Incidence of Adult Primary Immunoglobulin A Nephropathy among a Racially/Ethnically Diverse Population in the United States

IgA nephropathy (IgAN) is one of the most common forms of primary glomerulonephropathy and is a leading cause of kidney failure [1]. At least 30% of affected patients progress to kidney failure within 20–30 years of diagnosis despite receiving standard of care [1]. While incidence rates vary globally, individuals of Hispanic/Latino descent have been underrepresented in IgAN research, and little is known about incidence in this population [2].

Prior studies in the United States (US) have been conducted in areas that were predominantly White and therefore underrepresented other racial/ethnic groups [3, 4]. Given the variability of incidence by race and ethnicity in IgAN, examining data from diverse populations would help in estimating incidence for a multiracial/multiethnic country such as the US. Using a racially/ethnically diverse cohort within a large integrated health system (Kaiser Permanente Southern California [KPSC]), we identified and characterized patients with biopsy-proven IgAN and report annual incidence rates across racial/ethnic groups and standardized to the US nationally.

A cross-sectional study within KPSC (an integrated health system) was performed during January 1, 2010–December 31, 2021. The membership is large (>4.8 million members) and racially, ethnically, and socioeconomically diverse, reflecting the general population of Southern California [5]. All KPSC members have similar benefits and access to healthcare services, clinic visits, procedures, and copays for medications. Complete healthcare encounters are tracked using a common electronic health record from which study information was extracted. This study was approved by the Kaiser Permanente Southern California Institutional Review Board (#5815) and granted an exemption from requiring written informed consent given the retrospective data only approach. Details of the KPSC glomerulopathy population have been previously described [5, 6]. The study population included members in the period between January 1, 2010, and December 31, 2021, who underwent a native kidney biopsy. Patients (age >/= 18 years) identified as having immunoglobulin A nephropathy (IgAN) on biopsy were eligible if their pathology report demonstrated “IgA nephropathy.” For individuals who had multiple biopsies, the first biopsy result was used for inclusion and subsequent analyses in this study. Supplemental paper and electronic chart reviews were performed to identify and categorize biopsy findings and diagnoses. Kidney pathology data were obtained from the KPSC Pathology Database, which captures all KPSC kidney biopsies. Of note, more than 97% of all KPSC members have their kidney biopsies performed within KPSC.

Race and ethnicity information were entered into the electronic health record based on either patient self-report or provider assessment. Hispanic/Latino ethnicity was treated as a race in response to findings from a national survey of Hispanics/Latinos living in the USA reporting that Hispanic/Latino people considered themselves a race of people and not an ethnicity [7]. Nearly, all Hispanics/Latinos within KPSC are Hispanic/Latino White; Hispanic/Latino Black members account for <1% of KPSC members. Thus, the designation of Hispanic/Latino within our study refers to Hispanic/Latino White members. Kidney function was reported as estimated glomerular filtration rate (eGFR) calculated from serum creatinine measurements using the 2021 Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI 2021) [8]. We assessed concurrent disease burden using the Elixhauser Comorbidity Index which quantifies 31 patient comorbidities based on International Classification of Diseases codes [9].

Patient characteristics were compared among racial/ethnic categories using chi-square or Fisher’s exact test for categorical variables, and one-way analysis of variance or Kruskal-Wallis test for comparison of continuous or ordinal variables, as appropriate. Shapiro-Wilks test of normality was used to assess the normality assumption for parametric testing.

Incidence rates for IgAN were adjusted to the US population of 2020 using American Community Survey estimates [10]. The direct method was applied, standardizing by race/ethnicity (Asian/Pacific Islander, Black, Hispanic/Latino, White, and other), sex, and age (18–24, 25–44, 45–64, and ≥65 years).

Among a total of 9,392 KPSC members who underwent kidney biopsy during the observation period, primary IgAN was identified in 606 patients (online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000541869). The mean age was 46 years, with males accounting for 51.2%. The median eGFR at biopsy was 51 mL/min/1.73 m², and 18.8% of patients had eGFR <30 mL/min/1.73 m². The median urine protein creatinine ratio (uPCR) of the cohort was 1.8 g/g and hematuria was present in 377 (62.2%) patients (online suppl. Table S1). The mean baseline blood pressure was 130/77 mm Hg. Renin angiotensin system inhibitors were used in 366 (60.4%) patients at biopsy. The mean Elixhauser Comorbidity Index was score was 3.1 with diabetes mellitus present in 87 (14.4%) of the patients. Information on mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) and crescents (C) or MEST-C scores were available for only 31% of the study population (online suppl. Table S2).

The racial/ethnic composition was 30.4% Asian/Pacific Islander, 3.1% Black, 38.6% Hispanic/Latino, 25.6% White, and 2.3% other/unknown (online suppl. Table S1). The Black and White subgroups had higher proportions of male patients (Black, 68.4%; White, 69.0%) compared to the Asian/Pacific Islander (38.6%) and Hispanic/Latino (47.4%) subgroups. Asian/Pacific Islander patients had the lowest mean systolic blood pressure of 128 mm Hg, whereas Black patients had the highest mean value (135 mm Hg). Median eGFR was numerically highest among Black (61 mL/min/1.73 m²) and numerically lowest among White patients (49 mL/min/1.73 m²). uPCR was lowest in Black (0.8 g/g) and highest among Asian/Pacific Islander (2.2 g/g) and Hispanic/Latino (2.1 g/g) patients. Elixhauser Comorbidity Index was highest in White (3.6) and lowest in Black patients (2.6).

The crude annual IgAN incidence rates (per 100,000 person-years) ranged from 1.3 (years 2016 and 2020) to 2.2 (year 2012). Overall, a slight downward trend in incidence was observed over the study duration (Mann-Kendall trend test: Kendall’s τ = −0.45, p = 0.04). The mean US Census standardized incidence rate (per 100,000 person-years) of IgAN was 1.4 during the 12-year study duration. The adjusted annual incidence rates ranged from 1.0 (year 2018) to 1.8 (years 2010 and 2012) per 100,000 person-years (Table 1).

The mean annual incidence rate (per 100,000 person-years) of IgAN was 4.5, 1.7, 1.2, and 0.6 among Asian/Pacific Islander, Hispanic/Latino, White, and Black individuals, respectively (Table 2).

Based on a racially/ethnically diverse population from a single geographical region, we estimated a mean standardized incidence of 1.4 IgAN cases per 100,000 person-years. Hastings et al. [11] described a median survival of approximately 29 years after IgAN diagnosis among adults. Using disease duration after diagnosis as a multiplier to the reported incidence (prevalence = incidence x disease duration), we extrapolate an IgAN prevalence of about 40 cases per 100,000 persons among adults.

The rates for patients of Asian/Pacific Islander, White, and African descent were comparable to estimates previously obtained for East Asia (1.8–4.2), Europe (1.0–2.8), and Africa (0.1) [2]. Consistent with earlier research reports [2], we observed male predominance among White patients with IgAN, but the sex distribution among Hispanic/Latino patients was even. There were more female patients with IgAN than males among the Asian/Pacific Islander population. This is similar to previous data from Chinese and Japanese cohorts, in which higher proportions of women were observed among patients with IgAN [12, 13].

Our real-world IgAN cohort was at an advanced disease stage at time of biopsy/diagnosis, as evidenced by low eGFR values, which may reflect screening practices at KPSC and in the US compared to other countries. This finding is similar to recent research highlighting the need for improvement in diagnostic practices [14]. Furthermore, the current draft of 2024 KDIGO IgAN/IgA Vasculitis guidelines recommend threshold proteinuria for treatment starting at ≥0.5 g/day which underscores the rationale to screen and diagnose IgAN earlier in the US.

Limitations of our study include the fact that our data were obtained from an insured population and may not be representative of the entire US. Additionally, Southern California may not have the same environmental risk factors present in other parts of the country. Our kidney biopsy population may have oversampled individuals proactively seeking healthcare screenings that would lead to biopsy. Despite these limitations, our study is one of the few to report data on a large IgAN cohort across different racial/ethnic groups (including Hispanic/Latino individuals) that were biopsy confirmed.

Among a large diverse US population within Southern California, we observed an IgAN incidence of 1.7 which estimated to an annual US incidence of 1.4 cases (per 100,000 person-years) during the 12-year period. Incidence was highest among Asian/Pacific Islander and Hispanic patients. IgAN patients appear to be diagnosed at advanced kidney disease within our clinical environment. Our study provides racially and ethnically stratified IgAN incidence rates from a large and diverse US population, including under-researched subgroups such as Hispanic/Latino patients. These data might be used to inform targeted interventions for achieving earlier IgAN diagnosis.

The authors would like to thank Hema K. Gandhi, Sasikiran Nunna, and Dewilka Saleem, who are employees of Otsuka, for their critical review, administrative assistance, and input into the manuscript.

This study was approved by the Kaiser Permanente Southern California Institutional Review Board (#5815) and granted an exemption from requiring written informed consent given the retrospective data only approach.

J.J.S. currently has or has had research grant support from Otsuka Pharmaceutical Development and Commercialization, Vera Pharmaceuticals, NIH/Kidney Nutrition Obesity and Diabetes Study Section (co-investigator with primary investigator Manjula Tamura), and Kaiser Permanente Southern California clinician investigator award. A.W.F. and C.P. are employees of Otsuka Pharmaceutical Development and Commercialization, Inc. A.D.S. and M.M. are employees of Visterra, Inc. None of the other authors have any disclosures to report.

This study was supported by Otsuka Pharmaceutical Development and Commercialization, Inc., Princeton, NJ, USA (J.J.S. PI). The funder/supporter was involved in study design and analysis. The funder/supporter had no role in data collection, reporting, or the decision to submit for publication.

Research idea and study design: J.J.S., Q.C., and M.M; data acquisition: Q.C. and N.C; analysis or interpretation of data: J.J.S., Q.C., J.C., A.W.F., S.K.B., C.P., A.D.S., and M.M; study supervision: J.J.S; statistical analysis: Q.C. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

Individual-level data reported in this study involving human research participants are not publicly shared due to potentially identifying or sensitive patient information. Upon request, and subject to review, KPSC may provide the deidentified aggregate-level data that support the findings of this study. Anonymized data (deidentified data including participant data as applicable) that support the findings of this study may be made available from the investigative team in the following conditions: (1) agreement to collaborate with the study team on all publications, (2) provision of external funding for administrative and investigator time necessary for this collaboration, (3) demonstration that the external investigative team is qualified and has documented evidence of training for human subjects protections, and (4) agreement to abide by the terms outlined in data use agreements between institutions. Interested researchers can submit their request via the “Contact Us” form (see link: https://www.kp-scalresearch.org/aboutus/contact-us/). Further inquiries can be directed to the corresponding author.