Kidney Week

Abstract: FR-PO655

Genetic Testing in Biopsy-Confirmed Kidney Disease

Session Information

• Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Schmidt, Insa Marie, Boston Medical Center, Boston, Massachusetts, United States

Insa Marie Schmidt, MD, MPH

• Verma, Ashish, Boston Medical Center, Boston, Massachusetts, United States

Ashish Verma, MBBS, FASN

• Claudel, Sophie E., Boston Medical Center, Boston, Massachusetts, United States

Sophie E. Claudel, MD

• Palsson, Ragnar, Massachusetts General Hospital, Boston, Massachusetts, United States

Ragnar Palsson, MD, FASN

• Srivastava, Anand, University of Illinois Chicago, Chicago, Illinois, United States

Anand Srivastava, MD, MPH

• Stillman, Isaac Ely, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Isaac Ely Stillman, MD

• Waikar, Sushrut S., Boston Medical Center, Boston, Massachusetts, United States

Sushrut S. Waikar, MD, MPH

Background

Chronic kidney disease (CKD) is a major public health burden, with monogenic causes identified in approximately 10% of adult patients. Broad gene panels offer promising diagnostic avenues but the correlation between specific gene variants and distinct histologic patterns of injury has not been systematically explored in cohorts with biopsy-confirmed CKD.

Methods

We conducted genetic testing using a commercially available 385-gene kidney disease panel on 248 individuals who had biopsy-confirmed kidney disease and available DNA samples with pathologist-adjudicated semi-quantitative assessments of histopathology. Both pathogenic and likely pathogenic variants in autosomal dominant, X-linked, and autosomal recessive genes were reported.

Results

Positive genetic findings, specifically pathogenic variants, were identified in 8.1% (20/248) of cases. Mean baseline eGFR was 69±36 and 57±37 ml/min/1.73m² and median proteinuria [IQR] was 1.9 [0.2–4.6] and 1.7 [0.5–4.1] g/g creatinine in individuals with and without a positive genetic finding (p=0.19 and p=0.84, respectively). The most common primary clinicopathologic diagnosis of those with a positive genetic finding were proliferative glomerulonephritis (25.0%) and advanced chronic changes (20%) (Figure 1A). Positive results occurred most frequently in the COL4A3 (19%), COL4A1 (9.5%), COL4A4 (9.5%), CUBN (9.5%), and NF1 (9.5%) genes. Two variants in the same gene (CUBN) were identified in one case. Figure 1B illustrates the patterns of histopathologic changes observed in individuals with positive genetic findings. Pathogenic variants in genes such as INF2, KMT2D, and KRAS showed a trend towards severe patterns of injury, including high scores in interstitial fibrosis and tubular atrophy, glomerulosclerosis, and arterial and arteriolar sclerosis.

Conclusion

Integrating genetic data with detailed tissue-level changes may inform future research aimed at elucidating the genotype-phenotype relationships in CKD. This approach may help to identify potential areas for targeted interventions, ultimately aiming to improve patient outcomes by tailoring treatments to specific genetic and histologic profiles.

Figure 1. A. Baseline characteristics of Boston Kidney Biopsy Cohort (BKBC) participants with and without positive genetic findings. B. Shown are the histopathologic patterns of injury in patients with a pathogenic variant (n=20). The color intensity from yellow to red represents the histopathologic severity score, ranging from none to mild, moderate, and severe. eGFR, estimated glomerular filtration rate; non-fib., non-fibrosed interstitium; fib., fibrosed interstitium; IFTA, interstitial fibrosis and tubular atrophy