Patients with progressive IgAN showed lower expression of mRNA encoding for the complement inhibitory protein CD46, which may implicate a defective regulation of C3 convertase with uncontrolled complement activation.

The proteasome to immunoproteasome (iPS) switch consists of β1, β2 and β5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/β5 and LMP2/β1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/β5 (P < 0.0001). The LMP7/β5 switch was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Fast progressors (defined as the loss of eGFR >75th centile, i.e. −1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/β5 mRNA (P = 0.04) and low CD46 mRNA expression (P < 0.01). A multivariate logistic regression model, categorizing patients by different levels of kidney disease progression, showed a high prediction value for the combination of high LMP7/β5 and low CD46 expression.

The review of studies of international and national researchers on the impact of matrix metalloproteinases (matrix metalloproteinases, ММРs) and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) on physiological and pathological processes in children with kidney diseases. It is shown that MMPs play a significant role in organogenesis, i.e. nephrogenesis. Thus, MMP-2, MMP-9 and TIMPs play a large role in basal membranes remodeling associated with epithelial structures in a developing kidney. Immunohistochemistry assay showed that MMP-2 was localized in structures of immature nephrons undergoing epithelial differentiation, MMP-9 – only in vascular structures included in immature glomeruli. Decreased activity of MMP and /or increased synthesis of TIMPs in nephrocytes contribute to the reduction of intercellular substance components catabolism and serve as a basis for glomerular fibrosis and renal interstitium. MMPs are the major group of proteases which regulate metabolism in extracellular matrix and serve as the most important parameters in tissue remodeling observed in acute and chronic inflammatory processes in kidneys. The literature review gives an opportunity to assess the importance of drug design preventing and delaying the progression of nephrosclerosis.

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THE AIM: to study diagnostic and prognostic significance of blood serum cytokine status evaluation in children with different nosological forms of kidney diseases.PATIENTS AND METHODS. The study included 255 children with various kidney diseases (kidney stone disease (KSD) – 16, with  infectious kidney diseases (IKD) – 174, with a glomerulopathy (GP)  – 65). In all study groups were dominant children with 1st and 2nd  stage of CKD (100%, 97,5% and 95,4% respectively). The control group included 50 virtually healthy children. All patients  determined level of TNF-α, TNF-RI and TNF-RII, IL-10, TGF-β1 and TGF-β3, IL2, IL2-SR in blood serum.RESULTS.Increase of TNF-α level in blood serum can be considered as a highly specific marker of acute pielonephritis chronization, as  well as decrease of TNF-RII concentration can be considered as a  marker of full clinical and laboratory pielonephritis remission. The  increase in TNF-α and TNF-RI can also be considered as a marker of autoimmune inflammation. Deficiency of IL-2, IL-10 and TGF-β3  with an increase in IL-2 R in blood should be used as a marker of  bacterial-inflammatory and autoimmune kidney diseases, and TGF- β1 increase as an early marker of nephrosclerosis, especially in  patients with glomerulonephritis. The increase of the inflammatory  index TNF-α / IL-10 more than 4 times, gives us  the opportunity to  position it as an additional diagnostic criterion for infectious and  autoimmune process in the kidneys. The increase in urinary  excretion of TNF-α with the decrease of IL-10 by maintaining  consistently high concentrations of TGF-β1 is a marker of  inflammation and fibrosis in infectious kidney diseases and  glomerulonephritis. Modern nephroprotection therapy directed at  slowing progression of CKD and its complications should include  modulation of cytokine status.