To Örebro University

INTRODUCTION: IgA nephropathy is the most common primary kidney disease in the world and has a highly variable clinical presentation. While studies have indicated a link between glomerular disease and infections, large-scale studies on IgA nephropathy are missing.

METHODS: In our study, IgA nephropathy was defined as having a kidney biopsy record 1997-2011 in Sweden. Each IgA nephropathy patient was matched with five reference individuals based on age, sex, calendar year, and county of residence. We excluded individuals with earlier organ transplants, HIV, immunodeficiency, or end-stage kidney disease. Linear and Cox regressions, adjusted for age, sex, education, and diabetes, were performed to analyze total infections and antimicrobial treatments in both patients and reference individuals. Sibling analyses were also performed.

RESULTS: The linear regression analysis revealed a significant association between IgA nephropathy and the overall frequency of infections compared to the general population (β = 0.44; 95% CI: 0.35-0.53) and siblings (β = 0.36; 95% CI: 0.23-0.49). Similarly, antimicrobial prescriptions, especially antibiotics, were more common in IgA nephropathy compared to the general population and to siblings. Cox regression showed an elevated risk of any infection (adjusted hazard ratio [aHR] = 2.00; 95% CI: 1.84-2.18) and sepsis (aHR = 3.18; 95% CI: 2.17-4.65) corresponding to one extra case of sepsis per 63 patients followed for 10 years. The strongest associations were seen for urinary tract infections; ear, nose, and throat infections; and musculoskeletal and gastrointestinal infections.

CONCLUSION: Conclusively, our study demonstrates an increased prevalence of infections and antibiotic prescriptions in IgA nephropathy patients. The increased risk of sepsis warrants clinical awareness and prevention.

This thesis investigates the associations between IgA nephropathy (IgAN), a common form of primary glomerulonephritis, and several health outcomes including inflammatory bowel disease (IBD), cancer, infections, and the reliability of biopsy data from the Swedish Renal Registry (SRR).

In a population-based cohort study of 3,963 IgAN patients and 19,978 controls, IgAN was linked to a significantly higher risk of both future and preceding IBD diagnoses. IBD also increased the risk of developing end-stage renal disease (ESRD) in IgAN patients, underscoring the importance of monitoring gastrointestinal comorbidities in this population.

Another cohort study of 3,882 IgAN patients examined the association between IgAN and cancer. An elevated cancer risk was identified, but only in patients who progressed to ESRD, suggesting that the increased cancer incidence is related to advanced kidney disease rather than IgAN itself.

A third study explored the frequency of infections in IgAN patients, revealing a higher incidence of infections and increased antimicrobial use compared to both the general population and sibling controls. The study highlighted a marked risk of sepsis, emphasizing the need for proactive infection prevention in IgAN management.

Finally, validation of biopsy data from the SRR demonstrated a high positive predictive value (95%) for IgAN diagnosis. This reinforces the reliability of the SRR as a valuable tool for future research on IgAN.

Together, these findings contribute to a deeper understanding of IgAN’s broader clinical implications, and the potential risks associated with its progression.

Background and Aims: IgA nephropathy (IgAN) is the most common global kidney disease with a highly variable clinical presentation. Diagnosis IgAN requires a biopsy, and the immunohistologic examination is dominated by depositions of aberrant IgA1 antibodies. Since IgA antibodies are mainly produced by the mucosal associated lymphoid tissue the relationship between the mucosal immune system and IgAN has long been considered. The current theories on the origin of the disease involve genetic and environmental factors, with mucosal infections potentially playing a role. In some IgAN patients gastrointestinal and/or upper respiratory infections can aggravate the disease with episodic macrohematuria and/or increased proteinuria. Coincidently, these infections are also more common among patients with selective IgA deficiency. The aim of this study was to investigate whether the presence of IgAN confers an increased risk of infections in general to the IgAN patient.

Method: IgAN was defined by a computerized biopsy record from 1997 to 2011 in Sweden. Each IgAN patient was matched with up to five reference individuals based on age, sex, calendar year, and county of residence. Exclusions included those with organ transplants, HIV, immunodeficiency, or end-stage kidney disease before study entry, and follow-up data were censored for subsequent occurrences. Linear and Cox regressions, adjusted for age, sex, and education, were performed to analyze total infections and antimicrobial treatments in both patient and reference groups. Sibling analyses were also performed, adjusted for baseline age, sex and educational attainment.

Results: The linear regression analysis revealed a significant association between IgA nephropathy (IgAN) and the overall frequency of infections compared to the general population (β = 0.45; 95% CI: 0.37–0.54), women (β = 0.35; 95% CI: 0.19–0.50), men (β = 0.50; 95% CI: 0.40–0.60), and siblings (β = 0.37; 95% CI: 0.25–0.49) for women (β = 0.24; 95% CI: 0.06–0.41) and men (β = 0.43; 95% CI: 0.27–0.60). Similarly, a significant association was found for the frequency of prescribed antimicrobial agents compared to the general population (β = 0.66; 95% CI: 0.51–0.82), women (β = 0.92; 95% CI: 0.56–1.27), men (β = 0.55; 95% CI: 0.39–0.71), with similar estimates in the sibling analyses. The subtypes with the strongest association were urinary tract infections (β = 0.09; 95% CI: 0.07–0.11), ENT (ear, nose, and throat) infections (β = 0.08; 95% CI: 0.04–0.12), muscular infections (β = 0.08; 95% CI: 0.05–0.12), and infections in the GI (gastrointestinal) tract (β = 0.06; 95% CI: 0.04–0.09). Infections in the lower respiratory tract, skin and mycoses also had a significant positive association, however, no associations to infections in the central nervous system or infections caused by helminths and protozoans were identified. Cox regression showed an elevated risk of any infection with an adjusted hazard ratio (HR) of 2.05 (95% CI: 1.88–2.23), especially for sepsis (aHR = 3.13; 95% CI: 2.14–4.59), and time to the first prescription of antimicrobials with an aHR of 1.37 (95% CI: 1.30–1.45). Linear regression of prescribed antimicrobial treatments showed an overall β = 0.67; 95% CI: 0.51–0.82, and specifically for antibiotics (β = 0.64; 95% CI: 0.49–0.78).

Conclusion: Our study demonstrates an increased prevalence of infections and antibiotic prescriptions in IgAN patients compared to the general population and their siblings. Further studies on the potential impact of IgAN and its immunological aberrations on overall infection susceptibility is warranted.

AIM: The Swedish Renal Registry (SRR) is a unique national quality registry that monitors the clinical trajectory of patients with chronic kidney disease (CKD). We have validated the biopsy data registered in the SRR for IgA Nephropathy (IgAN) diagnosis.

METHODS: In total 25% of all patients (n = 142), registered with IgAN in the SRR after having performed a kidney biopsy during 2015-2019, were randomly selected. We obtained original biopsy and medical records for 139 (98%) patients. We evaluated the IgAN diagnosis using a standardized template, calculated its positive predictive value (PPV) with 95% confidence interval (CI) and reported clinical features at the time of diagnosis.

RESULTS: A histological and clinical diagnosis of IgAN was confirmed in 132 of the 139 patients, yielding a PPV of 95% (95% CI 90-98%). Median age was 46 years (range: 18-85) and the male:female ratio was 2.1:1. The median creatinine level was 123 µmol/L, with a corresponding estimated glomerular filtration rate (eGFR) level of 51 mL/min/1.73m2. Histological features of IgA deposits were seen in all patients, hypercellularity in 102/132 (77.2%), C3 deposits in 98/132 (72.4%) and C1q deposits in 27/132 (20.5%) of the cases.

CONCLUSION: Validating data is not research per se, but continuous validation of medical registries is an important feature necessary to ensure reliable data and the foundation of good epidemiological data for future research. Our validation showed a high PPV (95%) for IgAN diagnosis registered in the SRR. Clinical characteristics were consistent with previous reports. The biopsy data in the SRR will be a valuable resource in future IgAN research.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis affecting all ages and both sexes, but there is a lack of studies on its association with cancer and whether it is a paramalignant condition.

METHODS: In a Swedish population-based cohort study we compared the risk of cancer among 3,882 biopsy-verified IgAN patients diagnosed during 1974-2011 with 19,341 reference individuals and followed them until 2015. Cox regression was used to estimate hazard ratios (HRs) for cancer in IgAN patients versus controls, and conditional logistic regression assessed the risk of cancer before the IgAN was confirmed.

RESULTS: During a median follow-up of 12.6 years, 488 (12.6%) patients with IgAN and 1,783 (9.2%) matched reference individuals were diagnosed with cancer (HR 1.70; 95% confidence interval, 95%CI, 1.52-1.89). The increased risk was only seen in IgAN patients developing end stage renal disease (ESRD), with an HR of 4.01 (95%CI 3.33-4.82) for any cancer and HR of 2.22 (95%CI 1.79-2.75) when excluding non-melanoma skin cancer (NMSC). Non-ESRD IgAN patients did not have an increased overall cancer risk (HR 1.13; 95%CI 0.99-1.30). There was no increased risk of cancer preceding IgAN diagnosis (odds ratio 1.10; 95%CI 0.92-1.32).

CONCLUSION: We found no support for IgAN being a paramalignant condition. There was an increased risk of cancer in IgAN patients, but only for those with ESRD. Our results indicate approximately 6 extra cancer case per 100 IgAN patients with ESRD per 10 years, or >17 extra cases if including NMSC as well.