Increase In Glomerular Filtration Rate Research Articles

Losartan is more effective than angiotensin (1–7) in preventing thyroxine-induced renal injury in the rat

AimStudies have shown that renal hypertrophy seen in experimental hyperthyroidism induced by thyroxine (T4) is due to angiotensin (Ang) II. However, other renal effects of Ang II in experimental hyperthyroidism have not been investigated. In addition, Ang 1–7 is believed to be protective against renal injury, but its possible role in thyroxine-induced renal injury is not known. The aim of this study is to elaborate the role of Ang II in thyroxine-induced renal injury and the possible protective role of Ang 1–7. We hypothesize that Ang 1–7 will be as protective against thyroxine-induced renal injury as the use of an ACE inhibitor or an Ang II receptor blocker.MethodsAdult Sprague Dawley rats were used in this study and were divided into 5 groups: (1) Control (treated with vehicle), (2) Treated with thyroxine (T4, 100 µg/kg), (3) Treated with T4 and Ang 1–7 (500 µg/kg), (4) Treated with T4 and captopril (20 mg/kg), and (5) Treated with T4 and losartan (10 mg/kg). Parameters tested after fourteen days of treatment were creatinine clearance, protein excretion rate, glomerular volume, renal ACE1 and ACE2 protein expression. Data were compared using One-way-ANOVA followed by Tukey’s HSD post hoc test.ResultsThyroxine caused glomerular hypertrophy and proteinuria but had no effect on glomerular filtration rate (GFR). Glomerular hypertrophy was prevented by losartan and captopril, but not by Ang 1–7. Captopril and losartan had no effect on GFR; however, Ang 1–7 caused an increase in GFR in T4-treated rats. The increase in protein excretion rate was prevented by losartan but not by captopril or Ang 1–7. Renal expression of ACE1 protein was not altered in any of the treatment groups except in captopril treated rats were ACE1 expression was increased. Renal ACE2 protein expression was only increased in T4-losartan-treated rats and not affected by any of the other treatments.ConclusionWe conclude that losartan was more protective than captopril against thyroxine-induced renal changes while Ang 1–7 offered no protection.

Changes in glomerular filtration rate in patients with body mass index≥35kg/m2 treated with metabolic and bariatric surgery versus GLP-1 agonist at 1-year follow-up.

Metabolic and bariatric surgery (MBS) reduces glomerular hyperfiltration. The renoprotective effects of GLP-1 analogs were derived from clinical studies in type 2 diabetes (T2D). The objective of this study was to evaluate the changes in glomerular filtration rate (GFR) over time associated with weight loss in patients with a BMI ≥ 35kg/m2 treated with liraglutide compared with patients treated with MBS. A longitudinal study derived from a retrospective cohort of patients with BMI≥35kg/m2 treated with either MBS or liraglutide 3mg/day, with follow-up ≥1year. Clinical variables, baseline GFR, and 1-year GFR were analyzed. A generalized estimating equation (GEE) model was used to compare changes in GFR between both groups while controlling for confounding variables. A total of 159 patients were included in the analysis. Of these, 129 patients underwent MBS (median age 60.5years [IQR 51.8-66.6], body mass index (BMI) 40.9kg/m2 [IQR 0.68-0.89]), and 30 patients were treated with liraglutide (median age 56years [IQR 46-62], BMI 37.4kg/m2 [IQR 0.69-0.93]). No difference in baseline GFR or at 12months of follow-up was found between the two interventions. GEE analysis revealed an increase of 0.32mL/min/1.73m2 per month of follow-up. Factors associated with a greater increase in GFR were the percentage total weight loss (%TWL) (0.12mL/min/1.73m2, p=0.023) and baseline GFR (0.69mL/min/1.73m2, p>0.001) for both interventions, independent of a history of T2D. In patients with BMI≥35kg/m2, changes in GFR are related to %TWL and baseline GFR, regardless of the presence of diabetes or the type of intervention used.

#1994 Analysis of dynamics of parameters of safety and effectiveness of rivaroxaban in patients with stage IV chronic kidney disease and atrial fibrillation

Abstract Background and Aims Research in the field of comorbidity of chronic kidney disease (CKD) and atrial fibrillation (AF) is becoming increasingly relevant, especially given the continuously increasing prevalence of this arrhythmia and its contribution to the risk of adverse events, the unity of factors in the development and progression of these diseases. This comorbidity is accompanied by an increased risk of thromboembolic complications (TEC) and atherothrombotic events, as well as the incidence of bleeding during anticoagulant therapy (ACT), which undoubtedly underlies the higher rates of cardiovascular and overall mortality in this cohort of patients. In this regard, we set the following goal: analysis of the dynamics and assessment of the safety parameters and effectiveness of the use of rivaroxaban in patients with a glomerular filtration rate (GFR) of 15–29 ml/min/1.73 m2 with non-valvular atrial fibrillation. Method The medical records of 12,026 patients were analyzed; non-valvular AF was diagnosed in 3,715 cases. 502 (15%) patients had stage IV CKD or a sustained decrease in GFR to 15–29 l/min/1.73 m2 during hospitalization. Of these, 109 (3%) patients met the inclusion criteria and were randomized 2:1 to rivaroxaban 15 mg (n = 73) or warfarin (n = 36). The average follow-up period was 18 months. Of the 109 included patients, 2 refused to participate in the study, contact with 9 was lost, 8 patients started taking another direct oral anticoagulant, CKD progressed to stage V in 4 patients, and antiplatelet agents were added in 6 cases. Results To assess the dynamics of changes in creatinine levels and GFR, mixed linear models were constructed, where the individual dynamics of each patient's indicators were selected as random effects, and time and drug intake were selected as fixed effects. A graphical interpretation of the dynamics and differences is presented in Figs 1 and 2. There was a significant improvement in the dynamics of creatinine and GFR in the rivaroxaban group compared to the warfarin group: while patients receiving rivaroxaban had an increase in GFR and a decrease in creatinine levels, patients taking warfarin, on the contrary, showed inverse dynamics in renal function indicators. It should be noted that during the study, a transition from stage IV CKD to stage III was recorded in 43% of patients in the rivaroxaban group and in 34% in the warfarin group (p = 0.26). There were no significant differences in the incidence of any acute cerebrovascular accident, myocardial infarction and all-cause mortality (warfarin—1.4%; 6.9%; 6.8% versus rivaroxaban—5.6%; 2.85; 8.3% (p = 0.25; 0.66; 0.78). Patients taking warfarin were significantly more likely to develop minor bleeding compared to rivaroxaban (36.9% versus 61.1% (p = 0. 01)) and all clinically significant bleeding (10.9% vs. 27.7% (p = 0.03)) according to the ISTH scale. In the warfarin group, TTR>70% was achieved in 94% of patients. All-cause readmission rates were 43% in the rivaroxaban group and 48% in the warfarin group (p = 0.57). Among these patients, 36.9% and 40.7% (respectively) were hospitalized for emergency reasons (p = 0.96). Conclusion In patients with atrial fibrillation and a low glomerular filtration rate (eGFR <30 ml/min/1.73 m2), it is reasonable to consider the use of rivaroxaban based on the current study showing a slower rate of decline in renal function, as well as favorable efficacy and safety profiles of rivaroxaban compared with warfarin in this group of patients.

#2859 Clinical and morphological characteristics of biopsy-proven kidney graft rejection in Latvia

Abstract Background and Aims Kidney transplantation is a treatment for many patients with end stage renal disease leading to increased quality of life. In last decades results in kidney transplantation have been improving, but allograft rejection remains an important clinical problem. Graft biopsy remains the gold standard to assess the cause of kidney transplant status. This study aimed to determine clinical and histopathological characteristics, treatment and short-term outcomes of biopsy-proved kidney graft rejection in Latvia. Method In this retrospective observational study all kidney allograft biopsies performed in Pauls Stradins Clinical University Hospital from January 2014 till December 2022 was reviewed. Biopsies with rejection, ≥7 glomeruli, patients ≥18 years old were included. Acute rejection was diagnosed according to clinical, laboratory and biopsy-proven acute rejection (BPAR) histological criteria. BPAR was classified and subdivided using Banff criteria. All recipients universally received either depleting or non-depleting induction therapy. Most of the patient (82%) for maintenance immunosuppression (MI) received triple therapy with calcineurin inhibitor, mycophenolate mofetil, and prednisone, others—in different combinations with above and mammalian target of rapamycin (mTOR), azathioprine. Graft function was evaluated according to glomerular filtration rate (GFR), calculated with the CKD-EPI Creatinine, 2021 equation. Treatment strategies, laboratory data at the time of biopsy and after 1 year follow-up were analysed. Repeated-control biopsies after receiving therapy were excluded. Data were analysed using descriptive statistics and T-test. Results From all 523 biopsies, further included and analysed were 153 (total 146 patients). 58% were males, average patient age was 45.5 years. Most 84% of the grafts were from deceased, 8%—living donors. Mean time from transplantation to biopsy was 32 months. Acute antibody-mediated rejection (AAMR) was diagnosed in 41% cases, chronic-active antibody mediated (CAAMR)—25%, followed by mixed 16%, acute cellular (ACR) 10% and borderline 8% rejection. Besides augmented MI for almost all patients, pulse steroids (GCS) were the most commonly 70% administered treatment, followed by plasma exchange 59% (PEX), rituximab (RTX) 50%, immunoglobulins (IG) 24% and anti-thymocyte globulin (ATG) 10% in different, mostly non-homogenous combinations. Non adherence, advanced fibrotic changes in biopsy and serious comorbidities were the main reasons patients did not receive specific treatment besides intensified MI. The most favourable outcomes were in ACR where mean allograft GFR increased +20.7 ml/min after one year, compared to the worst outcome CAAMR group where GFR decreased −4.7 ml/min (p = 0.03). In ACR group 92% graft function stayed the same or improved, moreover 54% graft function increased ≥20% from baseline; similarly in mixed and AAMR group GFR increase ≥20% were for 45% and 48%, compared to CAAMR where it was only for 6% of patient. Furthermore, the CAAMR group was with the most patients (48%) who returned to dialysis or died. In AAMR and mixed rejection groups mean GFR changes were close +13.4 ml/min and +12.9 ml/min (p = 0.95). There were no statistically significant associations between treatment outcomes in PEX+RTX+GCS vs PEX+RTX+GCS+IG in the AAMR group (p = 0.382). Overall, 3.9% of patients died. Conclusion Overall BPAR prevalence between kidney graft biopsies was high (29%). Antibody mediated rejection was diagnosed most often with least favourable short-term outcomes in CAAMR group. Despite various improvements in immunosuppression, CAAMR remains a serious cause of transplant dysfunction or loss.

#1290 Adverse proinflammatory responses in the kidney after FGF23 administration in three murine kidney disease models

Abstract Background and Aims The hormone FGF23 is a biomarker associated with morbidity and mortality in individuals with and without kidney disease, but the role of FGF23 excess as a pathogenic factor is incompletely understood. Here, we investigated renal FGF23 signaling in kidney disease models. Method This study used three independent disease models: i) Male C57BL/6 mice (n = 16) were treated with Freud's adjuvant and nephrotoxic serum (NTS) to induce anti-glomerular basement membrane (anti-GBM) disease. ii) Female BALB/c mice (n = 8) were treated with adriamycin (doxorubicin) 10.5 mg/kg to induce focal and segmental glomerulosclerosis (FSGS). iii) Male DBA/2J mice (n = 20) were fed a diet containing adenine 0.2%. Control mice of the respective same strain and sex received vehicle injections. Mice of the anti-GBM and FSGS models and controls received intravenous injections of recombinant FGF23 1 µg or vehicle for six consecutive days (anti-GBM) or once (FSGS), with dissection 24 h after the last injection. Mice of the adenine model were dissected after 15 weeks. Following dissection, ex vivo precision-cut kidney slices (PCKS) were obtained from n = 4 mice and maintained for 24 at 37°C, 95% O2 and 5% CO2, followed by a 1 h treatment with recombinant FGF23 200 ng/ml or vehicle. Glomerular filtration rate (GFR) or renal retention parameters in serum and albuminuria were assessed. Kidneys underwent histological assessment using hematoxylin & eosin or Masson's trichrome. Renal RNA was isolated for bulk RNAseq. Differential gene expression was assessed to determine the effect of FGF23 treatment in disease-free controls, in each disease model, and the interaction between FGF23 X disease effect for the anti-GBM and FSGS groups. Gene set enrichment analysis was performed with a focus on the immune system. Results Anti-GBM mice showed a 45 ± 27% GFR decline (mean ± SD) compared to baseline, whereas controls showed an GFR increase of 11 ± 36% (p < 0.01). Kidney histology revealed an interstitial infiltrate. The FSGS model showed elevated serum creatinine and albuminuria, and hypercellularity in some glomeruli. Mice of the adenine model showed progressively increased blood urea nitrogen concentrations starting after 2 weeks, up to a 3-fold increase at week 14. Histology revealed interstitial fibrosis and tubular atrophy. Bulk RNAseq revealed proinflammatory transcriptional signatures after FGF23 treatment in all disease models, regardless of which timepoint or model: In the anti-GBM model, Hallmark gene sets of inflammatory response, interferon-α response, interferon-β response and allograft rejection were significantly increased after 6 days of FGF23 treatment, whereas disease-free controls showed no significantly changed immune gene sets after 6 days of FGF23. In FSGS mice, none of the Hallmark gene sets were changed after 1 FGF23 injection, but top individual gene expression affected by 1 FGF23 injection were an increased proinflammatory transcription factor Cebpb and an increased DNA damage transcript Dclre1b. Finally, the PCKS of adenine model revealed no significant Hallmark gene sets, but the two genes with differential expression were a proinflammatory macrophage/fibroblast chemokine Ccl4 (increased) and an immunoglobulin heavy variable Ighv2-2 (decreased). Conclusion FGF23-driven patterns of proinflammatory gene expression were observed in three experimental models of kidney disease, both in vivo and ex vivo assessment of FGF23 signaling, thus excluding effects of FGF23 on other organs. As these findings were limited to transcriptional analyses, the present data warrant further confirmation and exploration of FGF23 as a pathogenic agent in kidney disease.

The Role of Interleukin-6 in Regulating Glomerular Filtration Rate during Angiotensin II and High Salt Conditions

Previous results demonstrate that interleukin-6 (IL-6) increases mean arterial pressure (MAP) during Angiotensin II (Ang II)-salt hypertension. In addition, albumin excretion was lower in IL-6 knockout mice (KO) when compared to wild-type (WT). This study investigated the role of IL-6 on regulating glomerular filtration rate (GFR), renal plasma flow (RPF) and MAP in WT and IL-6 KO mice treated with a slow pressor dose of Ang II (200 ng/kg/min) +/- 6% high-salt (HS) diet. Male C57BL6 and IL-6 KO mice (12 weeks old) were treated with Ang II +/- 6% HS diet for 12 – 14 days. Mean arterial pressure, RPF and GFR were measured in anesthetized mice. MAP was 130 ± 7 mmHg and 91 ± 4 mmHg in control WT and IL-6 KO mice, respectively. Ang II treatment increased MAP in WT (153 ± 5 mmHg) and no change in IL-6 KO (83 ± 4 mmHg) mice. Ang II + 6% HS increased MAP to 150 ± 11 mmHg in WT and 93 ± 4 mmHg in IL-6 KO mice. Baseline RPF was 1822 ± 229 and 1912 ± 402 ml/min/g in control WT and IL-6 KO mice, respectively. Ang II treatment increased RPF in WT (3156 ± 753 ml/min/g), while lowering RPF in IL-6 KO (1648 ± 422 ml/min/g) mice. RPF during Ang II + 6% HS treatment was decreased in WT (1095 ± 305 ml/min/g) and IL-6 KO (1133 ml/min/g) mice. GFR was 756 ± ml/min/g and 788 ± ml/min/g in control WT and IL-6 KO mice, respectively. Ang II increased GFR in WT (1009 ± 63 ml/min/g) and no change in IL-6 KO (756 ± 23 ml/min/g). Ang II + 6% HS increased GFR in WT (1095 ± 146 ml/min/g) and no change in GFR of IL-6 KO (540 ± 207 ml/min/g) mice. Our results suggest that IL-6 reduces MAP during baseline, Ang II, and Ang II + 6% HS. The absence of IL-6 prevented increases in MAP, RPF and GFR during Ang II treatment. Our data also suggest that IL-6 contributes to increased MAP and GFR during Ang II + 6% HS treatment. K01HL092593-05. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Association Between Thyroid Hormones and Renal Function in Euthyroid Chinese Individuals: A Population-Based Cross-Sectional Study.

Objective This population-based cross-sectional study aimed to investigate the association between thyroid hormones and renal function in euthyroid Chinese individuals, as the relationship between thyroid hormones and renal function in this population remains unclear. Methods A total of 661 participants were included in the study after excluding individuals with thyroid diseases, incomplete clinical measurements, or those taking medications affecting thyroid function. Participants were categorized into three groups based on serum thyroid hormone and antibody levels. The study adjusted for covariates and assessed the glomerular filtration rate (GFR) and urine albumin-to-creatinine ratio (ACR) in relation to thyroid hormone levels. Results After adjusting for covariates, the study found a significant increase in GFR in the middle and highest tertiles of free triiodothyronine (FT3) and the highest tertile of total triiodothyronine (TT3). Serum FT3 and TT3 levels were significantly associated with GFR. Additionally, the study observed a significantly lower GFR in the highest tertile of thyroid-stimulating hormone (TSH) compared to the lowest tertile. However, thyroid hormone and antibody levels were not associated with the ACR. Furthermore, the highest tertiles of TT3 and total thyroxine (TT4) were associated with a decreased risk of chronic kidney disease (CKD). Conclusion In our study among euthyroid Chinese individuals, we observed a significant association between thyroid functionand GFR. Specifically, lower FT3, TT3, and higher TSH were associated with reduced GFR, indicating a potential role for thyroid hormones in maintaining renal function. Furthermore, lower levels of TT3and TT4were associated with an increased risk of CKD. These findings suggest a direct link between thyroid and renal function, even in euthyroid individuals, emphasizing the need for further investigation to elucidate the underlying mechanisms and potential therapeutic implications.

Percutaneous Nephrostomy as a Procedure in the Treatment of Urinary Tract Obstruction - Experiences in the University Clinic of Urology in Skopje.

Obstructive uropathy encompasses various urinary tract obstructions, leading to changes in urine flow, kidney pressure, and impaired kidney function. Predicting renal recovery from obstructive uropathy, can be challenging and necessitates treatment, as in percutaneous nephrostomy (PNS) drainage. The choice of drainage method depends on patient-specific factors and local expertise. According to the data for the Republic of North Macedonia, in the register of the European Renal Association, in the last few years, there has been an increase in the percentage of patients with obstructive nephropathy from 7.6% to 8.9% who end up on a chronic hemodialysis program. Prompt relief from urinary tract obstruction is essential to preserve renal function and prevent complications. The aim of this study is to present our initial data analysis of recent experience in the use of nephrostomies as a method for temporary or long-term resolution of obstructive nephropathy, in terms of safety and success in preserving kidney function and reducing the number of patients on hemodialysis. This study analyzed the medical records of 24 patients with obstructive uropathy who underwent PNS placement. Data were collected for the type and degree of obstruction from the ultrasonographic examination. A pig tail nephrostomy was used, with a dilator, guided under ultrasound and controlled with contrast and fluoroscope. Obstructive nephropathy was defined as an elevation of the serum creatinine > 109 µmol/L, before the intervention. Glomerular filtration rate (GFR) was calculated according to the formula CKD epi in ml/min. Each placement of the PNS was considered as an individual procedure and the data of 38 placed nephrostomies were analyzed. We compared the laboratory analyses from the day before (D0) PNS placement and on the seventh day (D7) after PNS placement. The reduction of values for red blood cells (RBC) and hemoglobin (Hb) baseline values from D0 to D7 and the need for transfusion after the procedure were defined as a complication-bleeding. The increase in total counts of the white blood cells (WBC) and C-reactive protein (CRP) from the baseline values from D0 to D7 were defined as a complication-infection. Standard statistical methods were used for data processing. Most patients, 17 (70%), had malignant disease as the cause of obstruction. Unilateral obstruction was more common, detected in 24 (63%) of procedures, with a high degree of hydronephrosis. Obstructive nephropathy, marked by elevated serum creatinine, was observed in 23 (60%) cases before PNS placement. Complications included bleeding and infection but did not result in any fatalities. When comparing the laboratory analysis before PNS placement (D0) and seven days later (D7), a statistically significant decrease in serum creatinine (225±161 vs. 162±145, p=0.005) and an increase in GFR (47±39 vs.59±34, p= 0.005) were observed. Percutaneous nephrostomy is a safe and effective treatment option for urinary tract obstruction, especially in patients with malignancies. Continuous monitoring is essential to assess long-term complications and the longevity of PNS functionality. This procedure offers a significant benefit in preserving renal function and minimizing the need for hemodialysis in these patients.

Comparison of different estimated glomerular filtration rates for monitoring of kidney function in oncology patients.

Tyrosine kinase inhibitors (TKIs) are associated with kidney function deterioration. A shift is ongoing towards glomerular filtration rate (GFR) equations based on other protein markers, such as cystatin C (CSTC) and β-trace protein (BTP). We evaluated various GFR equations for monitoring of kidney function in actively treated oncology patients. We monitored 110 patients receiving a TKI. Blood and urine were collected during therapy. Serum analysis included creatinine (Cr), CSTC and BTP; for consequent GFR determination. Urine was analysed for protein, albumin, immunoglobulin G, and α-1-microglobulin. A similar analysis was done in a patient subgroup receiving immune checkpoint inhibitors (ICI) as prior or subsequent line of therapy. Cr remained constant during TKI treatment (P=0.7753), whereas a significant decrease in CSTC (from week 2 onward, P<0.0001) and BTP (at weeks 2 and 4, P=0.0100) were noticed. Consequently, GFR estimations, using CSTC and/or BTP as a biochemical parameter, showed an apparent increase in GFR, whereas this was not observed for Cr-related GFR estimations. As a result, the GFR gap (ΔGFR) was significantly different from week 2 onward between Cr-based and CSTC-based GFR and between BTP-based and CSTC-based GFR. Glomerular damage was noticed with significant increase in urine protein-to-creatinine ratio, albumin-to-creatinine ratio and immunoglobulin G (all P<0.0001). No change in α-1-microglobulin was seen. ICI treatment had no effect on Cr (P=0.2262), CSTC (P=0.7341), and BTP concentrations (P=0.3592). GFR equations, in which CSTC is incorporated, fail to correctly estimate the GFR in oncology patients treated with TKIs. As TKI-treated patients show clear signs of glomerular injury, further assessment is needed on how to correctly monitor the kidney function in actively treated oncology patients.

Validation of Townes As Mice As a Model of Chronic Kidney Disease and Venous Thrombosis Associated with Sickle Cell Trait

Individuals with sickle cell trait (SCT) are heterozygous carriers of the sickle beta-globin gene. Systematic analyses of large cohort studies over the past decade have established that SCT is a risk factor for a limited number of complications, most notably chronic kidney disease (CKD) and venous thrombosis (VT). SCT red blood cells (RBCs) can undergo sickling, although the degree and duration of hypoxia required to produce sickling are much greater than in sickle cell disease due to the lower intra-erythrocyte sickle hemoglobin beta (HbS) concentration of 25-45%. Hypoxia-mediated HbS polymerization can be enhanced by cellular dehydration, hyperosmolarity and/or acidosis that may be encountered in the renal inner medulla. Furthermore, prolonged exposure of SCT RBCs to profound hypoxia, such as in the nidus of a venous clot, will also result in sickling. The objective of this study was to determine if Townes AS mice manifest kidney dysfunction analogous to their SCT human counterparts. Furthermore, we evaluated whether VT was more pronounced in a well-described model of inferior vena cava (IVC) stasis. We used humanized male sickle cell trait (AS) and age-matched genetic control (AA) mice (n=7-16). Analysis of urinary renal biomarkers (albuminuria, proteinuria, kidney injury marker 1 (KIM-1), osmolality) and kidney function (transcutaneous measurement of glomerular filtration rate (GFR)) were conducted at 4-week intervals from 8 to 40 weeks of age. VT was induced by complete occlusion of the IVC in AA and AS mice. Sickling of RBCs was determined by histological and electron microscopy analysis of the IVC clot. Senicapoc, an oral Gardos channel inhibitor, was administered twice daily (20mg/kg, bid) for 2 weeks to prevent AS RBC dehydration and subsequent sickling. Human HbS accounts for 30.1% of total Hb expression in AS mice. Consistent with human SCT, peripheral blood counts did not differ from AA controls. Basal plasma thrombin-antithrombin complex levels were also not different between AA and AS mice. We performed a longitudinal study of renal structure and function in AA and AS mice over 40 weeks. At 8 weeks of age, AS mice exhibited no differences in any parameter compared to AA controls. However, AS mice subsequently developed albuminuria and a moderate but statistically significant increase in GFR (Figure 1). At 36 and 40 weeks of age, we observed progressive loss of kidney function demonstrated by statistically significant decreased GFR accompanied by a significant increase in albuminuria in AS mice (Figure 1). Over time, proteinuria gradually increased in AS mice, and had doubled by 40 weeks of age compared to AA controls (4.6 ±1.1 vs. 2.3 ±0.4 mg/24h, p&amp;lt;0.05). Increased levels of urinary KIM-1, a marker of tubular damage, were observed in AS mice throughout the duration of the study, with the highest levels at 16 weeks (228.3 ± 32.6 pg/24h vs. 53.8 ± 8.5 pg/24h, respectively, p˂0.05). Urine osmolality was not different at 8 weeks of age, but progressively declined in AS mice with statistically significant changes vs. controls starting at 24 weeks until the end of study (1946 ±63 vs. 2672 ±135 mOsm/kg at 40 weeks, p=0.002). Histologic analysis confirmed glomerular injury (congestion, glomerulosclerosis) and tubular injury (medullary congestion, interstitial fibrosis) in 40 week old AS mice. Following 24 hours of IVC stasis, thrombus weight was significantly increased (p&amp;lt;0.01) in AS mice (mean±SEM; 29.0 mg +/- 1.7; n=8) compared to AA controls (20.0 mg ± 1.7; n=7). Histologic and electron microscopic evaluation demonstrated that severe hypoxia (pO 2 ≈ 10 mm Hg) present in the nidus of venous thrombi was associated with extensive sickling of RBCs in AS mice. To determine if the enhancement of VT observed in AS mice was mediated by RBC sickling, mice were pretreated with Senicapoc or vehicle. Compared to vehicle-treated AS mice (27.3 mg ± 2.2 n=9) pre-treatment with Senicapoc significantly reduced (p&amp;lt;0.05) clot weight (18.1mg ± 1.1; n=7) to that observed in untreated AA controls. In aggregate, our data demonstrate that Townes AS murine nephropathy closely mimics the renal abnormalities (impaired urinary concentration and albuminuria with later onset loss of GFR) described in humans with SCT. Furthermore, we have established a mouse model of the venous thrombotic complications associated with SCT and have demonstrated that hypoxia-induced sickling of RBCs may contribute to enhanced VT observed in AS mice.

Abstract 041: Adipocyte (Pro)Renin Receptor Via SPRR Regulates Renal Sodium-glucose Cotransporter-2 Expression And Glomerular Filtration Rate In Mice

Evidence is available to suggest a potential role of adipocyte-derived factors to control renal function but the nature of these endocrine factors largely remains elusive. Sodium-glucose&amp;nbsp;cotransporter 2 (SGLT2) controls Na + delivery to the macula densa thereby determining tubuloglomerular feedback and thus glomerular filtration rate (GFR), providing the molecular basis for attenuation of glomerular hyperfiltration and diabetic kidney disease by SGLT2 inhibitors. Furthermore, we previously reported that soluble (pro)renin receptor (sPRR) inhibits obesity-induced renal SGLT2 expression, thus reducing GFR and albuminuria in a mouse model of diet-induced obesity. In the present study, we examined adipocytes as a potential source of sPRR that acts in an endocrine manner to regulate renal function, particularly GFR, through regulation of renal SGLT2 expression. PRR floxed mice was crossed with Adipoq-CreERT2 mice and gene inactivation was induced by tamoxifen in adulthood (termed as Adipo PRR KO). Under basal condition, male 4-month old Adipo PRR KO mice exhibited a 33.65% increase in GFR as assessed by transdermal measurement of GFR as compared with floxed controls (1318.26± 38.35 in KO group vs . 986.33± 14.31 ul/min/100g b.w. in floxed group, n = 6, p &lt; 0.01). Dapagliflozin-sensitive SGLT2 activity as assessed by 6-h urinary glucose excretion was increased by 1.93 folds in Adipo PRR KO mice (SGLT2 activity: 13.19± 1.64 in KO group vs. 6.83± 1.20 mg/6h in floxed group, n=7-10, p &lt; 0.05). Immunoblotting analysis detected a more than 10-fold increase in renal protein abundance of SGLT2 in the null mice (12.38± 1.51 in KO group vs.1.00± 0.26 in floxed group, n=6, p &lt; 0.01) whereas the increase in renal SGLT2 mRNA was quite modest (1.25± 0.08 in KO group vs . 1.00± 0.06 in floxed group; n = 6, p &lt; 0.05). As compared with floxed mice, Adipo PRR KO mice showed a 44.62% fall in plasma sPRR concentration as assessed by ELISA (1.18± 0.09 in KO group vs . 2.12± 0.10 ng/ml in floxed group, n = 6, p &lt; 0.01). Taken together, the present study, for the first time, provides evidence for an endocrine action of adipocyte PRR to regulate renal SGLT2 expression and GFR likely through sPRR.

#3737 RENAL RESERVE IN LIVING KIDNEY DONORS: THE HIDDEN ROLE OF OVERWEIGHT

Abstract Background and Aims Renal reserve (RR) is the capacity to increase glomerular filtration rate (GFR) under certain stimuli such as obesity, hyperglycaemia, metabolic syndrome, etc. The importance of the presence or absence of RR is unknown. We investigated the prevalence and factors associated with RR in a group of living donors for renal transplantation. Method We investigated RR before donation in 52 living kidney donors. GFR was measured by iohexol clearance before and after the stimulation of RR by endovenous amino acid infusion. The presence of RR was defined as an increase greater than 10% of basal GFR. According with the presence or absence of RR, subjects were grouped in those without RR; with RR and using RR. The latter was defined as the lack of increase in GFR after stimulation in patients with GFR &amp;gt; 100 mL/min. GFR was unadjusted to body surface area (BSA). The characteristics of these three groups were evaluated. Results 13 (25%) had no RR, 24 (46%) had RR and 15 (29%) were using RR. Subjects without RR was predominantly female (92%) with lower BSA and BMI than those with RR or using RR (BMI: 22 ± 3 vs 28 ± 3 and 29 ± 4, p &amp;lt; 0.005); also had a lower GFR than the other groups (84 ± 10 vs 95 ± 14 and 131 ± 22, p &amp;lt; 0.005). Subjects with RR or using RR had more frequently metabolic syndrome traits i.e. prediabetes than those without RR. Finally, subject using RR present larger kidney length than the other groups (right kidney: 11.3 ± 0.8 vs 10.3 ± 0.36 and 10.4 ± 0.8, p &amp;lt; 0.005; left kidney: 11.8 ± 0.5 vs 10.4 ± 0.6 and 10.7 ± 0.7, p &amp;lt; 0.005). No differences were observed regarding dyslipidaemia and arterial hypertension. Conclusion overweight and prediabetes may be factors that stimulate RR in a healthy population such as living kidney donors. Future implications of these factors, particularly after donation both in donors and recipients, deserve attention.

#2730 MESENCHYMAL STEM CELLS FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS WITH NEPHRITIS

Abstract Background and Aims Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease of unknown aetiology affecting various organs and tissues. In the last decade, alternative therapeutic methods for SLE refractory to immunosuppressive therapy have been actively studied. Of interest are the data of transplantation of mesenchymal stem cells (MSCs) that demonstrated immunomodulatory properties, as well as the ability to self-renewal and multi-lineage differentiation. Objective to evaluate the efficacy and safety of MSCs in patients with severe refractory SLE. Method The search was conducted on PubMed and Google Scholar platforms using the following strategy: “Systematic lupus erythematosus” plus “Mesenchymal stem cells”. All articles presented in these domains published before 01.12.2022 in the format of case reports, clinical studies, clinical trials, multicentre studies were analysed. The effectiveness of MSCs was evaluated using the systemic lupus erythematosus activity index SELENA-SLEDAI, renal functional parameters (daily proteinuria, creatinine, glomerular filtration rate (GFR), and serum albumin), immunological parameters (anti-nuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA). The safety assessment included registration of various adverse events during and after transplantation. Results A total of 201 publications were retrieved for the period from 2000-2022, and 24 records about MSCs treatment in SLE patients met the above criteria and were included in the study. The analysed publications included data on the transplantation of MSCs obtained from various biological sources such as bone marrow, adipose tissue, and umbilical cord. In total, the results of MSCs transplantations in 806 patients were analysed. The average age of patients was 30.5±8.53 years old (from 12 to 62 years). The results obtained suggested that there was a significant decrease in the activity of SLE: 2.5-fold reduce in SELENA-SLEDAI score after 12 months (from 12.43±3.06 to 5.02±2.12). Anti-dsDNA titer dropped from 399.05±477.86 to 227.65±130.76. Some research also revealed decrease in ANA titer from 309.64±412.75 to 187.8±146.60. The improvement of kidney function was assessed by the 2.17-fold reduction of daily proteinuria from 2.48±0.66 to 1.14±0.56 g/l and an increase in GFR from 66.84±42.2 to 83.25±44.90 ml/min. Furthermore, in the majority of the cases of SLE patients who had been treated with conventional immunosuppressants and glucocorticoids with no response, the dosage of immunosuppressive therapy after MSCs transplantation was reduced. The safety of MSCs therapy is essential for clinical application. The assessment of all patients (n = 806) who underwent MSCs transplantation revealed a few side effects such as nausea (n = 7), herpes (n = 2), agranulocytosis with fungal pneumonia (n = 2), tuberculosis (n = 3). No tumor-related events was observed. Mortality consists in 2.6%, the majority of cases was from multiple organ failure (n = 19), others - from acute heart failure (n = 1) and severe pneumonia (n = 1). Thus, the survival rate during MSCs transplantation consists in 97.4%. Conclusion According to the analysis of currently available research data MSCs demonstrated a significant therapeutic effect in SLE with kidney injury: the decrease in the activity index SELENA-SLEDAI, the improvement in kidney function and the decrease in immunological indicators. According to the data from follow-up studies there were no serious adverse events, or tumor-related effects after MSCs transplantation in SLE patients.

The Cardiorenal Effects of Chronic Phosphodiesterase-V Inhibition in Preclinical Diastolic Dysfunction (Stage B Heart Failure)

ObjectiveTo determine whether chronic phosphodiesterase-V (PDEV) inhibition with tadalafil will improve urinary sodium excretion, glomerular filtration rate (GFR), plasma cyclic guanosine 3’, 5’-monophosphate (cGMP), and urinary cGMP excretion in response to volume expansion (VE) in patients with preclinical diastolic dysfunction (PDD) or stage B heart failure. BackgroundPDD is defined as abnormal diastolic function with normal systolic function, without clinical heart failure. PDD is predictive of development of heart failure and all-cause mortality. Impaired renal function and attenuated cGMP response to VE are hallmarks of PDD. MethodsA double-blind, placebo-controlled, proof-of-concept study was conducted to compare 12 weeks of tadalafil 20 mg daily (n = 14) vs placebo (n = 7). Subjects underwent 2 study visits 12 weeks apart. Renal, neurohormonal and echocardiographic assessments were performed before and after intravascular VE (normal saline 0.25 mL/kg/min for 1 hour). ResultsBaseline characteristics were similar. There was no increase in GFR, plasma cGMP or urinary cGMP excretion in response to VE in either group at visit 1. At visit 2, tadalafil did not result in significant change in GFR but increased plasma cGMP and urinary cGMP excretion at baseline. In response to VE, tadalafil resulted in increased urine flow, urinary sodium excretion, GFR (7.00 [-1.0, 26.3] vs -9.00 [-24.5, 2.0] mL/min/1.73m2; P = 0.02) and plasma cGMP (0.50 [-0.1, 0.7] vs -0.25 [-0.6, -0.1] pmol/mL; P = 0.02). It did not improve urinary cGMP excretion after VE. ConclusionIn PDD, chronic PDEV inhibition with tadalafil improved renal response to VE through increased urine flow, urinary sodium excretion, GFR, and plasma cGMP. Further studies are required to determine whether this enhanced renal response can mitigate progression to clinical heart failure.

Evaluation of Renal Function Recovery After Holmium Laser Enucleation of the Prostate in Patients with Chronic Kidney Disease.

Introduction: Holmium laser enucleation of the prostate (HoLEP) has become a new surgical gold standard treatment for benign prostatic hyperplasia (BPH). It is known that untreated BPH can lead to bladder outlet obstruction (BOO). A positive correlation exists between BOO and chronic kidney disease (CKD), but stability or recovery of renal function after HoLEP remains unknown. We sought to describe changes in renal function after HoLEP in men with CKD. Methods: A retrospective study was conducted of patients who underwent HoLEP with glomerular filtration rates (GFRs) <60, CKD stages III to V. Pre- and postoperative GFRs were selected within 3 months before the operation and within 1 year postoperatively. The presence of an indwelling catheter, preoperative hydronephrosis, history of kidney stones, and prostate size were also reviewed. Data were analyzed in accordance with preoperative CKD stage. Results: Of the reviewed patients, 138 met inclusion criteria with CKD stages III to V. Each CKD group was without significant postoperative complications. There was a significant increase between pre- and postoperative GFR for patients in CKD stages III (n = 116) and IV (n = 17) (p < 0.0001 and p = 0.010, respectively). The mean increase between pre- and postoperative GFR for the CKD stages III and IV patients were 6.4 and 6.49, respectively. There was no correlation between presence of preoperative hydronephrosis, history of kidney stones, catheter dependency, nor prostate size on change in postoperative GFR (p > 0.05). Conclusion: These findings suggest that patients in CKD stages III or IV undergoing HoLEP experience an increase in GFR. It is noteworthy that there appears to be no decline in renal function postoperatively in any group. HoLEP represents an excellent surgical option for patients with preoperative CKD and may prevent further renal decline.

Efficacy and safety of urate-lowering therapy in multimorbid patients in real clinical practice: results of clinical study

Background. Clinical studies of urate-lowering therapy (ULT) use in multimorbid patients, including those with chronic kidney disease (CKD), are important in modern medical science. The purpose was to determine the efficacy and safety of ULT in patients with hyperuricemia and comorbid conditions, including people with chronic kidney disease, in real clinical practice. Materials and methods. This prospective comparative clinical study “Liquestia: comparative efficacy and safety in gouty arthritis patients with comorbid diseases and in patients with hyperuricemia and chronic kidney disease” was conducted in real clinical practice with the involvement of 124 patients with hyperuricemia, who were prescribed either febuxostat (Liquestia, JSC “Farmak”/Adenuric, Berlin Chemie) or allopurinol as ULT. Results. Individuals who received febuxostat significantly more often and faster reached the target levels of uric acid compared to patients who underwent treatment by allopurinol, regardless of glomerular filtration rate (GFR), except those from dialysis subgroup, and the presence of comorbidities. Patients in febuxostat subgroups during the study showed an increase in GFR after 6 months of treatment — at the level of the trend in the group with baseline GFR ≥ 60 ml/min and at a statistically significant level — in CKD stage 3–4, which could be the evidence of renoprotective effect of febuxostat with reduced GFR, while people receiving allopurinol tended to further decrease of GFR in 31.8 % of cases. Conclusions. The use of Liquestia for the treatment of patients with hyperuricemia and various comorbid conditions is no less effective than the use of Adenuric and more effective than allopurinol and helps achieve the target levels of uric acid in 90 % of cases within 6 months of treatment, which accompanied by a statistically significant increase in GFR in patients with CKD stage 3–4.

ВЗАИМОСВЯЗИ ГИПЕРГОМОЦИСТЕИНЕМИИ И ФУНКЦИОНАЛЬНОГО СОСТОЯНИЯ ПОЧЕК У ДЕТЕЙ С НАРУШЕНИЕМ ПУРИНОВОГО ОБМЕНА

Among the modified risk factors for chronic kidney disease hyperhomocysteinemia (HHC) and hyperuricemia (HU) play an important role in the development of the cardiorenal continuum. The purpose of the research was to study the relationship between HHC and the functional state of the kidneys in children with impaired purine metabolism. Materials and methods used: a single-center one-stage (cross-sectional) study was conducted in 54 pediatric patients aged 9 to 15 y/o with purine metabolism disorders (in the form of isolated HU or in combination with hyperuricosuria) in Feb. 2017 - March 2021. The level of homocysteine in the blood serum was determined by enzyme immunoassay. Evaluated clearance, excreted fraction, filtered volume and reabsorption of uric acid; the glomerular filtration rate (GFR) was calculated. The two groups were distinguished: the [main] Group 1 of 26 children with HHC; and the [comparison] Group 2 of 28 children with normal homocysteine levels. Results: the frequency of diagnosis of HHC among the examined was 47.8%, which is almost 5 times higher than in the population. In the main group, the analysis of Spearman's rank correlation revealed a positive statistically significant correlation between the level of homocysteine and uric acid: Rs=0.32, p=0.048. In this group, the clearance of uric acid, its excreted fraction and filtered volume were statistically significantly lower, while reabsorption and GFR were higher relative to the comparison group. The daily excretion of uric acid directly correlated statistically significantly with its clearance (Rs=0.71, p&lt;0.001) and excreted fraction (Rs=0.66, p=0.004) and inversely significantly correlated with the level of its reabsorption (Rs=- 0.66, p=0.004). Statistically significant direct correlation of blood homocysteine and creatinine levels (Rs=0.38, p=0.020) and inverse correlation with uric acid excretion (Rs=-0.38, p=0.020) were obtained. Conclusion: in children with impaired purine metabolism, HHC is associated with the early formation of tubular dysfunction, which is evidenced by a statistically significant decrease in the clearance of uric acid, its excreted fraction and filtered volume. The increase in GFR in this case probably reflects the formation of hyperfiltration as the initial stage of metabolic renal damage.

Predictors of serum vancomycin levels in peritoneal dialysis-associated peritonitis.

Intraperitoneal (IP) vancomycin is often first-line empiric therapy for peritoneal dialysis (PD) peritonitis; however, whether dosing should be adjusted for patient-specific characteristics remains unclear. We sought to identify factors associated with the day 3 vancomycin serum level in patients receiving vancomycin for PD peritonitis. Retrospective single-centre adult cohort of 58 patients with PD peritonitis treated with IP vancomycin between January 2016 and May 2022. Linear regression was used to examine the association between day 3 vancomycin level and candidate predictors including age, sex, weight, glomerular filtration rate (GFR), urea and creatinine clearance (total, residual, dialysate), PD modality, peritoneal solute transfer rate and initial vancomycin dose. Logistic regression was used to evaluate the likelihood of achieving a level (≥15 mg/L) associated with these predictor variables. A 2-g loading dose was given in 51 cases, and 38 patients (66%) had a therapeutic day 3 level. Each 5 mg/kg increase in initial vancomycin dose was associated with a 1.38 mg/L (95% confidence interval 0.52, 2.23) increase in day 3 level. Each 1 mL/min increase in GFR was associated with a 0.29 mg/L decrease (95% confidence interval 0.05, 0.52) in day 3 level. The likelihood of achieving a therapeutic level was approximately four times higher with an initial dose of ≥25 mg/kg compared to <25 mg/kg (odds ratio 3.75, 95% confidence interval 1.05, 13.46). Following an average 2-g vancomycin loading dose for suspected PD peritonitis, one-third of patients were subtherapeutic on day 3. GFR and weight-based dosing were independently associated with day 3 vancomycin level, and their consideration could improve the likelihood of achieving an early therapeutic level.

Thrombodynamics Test in Assessing the Risk of Thrombus Formation in Patients with Atrial Fibrillation Taking Direct Oral Anticoagulants

Aim. To evaluate thrombus characteristics in patients with atrial fibrillation (AF) taking different direct oral anticoagulants (DOACs) using Thrombodynamics test.Materials and methods. Thrombodynamics test was performed in 100 patients with paroxysmal and permanent forms of AF taking different DOACs, dose choice was done in accordance with the instructions for drugs use. For analysis samples of fresh citrated platelet-free plasma were taken just before regular DOACs dose intake (trough concentration). Statistical data processing was carried out using R software packages.Results. All patients had no history of thrombosis or bleeding before inclusion in this study. All parameters of Thrombodynamics test taken at residual concentration of DOACs were in general within reference values, that is in the area of normal coagulation: spatial clot growth rate (V) – 26.56 (25.0; 29.2) μm/min, the time to the start of clot growth (Tlag) – 1.05 (0.85; 1.27) min, initial spatial clot growth rate (Vi) – 44.3±7.7 μm/min, stationary spatial clot growth rate (Vst) – 26.5 (24.9; 28.4) μm/min, clot size (CS) – 999.7 (912.9; 1084.7) μm, clot density (D) – 22883.1±3199.9 arb. units. D was appeared to be higher in women [22947.7 (21477.5; 22947.7) vs men [22124.8 (19722.8; 22124.8), p=0.035] and Tlag was significantly higher in patients with chronic heart failure [1.2 (1.0; 1.2) vs 1.0 (0.8; 1.0), p=0.008]. A correlation was found between level of creatinine and Tlag parameter, glomerular filtration rate (GFR) and clot density. With an increase in the level of creatinine in the blood and a decrease in GFR, respectively, there was an increase in Tlag parameter (p-value 0.038); with an increase in GFR, clot density decrease (p-value 0.005).Conclusion. All parameters of Thrombodynamics test on residual concentration of DOACs were within reference values that indicated optimal anticoagulant effect of all DOACs. The obtained data of normal coagulation at the residual concentration of the anticoagulant are consistent with the previously obtained data on the safety and effectiveness of DOACs using other methods. Further studies with clinical end points are needed to assess the clinical value of this method.

Defining improvement in chronic kidney disease: regression and remission.

International definitions exist for chronic kidney disease (CKD) progression and kidney failure but despite evidence that kidney function may improve, there are no agreed definitions for regression and remission of CKD. In the light of recent novel kidney protective therapies and the promise of regenerative medicine to reverse kidney damage, it is time to critically examine these neglected aspects of CKD epidemiology. We propose that CKD regression is viewed as a process of improvement defined as a sustained increase in glomerular filtration rate (GFR) by ≥25% and an improvement in GFR category or increase in GFR of 1≥ml/min/year, whereas remission is considered a category of improvement defined as GFR ≥60 ml/min/1.73m 2 and urine albumin to creatinine ratio &lt;30 mg/g. Several recent studies have reported improvement in kidney function in populations with CKD, even in the absence of specific therapy. Regression and remission of CKD are associated with increased likelihood of sustained improvement in kidney function as well as improved survival. Further research is warranted to validate the proposed definitions and investigate associated mechanisms. We look to a future in which the goal of therapy is not merely to slow CKD progression but to improve kidney function and seek a cure.