidney replacement therapy, or death (p < 0.05 in both univariate and multivariate models).

Six studies reported on the association between proteinuria during follow-up and composite kidney events. Five of these studies were conducted in Asia; Coppo 2020 was conducted in Europe [26]. Mohd 2021 found an association between increasing levels of TA proteinuria and increasing risk of a composite kidney event; the strength of the association was found in both univariate and multivariate models (p < 0.001) [32]. Li 2014 examined proteinuria levels at month 6 by 24-h urine protein collection and noted a significantly greater risk for the composite outcome per g/day increase in multivariate analyses (p < 0.001) [27]. Ni 2014 found an association of 24-h urinary protein excretion at month 3 (p = 0.003) and TA 24-h urinary protein excretion (p = 0.01) with a composite kidney event among patients with IgAN who had achieved remission [35]. In the South Asian (GRACE-IgANI) cohort, 24-h urine protein levels ≥ 1 g/day at 6 months were associated with an increased risk of a composite kidney event at 3 years (p = 0.02 in a multivariate model) [30]. Huang 2023 reported that remission of proteinuria, defined as follow-up urine protein ≤ 1.0 g/day, was predictive of a reduction in the risk of a composite kidney event in patients with persistent hematuria, even after controlling for other predictive factors (multivariate p < 0.001) [37].

Two studies conducted in China reported on the predictive value of hematuria [33, 38]. In Yu 2020, hematuria remission (i.e., average red blood cell count ≤ 5/high-power field [manual method] or ≤ 28 red blood cells/μL [automated method] during the first 6 months of follow-up) was significantly associated with a reduction in risk of composite kidney disease progression (hazard ratio [HR] 0.46; p < 0.001); 1-unit greater TA hematuria was associated with greater risk of composite kidney progression in unadjusted models and a series of models adjusted for demographics, clinical factors, and treatment with immunosuppressive agents (p < 0.01 for all models) [33]. In Weng 2022, persistent TA hematuria (defined as a mean of > 28 red blood cells/µL) was associated with an increased risk of a composite kidney event comprising doubling of serum creatinine or kidney failure (p = 0.042) [38].

Two studies conducted in China reported on the association between blood pressure and composite kidney events. In Li 2014, each additional 10-mmHg increment in SBP at month 6 was significantly associated with increased risk of a composite of 50% decline in eGFR or progression to kidney failure (HR 1.36, p = 0.02) [27]. Tang 2023 found associations between time-updated DBP and SBP and composite kidney events [39]. DBP of 80–89 mmHg and ≥ 90 mmHg were associated with an increased risk of a 30% decrease in eGFR or progression to kidney failure (HR 1.73, p = 0.029 and HR 2.09, p = 0.006, respectively, compared to DBP 70–79 mmHg). Time-updated SBP of 130–139 mmHg and ≥ 140 mmHg were predictive of increased risk of a combined kidney event (HR 2.21, p < 0.001 and HR 2.91, p < 0.001, respectively, compared to SBP 110–119 mmHg).

Time-averaged serum albumin was significantly associated with composite kidney outcomes in two Chinese cohorts in both univariate and multivariate models [35, 38]. The GRACE-IgANI investigators explored associations of MAP (p = 0.80), hemoglobin (p = 0.002), and serum albumin (p = 0.03) at 6 months with composite kidney events in univariate analyses, but significant associations were not sustained in multivariate models [30].

One study reported on the associations between M score, T score, and active lesions at second biopsy with composite kidney events in a Chinese population [40]; T score ≥ 25% at second biopsy had a significant association with later composite kidney events in a multivariate model. The association between M score and the kidney outcome was not statistically significant. Significant associations of other surrogate endpoints with composite kidney events were only reported by a single study each in the evidence base. These include TA MAP (p value not reported), total duration of first remission (p < 0.001), TA serum creatinine level (p < 0.0001), and BUN (3 months p < 0.001, 6 months p = 0.005, TA p < 0.001) [26, 31, 35]. Of these, it should be noted that only TA MAP and total duration of remission were evaluated in populations outside of Asia.

Surrogate Relationships with Kidney Failure

Six studies reported statistically significant associations of potential surrogate endpoints with kidney failure (Table 3) [3, 28, 29, 38, 41, 42]. In a large observational study conducted in Canada, Reich 2007 reported a strong predictive value of TA proteinuria for kidney failure, even after adjusting for other clinical parameters (HR 1.57, p < 0.01) [28]. Kamei 2016 examined the relationship between the degree of proteinuria (categorized into four groups: no proteinuria [< 0.2 g/day/1.73 m²], mild proteinuria [0.2–1.0 g/day/1.73 m²], heavy proteinuria without hypoalbuminemia [> 1.0 g/day/1.73 m² with serum albumin level 3.0 g/dL], and heavy proteinuria with hypoalbuminemia [> 1.0 g/day/1.73 m² with serum albumin level < 3.0 g/dL]) and both the initiation of dialysis/transplantation and chronic kidney insufficiency in Japanese patients. Significant relationships were found in both univariate and multivariate models (p < 0.0001 for all) [29]. Weng 2022 reported a significant association between persistent TA hematuria (mean > 28 red blood cells/µL) and risk of progression to kidney failure in a population of Chinese patients [38]. Russo 2020 and Sevillano 2017 reported significant associations between TA proteinuria and kidney failure in two European populations (adjusted HR 1.03 [p < 0.005] and 2.82 [p = 0.04], respectively) [41, 42]. Pitcher 2023 examined long-term outcomes of an IgAN cohort within the UK National Registry of Rare Kidney Diseases [3]. The study explored relationships between TA proteinuria and kidney survival across multiple population subgroups. In a cohort representative of a phase 3 randomized controlled trial population, TA proteinuria > 1.76 g/day at 6–12 months or 6–24 months was associated with a statistically higher risk of a composite kidney failure event at 10 years. Similar results were found in a population more representative of an incident IgAN population. It should be noted that baseline eGFR and urinary protein levels varied widely among the studies; Kamei 2016 had higher eGFR and urinary protein excretion levels than the remaining trials [29].

Table 3.

Studies assessing surrogate endpoints for kidney failure

Study	Number	Study design	Follow-up time	Country/region	Study objective	Kidney failure definition	Surrogate endpoint	Statistical results	Study conclusions
Proteinuria
Reich 2007 [28]	542	Observational study	6.5 years	Canada (Toronto)	To quantify the value of proteinuria reduction on outcome in patients with IgAN and to assess the prognostic relevance of achieving partial remission as defined by achieving sustained proteinuria values < 1 g/day	CrCl < 15 mL/min/1.73 m2, initiation of dialysis, or transplantation	TA proteinuria	TA proteinuria was the most important predictor of kidney survival, even when corrected for other parameters (multivariate hazard 1.57, 95% CI 1.39–1.77, p < 0.01)	In IgAN, proteinuria exposure over time (TA proteinuria) is the strongest predictor of the rate of kidney function decline. Each incremental gram per day above 1 is associated with a 10- to 25-fold more rapid rate of kidney function decline and similar differences in kidney survival
Kamei 2016 [29]	100	Retrospective study	Median 11.8 years	Japan (Tokyo)	To evaluate the long-term outcome and risk factors for poor prognosis in childhood IgAN	Initiation of dialysis or transplantation	Degree of proteinuria during follow-up, defined as the highest level of proteinuria during the period of more than 1 year after diagnosis Group 1, no proteinuria (< 0.2 g/day/1.73 m2) Group 2, mild proteinuria (0.2–1.0 g/day/1.73 m2) Group 3, heavy proteinuria without hypoalbuminemia (> 1.0 g/day/1.73 m2 with serum ALB level > 3.0 g/dL) Group 4, heavy proteinuria with hypoalbuminemia (> 1.0 g/day/1.73 m2 with serum ALB level < 3.0 g/dL)	Patients in group 4 during follow-up period were at statistically significant risk for kidney failure Univariate analysis: Group 4 during follow-up: HR not calculable, all events in group 4, p < 0.0001 Multivariate analysis: Group 4 during follow-up: HR not calculable, all events in group 4, p < 0.0001	Degree of proteinuria during follow-up period strongly correlated with the final prognosis
Kamei 2016 [29]	100	Retrospective study	Median 11.8 years	Japan (Tokyo)	To evaluate the long-term outcome and risk factors for poor prognosis in childhood IgAN	Chronic kidney insufficiency: eGFR < 60 mL/min/1.73 m2	Degree of proteinuria during follow-up, defined as the highest level of proteinuria during the period of more than 1 year after diagnosis Group 1, no proteinuria (< 0.2 g/day/1.73 m2) Group 2, mild proteinuria (0.2–1.0 g/day/1.73 m2) Group 3, heavy proteinuria without hypoalbuminemia (> 1.0 g/day/1.73 m2 with serum ALB level > 3.0 g/dL) Group 4, heavy proteinuria with hypoalbuminemia (> 1.0 g/day/1.73 m2 with serum ALB level < 3.0 g/dL)	Univariate analyses: Group 4 during follow-up: HR (95% CI) 49.9 (15.5–222.1), p < 0.0001 Multivariate analysis: Group 4 during follow-up: HR (95% CI) 78.0 (13.8–730.5), p < 0.0001	Patients who have no heavy proteinuria during follow-up period hardly develop kidney insufficiency
Russo 2020 [41]	145	Retrospective study	Mean 67 ± 6 months	Italy	To investigate the association of the incidence of KRT with the attainment of therapeutic BP targets recommended by guidelines in patients with a diagnosis of IgAN in a real-life setting	Start of dialysis or kidney transplantation	TA proteinuria	Univariate analysis: TA proteinuria indexed; HR 1.05, 95% CI 1.04–1.07, p < 0.001 Multivariate analysis: HR 1.03, 95% CI 1.01–1.05, p < 0.005	In the fully adjusted model, the only parameters associated with an increased need for KRT were TA proteinuria indexed and TA SBP
Sevillano 2017 [42]	112	Retrospective study	Mean 14 ± 10.2 months	Spain	To understand the influence of hematuria on a cohort of patients with IgAN followed over a long period of time	Not explicitly defined	TA proteinuria	Unadjusted HR: 4.88 (1.88–12.65, p = 0.01) Adjusted HR: 2.82 (1.04–7.66, p = 0.04)	Only TA values during follow-up of BP, proteinuria, and hematuria as well as kidney function at the time of kidney biopsy had a significant influence on kidney survival. Patients with persistent hematuria and proteinuria during follow-up are those at risk for progression to kidney failure
Pitcher 2023 [3]	2439	Retrospective study	Median 4.5 years	UK	To present relationships among proteinuria, eGFR slope, and lifetime risks for kidney failure	First occurrence of either long-term kidney replacement therapy, a confirmed eGFR < 15 mL/min/1.73 m2, or recorded CKD category 5	TA proteinuria	Population 1 (representative incident population) 10-year kidney failure risk, Cox PH model: Total TA proteinuria duration: 0.44 to < 0.88 g/g, HR (95% Wald CL) 1.07 (0.64–1.79) 0.88 to < 1.76 g/g, HR (95% Wald CL): 2.73 (1.78–4.16) ≥ 1.76 g/g, HR (95% Wald CL) 7.66 (5.09–11.52) 0–24 months’ TA proteinuria duration: 0.44 to < 0.88 g/g, HR (95% Wald CL) 1.32 (0.85–2.04) 0.88 to < 1.76 g/g, HR (95% Wald CL) 2.65 (1.79–3.92) ≥ 1.76 g/g, HR (95% Wald CL) 5.73 (3.92–8.38) Population 4 (representative of a typical phase 3 RCT) 6–12 months TA proteinuria duration: 0.88 to < 1.76 g/g, HR (95% CI) 1.43 (0.87–2.33) ≥ 1.76 g/g, HR (95% CI) 3.57 (2.24–5.70) 6–24 months’ TA proteinuria duration: 0.88 to < 1.76 g/g, HR (95% CI) 2.01 (1.24–3.26) ≥ 1.76 g/g, HR (95% CI) 4.49 (2.80–7.21)	In population 1 (representative incident population), with higher TA proteinuria significantly associated with worse kidney survival and more rapid eGFR loss. Considering TA proteinuria over total follow-up, this analysis demonstrates that 30% of patients with TA proteinuria of 0.44 to < 0.88 g/g (50 to < 100 mg/mmol) and approximately 20% of patients with TA proteinuria < 0.44 g/g developed kidney failure within 10 years Population 4 was selected to be representative of a typical phase 3 RCT In both the 6- to 12-month and 6- to 24-month analyses, higher TA proteinuria was associated with higher risk of kidney failure and greater mean eGFR loss
Systolic blood pressure
Russo 2020 [41]	145	Retrospective study	Mean 67 ± 6 months	Italy	To investigate the association of the incidence of KRT with the attainment of therapeutic BP targets recommended by guidelines in patients with a diagnosis of IgAN in a real-life setting	Start of dialysis or kidney transplantation	TA SBP	Univariate analysis: TA SBP; HR 1.06, 95% CI 1.03–1.08, p < 0.001, TA SBP < 130 mmHg; HR 0.42, 95% CI 0.18–0.96, p = 0.04 Multivariate analysis: TA SBP HR 1.07, 95% CI 1.01–1.13, p < 0.01 Lowest TA SBP tertile (i.e., those with TA SBP below 125 mmHg) vs others: HR 0.29, 95% CI 0.10–0.85, p = 0.02 Tertile 1 (vs tertile 3): HR 0.25, 95% CI 0.08–0.80, p = 0.02 Tertile 2 (vs tertile 3): HR 0.43, 95% CI 0.18–1.00, p = 0.05	There is no evidence of a J-curve relationship between TA SBP levels (even below 125 mmHg), and the progression to KRT in a population of relatively young individuals with a wide range of proteinuria and GFR levels was largely representative of real-life condition in IgAN. The independent relationship between TA SBP and the need for KRT were found in individuals with TA proteinuria above 1 g/24 h. Individuals in the two lowest SBP tertiles showed reduced risk of developing the kidney outcome
Other surrogate endpoints
Russo 2020 [41]	145	Retrospective study	Mean 67 ± 6 months	Italy	To investigate the association of the incidence of KRT with the attainment of therapeutic BP targets recommended by guidelines in patients with a diagnosis of IgAN in a real-life setting	Start of dialysis or kidney transplantation	eGFR slope	Yearly eGFR slope (mL/min/1.73 m2); HR 1.36 95% CI 1.19–1.55 p < 0.001
Sevillano 2017 [42]	112	Retrospective study	Mean 14 ± 10.2 months	Spain	To understand the influence of hematuria on a cohort of patients with IgAN followed over a long period of time	Not explicitly defined	TA hematuria	Unadjusted HR: 4.21 (1.66–10.64, p = 0.02) Adjusted HR: 2.84 (1.06–7.3, p = 0.04)	Only those patients with levels of proteinuria 0.75 g/day combined with persistent hematuria during follow-up showed a significantly worse prognosis, whereas those patients who present only proteinuria or hematuria during follow-up have a clearly better prognosis. Patients with persistent hematuria and proteinuria during follow-up are those at risk for progression to kidney failure
Weng 2022 [38]	182	Retrospective study	Mean 58.08 ± 23.51 months	China (Fuzhou)	To investigate the association of TA hematuria with the progression of IgAN	eGFR < 15 mL/min/1.73 m2	Persistent TA hematuria (mean of > 28 red blood cells/µL)	Persistent hematuria yes vs no: Progression to kidney failure: p = 0.047	Presence of persistent TA hematuria, persistent proteinuria, and persistent hypoalbuminemia can be used to predict prognosis in patients with IgAN However, additional studies are necessary to validate this approach

ALB albumin, CKD chronic kidney disease, CrCl creatinine clearance, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate, HR hazard ratio, IgAN immunoglobulin A nephropathy, KRT kidney replacement therapy, PH proportional hazards, RCT randomized controlled trial, SBP systolic blood pressure, TA time-averaged

Surrogate Relationships with Doubling of Serum Creatinine

Two studies conducted in Korea and China, respectively, reported a significant association of surrogate endpoints and the doubling of serum creatinine (Table 4) [38, 43]. In Lee 2018, GFR decline (p = 0.007 in rapid decliners [i.e., steepest eGFR slope quartile]; p = 0.011 in slow decliners [i.e., second-steepest eGFR slope quartile]) and TA uPCR (p = 0.009) were both significant risk factors for kidney progression in Korean patients, even after adjusting for other clinical and demographic characteristics [43]. The majority of this cohort (94%) had received renin–angiotensin suppression. In Weng 2022, the association between persistent TA hematuria (mean > 28 red blood cells/µL) and doubling of serum creatinine was studied, but the result was not statistically significant (p = 0.113) [38].

Table 4.

Studies assessing surrogate endpoints for doubling of serum creatinine

Study	Number	Study design	Follow-up time	Country/region	Study objective	Surrogate endpoint	Statistical results	Study conclusions
Lee 2018 [43]	214	Retrospective study	Median 5.9 (3.3, 10.4) years	Korea	To investigate clinicopathologic predictors of kidney survival in patients with IgAN, with a focus on eGFR decline slope	GFR decline slope	Univariate analyses: Slow decliners and rapid decliners had a 6.68-fold (95% CI 1.35–33.18; p = 0.02) and 16.36-fold (95% CI 3.7–72.09; p < 0.001) higher risk of kidney progression than non-decliners Multivariate analyses: eGFR slope groups were risk factor for kidney progression, independent of sex, smoking status, SBP and baseline eGFR. HR 8.84 (95% CI 1.64–47.57; p = 0.011) in slow decliners and 10.17 (95% CI 1.89–54.69; p = 0.007) in rapid decliners	GFR decline slope may be a reliable prognostic factor to guide therapeutic treatment in patients with IgAN. First-year eGFR slope was associated with increased risk of kidney progression, independently of proteinuria level and histologic findings
Lee 2018 [43]	214	Retrospective study	Median 5.9 (3.3, 10.4) years	Korea	To investigate clinicopathologic predictors of kidney survival in patients with IgAN, with a focus on eGFR decline slope	TA uPCR	Univariate analyses:TA uPCR (vs < 0.5 g/gCr) ≥ 1.0 g/gCr; HR 14.63 95% CI (1.94–110.37), p = 0.009 Multivariate analyses:TA uPCR (≥ 1 g/gCr) was a risk factor for kidney progression, independent of sex, smoking status, SBP and baseline eGFR
Weng 2022 [38]	182	Retrospective study	Mean 58.08 ± 23.51 months	China (Fuzhou)	To investigate the association of TA hematuria with the progression of IgAN	Persistent TA hematuria	Persistent hematuria yes vs no: Doubling of serum creatinine: p = 0.113	Presence of persistent TA hematuria, persistent proteinuria, and persistent hypoalbuminemia can be used to predict prognosis in patients with IgAN However, additional studies are necessary to validate this approach

eGFR estimated glomerular filtration rate, gCr gram of creatinine, HR hazard ratio, IgAN immunoglobulin A nephropathy, uPCR urinary protein-to-creatinine ratio, SCr serum creatinine, TA time-averaged

Surrogate Relationships with a Decline in eGFR

Significant associations of surrogate endpoints with a decline in eGFR were explored in seven studies [20, 27, 28, 44–47], presented in Table 5. Four of these studies examined the predictive value of proteinuria. Li 2014 and Reich 2007 found significant associations with TA proteinuria during follow-up (p < 0.001; p < 0.01); in the latter study, there was a trend of more rapid eGFR decline with each 1-unit increase in TA proteinuria above 1 g/day [27, 28]. In a meta-analysis of 12 randomized trials, Inker 2021 calculated the effects of 6 months of treatment to reduce proteinuria on the slope of eGFR over 3 years, estimating that a 30% reduction in proteinuria would improve the eGFR slope by 1.62, and a 50% reduction would improve the slope by 4.07 [20]. In a retrospective study conducted in Japan, Matsuzaki 2021 reported that remission of proteinuria, defined as three consecutive dipstick results of (−) to (±) for at least 6 months, exhibited significant association with lesser eGFR decline (beta coefficient 1.61; 95% CI 0.22–3.00; p = 0.02) [44]. One study each found a significant predictive relationship between degree of microhematuria (either severe, red blood cells ≥ 21/high-power field; moderate, 3–20/high-power field; or absent, < 3/high-power field) during follow-up (p = 0.01) [46] and TA MAP (p < 0.001) [27] with a decline in eGFR. Finally, one study associated urinary C5b-9 levels and serum C5b-9 levels with eGFR changes; changes in urinary C5b-9 levels were significantly correlated with changes in eGFR, while changes in serum C5b-9 levels showed no significant association [45].

Table 5.

Studies assessing surrogate endpoints for decline in eGFR

Study	Number	Study design	Follow-up time	Country/region	Study objective	Surrogate endpoint	Statistical results	Study conclusions
Proteinuria
Li 2014 [27]	703	Observational study	Mean 45 months	China	To evaluate kidney disease progression and its risk factors in a Chinese cohort under current therapy	TA proteinuria	Univariate analysis: Regression coefficient − 0.21, 95% CI − 0.26 to  − 0.17, p < 0.001 Multivariate analysis:Regression coefficient − 0.21, 95% CI  − 0.25 to  − 0.16, p < 0.001	Lower proteinuria was associated with slower eGFR patients currently being treated for IgAN
Reich 2007 [28]	542	Observational study	6.5 years	Canada (Toronto)	To quantify the value of proteinuria reduction on outcome in patients with IgAN and to assess the prognostic relevance of achieving partial remission as defined by achieving sustained proteinuria values < 1 g/day	TA proteinuria	TA proteinuria was a critical determinant of slope by univariate and multivariate analysis (p < 0.01) and the most important predictor of kidney function decline (R2 = 0.162, F = 104.5, p < 0.01) Slope (mean ± SD), mL/min/1.73 m2/month Group 1 (0–1 g/24 h): − 0.030 ± 0.46 Group 2 (1–2 g/24 h): − 0.326 ± 0.53 Group 3 (2–3 g/24 h): − 0.516 ± 0.66 Group 4 (> 3 g/24 h): − 0.719 ± 0.61	In IgAN, proteinuria exposure over time (TA proteinuria) is the strongest predictor of the rate of kidney function decline. Each incremental gram per day above 1 is associated with a 10- to 25-fold more rapid rate of kidney function decline and similar differences in kidney survival
Inker 2021 [20]	1037	Meta-analysis	Median 42.6 (IQR 34.9–78.0) months for analysis of change in urine protein at 6 months	–	To compare treatment effects on change in proteinuria versus change in eGFR slope	Change in urine protein level from baseline to 6 (range 2.5–14), 9 (2.5–14), and 12 (2.5–19) months	Change in urine protein from baseline to 6 months: slope − 7.18 (95% CI − 13.03 to − 1.80)	Observed treatment effects on the early changes in urine protein can inform investigators and sponsors of the longer-term treatment effects on GFR slope. The evidence supports the use of urine protein level as an initial surrogate endpoint followed by GFR slope for subsequent confirmatory studies and accumulation of safety data, or as parts of early-phase studies
Matsuzaki 2021 [44]	103	Retrospective study	Median 86.5 (range 71–104) months	Japan	To investigate the utility of these criteria as a surrogate endpoint in the progression of IgAN in present study	Remission of proteinuria	Univariate analysis: beta coefficient 1.54, 95% CI 0.13–2.94; p = 0.03 Multivariate analysis: beta coefficient 1.61, 95% CI 0.22–3.00; p = 0.02	Slope of decline in eGFR was steepest among patients who were in non-remission. Findings confirm the status of proteinuria remission during the early stage of disease as a significant kidney prognostic factor
Tatematsu 2012 [45]	81	Retrospective study	Median 38.7 months	Japan	To study the effectiveness of Pozzi’s regimen, focusing on changes in urinary abnormalities, and to clarify the associations among various clinical parameters, including CR, and kidney outcome	Reduction in proteinuria at 6 months	Univariate analysis: r = − 0.013, p = 0.909	Urinary protein reduction at 6 months was not associated with the kidney outcome of eGFR slope
Other surrogate endpoints
Bobart 2021 [46]	72	Retrospective study	Median 3.69 (IQR 2.07–6.96) years	USA (Rochester, MN)	To investigate whether the degree of microhematuria during follow-up is associated with change in eGFR, after adjusting for clinical and histological parameters	Microhematuria during follow-up	Multivariate analysis: An increase in the degree of microhematuria was significantly associated with an eGFR decline of − 0.81 mL/ min/1.73 m2 (95% CI − 1.44 to − 0.19, p = 0.01), after adjusting for follow-up time, proteinuria, and T score Median degree of hematuria throughout follow-up: eGFR decline rate (SE) 0: 5.80 (2.05) 1 to ≤ 3: 2.10 (1.44) 3–10: − 1.60 (1.14) 11–20: − 5.30 (1.38) 21–30: − 9.00 (1.96) 31–40: − 12.70 (2.67) 41–50: − 16.40 (3.43) 51–100: − 20.10 (4.22) > 100: − 23.80 (5.01)	Degree of microhematuria during follow-up is an independent predictor of eGFR decline after adjusting for clinical and histological parameters
Li 2014 [27]	703	Observational study	Mean 45 months	China	To evaluate kidney disease progression and its risk factors in a Chinese cohort under current therapy	TA MAP	Multivariate analysis: Regression coefficient − 0.15, 95% CI − 0.21 to − 0.00, p < 0.001 Univariate analysis: Regression coefficient − 0.19, 95% CI − 0.24 to − 0.13, p  < 0.001
Tatematsu 2012 [45]	81	Retrospective study	Median 38.7 months	Japan	To study the effectiveness of Pozzi’s regimen, focusing on changes in urinary abnormalities, and to clarify the associations among various clinical parameters, including CR, and kidney outcome	Complete or partial remission	Univariate analysis: CR within 2 years: r = 0.205, p = 0.067 PR within 2 years: r = 0.199, p = 0.075 Urine blood remission within 2 years: r = 0.127, p = 0.260 Multivariate analysis: CR within 2 years: beta coefficient 0.217, SE 0.970, p = 0.044	Study suggested that CR within 2 years would be a good prognostic marker after treatment. CR seems to be a better prognostic factor than PR. On univariate analysis, CR was associated more strongly with GFR slope than PR. The clinical significance of CR compared to PR needs further studies in larger cohorts with longer observation period
Yu 2022 [47]	33	Observational study	Median 4.0 years	Korea	To evaluate C5b-9 as a prognostic marker for IgAN	Changes in eGFR	Changes in corrected urinary C5b-9 levels were inversely correlated with changes in eGFR at 6 months after medical treatment. Changes in serum C5B-9 levels did not correlate with changes in eGFR: Urinary C5b-9: R2 = − 0.410, p = 0.018 Serum C5b-9: R2 = 0.147, p = 0.513	Current study showed that urinary C5b-9 levels are associated with short- and long-term clinical outcomes in patients with IgAN. However, currently urinary C5b-9 is not a promising prognostic biomarker for IgAN. Further studies with larger cohorts and long-term follow-up durations are needed to clarify this

CI confidence interval, CR complete remission, eGFR estimated glomerular filtration rate, HR hazard ratio, IgAN immunoglobulin A nephropathy, IQR inter-quartile range, MAP mean arterial pressure, PR partial remission, TA time-average

Discussion

Proteinuria and eGFR were the most commonly studied surrogate endpoints for the progression of IgAN. Levels at specific timepoints (e.g., 3 months, 6 months), as well as TA values of eGFR and proteinuria, were found to be predictive of composite kidney events in multiple studies. These results are consistent with and add evidence from observational studies to a recent meta-analysis of clinical trials in IgAN comparing treatment effects on proteinuria and eGFR slope, which suggested that early proteinuria change correlates with long-term outcome across treatments [20]. These studies included cohorts in Europe, Asia, and North America, lending robustness to the strength of the association. More recently, hematuria has been evaluated as a surrogate endpoint to predict worsening kidney function, although published evidence outside of Chinese populations is limited, so it is unclear whether these associations are also statistically meaningful in non-Asian populations [22].

Evidence on the predictive value of eGFR and proteinuria has been well established; however, both eGFR decline and sustained elevated proteinuria during follow-up were found to be stronger predictors of poor kidney outcomes than baseline eGFR or baseline proteinuria in several studies [30, 32, 37]. This finding supports suggestions that treatments targeting early changes in eGFR and proteinuria are likely to reduce risk of poor long-term kidney outcomes [20] and has been used to support accelerated FDA approvals of budesonide targeted-release, sparsentan, iptacopan and atrasentan [5–8]. Furthermore, patients with both persistent hematuria and proteinuria appear to be at higher risk for kidney function decline than patients with persistent hematuria or persistent proteinuria alone [33, 38]; there is also some evidence that this relationship is stronger in women than in men [38].

More recently, the relationship between blood pressure (SBP and DBP) and clinically important kidney outcomes has been established, indicating that blood pressure is a valuable treatment target for patients with IgAN [27, 39]. There is evidence that SBP may be less predictive of kidney outcome in a generally younger population [41]. In addition, there is evidence that TA serum creatinine levels are independently predictive of poor kidney outcomes [35], and that reversal of T lesions is associated with improvements in hematuria and proteinuria in Chinese patients, suggesting that there is benefit to patients with active glomerular lesions in receiving immunosuppressive treatment [40].

The relationships of TA proteinuria, TA SBP, TA hematuria, and eGFR slope with composite kidney events or eventual progression to kidney failure have been established in European cohorts [26, 41, 42]. Surrogate relationships of TA proteinuria and eGFR slope with poor kidney outcomes have also been demonstrated in the South Asian (GRACE-IgANI) cohort [30]. The significant associations between TA proteinuria and progression to kidney failure have since been further confirmed in a recent study of 2299 patients with IgAN in the UK National Registry of Rare Kidney Diseases IgAN cohort [3]. Relationships to other endpoints (doubling of serum creatinine and eGFR decline) have been studied largely in East Asian cohorts. Confirmation of associations of these surrogate endpoints to long-term outcomes would be required in cohorts outside of East Asia to verify the predictive value in these populations. It should also be noted that the standard of care treatment for IgAN differs between East Asia (China, Taiwan, South Korea, Japan) and North America/Europe/Australia [25]. Tonsillectomy and mycophenolate mofetil are recommended treatments in Japan and China, respectively, and rare outside of these countries. Elsewhere, the standard of care treatment typically involves angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, with glucocorticoids for patients at high risk for chronic kidney disease, as per the 2021 Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines [25]. As a result of these regional differences in recommended care, extrapolation from associations found in East Asian populations to a global context should be done with caution. It should be mentioned that proteinuria and eGFR have shown consistent association when evaluated as surrogate endpoints for kidney clinical outcomes across multiple geographical regions, with large, published studies in European, East Asian, and South Asian cohorts.

Surrogate endpoints have been evaluated as predictors of worsening kidney function both in unadjusted models and within multivariate models that include prognostic factors. Hematuria [33, 38, 42], proteinuria [3, 27, 30, 32, 37, 41, 42, 44], SBP [27, 41], serum albumin [35, 38], and GFR decline [28, 29, 41, 43] have all shown independent predictive value in models that adjust for other prognostic factors, strengthening evidence of potential use as surrogate endpoints. As a result of the variety of measures used for many surrogate endpoints (e.g., value at timepoint, TA values, highest value during follow-up), meta-analysis is not possible for most surrogate relationships.

The included studies differed with respect to the long-term kidney outcomes of interest considered. Four outcomes were included in this review: composite kidney events, progression to kidney failure, doubling of serum creatinine, and decline in eGFR. Most studies that included kidney failure as an outcome included dialysis or transplantation in the definition; Reich 2007 included a creatinine clearance < 15 mL/min/1.73 m² in the definition of kidney failure [28]. Composite kidney events were defined in a variety of ways. The greatest number of studies (n = 6) used a 50% decline in eGFR and kidney failure as component events. Three studies instead used a 30% decline in eGFR [37, 39, 40]. One study instead defined a composite event as an eGFR decrease of ≥ 5 mL/min/1.73 m²/year or doubling of serum creatinine [35].

A key utility of surrogate endpoints is for use in clinical trials as an outcome requiring shorter follow-up time, offering a means to demonstrate treatment efficacy over a shorter follow-up period. Recent data suggests rapid decline in eGFR post biopsy (≥ 5 mL/min/1.73 m²/year) might be a potentially valuable surrogate endpoint for clinical trials, as demonstrated in a South Asian IgAN cohort [30]. Additionally, TA proteinuria has a strong association with kidney failure in both a representative incident population and a population selected to be more representative of a typical phase 3 randomized controlled trial, which indicates that the use of this surrogate endpoint is potentially suitable for generalization of clinical trial results to a broader unselected population [3]. These observations support the conclusions of Inker 2021, which suggests that urinary protein levels could be useful for the selection of patients in clinical trials, particularly for confirmatory studies [20]. One drawback of TA proteinuria is the lack of a consensus definition or a standard method of calculation. Definitions in the studies included in this review included 24-h urinary protein excretion averaged over various time intervals (e.g., 3 or 6 months) [28, 35, 42], 24-h urinary protein excretion indexed for eGFR (i.e., [24-h protein excretion/eGFR] × 100) [41], and a time-weighted average for uPCR calculated from the area under the curve of serial measurements divided by the length of follow-up [3]. It would be useful to establish the minimum number of proteinuria measurements and time frame of observation needed to establish a valid assessment of TA proteinuria in clinical trials. TA hematuria also appears to be a potentially strong surrogate endpoint in a clinical trial context, especially in Asian women; however, the relative value of this surrogate endpoint over TA proteinuria is unclear. Quantified hematuria data is less likely to be available outside of clinical trials, as microscopic analysis is not standard in clinical practice [48].

This review provides a comprehensive overview of the current state of the identification and validation of surrogate endpoints suitable for use in clinical trials in IgAN. Associations of identified surrogate endpoints with several clinically important long-term kidney outcomes are explored; these associations highlight the evidence on widely acknowledged surrogate endpoints, such as eGFR and proteinuria, and show the utility of other potentially useful surrogate endpoints with emerging evidence. Results are consistent with the research of Barbour et al., who developed prediction models for IgAN progression incorporating baseline proteinuria, eGFR, and SBP as risk factors for 50% decline in eGFR or kidney failure in a multiethnic cohort [49]. For regular clinical practice, the literature supports the use of conveniently assessed cutoffs for eGFR (60 mL/min/1.73 m²) and proteinuria (1 g/day) in risk determination, although the most recent research on the predictive value of proteinuria suggests that a lower proteinuria cutoff may be indicative of increased progression risk [3].

Notwithstanding the comprehensive literature searches underpinning this systematic review, the findings are limited by the availability of published data. This review focuses only on observational studies explicitly reporting on surrogate relationships, given that we did not include clinical trials reporting potential surrogate endpoints as post hoc outcomes, secondary to primary efficacy or safety outcomes. Moreover, restricting the search to studies in IgAN populations may have excluded surrogate relationships identified in broader populations with kidney disorders, limiting generalizability. While IgAN-specific data remains essential for clinical trial endpoint validation, findings from other glomerular diseases may provide additional context on the predictive value of certain surrogate endpoints. Geographical bias may limit the extrapolation and applicability of data. Most included studies were conducted in Asian populations. While this reflects the higher prevalence of IgAN in these regions, differences in treatment practices, healthcare infrastructure, disease presentation and progression, and genetic risk factors may exist. These studies provide important contributions to the field; however, the reported surrogate–outcome associations could therefore reflect region-specific clinical practices rather than universally applicable trends. Future research in diverse cohorts should be considered to ensure a more comprehensive understanding of whether these surrogate relationships hold across different racial, ethnic, and healthcare system contexts.

Methodological limitations of this review include a reliance on retrospective cohort studies, which can be associated with shortcomings like selection bias, data gaps, variability in data reporting, and not accounting for changes in clinical practice over time [50]. We attempted to mitigate these risks by assessing methodological quality with appropriate tools. Also, the reliance on observational studies may affect the strength of conclusions regarding surrogate relationships. Furthermore, statistical limitations should be considered when interpreting the conclusions. The statistical significance of associations varied across studies as a result of differences in study design, sample sizes, and follow-up durations, making it challenging to directly compare results and quantify the predictive value of surrogate endpoints for long-term kidney outcomes in IgAN. Additionally, for some of the surrogate markers evaluated, only a single study reported an association with long-term outcomes, limiting the ability to confirm the association through independent replication, and conclusions regarding these associations should be made with caution.

Another limitation is the absence of a meta-analysis as a result of the heterogeneity of study designs, definitions of surrogate endpoints, and outcome measures. The heterogeneity precluded a pooled statistical analysis. For example, the predictive utility of eGFR as a surrogate endpoint was assessed using eGFR at specified short-term time points (e.g., month 3 or 6), a threshold for eGFR decline (e.g., < 60 mL/min/1.73 m²), or rate of eGFR change over time. The use of proteinuria as a surrogate endpoint is not straightforward, given that multiple proteinuria measures and urine collection methods exist, each with their own strengths and weaknesses [51]. Urinary albumin-to-creatinine ratio is guideline-recommended over uPCR for some purposes but is not always available, and 24-h urine collection can be cumbersome and hence is more feasible in clinical trial contexts, whereas spot values may be more common in registry data. Time of collection (e.g., first void or after) can affect proteinuria values. Long-term outcome measures also varied among the reviewed studies, with some assessing the doubling of serum creatinine and others a 50% rise in serum creatinine [35, 36, 38, 43], and with some evaluating a 30% decrease in eGFR and others a 50% decrease [26, 27, 30–33, 37, 39, 40]. Future research using standardized definitions and harmonized methodologies would allow for the quantification of the predictive value of surrogate endpoints in IgAN.

Finally, this review excluded publications published before 2006 and after September 2023 and is regarded as a limitation given the increasing pace of clinical trial research in IgAN. Future updates incorporating emerging evidence could strengthen the findings, adding to the comprehensive understanding of surrogate endpoints in IgAN. Clinical trial data validating novel targets in IgAN pathogenesis continue to provide new insights on relationships among disease pathways, short-term endpoints, and longer-term outcomes [52].

Conclusions

Findings from this review present compelling evidence of the association of proteinuria and eGFR with clinically important long-term kidney outcomes in IgAN, particularly kidney failure, across multiple studies and geographic regions. Other potential surrogate markers of kidney disease progression that can serve as surrogate endpoints suitable for clinical trials in IgAN such as TA proteinuria, TA SBP, TA hematuria, and eGFR decline have also been shown to predict clinically important kidney endpoints in European, South Asian, and East Asian cohorts; however, further validation in cohorts with a wider spectrum of IgAN severity is required.

This review extends beyond previous reviews that assessed single surrogate endpoints [19–22], providing a comprehensive assessment of potential surrogate relationships in IgAN and demonstrating the strength of surrogate endpoints. The current literature suggests that treatments that target urine protein, hematuria, albuminuria, or blood pressure may lower future risk of kidney events (composite events, kidney failure). Further study is required to quantify these associations in populations across the spectrum of IgAN severity, though current evidence suggests that long-term kidney outcomes are worse in patients with both persistent hematuria and proteinuria, compared to patients with only one of these conditions. Differences in regional standards of care introduce some heterogeneity in the strength of associations, which may affect the generalizability of findings. However, the consistency of association across Europe, South Asia, and East Asia highlights the strength and use of proteinuria and eGFR as surrogate endpoints for clinically important long-term kidney outcomes in IgAN.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Maria Lorenzi contributed to the methodology of the review, synthesized the findings, and served as the principal author of the manuscript. Sarah Cadarette designed and supervised the systematic literature review; Stephen Ebohon performed screening and extraction of data. Sarah N. Ali, Vakaramoko Diaby, Mohit Mathur, and Ancilla W. Fernandes contributed to the conceptualization and methodology of the review and contributed extensively to the review and editing of the manuscript. All authors read and approved the final manuscript.

Funding

This work and the journal’s rapid service and open access fees were funded by Otsuka Pharmaceutical Development and Commercialization, Inc., Princeton, New Jersey.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or used in the current study. Information on studies included in the review is included in the Supplementary Material.

Declarations

Conflict of Interest

Sarah N. Ali, Vakaramoko Diaby, and Ancilla W. Fernandes are employees of Otsuka, which provided funding for this study. Maria Lorenzi, Sarah Cadarette, and Stephen Ebohon are employees of Cencora, which was a paid vendor for this work. Mohit Mathur is an employee of Visterra, which is a wholly owned subsidiary of Otsuka.

Ethical Approval

This article is based on previously conducted studies and does not include any new studies involving human participants or animals performed by the authors.