Role of C4d and CD68 in kidney biopsy as novel prognostic markers for IgA nephropathy; a single-center study from India

Pritam Khomane ¹ , Ashwin Somwarpet Prabhakar ² , Shankar Prasad Nagaraju ³^* , Indu Ramachandra Rao ³ , Kiran Krishne Gowda ⁴ , Mahesha Vankalakunti ⁴, Ravindra Prabhu Attur ³ , Srinivas Vinayak Shenoy ³ , Dharshan Rangaswamy ³ , Mohan Varadanayakanahalli Bhojaraja ³ , Nisha Abdul Khader ³ , Divya Datta ³ , Shilna Muttickal Swaminathan ³ , Vasudeva Guddattu ⁵

¹ Department of Nephrology, Jupiter Hospital, Thane, Maharashtra, India
² Department of Nephrology, Father Muller Medical College, Mangalore, Karnataka, India
³ Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
⁴ Consultant Nephropathologist, Manipal Hospitals Bangalore, Karnataka, India
⁵ Department of Apllied Statistics and Data Science, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India

*Corresponding Author: Shankar Prasad Nagaraju, Email: shankar.prasad@manipal.edu, Email: shankarmmcmed@gmail.com

Abstract

Introduction: IgA nephropathy (IgAN) is a common primary glomerulonephritis worldwide. C4d and CD68 could be useful prognostic markers in this disease.

Objectives: This study was conducted to assess the clinical and prognostic implications of C4d and CD68 staining in patients with IgAN.

Materials and Methods: This is a retrospective single-center observational study. Baseline characteristics and laboratory details were recorded. Renal biopsy was reported according to the MEST-C classification along with further staining for C4d and CD68 by immunohistochemistry. Primary and secondary outcomes were progression to end-stage renal disease (ESRD) and all-cause mortality during follow-up, respectively. The effect of C4d and CD68 along with other risk factors on outcomes was studied.

Results: Sixty patients with primary IgAN were analyzed with a median follow-up of 17 months. Forty were males, with a mean age of 39±16 years, and median estimated glomerular filtration rate (eGFR) of 36.5 mL/min/1.73 m² with a median urine protein/creatinine ratio of 1.9 g/g, at the time of kidney biopsy. In our patients, macroscopic hematuria (n=2: 3.3%) was rare, while 15 (25%) of patients had nephrotic-range proteinuria. Most biopsies showed sclerosis 43 (71.7%) followed by interstitial fibrosis and tubular atrophy (IFTA) 32(53.3%). Meanwhile, crescents were seen in 20 (33.3%). About 39 (65%) of patients had glomerular C4d positivity and 10 (16.7%) had tubulointerstitial CD68 positivity while, none having glomerular CD68 positivity. Glomerular C4d and tubulointerstitial CD68 positivity had lower eGFR, higher proteinuria at presentation (P<0.05) and faster progression to ESRD (glomerular C4d-odds ratio [OR]: 5.7 [95% CI: 1.4-22.5]); tubulointerstitial CD68 OR: 5.4 [ 95% CI: 1.2-23.95]. Other risk factors predicting progression were eGFR at presentation (OR: 0.9 [95% CI: 0.89-0.99], presence of sclerosis OR: 6.5 [95% CI: 1.32-32.06] and IFTA OR: 21.4 [ 95% CI: 4.3-108]).

Conclusion: In our study, IgAN patients presented in the later stages of chronic kidney disease, with the majority being diagnosed at stage 3 of this disease. Macroscopic hematuria was rare and nephrotic syndrome and crescents were common. Glomerular C4d and tubulointerstitial CD68 were associated with lower eGFR and more rapid progression.

Keywords: Complement 4d, CD68 antigen, End-stage kidney disease, IgA nephropathy, Hematuria, Proteinuria, Chronic kidney disease

Implication for health policy/practice/research/medical education:

In IgA nephropathy (IgAN) renal function can rapidly worsen to end-stage kidney disease. To develop methods for preventing or delaying disease progression, it is important to identify potential markers that might be helpful for risk stratification of IgAN.

Please cite this paper as: Khomane P, Somwarpet Prabhakar A, Nagaraju SP, Rao IR, Krishne Gowda K, Vankalakunti M, Attur RP, Shenoy SV, Rangaswamy D, Bhojaraja MV, Khader NA, Datta D, Swaminathan SM, Guddattu V. Role of C4d and CD68 in kidney biopsy as novel prognostic markers for IgA nephropathy; a single-center study from India. J Nephropathol. 2025;x(x):e26554. DOI: 10.34172/jnp.2025.26554.