The system of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may play a key role in atherogenesis of chronic kidney disease (CKD) patients by its impact on matrix accumulation. Connections with inflammation, stress, or endothelial dysfunction are also probable. However, the data on correlations between these parameters in CKD patients are scarce in adults and absent in children. The aim of our study was to evaluate serum concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2, as well as their correlations with markers of stress response (Hsp90-α, anti-Hsp60), endothelial dysfunction (sE-selectin), and inflammation (high-sensitivity C-reactive protein) in CKD children treated conservatively. Thirty-seven patients were divided into two groups according to the CKD stage (gr.CKDI, 19 children with CKD stages 2–3; gr.CKDII, 18 subjects with CKD stages 4–5). Twenty-four age-matched healthy subjects served as controls. Serum concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, Hsp90-α, anti-Hsp60, and sE-selectin were assessed by ELISA. Median values of MMP-2, MMP-9, TIMP-1, and TIMP-2 were significantly higher in all CKD children vs. controls and were increased in patients with CKD stages 4–5 vs. CKD stages 2–3. Hsp90-α, anti-Hsp60, sE-selectin, and glomerular filtration rate predicted the values of MMPs and TIMPs. Chronic kidney disease in children is characterized by MMP/TIMP system dysfunction, aggravated by the progression of renal failure. Correlations between examined parameters, heat shock proteins, and markers of endothelial damage suggest the possibility of MMP/TIMP application as indicators of stress response and atherogenesis in children with CKD on conservative treatment.

The system of membrane receptor Fas and its ligand FasL compose one of the main pathways triggering apoptosis. However, the role of their soluble forms has not been clarified yet. Although sFasL can be converted from the membrane-bound form by matrix metalloproteinases (MMPs), there are no data on relations between sFas/sFasL, MMPs and their tissue inhibitors (TIMPs) in patients on chronic dialysis—neither children nor adults. The aim of our study was to evaluate serum concentrations of sFas, sFasL, and their potential regulators (MMP-2, MMP-7, MMP-9, TIMP-1, TIMP-2), in children and young adults chronically dialyzed. Twenty-two children on automated peritoneal dialysis (APD), 19 patients on hemodialysis (HD) and 30 controls were examined. Serum concentrations of sFas, sFasL, MMPs and TIMPs were assessed by ELISA. Median values of sFas, sFasL, sFas/sFasL ratio, MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 were significantly elevated in all dialyzed patients vs. controls, the highest values being observed in subjects on HD. A single HD session caused the decrease in values of all parameters to the levels below those seen in children on APD. Regression analysis revealed that MMP-7 and TIMP-1 were the best predictors of sFas and sFasL concentrations. Children and young adults on chronic dialysis are prone to sFas/sFasL system dysfunction, more pronounced in patients on hemodialysis. The correlations between sFas/sFasL and examined enzymes suggest that MMPs and TIMPs take part in the regulation of cell death in the pediatric population on chronic dialysis, triggering both anti- (sFas) and pro-apoptotic (sFasL) mechanisms.

P < 0.001 (Fisher exact probability test).c l i n i c a l i n v e s t i g a t i o n AM _ Zurowska et al.: Mild Alport syndrome due to founder COL4A5 p.G624D AM _ Zurowska et al.: Mild Alport syndrome due to founder COL4A5 p.G624D c l i n i c a l i n v e s t i g a t i o n Kidney International (2021) -, ---AM _ Zurowska et al.: Mild Alport syndrome due to founder COL4A5 p.G624Dc l i n i c a l i n v e s t i g a t i o n

Children and young adults with chronic renal failure (CRF) present with an impaired immune response. Our aim was to analyze whether leukocyte migration, determined by adhesion molecules, is disturbed in the course of CRF, hemodialysis (HD), and peritoneal dialysis (PD). Soluble (s) VCAM-1, ICAM-1, and L-selectin serum levels were evaluated by ELISA in 15 patients with CRF, 22 patients on cuprophane membrane HD, 24 patients on PD, and in 15 controls. The sVCAM-1 levels in all groups were significantly elevated compared with controls. The levels in HD patients were higher than in CRF patients (P<0.05), while levels in PD patients were higher than in CRF and HD (P<0.001 and P<0.01, respectively). The sICAM-1 concentrations in CRF and PD patients were significantly elevated compared with controls (P<0.001 and P<0.0001, respectively); in PD patients sICAM-1 levels were higher than in HD patients (P<0.001), but there were no differences between other groups. sL-selectin levels were decreased in all groups compared with controls. The levels in HD patients were the lowest and the differences, compared with CRF and PD patients, were significant (P<0.05 and P<0.01, respectively). Children and young adults with CRF and on maintenance dialysis have altered concentrations of soluble adhesion molecules, resulting from either inadequate clearance or disturbed synthesis and release. The differences in sVCAM-1 levels between CRF and both groups of patients on dialysis, as well as the differences in sL-selectin concentrations between HD and CRF patients, indicate that these disturbances are aggravated by maintenance dialysis, particularly HD.

Heat shock proteins (HSP) form a heterogenous, evolutionarily conserved group of molecules with high sequence homology. They mainly act as intracellular chaperones, protecting the protein structure and folding under stress conditions. The extracellular HSP, released in the course of damage or necrosis, play a pivotal role in the innate and adaptive immune responses. They also take part in many pathological processes. The aim of this review is to update the recent developments in the field of HSP in chronic kidney disease (CKD), in regard to three different aspects. The first is the assessment of the role of HSP, either positive or deleterious, in the pathogenesis of CKD and the possibilities to influence its progression. The second is the impact of dialysis, being a potentially modifiable stressor, on HSP and the attempt to assess the value of these proteins as the biocompatibility markers. The last area is that of kidney transplantation and the potential role of HSP in the induction of the immune tolerance in kidney recipients.

The observed parameter changes indicate apoptosis, tissue remodeling and fibrosis in CKD children. Urine survivin may become a new biomarker of kidney-specific EMT.

Background: Transforming growth factor (TGF)beta1 and matrix metalloproteinases (MMPs) play an essential role in CKD-related tissue remodeling. However, there are no data on urine MMPs and their extracellular inducer EMMPRIN in CKD patients. The aim of study was to assess the concentrations of MMP-2, MMP-7, MMP-9, EMMPRIN and TGFbeta1 in serum and urine of CKD children and to analyze the potential relations between those parameters. Methods: Forty-one pre-dialysis CKD children and 23 age-matched controls were enrolled in the study. The concentrations of analyzed parameters were assessed by ELISA. Results: Serum and urine values of MMP-2, MMP-7, MMP-9, EMMPRIN and TGFbeta1 were significantly elevated in CKD patients versus controls. The MMP-2 and MMP-9 levels in urine correlated significantly with the corresponding values in serum, whereas MMP-7, EMMPRIN and TGFbeta1 urine concentrations did not. There were also significant correlations between urine values of all parameters. Conclusions: The increased urine levels of MMPs, EMMPRIN and TGFbeta1 indicate enhanced proteolysis and renal tissue remodeling. In the case of MMP-7, EMMPRIN and TGFbeta1 those disturbances seem independent of enhanced serum activity of the corresponding enzymes. The urine MMP-7 and EMMPRIN concentrations may serve as new independent indices of tissue remodeling and renal interstitial fibrosis in children with CKD.

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