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. 2026 Aug 20;11(11):107038. doi: 10.1016/j.ekir.2026.107038

Systematic Review of Persistent Microscopic Hematuria and Kidney Outcomes in IgAN

Gian Marco Berti 1,4, Daniele Vetrano 1,4, Edoardo Tringali 2, Francesco Tondolo 3, Chiara Cantarelli 1,3, Gisella Vischini 3, Elisa Gessaroli 1, Giorgia Comai 1,3, Gaetano La Manna 1,3,∗, Federica Martitati 3
PMCID: PMC13634875  PMID: 42835070

Abstract

Background

IgA nephropathy (IgAN) is a common glomerulonephritis, but the prognostic relevance of persistent microscopic hematuria remains uncertain. Persistent hematuria may reflect glomerular inflammation and complement proteinuria and estimated glomerular filtration rate (eGFR) in longitudinal assessment. We evaluated its association with kidney outcomes.

Methods

MEDLINE, Embase, and Web of Science were searched through July 28, 2026, for studies evaluating longitudinal or persistent microscopic hematuria in IgAN. Categorical time-to-event estimates were pooled as hazard ratios (HRs) using random-effects models. Adjusted estimates were prioritized, and heterogeneity was assessed using the I2 statistic and restricted maximum likelihood estimation. Continuous estimates were summarized because of heterogeneous definitions and scales.

Results

A total of 9 reports representing 8 independent cohorts and 4776 participants were eligible. In the analysis including the Yu et al. cohort, 6 studies (n = 3,031; 423 events) showed that persistent microhematuria was associated with kidney disease progression (HR: 2.64; 95% confidence interval [CI]: 2.00–3.47; I2 = 0%). Results remained consistent after Hartung–Knapp adjustment (HR: 2.64; 95% CI: 2.25–3.09). An alternative analysis replacing Yu et al. with the updated Tang et al. cohort confirmed this association (n = 3,469; 703 events; HR: 2.26; 95% CI: 1.54–3.31; I2 = 26.5%), with similar Hartung–Knapp estimates (HR: 2.26; 95% CI: 1.53–3.33). Leave-one-out analyses showed that the findings were not driven by any single study. Continuous hematuria measures generally indicated higher kidney risk but were not pooled because of incompatible effect scales.

Conclusions

Persistent microscopic hematuria is associated with kidney disease progression in IgAN. Longitudinal assessment may provide additional prognostic information alongside conventional biomarkers. Prospective studies should define its role in risk stratification and treatment monitoring.

Keywords: glomerular filtration rate, hematuria, IgA nephropathy, kidney disease progression, prognosis, meta-analysis

Graphical abstract

graphic file with name ga1.webp

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IgAN represents the most prevalent immune-mediated glomerulonephritis worldwide.1 Diagnosis of primary IgAN relies on histologic evidence of IgA-dominant or codominant mesangial immune deposits on kidney biopsy, together with clinical assessment aimed at ruling out other causes, including IgA-dominant infection-related glomerulonephritis and secondary forms linked to liver disease or autoimmune conditions.2 IgAN is characterized by substantial heterogeneity in its clinical presentation and course.

Most patients present with microscopic hematuria and nonnephrotic proteinuria, although the spectrum extends even to rapidly progressive crescentic disease. Episodic macroscopic hematuria, especially in early phases of disease, may also occur, often in association with intercurrent triggers.3 However, microscopic hematuria represents the most common clinical manifestation of IgAN, resulting from mesangial deposition of IgA immune complexes, causing direct active glomerular inflammation and capillary wall damage. This pathophysiologic mechanism implies a close relationship between hematuria and disease activity in IgAN.4,5

Although it represents a relevant biomarker in IgAN, microscopic hematuria has often received limited attention in both clinical practice and research settings.6 This may be related to the predominant focus on proteinuria, as reflected in current proteinuria-based guideline recommendations.7 This distinction is clinically relevant because current Kidney Disease: Improving Global Outcomes guidelines identify proteinuria as the only validated early modifiable biomarker for guiding treatment decisions, with recommended maintenance below 0.5 g/d and, ideally, below 0.3 g/d. In contrast, longitudinal microscopic hematuria is not yet incorporated into formal therapeutic targets. Accordingly, microscopic hematuria has been regarded as a nonspecific, or even “benign” manifestation of glomerular barrier derangement, rather than as a potentially informative dynamic marker of disease activity and prognosis.8 Nevertheless, evidence from centers with particular attention to accurate urinary sediment analysis at diagnosis and throughout follow-up suggests that persistent microscopic hematuria is significantly associated with an increased risk of disease progression.9,10

This question has gained renewed prominence with the recent publication of 2 opposing expert viewpoints, bringing into sharper focus the unresolved debate over whether hematuria in IgAN is merely a marker of disease activity or a biomarker with potential relevance for therapeutic decision-making.11,12

In this context, we performed a systematic review and meta-analysis to clarify the prognostic significance of microhematuria in IgAN, with particular emphasis on persistent and longitudinal hematuria as predictors of adverse kidney outcomes amid the current debate over its therapeutic relevance.

Methods

Literature Search Strategy and Eligibility Criteria

This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020. The protocol was registered in PROSPERO (ID: CRD420261282641.).

A systematic literature search was conducted in MEDLINE (through PubMed), Embase, and Web of Science to identify studies evaluating the association between persistent microhematuria, focusing on longitudinally assessed microhematuria (e.g., persistent hematuria, time-averaged hematuria, and hematuria trajectories) and renal outcomes in patients with IgAN. The search was last updated on July 28, 2026. No date restrictions were applied; the search was restricted to human studies and English-language publications. Reference lists of eligible studies and relevant review articles were screened to identify additional records.

Studies were eligible if they: enrolled patients with IgAN; quantified hematuria longitudinally (persistent, time-averaged, or trajectory-based definitions); reported an association with renal outcomes using an effect estimate (or provided sufficient data to derive it); and used a kidney end point including end-stage kidney disease and/or a sustained 50% decline in eGFR, either as standalone outcomes or within composite end points consistent with those used in the International IgAN Prediction Tool. If multiple eligible end points were available, we prioritized the most severe/hard outcome.

We excluded case reports or series, cross-sectional studies without longitudinal renal outcomes, editorials or commentaries, and conference abstracts without an accessible full text. After duplicate removal, titles and abstracts were screened and potentially relevant articles underwent full-text assessment.

Study selection was performed independently by two reviewers, with disagreements resolved by consensus (Figure 1).

Figure 1.

Figure 1

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Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 flow diagram of study selection.

Data Extraction and Operational Definitions

For each included study, we extracted study-level characteristics (country/setting, sample size, and follow-up duration), baseline patient characteristics, the hematuria metric, and its longitudinal operational definition, the renal outcome definition, the number of events when reported, and the most fully adjusted effect estimate.

Given the expected heterogeneity in hematuria assessment across studies, we accepted author-defined categorical measures provided they captured longitudinal hematuria burden rather than cross-sectional exposure. When multiple eligible contrasts were reported within a study, we prespecified extraction of 1 estimate per study to avoid double counting; for trajectory-based analyses, we preferentially selected the comparison most representative of sustained high exposure (e.g., high-stable vs. low-stable). Multivariable-adjusted estimates were prioritized over unadjusted results.

For studies reporting annual eGFR decline, we extracted group-level slopes (ml/min per 1.73 m2/yr) or model-derived slope differences and calculated mean differences (MDs) and corresponding standard errors when not directly provided.

Risk of Bias and Certainty Assessment

Risk of bias was assessed using the Quality in Prognosis Studies tool, which evaluates potential bias across domains relevant to observational prognostic cohort studies (study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, and statistical analysis/reporting). Assessments were performed independently by 2 reviewers, with disagreements resolved by consensus. Risk of bias judgments were used to inform qualitative interpretation of the evidence (Supplementary Figure S1). Certainty of evidence was assessed using the GRADE approach for prognostic factors, with observational prognostic evidence initially rated as high certainty and downgraded, where appropriate, for risk of bias, inconsistency, indirectness, imprecision, and publication bias (Supplementary Table S1).

Effect Measure and Data Handling

Given the substantial heterogeneity in methods, units, and definitions used to assess microscopic hematuria across studies, only studies reporting categorical hematuria definitions were included in the quantitative data synthesis to reduce methodological heterogeneity. The primary objective was to quantify the association between categorical persistent microscopic hematuria and adverse kidney outcomes. The secondary objective was to assess the association between categorical persistent microscopic hematuria and annual eGFR decline.

For both quantitative analyses, the higher-risk hematuria group was defined as the study-specific category reflecting persistent, nonremitting, high-degree, or high-stable hematuria, whereas the lower-risk comparator group reflected hematuria remission or negative or minimal, low-degree, or low-stable hematuria. The primary effect measures were HRs for time-to-event kidney outcomes and MDs in annual eGFR slope between higher- and lower-risk hematuria groups.

HRs were analyzed on the logarithmic scale. For each study, we computed the log effect size as log(HR) and derived its standard error from the reported 95% CI as: SE (log[HR]) = (log[CI_high]−log[CI_low])/(2 × 1.96). When studies reported HRs for a decrease in hematuria (i.e., HR < 1 because the predictor was coded as “reduction”), we inverted the estimate to express risk per increase in hematuria: HR_increase = 1/HR_decrease, with confidence limits inverted accordingly.

For annual eGFR decline, the effect measure was the MD in eGFR slope (ml/min per 1.73 m2/yr) between higher- versus lower-microhematuria groups. When not directly provided, MDs and their standard errors were derived from group-level slopes (mean ± SD with sample sizes) or from model-based estimates and CIs. Effect directions were harmonized such that more negative MD values indicate faster eGFR decline in the higher-microhematuria group. Bobart et al.5 used generalized estimating equations with repeated eGFR measurements, Yano et al.13 used linear mixed regression models, and Sevillano et al.10 calculated individual eGFR slopes expressed as annual rates of renal function loss; Ma et al.14 reported annualized rates of renal function decline, although the precise slope-estimation method was not described.

Studies reporting continuous hematuria metrics were included in the systematic review and summarized narratively but were not pooled quantitatively.

Statistical Analysis

Meta-analyses were conducted using an inverse-variance approach. For time-to-event outcomes, HRs were pooled on the log scale and back-transformed for presentation. Annual eGFR decline was synthesized as the MD in eGFR slope (ml/min per 1.73 m2/yr) between higher- and lower-microhematuria groups, with effect directions harmonized so that more negative MD values indicate faster decline.

Pooled estimates were obtained using random-effects models to account for between-study variability, with τ2 estimated by restricted maximum likelihood. CI for the main analyses were calculated using the conventional normal approximation (“classic” random-effects), and Hartung–Knapp-adjusted CIs were computed as a sensitivity analysis. The influence of individual studies on the primary categorical analysis was further assessed using leave-one-out analyses. Statistical heterogeneity was assessed using Cochran Q test and quantified using I2 and τ2.

Small-study effects were explored through visual inspection of funnel plots and formally tested using Egger regression, acknowledging the limited power of these methods when the number of included studies is small.

All tests were two-sided, with p < 0.05 considered statistically significant. Analyses were performed in R (version 4.5.2; R Foundation for Statistical Computing, Vienna, Austria) using the meta package.

Results

Across 9 reports5,9,10,13, 14, 15, 16, 17 representing 8 independent observational cohorts (sample size range, 72–1,771; 4776 unique participants), longitudinal microhematuria was assessed using heterogeneous metrics and related to hard kidney outcomes, including end-stage kidney disease and/or sustained eGFR decline, either alone or within composite end points. Baseline eGFR ranged approximately from 55 to 91 ml/min per 1.73 m2, whereas baseline proteinuria was generally between 0.9 and 2.5 g/24 h (Table 1).

Table 1.

Main characteristics of studies included in the systematic review and meta-analysis of persistent microscopic hematuria and kidney outcomes in IgA nephropathy

Study Design/setting N Hematuria definition Baseline eGFR (ml/min per 1.73 m2) Baseline proteinuria Oxford MEST-C Renal outcome (includes ESKD) Index date Follow-up Events Adjusted HR (95% CI) Adjustment variables
Bobart et al.5 Retrospective cohort 72 Persistent hematuria, categorical (> 21 RBCs/HPF: yes vs. no) 55 ± 29 2.5 ± 2.7 g/24h Yes ESKD Kidney biopsy 3.69 (2.07, 6.96) years 9 Categorical: 1.87 (0.36–9.61) Follow-up time, TA proteinuria, and T1-T2 lesions.
Yu et al.9 Retrospective cohort 1333 Hematuria remission status, categorical (non-remission vs. remission)
Time-varying hematuria, continuous (per 1-unit increase in log-transformed urinary RBC count)		 82.2 ± 30.6 1.31 (0.68–2.54) g/24 h Yes Composite: 50% eGFR decline or ESKD Kidney biopsy Median 45 mos 207 Categorical: 2.44 (1.64-3.57)
Continuous 1.46 (1.13–1.87)		 Age, sex, time-varying log-transformed proteinuria, time-varying mean arterial pressure, baseline eGFR, Oxford MEST-C score, and steroid or other immunosuppressive treatment.
Sevillano et al.10 Retrospective cohort 112 Time-averaged hematuria, categorical (> 5 vs. ≤ 5 RBCs/HPF). 58 ± 34.6 1.4 (0.4–2.7) g/24 h Yes ESKD Kidney biopsy 14.0 ± 10.2 yrs 21 Categorical: 2.84 (1.06–7.30) Age at baseline, baseline renal function, TA proteinuria, and T1–T2 lesions.
Weng et al.15 Retrospective cohort 152 Automated urinary RBC count, continuous (per 1 RBC/μl increase) 90.5 (60.3–115.5) 1.11 (0.44–2.02) g/24h Yes Composite: doubling SCr or ESKD Kidney biopsy (time origin not explicitly stated) 58.1 ± 23.5 mos 19 Continuous: 1.004 (≈1.001–1.008) Hypertension, history of macroscopic hematuria, baseline microscopic hematuria severity, blood urea nitrogen, hemoglobin, uric acid, baseline eGFR, baseline 24-hour proteinuria, T1–T2 lesions, and time-averaged serum albumin.
Huang et al.16 Retrospective; PSM 1:1 456 Persistent hematuria, categorical (high hematuria: ≥330 RBCs/μL vs. low hematuria: < 330 RBCs/μl)
Continuous urinary RBC analysis; effective model scale not explicitly reported.		 ∼87.5–87.9 ± 27 1.52 vs. 1.89 g/24 h (median) Yes Composite: sustained ≥30% eGFR decline or ESKD/death Kidney biopsy ∼45–48 mos 72 Categorical: 3.93 (1.33–11.6)
Continuous: 1.05 (1.04–1.08)		 Serum uric acid, triglycerides, and proteinuria remission. In addition, the cohorts were propensity-score matched for age, sex, baseline eGFR, and follow-up duration.
Ma et al.14 Retrospective cohort (crescentic IgAN) 169 Persistent dipstick hematuria (positive urine occult blood test ≥±), categorical (yes vs. no) 83.1 ± 30.4 2.1 ± 2.9 g/24 h Yes Composite: ≥ 50% eGFR decline or ESKD Kidney biopsy 51.7 ± 24.7 mos 29 Categorical 3.07 (1.12–8.48) Age, sex, smoking status, percentage of crescents, TA proteinuria, persistent hematuria, and TA mean arterial pressure
Le et al.17 Registry/multicenter cohort 1155 Time-averaged hematuria, continuous (author-defined scale) 89 ± 33 0.89 (0.51–1.59) g/24h No Composite: ≥50% eGFR decline or ESKD Kidney biopsy 5.4 (4.1 to 7.2) yrs 163 Continuous 2.1 (1.6–2.7) TA proteinuria and TA mean arterial pressure.
Yano et al.13 Registry/multicenter cohort 889 Dipstick hematuria trajectory, categorical (high-stable vs. low-stable) 62.0 ± 28.8 Dipstick categories No ≥ 50% eGFR decline First recorded IgAN diagnosis or earliest available clinical encounter Median 49 mos (IQR 20–57) 85 Categorical: 2.69 (1.54–4.70) Age, sex, hypertension, diabetes, eGFR at the index date, use of SGLT2 inhibitors use, ACE inhibitors or ARBs use of immunosuppressive drugs during follow-up.
Tang et al.18 Prospective observational, single-center cohort; updated and expanded report based on the cohort previously described by Yu et al.9 1771 Automated time-updated urinary RBC count, categorical: < 10, 10 to < 20, 20 to < 100, and ≥ 100 RBC/μl; primary comparison ≥ 100 vs. < 10 RBC/μl 74.2 (49.8–99.0) 1.28 (0.66–2.34) g/24 h Yes Composite: ≥ 40% decline in eGFR or ESKD, defined as eGFR < 15 ml/min per 1.73 m2, dialysis initiation, or kidney transplantation Kidney biopsy Median 48 mos (IQR 30–78) 487 Categorical: 1.53 (1.14–2.06) Age, sex, BMI, albumin, proteinuria, eGFR, mean arterial pressure, diabetes, and Oxford MEST-C scores; time-updated albumin, proteinuria, eGFR, mean arterial pressure, RAS inhibitors, other antihypertensive drugs, hydroxychloroquine, SGLT2 inhibitors, corticosteroids, and other immunosuppressants.
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ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HPF, high-power field; HR, hazard ratio; IgAN, IgA nephropathy; IQR, interquartile range; MEST-C, mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubular atrophy/interstitial fibrosis, and crescents; N, number of participants; PSM, propensity score matching; RAS, renin angiotensin; RBC, red blood cell; SCr, serum creatinine; SGLT2, sodium–glucose cotransporter 2; T1–T2, tubular atrophy/interstitial fibrosis grades 1–2 in the Oxford MEST-C classification.

Categorical Persistent Microhematuria and Composite Kidney Outcome Risk

Overall, 7 reports representing 6 independent study populations were eligible for the categorical analysis. Because the reports by Yu et al.9 and Tang et al.18 were based on substantially overlapping cohorts, they were not included simultaneously but were evaluated in 2 separate analyses, each comprising 6 nonoverlapping reports.

In the analysis incorporating Yu et al., 6 studies comprising 3031 participants and 423 kidney events were included. Using a random-effects model with the restricted maximum likelihood estimator and conventional CIs, persistent or higher-burden microhematuria was associated with a markedly increased risk of the composite kidney outcome (pooled HR: 2.64; 95% CI: 2.00–3.47; P < 0.0001) (Figure 2a). Between-study heterogeneity was negligible (τ2 = 0; I2 = 0%; Q = 0.96; df = 5, P = 0.966). The results were consistent after applying the Hartung–Knapp adjustment (pooled HR: 2.64; 95% CI: 2.25–3.09; P < 0.0001) (Supplementary Figure S2A). Leave-one-out analyses showed that the pooled association remained statistically significant and was not materially altered after the sequential omission of any individual study, indicating that no single cohort, including the largest contributing cohort, disproportionately drove the overall estimate (Figure 3a). Visual inspection of the funnel plot did not suggest clear asymmetry, and Egger regression test was not statistically significant (t = 0.91; df = 4; P = 0.414); however, these assessments should be interpreted cautiously given the limited number of studies (Supplementary Figures S3A and S4A).

Figure 2.

Figure 2

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Association between categorical persistent microscopic hematuria and risk of composite kidney outcome. HR, hazard ratio.

Figure 3.

Figure 3

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Leave-one-out sensitivity analysis of association between categorical persistent microscopic hematuria and composite kidney outcome.

In the additional analysis replacing Yu et al.9 with the updated Tang et al.18 cohort, persistent microhematuria remained strongly associated with kidney disease progression under conventional random-effects CIs (HR: 2.26; 95% CI: 1.54–3.31; P < 0.0001), with low between-study heterogeneity (τ2 = 0.077; I2 = 26.5%; Q = 6.81, df = 5, P = 0.235) (Figure 2b). Results were nearly identical using the Hartung–Knapp model (pooled HR: 2.26; 95% CI: 1.53–3.33; P = 0.003) (Supplementary Figure S2B). Leave-one-out analyses further supported the robustness of the association, with pooled HRs ranging from 2.11 to 2.85 and remaining statistically significant irrespective of the study omitted (Figure 3b).

Categorical Persistent Microhematuria and Annual eGFR Decline

A total of 4 studies reported differences in annual eGFR slope between higher-risk versus lower-risk microhematuria categories. Across studies, higher-risk microhematuria was generally associated with a faster decline, with study-level effects ranging from MD −0.85 to MD −5.30 ml/min per 1.73 m2/yr.

In the random-effects (restricted maximum likelihood) model with classic CI, microhematuria was associated with a significantly greater eGFR decline (pooled MD = −2.58 ml/min per 1.73 m2/yr, 95% CI: −4.57 to −0.59; P = 0.011) (Figure 4); however, heterogeneity was substantial ((I2 = 77.5%; 95% CI 38.9%–91.7%; Q = 13.32, df = 3, P = 0.004; τ2 = 2.96) and the Hartung–Knapp CI crossed the null (−2.58 ml/min per 1.73 m2/yr; 95% CI: −5.78 to 0.62; P = 0.083) (Supplementary Figure S2C).

Figure 4.

Figure 4

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Association between categorical persistent microscopic hematuria and annual eGFR decline.

Funnel plot interpretation was limited, and Egger test suggested a borderline signal (t = −3.62; df = 2; P = 0.068); given the very small number of studies, this finding is unstable and should be interpreted with caution (Supplementary Figures S3B and S4B).

Continuous Persistent Microhematuria and Composite Kidney Outcome Risk

A total of 4 studies including 3096 participants and 461 kidney events evaluated longitudinal microscopic hematuria as a continuous exposure (Table 2).

Table 2.

Studies reporting continuous longitudinal microscopic hematuria measures and kidney outcome associations in IgA nephropathy

Study Yr Hematuria assessment method Exposure scaling Adjusted risk coefficient
Le et al.17 2012 Urine sediment microscopy; serial urinary RBC counts summarized as time-averaged hematuria Per 10-fold increase in time-averaged microscopic hematuria HR: 2.10 (95% CI: 1.60–2.70)
Yu et al.4 2020 Fresh urine assessed at each visit by automated urine particle analysis and manual urine sediment microscopy; mean hematuria within each 6-mo interval was modeled as a time-varying measure Per 1-unit increase in log-transformed mean hematuria HR: 1.46 (95% CI: 1.13–1.87)
Weng et al.15 2022 Automated urine particle analysis; time-averaged hematuria calculated from serial urinary RBC measurements during follow-up Per 1 RBC/μl increase in time-averaged hematuria HR: 1.004 (95% CI: 1.001–1.008)
Huang et al.16 2023 Fully automated urine particle analysis; repeated uRBC measurements summarized over sequential 6-mo blocks Numeric uRBC variable; effective unit of increase not explicitly reported HR: 1.05 (95% CI: 1.04–1.08)
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CI, confidence interval; HR, hazard ratio; RBC, red blood cell; uRBC, urinary red blood cell.

Across studies, higher hematuria burden was consistently associated with a higher risk of kidney disease progression after multivariable adjustment. However, the methods used to quantify hematuria and the corresponding exposure scales differed substantially, including time-varying log-transformed measures, time-averaged urinary red blood cell counts, and numeric variables with incompletely specified scaling. Therefore, continuous estimates were not pooled quantitatively. Overall, these study-specific analyses support a consistent directional association between greater longitudinal hematuria burden and higher kidney risk, whereas direct comparison of effect magnitudes across studies is not appropriate.

Discussion

Microscopic hematuria is characterized by the presence of dysmorphic red blood cells in the urine, consistent with glomerular filtration barrier disruption in the absence of secondary causes, such as malignancy, medications, gynecological conditions, and lower urinary tract bleeding.19 The broad clinical and pathologic spectrum of IgAN underscores marked disease heterogeneity, challenging its classification as a single disease entity. Relying on a single parameter, such as proteinuria to define prognosis and disease severity risks oversimplifying and inappropriately grouping distinct disease phenotypes that, particularly in the era of targeted therapies, would benefit from a more refined risk stratification.17,20, 21, 22, 23 A key aspect of IgAN management is the accurate identification of patients with active disease who are at highest risk of rapid progression.24 This requires a tailored approach to patient stratification and management. Initial disease presentation is often asymptomatic or nonspecific, partly because serum creatinine rises late and is an insensitive marker of early kidney damage, and because microscopic hematuria is frequently overlooked; as a result, many patients present with established chronic kidney disease at the time of diagnosis.25,26 Although histologic features summarized by the mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubular atrophy/interstitial fibrosis, and crescents score (MEST-C) provide valuable prognostic information, they are insufficient on their own to guide therapy.27,28 Consequently, clinical parameters that reflect disease risk and define therapeutic goals play a central role in disease management. These include reduction of proteinuria, stabilization of eGFR, and resolution of microscopic hematuria.10,29,30 The integration of these parameters is essential; active histologic lesions have been shown to be closely associated with microscopic hematuria, and the prognostic and pathogenetic significance of proteinuria in the presence of hematuria is clearly distinct from that of isolated proteinuria.5,31,32 Likewise, a decline in eGFR attributable to disease activity, after exclusion of potentially reversible and/or modifiable confounding factors, such as inadequate blood pressure control, obesity, diabetes, and other risk factors, enables a more accurate risk stratification in patients with IgAN.33, 34, 35 Longitudinal assessment of microscopic hematuria using standardized measurements has shown that persistent hematuria is independently associated with kidney disease progression, whereas its resolution during follow-up is linked to improved kidney outcomes.10

Evidence from other inflammatory glomerular diseases shows hematuria as a marker of active glomerular inflammation, supporting its consideration as a meaningful marker also in IgAN.36, 37, 38 It is important to distinguish hematuria reflecting active disease from that because of structural glomerular barrier defects, as in Alport syndrome or thin basement membrane nephropathy. In this meta-analysis, we extend this concept by showing that persistent microscopic hematuria is significantly associated with adverse renal outcomes and disease progression in patients with IgAN. These findings indicate that it is not merely an innocuous epiphenomenon of glomerular injury, but rather a clinically meaningful biomarker with independent prognostic relevance.

From a pathophysiologic perspective, IgAN is driven by the deposition of immune complexes composed of galactose-deficient IgA1 bound by antiglycan IgG antibodies, which induce cytokine release, leukocyte migration, and activation of the complement system, particularly through the alternative and lectin pathways, thereby amplifying glomerular injury.39, 40, 41 Sustained inflammation promotes extracellular matrix expansion and structural damage of the glomerular filtration barrier, and, together with increased permeability resulting from the proinflammatory milieu, favors dysmorphic erythrocyte leakage into the urinary space, clinically manifesting as microscopic hematuria.4,42 Moreover, hemoglobin and heme-related products released from lysed red blood cells further induce the generation of reactive oxygen species, lipid peroxidation, and other proinflammatory processes, thereby perpetuating a self-amplifying loop.43 Persistence of these processes contributes to both downstream tubulointerstitial injury, through direct epithelial cell toxicity and red blood cell cast-induced acute tubular injury, and upstream podocyte damage, leading to cellular dysfunction, apoptosis, and detachment from glomerular capillaries.44 Consequently, microscopic hematuria in IgAN likely represents not only a marker of active glomerular injury, but also a pathogenic contributor to proteinuria.45,46 Sevillano et al.10 showed that persistent microscopic hematuria identified, among patients with residual proteinuria, a subgroup with significantly worse outcomes, supporting the concept that time-averaged hematuria enhances the predictive value of time-averaged proteinuria. In this context, the coexistence of microscopic hematuria may help distinguish proteinuria driven by ongoing inflammatory activity, requiring closer surveillance and potential immunosuppressive treatment, from proteinuria predominantly reflecting chronic, noninflammatory glomerular damage, typically occurring in the absence of hematuria and managed with nephroprotective therapy alone.8,21,31,47

In line with this concept, histologic features of active glomerular inflammation, including mesangial hypercellularity (M), endocapillary hypercellularity (E), and cellular crescents (C) have been clearly correlated with hematuria presence at the time of kidney biopsy. Notably, the degree of microscopic hematuria during follow-up and its modification were independently associated with a faster decline in eGFR, even after adjustment for proteinuria, MEST-C score components, and treatment, with severe hematuria conferring the highest risk of functional deterioration.5

Previous studies investigating the prognostic role of microscopic hematuria in IgAN have yielded conflicting results. In this context, the findings of the present meta-analysis need to be interpreted in relation to the existing and often conflicting literature on the prognostic value of microscopic hematuria in IgAN. Although several studies evaluating microscopic hematuria at baseline did not show an independent association with renal outcomes,20,48,49 cohorts assessing persistent hematuria have largely reported a significant association with adverse kidney outcomes (Table 1). A previous meta-analysis of 13 studies and 5660 patients already investigated the value of hematuria at biopsy, and even if a significant association was observed only in the subgroup of microscopic hematuria, the overall pooled estimate for baseline hematuria (both microscopic or macroscopic) was not statistically significant, and no formal test for interaction was reported. Therefore, these findings should be interpreted with caution and do not allow definitive conclusions regarding the independent prognostic value of baseline hematuria.50 In contrast, our study focused exclusively on microscopic and persistent hematuria to identify high-risk patient profiles during follow-up. Our results suggest the prognostic impact of persistent microscopic hematuria on adverse renal outcomes, including both hard and surrogate end points. Our primary categorical analysis showed a consistent association between persistent microscopic hematuria and adverse kidney outcomes (Figure 2). Studies reporting continuous longitudinal hematuria metrics showed a similar direction of association, although direct comparison of effect magnitudes was limited by heterogeneity in exposure definitions, measurement methods, and scaling (Table 2). The use of persistent microscopic hematuria as a marker of disease activity appears more informative than hematuria assessed at baseline (kidney biopsy), as a single static measurement at diagnosis may not reflect subsequent treatment response or long-term disease trajectory. In contrast, persistent microscopic hematuria may identify patients with ongoing inflammatory activity who require closer monitoring and prospective evaluation for treatment escalation. In this context, persistent microscopic hematuria may be considered a reliable biomarker, alongside residual proteinuria and eGFR decline, to stratify patients who remain at high risk of progression despite previous therapy and who may benefit from novel, more tailored therapeutic strategies in the emerging era of disease-modifying agents (Figure 5). Notably, recent clinical trials investigating B-cell modulators, BAFF/APRIL inhibitors, and complement-directed therapies have increasingly included microscopic hematuria among treatment response end points further supporting its broader integration into clinical practice.51, 52, 53

Figure 5.

Figure 5

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Proposed clinical integration of persistent microscopic hematuria in risk stratification and longitudinal monitoring in IgAN (Created in https://BioRender.com). MEST-C, mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubular atrophy/interstitial fibrosis, and crescents.

The substantial methodological heterogeneity in hematuria quantification across studies likely reflects current real-world variability in urinary sediment assessment and underscores the need for standardized longitudinal hematuria definitions in IgAN.8 Future clinical implementation will need to address real-world discrepancies encountered in everyday care. A major source of variability lies in the assessment techniques themselves, which range from semi-quantitative dipstick testing to time-consuming but more accurate urinary sediment examination. Results are further influenced by preanalytical factors, the lack of standardized procedures, and the absence of shared clinical thresholds, all of which limit cross-study comparability.54, 55, 56 In this context, alternative methods such as hemoglobinuria detection may help confirm hematuria or address false-negative urinalysis results, especially when laboratory findings are discordant with the clinical course.30 Hemoglobinuria detected by dipstick may complement urine microscopy when preanalytical delay or sample degradation causes erythrocyte lysis and reduces the number of intact red blood cells detected. In the appropriate clinical context, discordant hemoglobinuria with negative or low-grade microscopic hematuria should prompt repeat testing of a fresh urine specimen (especially in patients with declining kidney function) and may help identify otherwise underestimated glomerular hematuria. Further evidence is needed to support its routine use.

Against the background of the recent pro–con debate, emerging in parallel with the rapid expansion of disease-modifying therapies for IgAN, our meta-analysis provides a quantitative synthesis supporting persistent microscopic hematuria as a clinically relevant prognostic marker of adverse kidney outcomes. Nonetheless, these findings should not yet be taken to imply that hematuria is a fully validated standalone biomarker for treatment selection, because its integration into therapeutic algorithms will require standardized measurement and prospective validation.11,12

Limitations

This meta-analysis has several limitations. First, the small number of included studies limited the precision of the pooled estimates and the reliability of statistical assessments of between-study heterogeneity and small-study effects. Accordingly, the absence of statistically detectable heterogeneity in the categorical analysis should not be interpreted as evidence of true homogeneity, whereas funnel plots and Egger regression should be considered exploratory because these methods are unreliable when fewer than 10 studies are available. Nevertheless, the primary categorical association remained statistically significant after the more conservative Hartung–Knapp adjustment, and leave-one-out analyses showed that its direction and magnitude were not materially altered by omission of any individual study, including the largest contributing cohort.

Second, although multivariable-adjusted estimates were preferentially extracted, adjustment strategies varied across studies with respect to kidney function, proteinuria, blood pressure, histopathological lesions, and treatment exposure. Residual confounding therefore cannot be excluded, particularly because all included studies were observational and some analyses incorporated time-varying clinical variables that may themselves have been influenced by previous treatment or disease activity. The pooled estimates should therefore be interpreted as evidence of an independent prognostic association rather than proof of a causal effect of persistent microscopic hematuria on kidney disease progression.

Finally, the eGFR-slope analysis was based on only four studies and was affected by heterogeneity in follow-up duration, baseline kidney function, definitions of hematuria exposure, and methods used to estimate eGFR slope. Moreover, although the pooled estimate was statistically significant using the conventional random-effects approach, its CI crossed the null after Hartung–Knapp adjustment. This finding should therefore be interpreted cautiously and regarded as hypothesis-generating rather than definitive.

Conclusion

Collectively, these findings help reconcile previously conflicting evidence and clarify that prognostic information in IgAN is conveyed not by the mere presence of microscopic hematuria, but by its persistence and cumulative burden over time, supporting its role as a dynamic biomarker of ongoing glomerular inflammation and disease activity. Alongside traditional clinical (residual proteinuria and eGFR decline) and histologic (MEST-C) risk factors routinely used to guide treatment decisions, these results underscore the importance of systematically tracking microscopic hematuria longitudinally as a clinically meaningful indicator for risk stratification, tailoring treatment selection and intensity, and longitudinal monitoring of disease activity.

Disclosure

All the authors declared no competing interests.

Footnotes

Supplementary File (PDF)

Figure S1. QUIPS risk-of-bias assessment.

Figure S2. Sensitivity analyses using the Hartung–Knapp adjustment. (A) categorical hematuria and kidney outcome with Yu et al. (B) categorical hematuria and kidney outcome with Tang et al. (C) categorical hematuria and annual eGFR decline.

Figure S3. Funnel plots for the main meta-analyses. (A) categorical hematuria and kidney outcome. (B) categorical hematuria and annual eGFR decline.

Figure S4. Egger’s regression tests for the main meta-analyses. (A) categorical hematuria and kidney outcome. (B) categorical hematuria and annual eGFR decline.

Table S1. GRADE certainty of evidence for the main outcomes.

PRISMA 2020 checklist.

Supplementary Material

Supplementary File (PDF)

Figure S1. QUIPS risk-of-bias assessment. Figure S2. Sensitivity analyses using the Hartung–Knapp adjustment. (A) categorical hematuria and kidney outcome with Yu et al. (B) categorical hematuria and kidney outcome with Tang et al. (C) categorical hematuria and annual eGFR decline. Figure S3. Funnel plots for the main meta-analyses. (A) categorical hematuria and kidney outcome. (B) categorical hematuria and annual eGFR decline. Figure S4. Egger’s regression tests for the main meta-analyses. (A) categorical hematuria and kidney outcome. (B) categorical hematuria and annual eGFR decline. Table S1. GRADE certainty of evidence for the main outcomes. PRISMA 2020 checklist.

mmc1.pdf (1.3MB, pdf)

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Associated Data

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Supplementary Materials

Supplementary File (PDF)

Figure S1. QUIPS risk-of-bias assessment. Figure S2. Sensitivity analyses using the Hartung–Knapp adjustment. (A) categorical hematuria and kidney outcome with Yu et al. (B) categorical hematuria and kidney outcome with Tang et al. (C) categorical hematuria and annual eGFR decline. Figure S3. Funnel plots for the main meta-analyses. (A) categorical hematuria and kidney outcome. (B) categorical hematuria and annual eGFR decline. Figure S4. Egger’s regression tests for the main meta-analyses. (A) categorical hematuria and kidney outcome. (B) categorical hematuria and annual eGFR decline. Table S1. GRADE certainty of evidence for the main outcomes. PRISMA 2020 checklist.

mmc1.pdf (1.3MB, pdf)

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