Loss Of Glomerular Filtration Rate Research Articles

Amino Acid Infusion for Perioperative Functional Renal Protection: A Meta-analysis

ObjectiveAcute kidney injury (AKI) is a common perioperative complication. To date, no single intervention has been proven effective for AKI prevention in this setting. However, intravenous amino acids (AA) administration may recruit renal functional reserve and, thereby, attenuate the perioperative loss of glomerular filtration rate. Accordingly, we performed a meta-analysis to assess the efficacy of AA infusion for perioperative renal functional protection. MethodsWe performed a meta-analysis of controlled studies in perioperative patients (P) evaluating intravenous AA infusion (I) versus any comparator (C). The primary outcome was AKI at longest follow-up (O). We performed a random effects meta-analysis on the relative risk (RR) scale to assess the effect of AA infusion. We used a Bayesian approach to estimate the probability of benefit (RR<1) for the primary outcome. Secondary outcomes included renal-replacement therapy, serum creatinine, and estimated glomerular filtration rate. Tertiary outcomes included mechanical ventilation duration, intensive care unit and hospital length of stay and mortality. (PROSPERO: CRD42024547225). ResultsWe identified 15 studies (14 RCTs and one prospective before-after study) reporting at least one outcome of interest (4,544 patients), with six studies (4,084 patients) reporting the primary outcome. AKI occurred 504/2,041 (24.7%) in AA patients vs 614/2,041 (30.1%) in controls (RR=0.66; 95% CI, 0.47 to 0.94; I2=50%; p=0.02), which corresponded to a 99.1% probability of AKI reduction with AA. Moreover, coherent with such findings, AA reduced serum creatinine, and hospital length of stay, and increased eGFR. ConclusionsThis meta-analysis suggests that AA administration likely reduces the perioperative incidence of AKI.

Plasma metals, genetic risk, and rapid kidney function decline among type 2 diabetes

BackgroundRapid kidney function decline (RKFD) is a main clinical feature of early chronic kidney disease (CKD) in type 2 diabetes (T2D). Environmental and genetic factors influencing RKFD remain inadequately elucidated. ObjectivesThis study aimed to examine the associations of metals with RKFD among T2D and to further investigate the effect of metal mixtures on RKFD with the modifying effect of genetic susceptibility. MethodsThis study included 2209 people with T2D (1942 had genotyping data) free of CKD at baseline from the Dongfeng-Tongji cohort. We used inductively coupled plasma-mass spectrometry (ICP-MS) to measure 23 metals in baseline plasma. Using elastic net (ENET), multivariate logistic regression, and Bayesian kernel machine regression (BKMR) model, we examined independent associations of multiple metals with RKFD. We calculated the environmental risk score (ERS) to assess the effects of metal mixtures on RKFD and the genetic risk score (GRS) to assess genetic susceptibility. RKFD was defined as estimated glomerular filtration rate (eGFR) loss > 3 mL/min/1.73 m2/year. ResultsDuring a median of 9.8 years follow-up, 262 participants developed RKFD. Aluminum, vanadium, zinc, selenium, rubidium, tin, barium, and tungsten were screened from ENET. In multivariate logistic models, vanadium, selenium, and tungsten were negatively associated with RKFD, while zinc, tin, and rubidium were positively associated. The BKMR showed a nonlinear association of vanadium and rubidium with RKFD and interactions between metals (barium‑vanadium, barium‑rubidium). The ERS was positive associated with RKFD (per SD increase in ERS, OR = 1.94, 95% CI: 1.66, 2.27). No significant interaction between ERS and GRS was observed on RKFD, however, participants in the highest ERS and GRS group had the highest RKFD risk. ConclusionVanadium and rubidium were associated with RKFD in T2D. Metal mixtures was associated with an increased risk of RKFD in T2D, particularly in those at high genetic risk.

#873 Membranous nephropathy has higher all-cause mortality rate in comparison to focal segmental glomerulosclerosis and IgA nephropathy: a long-term study

Abstract Background and Aims Membranous nephropathy, focal segmental glomerulosclerosis (FSGS) and IgA nephropathy are the most frequent types of primary glomerulonephrites in the adulthood. Glomerulonephritides may progress into end-stage renal disease despite appropriate treatment. Both the manifestations of the glomerulonephritides and medications for treatment might yield cardiovascular events such as venous thromboembolism, coronary artery disease and stroke. The purpose of this study is to compare three different types of primary glomerulonephritides in terms of all-cause mortality, kidney-related and cardiovascular outcomes. Method All patients who underwent kidney biopsy between 01.01.2000 and 01.06.2022 in Hacettepe University Hospital were screened and cases with primary glomerulonephritis and follow-up data were enrolled. Data regarding baseline demographics, laboratory and kidney pathology reports and outcomes were obtained. The primary end-point was defined as all-cause mortality. Kidney related and cardiovascular outcomes were determined as secondary end-points. Results population was 39 (18-81) years. Membranous nephropathy was present in 36.5% (n = 172), focal segmental glomerulosclerosis was present in 25.9% (n = 122) and IgA nephropathy was present in 37.6% (n = 177) of the cases. Age (p &amp;lt; 0.001), frequency of diabetes (p = 0.004) and smoking history (p = 0.020) were significantly higher in patients with membranous nephropathy than both FSGS and IgA nephropathy. Serum albumin levels were lower (p &amp;lt; 0.001), while total cholesterol (p &amp;lt; 0.001), LDL cholesterol (p &amp;lt; 0.001) and proteinuria levels (p &amp;lt; 0.001) were higher both in patients with membranous nephropathy than the other two groups and in patients with FSGS than IgA nephropathy. Median duration of follow-up was 120.2 (1.7-273.3) months (Table 1). All-cause mortality rate was significantly higher in patients with membranous nephropathy than the other two groups (p = 0.005); however the type of glomerulonephritides was not found to be related to all-cause mortality (HR: 1.07; 95% CI: 0.65-1.77; p = 0.770). Age (HR: 1.079; 95% CI: 1.05-1.10; p &amp;lt; 0.001), serum creatinine (HR: 1.35; 95% CI: 1.10-1.66; p = 0.003) and serum albumin (HR: 0.60; 95% CI: 0.38-0.95; p = 0.030) levels were found to be associated with all-cause mortality in patients with primary glomerulonephritides. The rates of ischemic stroke, atrial fibrillation and steroid induced diabetes were similar between all of the glomerulonephritides subgroups. Acute coronary syndrome (p = 0.015), coronary revascularization (p = 0.021) and venous thromboembolic events were more frequent in patients with membranous nephropathy than IgA nephropathy. There was no difference in terms of cardiovascular outcomes between the patients with FSGS and IgA nephropathy (Table 1). Although the remission rate was significantly higher in patients with membranous nephropathy than the other two groups (p &amp;lt; 0.001); there was not a distinct difference in relapse rates. Progression to end-stage renal disease was prominently lower in patients with membranous nephropathy than the other groups (p = 0.003) and loss of glomerular filtration rate per year was significantly higher in cases with FSGS compared to other groups (p = 0.021). Conclusion All-cause mortality risk was higher in patients with membranous nephropathy because of higher age at diagnosis and accompanying higher burden of comorbidities including diabetes and dyslipidemia. FSGS had a worse prognosis in terms of kidney related outcomes compared to other glomerulonephritides due to higher loss of glomerular filtration rate per year and increased rates of progression to end-stage renal disease. Intensive cardiovascular risk reduction strategies should be applied especially in patients with membranous nephropathy due to increased mortality rates.

#1827 Myeloma cast nephropathy: is high cut-off hemodialysis effective?

Abstract Background and Aims Light-chain cast nephropathy is the result of intra-tubular precipitation of light-chains produced by a multiple myeloma. Treatment often includes high cut-off filters hemodialysis (HCO) with the purpose of purifying these chains until the chemotherapy response is achieved. The main goal of this study is to analyze our experience and determine if there is a correlation between the amount of chain purified and the conservation of renal function. Method We conducted a retrospective study that includes all patients suffering from myeloma cast nephropathy treated with hemodialysis in our hospital between 2008 and 2023. HCO filters were used in all of the cases and the diagnosis was established by clinical criteria. In the early stages of the study, only those patients who required kidney replacement therapy underwent dialysis. However, in recent years some cases which did not meet the renal replacement criteria were included. Results 27 patients received the treatment, 59,3% were male and the average age was 68,7+/-8 years. Even though the average of glomerular filtration rate (GFR) previous to the myeloma was 72,65+/-20ml/min, it should be underlined that 8 of them suffered from 3-4 stage chronic kidney disease. The mean follow-up was 55 months, after which 16 had passed away. 59,3% were kappa gammapathy and 75% of them had bone disease. Chemotherapy schemes were variable (85% included Bortezomib). The average of dialysis sessions was 8+/-3,8. 7 patients continued undergoing conventional hemodialysis during the hospital stay but only one of them remained in chronic dialysis. The average GFR at the beginning was 12,2+/-7ml/min. Despite the improvement of the renal function, when compared to the previous GFR, a statistically significant reduction in both hospital discharge (43,67ml/min) and after 1- and 2-year periods (51,94 and 39,91ml/min) was observed. No differences in renal function between patients who started dialysis prematurely (GFR&amp;gt;10ml/min) and those who did not were noticed. The light-chain reduction ratio in each dialysis was examined; it was remarkably variable (2-87%). In order to establish a connection between the amount of chain purified and the preservation of renal function, we conducted a correlation analysis between the intra-dialysis reduction of chains and the GFR at hospital discharge and after 1-year, but not statistically interrelations were observed (p=0,376 and 0,633 respectively). Lastly, no connection between the intra-dialysis light-chain reduction and the loss of GFR was detected. Conclusion In patients with myeloma cast nephropathy, a higher purification of light-chains in HCO hemodialysis is not associated with a better preservation of renal function.

#855 Cyclophilin D in cholesterol crystal-induced acute kidney injury

Abstract Background and Aims Cholesterol crystal embolism (CCE) occurs when cholesterol crystal (CC) clots move from an atherosclerotic plaque in a large artery to a smaller artery, leading to obstruction, ischemia, and organ failure. CCE directly impairs blood flow by provoking a local inflammatory response and triggering arterial thrombus formation, consisting of collagen and fibrin mesh, platelet and neutrophil activation, and extracellular DNA trap formation. Activated platelets form a procoagulant surface that supports adhesion to collagen and fibrin mesh, promoting thrombus growth and the recruitment of immune cells. CCE often targets kidney tissue, leading to thrombotic angiopathy, acute loss of glomerular filtration rate (GFR), and necrosis in tubular cells. Cyclophilin D (CypD) plays a central role in regulating platelet procoagulant activity by triggering calcium bursts and mitochondrial depolarization. While the increased number of procoagulant platelets contributes to thrombosis, CypD-mediated procoagulant pathomechanisms in the kidney during CCE remain unknown. In our study presented here, we hypothesized that CypD deficiency might attenuate procoagulant platelet activity, thereby inhibiting CCE-induced kidney infarction and organ injury. Method 6-week-old wild-type (WT) and CypD-/- mice were administered 10 mg/kg CC through injections into the left kidney arteries in vivo. Kidneys were collected 24 hours later, and kidney function, infarct size, necroinflammation and kidney injury were evaluated using GFR measurements, TTC colorimetric assay, immunohistochemistry, and immunofluorescence microscopy. For in vitro studies, whole blood samples were isolated from WT and CypD-/- mice and perfused on a collagen-coated surface in the presence or absence of CC under arterial shear conditions of 1000s-1. Results After CC injection in mice, CypD deficiency ameliorated immunothrombosis, acute kidney injury, and organ failure. CypD-/- mice were protected from the sudden drop in GFR, i.e., acute kidney injury, which resulted from the reduced number of arteries obstructed by crystal clots. Kidney infarct size consistently decreased in CypD-/- mice. CypD-/- mice displayed reduced neutrophil recruitment to thrombotic microangiopathic lesions, indicating diminished immunothrombosis. Preemptive injection of the CypD inhibitor cyclosporin A could prevent CC-mediated vessel obstruction and infarct size, thereby improving kidney function. Interestingly, WT platelets showed increased platelet adhesion and phosphatidylserine (PS) exposure on a collagen-coated surface in the presence of CC under shear conditions in whole blood, suggesting increased procoagulant activity, which was strongly reduced in CypD-/- platelets. Conclusion During CCE-mediated kidney injury, CypD-mediated platelet activation and consequent procoagulant activity accelerate ischemic tissue necrosis and the recruitment of neutrophils. Inhibition of CypD-mediated signaling could be a potential therapeutic approach to inhibit acute kidney injury in patients with CCE.

Impact of Arterial Calcification on Cardiovascular and Renal Outcomes in Kidney Transplant Patients

Plain Language SummaryArterial calcification, accumulation of calcium in the arterial walls, vascular stiffness, and loss of elasticity of blood vessels can contribute to the development of cardiovascular diseases. Patients with chronic kidney disease and those undergoing dialysis have a considerably increased risk of vascular calcification. Even after kidney transplantation when kidney function has been restored, the prevalence of vascular calcification and subsequent cardiovascular disease remains high. Coronary artery calcification score and abdominal aortic calcification score are both well-established markers of vascular calcification. However, the impact of pretransplant vascular calcification scores on cardiovascular and renal outcomes in kidney transplant patients has not been established. When we analyzed 944 Korean kidney transplant patients, both vascular calcification scores were significantly associated with cardiovascular outcomes after kidney transplantation, but were not associated with renal outcomes. We also demonstrated that the addition of coronary artery calcification scores led to a modest improvement in the prediction performance for kidney transplant outcomes. Our findings suggest a potential role of pretransplant screening of coronary calcification scores and aortic calcification scores in risk stratification for post-kidney transplant outcomes.

Parenchymal volume preservation during partial nephrectomy: improved methodology to assess impact and predictive factors.

To rigorously evaluate the impact of the percentage of parenchymal volume preserved (PPVP) and how well the preserved parenchyma recovers from ischaemia (Recischaemia) on functional outcomes after partial nephrectomy (PN) using an accurate and objective software-based methodology for estimating parenchymal volumes and split renal function (SRF). A secondary objective was to assess potential predictors of the PPVP. A total of 894 PN patients with available studies (2011-2014) were evaluated. The PPVP was measured from cross-sectional imaging at ≤3 months before and 3-12 months after PN using semi-automated software. Pearson correlation evaluated relationships between continuous variables. Multivariable linear regression evaluated predictors of ipsilateral glomerular filtration rate (GFR) preserved and the PPVP. Relative-importance analysis was used to evaluate the impact of the PPVP on ipsilateral GFR preserved. Recischaemia was defined as the percentage of ipsilateral GFR preserved normalised by the PPVP. The median tumour size and R.E.N.A.L. nephrometry score were 3.4 cm and 7, respectively. In all, 49 patients (5.5%) had a solitary kidney. In all, 538 (60%)/251 (28%)/104 (12%) patients were managed with warm/cold/zero ischaemia, respectively. The median pre/post ipsilateral GFRs were 40/31 mL/min/1.73 m2, and the median (interquartile range [IQR]) percentage of ipsilateral GFR preserved was 80% (71-88%). The median pre/post ipsilateral parenchymal volumes were 181/149 mL, and the median (IQR) PPVP was 84% (76-92%). In all, 330 patients (37%) had a PPVP of <80%, while only 34 (4%) had a Recischaemia of <80%. The percentage of ipsilateral GFR preserved correlated strongly with the PPVP (r = 0.83, P < 0.01) and loss of parenchymal volume accounted for 80% of the loss of ipsilateral GFR. Multivariable analysis confirmed that the PPVP was the strongest predictor of ipsilateral GFR preserved. Greater tumour size and endophytic and nearness properties of the R.E.N.A.L. nephrometry score were associated with a reduced PPVP (all P ≤ 0.01). Solitary kidney and cold ischaemia were associated with an increased PPVP (all P < 0.05). A reduced PPVP predominates regarding functional decline after PN, although a low Recischaemia can also contribute. Tumour-related factors strongly influence the PPVP, while surgical efforts can improve the PPVP as observed for patients with solitary kidneys.

Kidney Failure Events, Cardiovascular Disease Events, and All-Cause Mortality in Patients with IgA Nephropathy in a Real-World Database.

IgA nephropathy (IgAN) associated glomerular injury leads to proteinuria, hematuria, and progressive loss of glomerular filtration rate, with progression to kidney failure (KF). This retrospective study evaluated the prognostic effects of proteinuria and progression to KF on cardiovascular disease (CVD)/mortality events and KF/mortality events in the United States. We conducted a non-interventional, retrospective cohort study in adult IgAN patients using Optum's de-identified Market Clarity Data (01/01/2007 to 03/31/2021). Adult (≥18 years old) patients with at least two signs, disease, symptoms natural language processing term entries for IgAN, within 180 days and ≥30 days apart within the identification period were included. Outcomes were assessed by time-dependent proteinuria (≥1 g/day vs. <1 g/day) and KF status (pre vs. post). Descriptive statistics were used for categorical and continuous variables. Multivariable Cox proportional hazard models with time-dependent predictors were used to estimate differences across groups. Pre-KF patients with proteinuria ≥1 g/day were more likely to have a CVD/mortality event during follow-up (adjusted hazard ratio [HR; 95% CI]: 1.80 [1.12-2.89]; p<0.001) or a KF/mortality event (adjusted HR [95% CI]: 2.10 [1.73-2.56]; p<0.001). Post-KF patients were more likely to have a CVD/mortality event during follow-up (adjusted HR [95% CI]: 3.28 [2.82-3.81]; p<0.001). Elevated proteinuria and progression to KF was associated with higher risk of CVD/mortality events. Elevated pre-KF proteinuria was also associated with progression to KF/mortality events. Based on our real-world retrospective database analysis, we hypothesize that novel IgAN therapies that reduce proteinuria and slow the rate of progression to KF have the potential to reduce CVD risk, improve kidney outcomes and prolong/increase overall survival.

Poor Glycemic Control Is Associated With More Rapid Kidney Function Decline After the Onset of Diabetic Kidney Disease.

The role of glycemic control and its variability on the rate of kidney function decline after the onset of diabetic kidney disease (DKD) remains unclear. The association between baseline glycated hemoglobin (HbA1c) and rates of estimated glomerular filtration rate (eGFR) loss during follow-up was examined by mixed-effects linear regression in 530 individuals with type 1 diabetes and early-to-moderate DKD from the Preventing Early Renal Loss (PERL) trial and 2378 individuals with type 2 diabetes and established DKD from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The benefit of intensive vs standard glycemic control in slowing eGFR decline was examined in ACCORD. The associations between continuous glucose monitoring-derived short-term glycemic variability indices and rate of eGFR decline were also evaluated in PERL. A higher baseline HbA1c was associated with a more negative eGFR slope in both PERL and ACCORD (-0.87 and -0.27 mL/min/1.73 m2/year per Hba1c unit increment, P < .0001 and P = .0002, respectively). In both studies, the strength of this association progressively increased with increasing levels of albuminuria (P for interaction <.05). Consistent with this, the benefit of intensive glycemic control on eGFR decline was greater in ACCORD participants with severe rather than moderate albuminuria (+1.13 vs + 0.26 mL/min/1.73 m2/year, P = .01). No independent associations were found in PERL between short-term glycemic variability indices and rate of eGFR decline. In both type 1 and type 2 diabetes, poor glycemic control is associated with a more rapid rate of glomerular filtration rate decline after DKD onset, especially in persons with severe albuminuria.

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.

Medication profiling in women with type 1 diabetes highlights the importance of adequate, guideline-based treatment in low-risk groups

Effective treatment may prevent kidney complications, but women might be underprescribed. Novel, data-driven insights into prescriptions and their relationship with kidney health in women with type 1 diabetes may help to optimize treatment. We identified six medication profiles in 1164 women from the FinnDiane Study with normal albumin excretion rate based on clusters of their baseline prescription data using a self-organizing map. Future rapid kidney function decline was defined as an annual estimated glomerular filtration rate (eGFR) loss > 3 ml/min/1.73 m2 after baseline. Two profiles were associated with future decline: Profile ARB with the highest proportion of angiotensin receptor blockers (odds ratio [OR] 2.75, P = 0.02) and highly medicated women in profile HighMed (OR 2.55, P = 0.03). Compared with profile LowMed (low purchases of all), profile HighMed had worse clinical characteristics, whereas in profile ARB only systolic blood pressure was elevated. Importantly, the younger women in profile ARB with fewer kidney protective treatments developed a rapid decline despite otherwise similar baseline characteristics to profile ACE & Lipids (the highest proportions of ACE inhibitors and lipid-modifying agents) without a future rapid decline. In conclusion, medication profiles identified different future eGFR trajectories in women with type 1 diabetes revealing potential treatment gaps for younger women.

Cellular senescence in kidney biopsies is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with karyomegalic interstitial nephropathy.

Karyomegalic interstitial nephropathy (KIN) has been reported as an incidental finding in patients with childhood cancer treated with ifosfamide. It is defined by the presence of tubular epithelial cells (TECs) with enlarged, irregular, and hyperchromatic nuclei. Cellular senescence has been proposed to be involved in kidney fibrosis in hereditary KIN patients. We report that KIN could be diagnosed 7-32 months after childhood cancer diagnosis in 6/6 consecutive patients biopsied for progressive chronic kidney disease (CKD) of unknown cause between 2018 and 2021. The morphometry of nuclear size distribution and markers for DNA damage (γH2AX), cell-cycle arrest (p21+, Ki67-), and nuclear lamina decay (loss of lamin B1), identified karyomegaly and senescence features in TECs. Polyploidy was assessed by chromosome fluorescence in situ hybridization (FISH). In all six patients the number of p21-positive TECs far exceeded the typically small numbers of truly karyomegalic cells, and p21-positive TECs contained less lysozyme, testifying to defective resorption, which explains the consistently observed low-molecular-weight (LMW) proteinuria. In addition, polyploidy of TEC was observed to correlate with loss of lysozyme staining. Importantly, in the five patients with the largest nuclei, the percentage of p21-positive TECs tightly correlated with estimated glomerular filtration rate loss between biopsy and last follow-up (R2 = 0.93, p < 0.01). We conclude that cellular senescence is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with KIN and appears to be a prevalent cause of otherwise unexplained CKD and LMW proteinuria in children treated with DNA-damaging and cell stress-inducing therapy including ifosfamide. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Объем интраоперационной кровопотери и функциональное состояние почек при различных способах хирургического лечения крупных и сложных камней почек.

Introduction. Despite the development of minimally invasive technological methods for the treatment of urolithiasis, improving the functional state of the kidneys in the postoperative period does not lose its importance at the present time. The decrease and loss of renal function after surgical treatment of complex forms of nephrolithiasis in various ways creates the problem of choosing one or another surgical technique in order to avoid negative results of surgical treatment. modern urology. Purpose of the work: to assess the correlation between the volume of intraoperative blood loss and dynamic changes in glomerular filtration rate (GFR) in the postoperative period with various methods of surgical treatment of large and complex kidney stones. Purpose: to assess the correlation between the volume of intraoperative blood loss and dynamic changes in the GFR in the postoperative period with various methods of surgical treatment of large and complex kidney stones. Materials and methods. The study selected data from 97 patients with urolithiasis, large and complex kidney stones of the urological department of the city hospital No 2 of the city of Nur-Sultan of the Republic of Kazakhstan. The median age was 52 (23–73) years. The average area of a kidney stone was 428.3±36.1 mm2, its average density according to Hounsfield was 1042.9±34.8 HU. All patients were divided into 3 cohort comparison groups according to the method of surgical treatment: percutaneous nephrolithotripsy (PCNL) on prone position (1 group) – 44 patients (45.4%), PCNL on the supine position (2 group) – 29 patients (29.9%), laparoscopic pyelolithotomy (3 group)– 24 patients (24.7%). The median baseline GFR in the 1 group was 91 ml/min/1.73 m2, in the 2 group 95 ml/min/1.73 m2, in the 3 group 101 ml/min/1.73 m2. The average duration of surgical intervention for 1 group was 92.8±6.8 min, for 2 group – 119.6±10.9 min, for 3 group-146.9 ± 6.1 min. The mean blood loss in 1 group was 144.5±9.1 ml, in 2 group 235.3±19.1 ml, in 3 group 43.1±5.2 ml. Results. A decrease in GFR below 60 (ml/min/1.73 m2), corresponding to stage III of chronic kidney disease (CKD), was most pronounced in the 2 group: from 3 (3.1%) cases before surgery to 7 (7.2%) cases in postoperative period. A decrease in GFR below 30 (ml/min/1.73 m2), which corresponds to stage IV CKD, also had negative dynamics in the group of patients with 2 group: from 2 (2.1%) to 3 (3.1%) cases respectively. In the rest of the studied groups, there was no negative dynamics of GFR. A correlation was found between GFR in the postoperative period and intraoperative blood loss (r = 0.410, p&lt;0.001). Conclusions. Surgical treatment of urolithiasis of the kidneys is associated with risks of intraoperative blood loss, the volume of which directly correlates with the deterioration of the functional state of the kidneys in the postoperative period. Reducing the volume of intraoperative blood loss in various surgical methods for the treatment of urolithiasis helps to minimize the risk of developing acute kidney injury in the postoperative period.

IL-6 mediates the hepatic acute phase response after prerenal azotemia in a clinically defined murine model.

Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6-/- mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response.NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response.

Effects of Renin–Angiotensin Blockade on the Components of Early Interstitial Expansion in Patients with Type 1 Diabetes

Interstitial expansion is associated with glomerular filtration rate (GFR) loss in many renal diseases, including diabetic nephropathy. The Renin–Angiotensin System Study (RASS) tested whether a 5-year renin–angiotensin system (RAS) blockade with enalapril or losartan versus placebo slowed progression of early diabetic nephropathy lesions in 285 normoalbuminuric, normotensive, normal/high GFR patients with type 1 diabetes. RASS found no benefit to the RAS blockade on diabetic glomerular lesions but observed an unexpected 50% increase in the fractional volume of the renal cortex which is the interstitium. The effects of the RAS blockade on individual interstitial components––striated collagen, interstitial cells, and peritubular capillaries––were not assessed. We evaluated by electron microscopy changes in fractional volume of each component in seven patients from each group between baseline and five years. At baseline, 49% of the interstitium was collagen, 12% cells, 26% peritubular capillaries, 7% space, and 2% artifact. There was no overall change in the interstitial composition during the RASS. There were no statistically significant effects of treatment group on any interstitial components. Renal volume remained stable in all groups. The RAS blockade affected neither the approximately 50% increase in interstitium fractional volume per cortex nor the parallel increase in all interstitial components that occurred over the five years of the RASS.

Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts.

Previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among persons with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N=469) and with type 2 diabetes (T2D) from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (N=7,973). Baseline CAN was ascertained using ECG-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss ≥-5 ml/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed effect, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 (95%CI [-1.93, -0.37], P= 4.0x10-3) ml/min/1.73m2/year in PERL and 0.34 (95%CI [-0.49, -0.19], P= 6.3x10-6) ml/min/1.73m2/year in ACCORD. This translated in 2.11 (95% CI [1.23-3.63], P=6.9x10-3) and 1.39 (95% CI [1.20-1.61], P=1.1x10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (HR=2.60, 95%CI [1.15-5.45], p=0.02 in PERL and HR=1.54, 95%CI [1.28-1.84], P=3.8×10-6 in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help develop new therapies to prevent kidney function decline in patients with diabetes.

Plant food in а diet, vegetarianism and kidney function

A vegetarian diet as a common dietary pattern in the real world is an attractive target for study. Previous studies from different years have shown that a vegetarian diet is associated with a reduced risk of chronic kidney disease progression and a reduction in the annual percentage of physiological loss of glomerular filtration rate. An interesting topic to discuss is vegetarian patients with kidney diseases, in whom we need to monitor kidney function with estimated glomerular filtration rate. In connection with their diet, it is necessary to remember that glomerular filtration rate and blood creatinine level will be low compared to those who consume a lar­ger amount of animal proteins. This is a feature of metabolism and it is related to the way of eating. Monitoring of kidney function in such patients requires reliable diagnostic markers. Here you need to know the nephrological subtleties of excretion of creatinine, urea, uric acid and cystatin C, take into account individual characteristics and use scientific justifications. In order not to miss the progression of kidney disease in vegetarian patients, it is necessary to make a comprehensive assessment of blood parameters: creatinine, urea and uric acid. An alternative to these markers is the possibi­lity of using and prescribing cystatin C to evaluate estimated glomerular filtration rate. Cystatin C would be a more reliable marker than creatinine alone. It will be at the discretion of the nephrologist depending on the situation to decide and use one of the diagnostic options for vegetarian patients.

Effect of valproic acid upon skeletal muscle subjected to prolonged tourniquet application

BackgroundValproic acid (VPA), a histone deacetylase inhibitor, has shown improved outcomes when used as a pharmaceutical intervention in animal studies of hemorrhage, septic shock, and combined injuries. This study was...

The Association Between Metabolic Syndrome, Hyperfiltration, and Long-Term GFR Decline in the General Population

One-quarter of adults worldwide meet the criteria of metabolic syndrome (MetS). MetS increases the risk of diabetes, chronic kidney disease (CKD), and cardiovascular disease. However, the association between MetS, hyperfiltration, and long-term glomerular filtration rate (GFR) decline in the general population is unknown. In the Renal Iohexol Clearance Survey (RENIS), we investigated 1551 people aged 50 to 63 years; representative of the general population without diabetes, cardiovascular disease, or kidney disease. The GFR was measured using iohexol clearance at baseline and twice during 11 years of follow-up. Hyperfiltration at baseline was defined as an absolute GFR (ml/min) above the 90th percentile adjusted for sex, age, and height, because these variables correlate with nephron number. MetS was defined as increased waist circumference and 2 risk factors among hypertension, hyperglycemia, elevated triglycerides, and low high density lipoprotein (HDL)-cholesterol levels. The GFR decline rate was calculated using linear mixed models. MetS was associated with hyperfiltration at baseline (odds ratio [OR] 2.4; 95% CI: 1.7-3.5, P< 0.001) and a steeper GFR decline rate during follow-up (-0.30 [-0.43 to-0.16] ml/min per 1.73 m2/yr). Compared to those without MetS, GFR decline was-0.83 (95% CI:-1.13 to-0.53) ml/min per 1.73 m2/yr in those with MetS and baseline hyperfiltration and-0.15 (-0.30 to 0.00) in those MetS without hyperfiltration, P= 0.2 for interaction. In the nondiabetic general population, those with MetS had an increased OR of hyperfiltration and steeper long-term GFR decline. Randomized controlled trials are needed to explore whether treatment of hyperfiltration can prevent loss of GFR in persons with MetS.

Impact of Resolved Preformed, Persistent Preformed, and De Novo Anti-HLA Donor-Specific Antibodies in Kidney Transplant Recipients on Long-Term Renal Graft Outcomes.

The post-transplant evolution of antihuman leukocyte antigen donor-specific antibodies (anti-HLA DSAs) includes three clinical patterns: resolved preformed DSAs, persistent preformed DSAs, and de novo DSAs. The aim of this retrospective study was to analyze the impact of resolved preformed, persistent preformed, and de novo anti-HLA-A, -B, and -DR DSAs in kidney transplant recipients on long-term renal allograft outcomes. This is a post hoc analysis of the study conducted in our transplant center. One hundred eight kidney transplant recipients were included in the study. Patients were followed for a minimum of 24 months after allograft biopsy, which was performed 3 to 24 months after kidney transplantation. The identification of persistent preformed DSAs at the time of biopsy was the most significant predictor of the combined endpoint of the study (>30% decline in estimated glomerular filtration rate or death-censored graft loss; HR = 5.96, 95% CI 2.041-17.431, p = 0.0011), followed by the occurrence of de novo DSAs (HR = 4.48, 95% CI 1.483-13.520, p = 0.0079). No increased risk was observed in patients with resolved preformed DSAs (HR = 1.10, 95% CI 0.139-8.676, p = 0.9305). Patients with resolved preformed DSAs have similar graft prognoses as patients without DSAs, therefore, the persistence of preformed DSAs and development of de novo DSAs are associated with inferior long-term allograft outcomes.