Progressive Renal Dysfunction Research Articles

Amyloid beta, a marker of vascular aging and cardiovascular disease, is associated with accelerated progression of renal dysfunction

Abstract Background Amyloid-beta (1-40) (Αb1-40), a proinflammatory and pro-atherosclerotic peptide, is involved in Alzheimmer’s disease and vascular aging and is considered an emerging prognostic marker of atherosclerotic cardiovascular disease (ASCVD) and heart failure. Because Ab1-40 clearance is largely dependent on renal function while clinical data consistently associate this peptide with renal function, we hypothesized that Ab1-40 circulating levels would serve as a predictor of progression of renal dysfunction. Purpose To examine the potential cross-sectional and prospective bidirectional association of Ab1-40 levels with renal function in a population with a wide range of ASCVD risk. Methods In the settings of the Athens Cardiometabolic registry, data from consecutively recruited subjects with (n=137) and without clinically overt ASCVD (n=674) with available both Ab1-40 plasma levels and GFR values (total n=811) were analyzed. Αb1-40 was measured by enzyme-linked immunosorbent assay and renal function was assessed by estimation of glomerular filtration rate (GFR). Of these subjects, 182 individuals consented to be followed up and re-assessed after a minimum period of 12 months in order to examine a potential bidirectional link between changes in Ab1-40 levels and GFR. Results Patients with increased Ab1-40 levels at baseline had significantly worse renal function, reflected as lower GFR values, compared with their counterparts with lower Ab1-40 levels (GFR= 74.8 vs 93.3 vs 100.2 ml/min/1.73m2 for high, middle and low tertile of Ab1-40 levels, p<0.001). Elevated Ab1-40 levels were associated with chronic kidney disease (CKD) stage 2 [odds ratio (OR)=2.29, 95% confidence intervals (CI)= 1.58-3.31, p<0.001] and CKD stage 3 (OR=3.67, 95% CI=2.37-5.70, p<0.001) at baseline. Furthermore, increased Ab1-40 at baseline was prospectively associated with accelerated progression of renal dysfunction as assessed by changes in GFR values between baseline and follow-up [mean adjusted rate of decrease=-7.20 (95% CI=-1.33, -13.07) for higher vs lowest tertiles of Ab1-40 levels across a follow-up period of 12 months, p=0.017 for interaction). On the contrary, baseline GFR values were not prospectively associated with Ab1-40 levels at follow-up visits (p>0.05). Conclusion In a population with a wide range of ASCVD risk, high Αb1-40 levels at baseline were associated both with renal function at baseline and with accelerated rate of progression of GFR deterioration at follow-up irrespective of its baseline levels. These findings suggest a mechanistic background for the established association of Ab1-40 with renal function and warrant further research to clarify the clinical value of monitoring its circulating levels as a novel biomarker which could reflect enhanced risk for renal dysfunction.

Association of hs-CRP with Serum Creatinine Levels in Chronic Kidney Diseases

Introduction Chronic kidney disease (CKD) is a prevalent condition characterized by a progressive decline in kidney function over time. It is associated with various complications, including cardiovascular disease and mortality. Inflammation, as indicated by elevated levels of high-sensitivity C-reactive protein (hs-CRP), has been implicated in the pathogenesis and progression of CKD. Serum creatinine (S. creatinine) levels, on the other hand, are commonly used as a marker to estimate kidney function. Aim The objective of this study was to examine the relationship between hs-CRP levels and S. creatinine levels in CKD patients. By investigating this association, this study aimed to shed light on the potential interplay between inflammation and kidney dysfunction in CKD. Methods We conducted a cross-sectional study in the Parul Sevashram Hospital, Vadodara. The study consisted of 80 CKD patients with 51 males and 29 females. The hs-CRP and creatinine levels were estimated for the study and further evaluated statistically for finding the association between them. Results The study observed a gender distribution with 63.75% male and 36.25% female patients. Among males, 41.17% had hs-CRP levels >2 mg/L, with a mean ± standard deviation (SD) creatinine value of 4.63 ± 0.32 mg/dL. In females, only 13.79% had hs-CRP levels >2 mg/L, with a mean ± SD creatinine value of 4.62 ± 0.30 mg/dL. The statistical analysis using Fisher’s exact test showed a highly significant association between hs-CRP and S. creatinine levels ( P < .01). Conclusion This study demonstrated a strong association between hs-CRP levels and S. creatinine levels in patients with CKD. As S. creatinine levels increased, there was a corresponding rise in hs-CRP levels. This suggests that monitoring hs-CRP levels could be valuable in assessing the progression of renal dysfunction and predicting cardiovascular complications in CKD patients. Further research is needed to fully comprehend the underlying mechanisms driving this association.

Aberrant serum-derived FN1 variants bind to integrin β1 on glomerular endothelial cells contributing to thin basement membrane nephropathy

The glomerular basement membrane (GBM) is a critical component of the glomerular filtration barrier (GFB), with its thickness directly influencing renal function. While a uniformly thinned GBM can cause hematuria while preserving normal renal function, this condition is typically diagnosed as thin basement membrane nephropathy (TBMN). However, the pathogenesis and potential progression to renal insufficiency of TBMN are not fully understood. In this study, we analyzed clinical cohorts presenting with microscopic hematuria who underwent genetic testing and identified five novel pathogenic FN1 mutations. Through bioinformatics analysis of these variants, expression localization analysis of GBM-related molecules in renal biopsies, and functional studies of the mutants, we found that these variants exhibited gain-of-function characteristics. This led to the excessive deposition of aberrant serum-derived FN1 variants on glomerular endothelial cells rather than cell-type-specific variants. The deposition competitively binds FN1 variants to Integrin β1, disrupting the interaction with Laminin α5β2γ1 and subsequently reducing the expression of key GBM components, resulting in TBMN. This study elucidated, for the first time, the genetic pathogenesis of TBMN caused by FN1 variants. It provides a crucial foundation for understanding the progression of renal dysfunction associated with simple hematuria, highlights the potential for targeted therapeutic strategies, and differentiates TBMN from early-stage Alport syndrome.

Integrated bioinformatics analysis for identifying fibroblast-associated biomarkers and molecular subtypes in human membranous nephropathy

BackgroundMembranous nephropathy (MN) is characterized by immune complex deposition in the glomerular basement membrane, leading to proteinuria and potentially progressive renal dysfunction. Fibroblasts have been implicated in the pathogenesis of MN through their involvement in tissue remodeling and immune modulation. MethodsWe employed integrated bioinformatics analyses to identify fibroblast-associated biomarkers and molecular subtypes in MN. The xCell algorithm was used to assess fibroblast infiltration, and weighted gene co-expression network analysis (WGCNA) identified fibroblast-related gene modules. Differentially expressed fibroblast-associated genes (DEFAGs) were screened between MN and healthy controls (HC) using differential expression analysis and protein-protein interaction (PPI) network construction. Consensus clustering categorized MN patients into distinct subtypes based on DEFAG expression profiles. ResultsFibroblast scores were a significant elevation in MN compared to HC, indicating increased fibroblast involvement in MN pathogenesis. WGCNA identified 13 fibroblast-related gene modules, with the brown and turquoise modules showing strong correlation with fibroblast scores (correlation coefficient = 0.79 and 0.75, respectively, p < 0.01). DEFAG analysis revealed 308 genes overlapping between WGCNA and differentially expressed genes (DEGs) in MN. Consensus clustering identified two molecular subtypes (C1 and C2) based on DEFAG expression patterns, with differential gene expression enriching pathways related to immune response and extracellular matrix remodeling. Core biomarker analysis highlighted COL3A1 and TGFB1 as central genes associated with MN, with elevated expression validated across multiple datasets. ConclusionIntegrated bioinformatics analysis identified fibroblast-associated molecular subtypes in MN, revealing distinct immune profiles and biomarkers. COL3A1 emerged as a potential diagnostic and therapeutic target, implicating its role in immune regulation and disease progression in MN.

Circulating corin concentration is associated with risk of mortality and acute kidney injury in critically ill patients

Elevated serum corin concentrations in patients with cardiac diseases have been associated with adverse cardiovascular events and progressive renal dysfunction. This study aimed to determine the role of serum corin levels in predicting the incidence of acute kidney injury (AKI) and mortality in critically ill patients admitted to intensive care units (ICUs). We screened 323 patients admitted to the ICU in our institution from May 2018 through December 2019. After excluding patients receiving renal replacement therapy, 288 subjects were enrolled. Cases were divided equally into high (n = 144) and low (n = 144) corin groups according to median serum corin levels, using 910 pg/mL as the cut-off point. Patient characteristics and comorbidities were collected from medical records. The primary outcome was AKI within 48 h after ICU admission, while the secondary outcome was all-cause of mortality within 1 year. Compared with the low corin group, patients in the high corin group had higher prevalence rates of diabetes, cirrhosis, and nephrotoxic agent exposure; higher Sequential Organ Failure Assessment scores, white blood cell counts, proteinuria, and serum N-terminal pro-brain natriuretic peptide levels; but had lower initial estimated glomerular filtration rates. Furthermore, elevated serum corin was associated with higher risks of AKI within 48h of ICU admission (43.1% vs. 18.1%, p < 0.001) and all-cause mortality within one year (63.9% vs. 50.0%, p = 0.024). High corin level showed strongly positive results as an independent predictor of AKI (OR 2.15, 95% CI 1.11–4.19, p = 0.024) but not for the all-cause mortality after adjusting for confounding factors in multivariate analyses. Elevated circulating corin predicted AKI in critically ill patients, but did not predict all-cause mortality within 1 year. As a key enzyme in renin–angiotensin–aldosterone system, corin expression may be regulated through a feedback loop following natriuretic peptide resistance and desensitization of natriuretic peptide receptors in different critically ill status.

What is confirmed in the treatment of Fabry's disease?

Fabry's disease is arare X chromosome-linked inherited lysosomal storage disease characterized by insufficient metabolism of the substrate globotriaosylceramide (Gb3) due to reduced alpha-galactosidaseA (AGAL) activity. Lysosomal Gb3 accumulation causes amultisystemic disease which, if untreated, reduces the life expectancy in females and males by around 10and 20years, respectively, due to progressive renal dysfunction, hypertrophic cardiomyopathy, cardiac arrhythmia and early occurrence of cerebral infarction. The diagnosis is confirmed by determining the reduced AGAL activity in leukocytes in males and molecular genetic detection of a-mutation causing the disease in females. The treatment comprises enzyme replacement therapy (ERT), agalsidase alfa, 0.2 mg/kg body weight (BW), agalsidase beta 1.0 mg/kg BW or pegunigalsidase alfa 1.0 mg/kg BW every 2weeks i.v. or oral chaperone therapy (one capsule of migalastat 123 mg every other day) in the presence of amenable mutations. This article summarizes the data on the treatment of Fabry's disease and on complications in practice. The current guideline recommendations are addressed and new study results that could expand the therapeutic repertoire in the future are discussed.

Long-term outcomes of percutaneous transluminal renal artery intervention: a retrospective study at a single center

BackgroundThe indications, benefits, and outcomes of percutaneous transluminal renal artery intervention (PTRI) remain controversial. The study purpose was to evaluate the long-term outcomes of PTRI in clinical practice.MethodsA retrospective review of 217 subjects (254 renal arteries; mean age, 59.8 years) who underwent PTRI based on medical database.ResultsThe most common cause of renal artery stenosis was atherosclerosis in 217 (85.4%), followed by Takayasu arteritis (TA) in 23 (9.1%), fibromuscular dysplasia in five (2.0%) and others in nine (3.5%). Mean follow-up duration was 5.7 ± 3.7 years. The first restenosis rate was 7.5% (n = 19; highest in TA: n = 9, 47.4%) and second restenosis occurred in six arteries (five TAs, one fibromuscular dysplasia). Follow-up blood pressure improved from 142.0/83.5 to 122.8/73.5 mmHg (P < 0.001). There was no change within 5 years’ follow-up in estimated glomerular filtration rate (P = 0.44), whereas TA changed from 69.8 ± 20.5 to 84.2 ± 17.9 mL/min/1.73 m² (P = 0.008). Progressive renal dysfunction was related to diabetes mellitus, chronic kidney disease, and peripheral artery obstructive disease on multivariate analysis with hazard ratios (95% confidence intervals) of 2.24 (1.21–4.17), 2.54 (1.33–4.84), and 3.93 (1.97–7.82), respectively.ConclusionsPTRI was associated with a blood pressure reduction. Despite a higher rate of restenosis, patients with TA showed significant improvement in estimated glomerular filtration rate. Diabetes mellitus, chronic kidney disease, and peripheral artery obstructive disease were related with progressive renal dysfunction after PTRI.

The impact of acute kidney damage in the community.

Assess incidence of Acute Kidney Diseas and Disorders (AKD) and Acute Kidney Injury (AKI) episodes and impact on progression of renal dysfunction and risk of all-cause mortality in the community. Community of 1863731 aged>23 years with at least two serum creatinine measurements. eGFR was calculated using CKD-EPI formula. CKD, AKD and AKI were defined according to the harmonized KDIGO criteria (Lameire 2021). The sCr values and RIFLE scale was used to classify episodes. Progression of renal dysfunction and mortality were evaluated. 56850 episodes of AKD in 47972 patients in 4.8 years were identified. AKD incidence of AKD was 3.51 and 12.56/1000 patients/year in non-CKD and CKD, respectively. One AKD episode was observed in 87.3% patients, two in 9.3% and three or more in 3.4%. A second episode was less common in patients without CKD (10.3%) compared to those with CKD (18.4%). Among patients without CKD a total of 43.8% progressed to CKD, and those with previous CKD 63.1% had eGFR decline of>50%. The risk of progression to CKD was higher in women, older, overweight-obesity and heart failure, as was the risk of eGFR decline>50% in CKD patients, although the number of AKD episodes was also a risk factor. AKI episodes were observed in 5646 patients with or without CKD. Of these, 12.7% progressed to CKD and of those with pre-existing CKD, 43.2% had an eGFR decline of>20%. In the toal population mortality within 3 months of detection of AKD episode occurred in 7% patients, and was even higher in patients with AKI, 30.1%. Acute elevations in serum creatinine in the community may pose a health risk and contribute to the development of CKD. Identification of therapeutic targets and provision of appropriate follow-up for those who survive an episode is warranted.

Fanconi syndrome with karyomegalic interstitial nephritis after ifosfamide treatment for osteosarcoma: a case report.

Patients with ifosfamide-induced renal damage present with Fanconi syndrome. Karyomegalic nephropathy/interstitial nephritis (KNIN) is a rare form of chronic tubulo-interstitial nephritis that was initially considered a type of familial nephropathy. However, several reports of drug-induced KNIN, i.e., KNIN-like nephropathy, have been reported in recent years. We present the case of an 18-year-old man who presented with Fanconi syndrome and progressive renal dysfunction after receiving chemotherapy including ifosfamide and cisplatin for right femoral osteosarcoma. Renal biopsy revealed numerous atrophied tubular epithelial cells with large, polymorphic nuclei, and the definitive diagnosis was KNIN. Most patients with KNIN-like nephropathy who receive ifosfamide are concomitantly treated with cisplatin, indicating that ifosfamide and cisplatin might act synergistically to increase the risk for KNIN-like nephropathy. Further investigation in case series is warranted to reveal potential treatment approaches and to evaluate prognosis.

Following a strict renal protection protocol in cloacal malformations: A descriptive analysis

In children with cloacal malformations, renal dysfunction is a constant concern, with reported incidence as high as 50%. Multiple factors exist that may impair renal function. Our institution follows a strict renal protection protocol in this population. Incidence of renal dysfunction in these patients is unknown. We aimed to evaluate incidence of renal dysfunction while implementing this protocol in a cohort of children with cloacal malformation. We reviewed a prospectively collected database of children with cloacal malformations managed at a single institution since implementation of a renal protection protocol. This involves regular laboratory evaluation, appropriate selection of total urogenital mobilization or urogenital separation, proactive imaging in patients with signs of impending renal dysfunction or urinary retention, and early catheterization teaching and implementation if necessary. Glomerular filtration rate (GFR) was calculated with the Schwartz formula and CKD grades assigned per standard definitions. Renal dysfunction was defined as CKD grade 3b or higher, need for renal replacement therapy (RRT) or transplantation. Descriptive statistics were computed. A total of 105 children were managed under this protocol with a median follow-up of 4.2 years [IQR: 2.0-5.9]. Six children (5.7%) had renal dysfunction at most recent follow-up; of these children, only three (2.9%) progressed from normal renal function at initial evaluation to renal dysfunction (Table). No child with normal presenting renal function thus far has progressed to require dialysis or transplantation. Previous literature estimated rates of renal dysfunction in cloaca patients as high as 50%; in contrast, we demonstrate a rate of progression to renal dysfunction of 2.9% in girls following a strict renal protection protocol. Most children who developed renal dysfunction had dysfunctional kidneys on presentation. This suggests that preservation of renal function may be possible in early childhood with a strict, multi-disciplinary renal protection protocol. In our cohort of patients with cloacal malformations following a strict renal protection protocol, incidence of progressive renal dysfunction is low at 2.9%. Most who go on to renal dysfunction present with impaired renal function.

Renal impairment is prevalent in pediatric NAFLD/MASLD and associated with disease severity.

Renal impairment is prevalent in adults with nonalcoholic fatty liver disease (NAFLD/metabolic dysfunction associated steatotic liver disease [MASLD])and is associated with increased mortality. Pediatric data are limited. Our objective was to determine the prevalence of hyperfiltration or chronic kidney disease (CKD) in children with NAFLD/MASLD and determine links with liver disease severity. Data from children who had previously participated in prospective, multicenter, pediatric studies by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH-CRN) were collected. Renal function was determined using the calculated glomerular filtration rate (cGFR). Hyperfiltration was defined as cGFR > 135 mL/min/1.73m2, while CKD stage 2 or higher as cGFR < 90 mL/min/1.73 m2. Renal dysfunction progression was defined as transition from normal to hyperfiltration or to CKD stage ≥ 2, or change in CKD by ≥1 stage. Multinomial logistic regression models were used to determine the prevalence of CKD and independent associations between CKD and liver disease severity. The study included 1164 children (age 13 ± 3 years, 72% male, 71% Hispanic). The median cGFR was 121 mL/min/1.73 m2; 12% had CKD stage 2-5, while 27% had hyperfiltration. Hyperfiltration was independently associated with significant liver fibrosis (odds ratio: 1.45).Baseline renal function was not associated with progression in liver disease over a 2-year period (n = 145). Renal dysfunction worsened in 19% independently of other clinical risk factors. Progression of renal impairment was not associated with change in liver disease severity. Renal impairment is prevalent in children with NAFLD/MASLD and hyperfiltration is independently associated with significant liver fibrosis. Almost 1/5 children have evidence of progression in renal dysfunction over 2 years, not associated with change in liver disease severity. Future assessments including additional renal impairment biomarkers are needed.

Association between serum 25-hydroxyvitamin D3 level and cognitive impairment in older chronic kidney disease patients

This study aims to examine whether hypovitaminosis D was associated with cognitive impairment among chronic kidney patients with different level of albuminuria. This population-based cross-sectional study was conducted on elderly (over 60 years old) with urine albumin to creatinine ratio (UACR) ≥ 30 mg/g from 2011 to 2014 in the US National Health and Nutrition Examination Survey (NHANES). Cognitive function was assessed by the Consortium to Establish a Registry for Alzheimer’s Disease Word List Learning (CERAD). Subjects were divided into 2 groups according to the absence or presence of cognitive impairment and a propensity score matching (PSM) was further conducted. The association was assessed with Spearman correlation and logistic regression analysis. The positive association of 25-hydroxyvitamin D3 (25(OH)D3) and cognitive score was presented. PSM analysis revealed that a higher level of 25(OH)D3 correlated to a better cognitive function in CKD patients with albuminuria, especially in patients with 30 mg/g ≤ UACR < 300 mg/g. This study indicated that a low 25(OH)D3 level was associated with poor cognitive performance, especially in patients with microalbuminuria. Thus, early diagnosis of vitamin D insufficiency and an effective intervention might be a useful therapeutic strategy to prevent cognitive decline in patients with the progression of renal dysfunction.

Exploration of Gene Therapy for Alport Syndrome.

Alport syndrome is a hereditary disease caused by mutations in the genes encoding the alpha 3, alpha 4, and alpha 5 chains of type IV collagen. It is characterized by hematuria, proteinuria, progressive renal dysfunction, hearing loss, and ocular abnormalities. The main network of type IV collagen in the glomerular basement membrane is composed of α3α4α5 heterotrimer. Mutations in these genes can lead to the replacement of this network by an immature network composed of the α1α1α2 heterotrimer. Unfortunately, this immature network is unable to provide normal physical support, resulting in hematuria, proteinuria, and progressive renal dysfunction. Current treatment options for Alport syndrome include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which aim to alleviate glomerular filtration pressure, reduce renal injury, and delay the progression of renal dysfunction. However, the effectiveness of these treatments is limited, highlighting the need for novel therapeutic strategies and medications to improve patient outcomes. Gene therapy, which involves the use of genetic material to prevent or treat diseases, holds promise for the treatment of Alport syndrome. This approach may involve the insertion or deletion of whole genes or gene fragments to restore or disrupt gene function or the editing of endogenous genes to correct genetic mutations and restore functional protein synthesis. Recombinant adeno-associated virus (rAAV) vectors have shown significant progress in kidney gene therapy, with several gene therapy drugs based on these vectors reaching clinical application. Despite the challenges posed by the structural characteristics of the kidney, the development of kidney gene therapy using rAAV vectors is making continuous progress. This article provides a review of the current achievements in gene therapy for Alport syndrome and discusses future research directions in this field.

#1181 The relationship between renal ischaemia-reperfusion injury and circadian rhythm

Abstract Background and Aims Kidney disease is a global health problem in which various aetiologies contribute to renal injury and dysfunction. Renal ischaemia-reperfusion injury (IRI) is a condition caused by early oxidative stress due to renal tissue ischaemia and a rapid immune response after reperfusion. Circadian rhythms are important regulators of metabolism and their disruption can lead to heart disease and fibrosis in various organs. Although recent reports have shed light on the impact of renal injury and disease on the renal circadian clock, the exact mechanisms by which circadian rhythm genes contribute to the progression of renal dysfunction in IRI and the onset of chronic kidney disease (CKD) are not fully understood. Method Male Wistar rats (8-9 weeks old, 250-280 g body weight) were used to establish the I/R model. To induce renal I/R injury, the left renal artery was clamped for 30 or 45 min and then removed to restore blood flow. Simultaneously, nephrectomy of the right kidney was performed; renal tissue and blood were collected 14 days after I/R. HE staining, Sirius red staining and immunostaining (F4/80 staining) were performed. Kidney tissue was RNA-seq'd and qPCR'd for circadian rhythm genes and fibrosis genes involved in kidney failure that were altered by I/R. Kidney tissue was also RNA-seq'd and qPCR'd for circadian rhythm genes and fibrosis genes involved in kidney failure. We also established an in vitro hypoxia-reoxygenation (H/R) model using single cell RPTECs and performed qPCR and Western blotting. Results In the IRI rat group, the expression of circadian repressor genes Nr1d1 and Nr1d2, which are important for reducing inflammation, decreased, while the expression of Bmal1 and Cry1, which regulate renal deterioration, increased. Using RNA-seq, we also identified the involvement of the TGFβ pathway in linking the circadian clock to kidney injury and fibrosis, and observed similar results in the H/R group using RPTEC cells in vivo. Conclusion Fibrosis and circadian rhythms were found to be closely related in renal IRI. The findings described here may help in the development of new therapeutic approaches to ameliorate the effects of renal IRI and improve the outcome of kidney disease, including kidney transplantation, offering hope to patients worldwide.

Outcomes of hemolytic-uremic syndrome in children

It is proved that HUS in children is the cause of the formation and progression of renal dysfunction with the formation of CKD. At the same time, the outcomes of HUS in childhood remain insufficiently studied. Purpose. To establish the outcomes of hemolytic-uremic syndrome in children and to develop an algorithm for their prediction.Results. Seasonality is established (May and June) HUS in children, an increase in the incidence rate. In the structure of HUS in children of the Orenburg region, STEC-HUS prevails (96.5 %), more often (68.6 %) in infants and young children. Chronic kidney diseases associated with HUS are characterized by a violation of the structure of the kidneys, a decrease in intrarenal hemodynamics, increased blood pressure, microalbuminuria, tubular dysfunction and a decrease in glomerular filtration rate in combination with an increase in the level of endothelin-1 blood, cystatin From urine and blood, uNGAL. An increase in endothelin-1 in blood, cystatin From urine and blood, uNGAL correlates with the level of increased blood pressure, a decrease in intrarenal hemodynamics, GFR and tubular dysfunction and are pathogenetic criteria for kidney damage in HUS convalescent children. Discussion. Clinical and pathogenetic markers of the formation of CKD have been established: an increase in the level of blood EТ-1, blood cystatin, urine lipocalin in combination with arterial hypertension, a decrease in GFR and intrarenal hemodynamics, an increase in tubular dysfunction and the level of microalbuminuria. Conclusion. The outcomes of HUS in children are- favorable (recovery); unfavorable (formation of chronic kidney pathology): TIBP, occurring with isolated urinary syndrome; nephropathies with isolated prenephrotic proteinuria; chronic kidney disease; fatal outcome. The developed «Algorithm for predicting chronic kidney damage in children with HUS convalescents», «Method for predicting tubulo-interstitial kidney disease in children associated with hemolytic-uremic syndrome», allow optimizing the early diagnosis of chronic kidney pathology in children after HUS, contribute to the timely appointment of preventive measures to prevent the progression of renal dysfunction and is recommended for use in the practice of pediatricians, nephrologists.

Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron-deficient heart failure.

The available evidence suggests that the kidney may contribute importantly to the development of an iron deficiency state in patients with heart failure and may be injured by therapeutic efforts to achieve iron repletion. The exceptional workload of the proximal renal tubule requires substantial quantities of iron for ATP synthesis, which it derives from Fe3+ bound to transferrin in the bloodstream. Following ferrireduction, Fe2+ is conveyed by divalent transporters (e.g. DMT1) out of the endosome of the proximal renal tubule, and highly reactive Fe2+ can be directed to the mitochondria, sequestered safely in a ferritin nanocage or exported through the actions of hepcidin-inhibitable ferroportin. The actions of ferroportin, together with transferrin endocytosis and DMT1-mediated transport, play a key role in the recycling of iron from the tubular fluid into the bloodstream and preventing the loss of filtered iron in the urine. Activation of endogenous neurohormonal systems and proinflammatory signalling in heart failure decrease megalin-mediated uptake and DMT1 expression, and increase hepcidin-mediated suppression of ferroportin, promoting the loss of iron in the urine and contributing to the development of an iron deficiency state. Furthermore, the failure of ferroportin-mediated efflux at the basolateral membrane heightens the susceptibility of the renal tubules to cytosolic excesses of Fe2+, causing lipid peroxidation and synchronized cell death (ferroptosis) through the iron-dependent free radical theft of electrons from lipids in the cell membrane. Ferroptosis is a central mechanism to most disorders that can cause acute and chronic kidney disease. Short-term bolus administration of intravenous iron can cause oxidative stress and is accompanied by markers of renal injury. Experimentally, long-term maintenance of an iron-replete state is accompanied by accelerated loss of nephrons, oxidative stress, inflammation and fibrosis. Intravenous iron therapy increases glomerular filtration rate rapidly in patients with heart failure (perhaps because of a haemodynamic effect) but not in patients with chronic kidney disease, and the effects of intravenous iron on the progression of renal dysfunction in the long-term trials - AFFIRM-AHF, IRONMAN and HEART-FID - have not yet been reported. Given the potential role of dysregulated renal iron homeostasis in the pathogenesis of iron deficiency and the known vulnerability of the kidney to intravenous iron, the appropriate level of iron repletion with respect to the risk of acute and chronic kidney injury in patients with heart failure requires further study.

ALBUMINURIA IS ASSOCIATED WITH LESS EFFORT TOLERANCE IN HYPERTENSION AND DIABETES

Introduction: The presence of albuminuria is an adverse marker of renal dysfunction progression. Hypertension and diabetes mellitus predispose to albuminuria. However, not all hypertensive and diabetic patients have albuminuria, so it is relevant to identify risk factors associated to this abnormality. The acute effect of intense physical activity may lead to transient albuminuria. On the other hand, physical inactivity is associated with risk factors for albuminuria Objective: To analyze the association between activity levels or physical performance and albuminuria in hypertensive and/or diabetic patients treated at basic health services. Methodology: A prospective cross-sectional study with hypertensives and/or diabetics subjects. The patients were evaluated in regard of albuminuria, clinical, laboratory and physical test performance variables. Results: There was no association between the degree of albuminuria and demographic, anthropometric, laboratory variables, functional capacity and level of physical activity. The degree of albuminuria was associated with systolic blood pressure, as well as the perception of effort, obtained by Borg Scale during the test in univariate analysis (odds ratio 4.11 with 95% confidence interval from 1.18 to 14.37, p = 0.027) and adjusted for systolic blood pressure and diabetes (odds ratio 3.02 with 95% confidence interval from 1.35 to 6.75; p = 0.007). Conclusion: there was association between albuminuria and perceived effort, as well with systolic blood pressure. There was not with association physical performance or level of activity. Further studies are needed to elucidate the association of albuminuria with Borg Scale.

A short treatment with resveratrol after a renal ischaemia-reperfusion injury prevents maladaptive repair and long-term chronic kidney disease in rats.

Acute kidney injury (AKI) often triggers physiological processes aimed at restoring renal function and architecture. However, this response can become maladaptive, leading to nephron loss and fibrosis. Although the therapeutic effects of resveratrol (RSV) are well established, its impact after AKI and for subsequent chronic kidney disease (CKD) remains unclear. This study assessed whether transient administration of RSV following ischaemia-reperfusion injury (IRI) could prevent the progression to CKD. Forty-one male Wistar rats were assigned randomly to sham surgery, bilateral renal ischaemia for 30min (IR) or IR+RSV. The RSV treatment commenced 24h after IRI and continued for 10days. The rats were studied for either 10days or 5months, after which kidney function and structure were evaluated. Mitochondrial homeostasis, oxidant defence and renal inflammation state were also evaluated. Despite having the same severity of AKI, rats receiving RSV for 10days after IRI exhibited significant improvement in kidney histological injury and reduced inflammation, although renal haemodynamic recovery was less pronounced. Resveratrol effectively prevented the elevation of tubular injury-related molecules and profibrotic signalling with reduced myofibroblast proliferation. Furthermore, RSV substantially improved the antioxidant response and mitochondrial homeostasis. After 5months, RSV prevented the transition to CKD, as evidenced by the prevention of progressive proteinuria, renal dysfunction and tubulointerstitial fibrosis. This study demonstrates that a brief treatment with RSV following IRI is enough to prevent maladaptive repair and the development of CKD. Our findings highlight the importance of the early days of reperfusion, indicating that maladaptive responses can be reduced effectively following severe AKI. KEY POINTS: Physiological processes activated after acute kidney injury (AKI) can lead to maladaptive responses, causing nephron loss and fibrosis. Prophylactic renoprotection with resveratrol (RSV) has been described in experimental AKI, but its impact after AKI and for subsequent chronic kidney disease (CKD) remains unclear. In this study, we found that histological tubular injury persists 10days after ischaemia-reperfusion injury and contributes to a failed repair phenotype in proximal tubular cells. Short-term RSV intervention influenced the post-ischaemic repair response and accelerated tubular recovery by reducing oxidative stress and mitochondrial damage. Furthermore, RSV targeted inflammation and profibrotic signalling during the maladaptive response, normalizing both processes. Resveratrol effectively prevented AKI-to-CKD transition even 5 months after the intervention. The study serves as a proof of concept, proposing RSV as a valuable candidate for further translational clinical studies to mitigate AKI-to-CKD transition.

Long-Term Effects of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Predictors of Treatment Response and Safety over 6 Years of Continuous Therapy.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (-8.77-20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis-a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

P-29 Metformin poisoning without lactic acidosis: Case report

Abstract Introduction Metformin is the most widely used oral antidiabetic, which belongs to the biguanide pharmacological group. Metformin-associated lactic acidosis (MALA) is a rare event with an incidence of approximately 19 cases per 100,000 patient-years. The risk of developing lactic acidosis, when taking metformin is enhanced by several factors such as: age &amp;gt; 65 years; concomitant diseases that have the ability to induce hypoxemia (chronic renal failure, congestive heart failure, cardiogenic shock, severe lung disease, sepsis, advanced liver disease, history of lactic acidosis); an excessive alcohol consumption; an administration of iodinated contrast agents. Clinical Case A 46-year-old man was urgently admitted with the following symptoms: drowsiness, repeated vomiting, lethargy, dizziness. The symptoms started after he administered outpatient and at own initiative 50 tablets of metformin, each tablet contains a dose of 500 mg (total dose 25g). Concomitant pathologies: diagnosed with Type 2 Diabetes for 8 years; Toxic liver cirrhosis, compensated Child-Pugh A (recently diagnosed); hypertension; CKD G3aA2 KDIGO. The patient's condition at admission was assessed as extremely serious, Glasgow scale - 11 points, mild hypertension, tachycardia, tachypnea. The paraclinical investigations revealed the presence of metabolic acidosis, but with lactate &amp;lt;5 mmol/l; the progressive renal dysfunction with creatinine values in the first 24 hours up to 1184 µmol/l, urea – 24.5 mmol/l; a severe hypoglycemia - 1.68 mmol/l; a moderate cytolytic syndrome; a cholestatic syndrome, an inflammatory and hepatoprive syndrome; coagulation disorders; a pancreatic dysfunction. In the context of the evident increase of urea and creatinine, the decision was made to initiate the intermittent hemodialysis, a total of 14 sessions were required during hospitalization. The particularity of this case is represented by the absence of lactic acidosis, despite metformin intoxication with altered neurological status, acute renal failure, developed due to chronic kidney disease, liver cirrhosis of toxic etiology and severe hypoglycemia. Conclusion Metformin should be administered with caution in patients with multiple comorbidities. Metformin intoxication can induce lactic acidosis with an increased risk of serious, potentially fatal adverse events. It is essential to identify metformin intoxication as early as possible, with prompt initiation of renal replacement measures and dynamic monitoring of biochemical parameters.