Contribution of immune and non-immune mechanisms to the development of chronic kidney disease

Introduction. Chronic kidney disease (CKD) develops as an outcome both of immune-mediated glomerulonephritides and predominantly metabolic or hemodynamic nephropathies. Despite differences in etiology, common pathogenetic mechanisms are involved in CKD progression, including metabolic disturbances, immune inflammation, and development of glomerulosclerosis.
Objective: To determine the contribution of immune and non-immune (hemodynamic and metabolic) mechanisms to the development of chronic kidney disease (CKD).
Materials and methods. A single-center retrospective analysis of 119 patients with CKD who underwent kidney biopsy was performed. Based on the totality of clinicopathological features (type of glomerulopathy, pattern of immune deposits), patients were divided into two groups: predominantly immune-mediated lesions (n = 72) and predominantly non-immune lesions (n = 47). Clinical and laboratory parameters, 24-hour proteinuria, urinalysis data, as well as morphological indices of inflammatory activity and glomerulosclerosis were analyzed.
Results. In the overall cohort, the presence of arterial hypertension was associated with higher 24-hour proteinuria, increased blood urea and creatinine levels, and reduced estimated glomerular filtration rate (eGFR); patients also had more pronounced interstitial infiltration and a higher degree of glomerulosclerosis. Metabolic syndrome, diabetes mellitus, and obesity were accompanied by increased 24-hour proteinuria and thickening of the glomerular basement membranes, but were not associated with eGFR. In patients with predominantly non-immune lesions, the presence of immune deposits on immunofluorescence and high morphological inflammatory activity were associated with more pronounced eGFR decline, azotemia, electrolyte disturbances, greater proteinuria, and anemia. In the group with predominantly immune-mediated lesions, CKD severity was determined mainly by the degree of glomerulosclerosis and the presence of arterial hypertension, whereas indices of morphological inflammatory activity were not associated with nitrogen-excreting kidney function.
Conclusion. In the progression of CKD in patients with biopsy-proven nephropathies, arterial hypertension, the extent of glomerulosclerosis, and inflammatory activity in renal tissue play a key role. For predominantly non-immune nephropathies, immune deposits and high morphological inflammatory activity are of greatest importance, whereas in predominantly immune glomerulopathies CKD severity is largely determined by chronic changes (glomerulosclerosis) and the presence of hypertension.

For citation: Stanchuliak AE, Krasnova TN, Georginova OA, Shakhnova EA, Osipova AV, Avdeev VG, Manuilova YuA, Pavlikova EP. Contribution of immune and non-immune mechanisms to the development of chronic kidney disease. Therapy (Moscow). 2026;12(5S):31–38.
https://doi.org/10.18565/therapy.2026.5-s5.31-38

INTRODUCTION

Nephropathies comprise a broad group of disorders characterized by kidney damage, impaired kidney function, and reduced excretion of metabolic waste products, resulting in the retention of nitrogenous waste products and a decrease in glomerular filtration rate (GFR). Collectively, these abnormalities are referred to in the contemporary literature as chronic kidney disease (CKD).

CKD may develop as a consequence of both immune-mediated glomerulonephritis (GN) and predominantly metabolic or hemodynamic nephropathies, such as hypertensive nephrosclerosis and diabetic nephropathy. Although immunopathologic mechanisms underlie GN, several nonimmune factors, including hypertension (HTN), disturbances in carbohydrate and lipid metabolism, and obesity, may play a critical role in the development and progression of these diseases [1]. Recent evidence indicates that metabolic nephropathies traditionally regarded as nonimmune, such as diabetic nephropathy, are often accompanied by activation of innate and adaptive immune responses and the formation of immune deposits [2], thereby blurring the distinction between immune and nonimmune forms of kidney injury. Thus, CKD progression is driven by synergistic interactions among metabolic, hemodynamic, inflammatory, and immune factors, necessitating a comprehensive approach to diagnosis and treatment.

The objective of this study is to determine the contributions of immune and nonimmune (hemodynamic and metabolic) mechanisms to the development of CKD.

METHODS

The study was conducted at the Medical Research and Educational Institute of Lomonosov Moscow State University; kidney biopsy specimens were evaluated at Moscow Clinical Research Center Hospital No. 52 of the Moscow Department of Health, Moscow. The retrospective analysis included 119 consecutively followed patients (71 men and 48 women) older than 18 years with established CKD who underwent kidney biopsy for clinical indications.

The inclusion criteria were a kidney biopsy pathology report that included assessment of the glomerular, tubulointerstitial and vascular compartments and the availability of clinical and laboratory data at the time of biopsy, including serum creatinine and urea, estimated glomerular filtration rate (eGFR), parameters of nitrogen metabolism and electrolyte balance, urinalysis findings, and 24-hour urinary protein excretion (24-h UPE). Patients with acute GN without evidence of CKD, active systemic vasculitis, or incomplete biopsy data were excluded.

Based on the clinical diagnosis and morphologic findings, the patients were divided into two groups:

• predominantly immune-mediated kidney injury group (n = 72), comprising patients with immune complex–mediated or complement-mediated forms of GN, including IgA nephropathy, membranous nephropathy, membranoproliferative GN, and other forms, with characteristic immunoglobulin and/or complement deposits on immunofluorescence (IF);
• predominantly nonimmune kidney injury group (n = 47), comprising patients with diabetic nephropathy, hypertensive nephrosclerosis, and other metabolic or hemodynamic nephropathies without prominent immune deposits.

Clinical characteristics included age, disease duration, CKD stage, body mass index (BMI), and the presence of HTN, diabetes mellitus (DM), obesity, and metabolic syndrome (MetS). The laboratory data included hematologic and biochemical parameters (hemoglobin, C-reactive protein, urea, creatinine, uric acid, glucose, lipid profile, total and ionized calcium, phosphorus, potassium, sodium, parathyroid hormone, thyroid-stimulating hormone, glycated hemoglobin, and eGFR), urinalysis findings (proteinuria, hematuria, and leukocyturia), and 24-h UPE.

A histologic inflammatory activity score was calculated from the kidney biopsy findings based on the presence and severity of mesangial hypercellularity, basement membrane thickening, positive IF staining for immunoglobulins and/or complement components, interstitial inflammation, and fibrous crescents.

The proportions of glomeruli with global or segmental sclerosis were also assessed and used to calculate the glomerulosclerosis index. The associations of metabolic factors (HTN, DM, obesity, and MetS), immune deposits identified by positive IF findings, the inflammatory activity score, and the glomerulosclerosis index with kidney function parameters (eGFR and serum urea, creatinine, and electrolyte levels), 24-h UPE, and other morphologic biopsy findings were analyzed.

Statistical analyses were performed using Microsoft Excel 2021 and IBM SPSS Statistics, version 27. The normality of continuous variable distributions was assessed using the one-sample Kolmogorov–Smirnov test with the Lilliefors correction. Normally distributed continuous variables are presented as the mean ± standard deviation (M ± SD), whereas non-normally distributed continuous variables are presented as the median (25th and 75th percentiles) (Me [Q25–Q75]). Normally distributed c...

A.E. Stanchuliak, T.N. Krasnova, O.A. Georginova, E.A. Shakhnova, A.V. Osipova, V.G. Avdeev, Yu.A. Manuilova, E.P. Pavlikova