Renal Filtration Research Articles

Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome.

Mucopolysaccharidoses (MPS) are rare lysosomal storage disorders (LSD) characterized by the excessive accumulation of glycosaminoglycans (GAG). Conventional MPS, caused by inborn deficiencies of lysosomal enzymes involved in GAG degradation, display various multisystemic symptoms—including progressive neurological complications, ophthalmological disorders, hearing loss, gastrointestinal and hepatobiliary issues, cardiorespiratory problems, bone and joint abnormalities, dwarfism, and coarse facial features. Mucopolysaccharidosis-Plus Syndrome (MPSPS), an autosomal recessive disease caused by a mutation in the endo-lysosomal tethering protein VPS33A, shows additional renal and hematopoietic abnormalities (“Plus symptoms”) uncommon in conventional MPS. Here, we analyze data from biochemical, histological, and physical examinations—particularly of blood counts and kidney function—to further characterize the clinical phenotype of MPSPS. A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow. High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction. Histological analyses of MPSPS kidneys similarly suggest the extensive destruction of glomerular structures by foamy podocytes. Height and weight did not significantly deviate from the average, but in some cases, growth began to decline at around six months or one year of age.

Cellular uptake, tissue penetration, biodistribution, and biosafety of threose nucleic acids: Assessing in vitro and in vivo delivery.

Compared with siRNAs or other antisense oligonucleotides (ASOs), the chemical simplicity, DNA/RNA binding capability, folding ability of tertiary structure, and excellent physiological stability of threose nucleic acid (TNA) motivate scientists to explore it as a novel molecular tool in biomedical applications. Although ASOs reach the target cells/tumors, insufficient tissue penetration and distribution of ASOs result in poor therapeutic efficacy. Therefore, the study of the time course of drug absorption, biodistribution, metabolism, and excretion is of significantly importance. In this work, the pharmacokinetics and biosafety of TNAs in living organisms are investigated. We found that synthetic TNAs exhibited excellent biological stability, low cytotoxicity, and substantial uptake in living cells without transfection. Using U87 three-dimensional (3D) multicellular spheroids to mimic the in vivo tumor microenvironment, TNAs showed their ability to penetrate efficiently throughout the whole multicellular spheroid as a function of incubation time and concentration when the size of the spheroid is relatively small. Additionally, TNAs could be safely administrated into Balb/c mice and most of them distributed in the kidneys where they supposed to excrete from the body through the renal filtration system. We found that accumulation of TNAs in kidneys induced no pathological changes, and no acute structural and functional damage in renal systems. The favourable biocompatibility of TNA makes it attractive as a safe and effective nucleic acid-based therapeutic agent for practical biological applications.

Evaluation of renal function after pyeloplasty determined by 99mTc DTPA renogram

Background: Hydronephrosis (HDN) due to pelviureteric junction (PUJ) obstruction is a common congenital anomaly of urinary tract which is generally treated by pyeloplasty. But the extent of functional recovery is still debated. Considering the existing controversies, this study was designed to evaluate the changes of renal function after pyeloplasty measured by 99mTc-DTPA renography.
 Methods: This study was done in the department of urology, National Institute of Kidney Diseases and Urology (NIKDU) and Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) General Hospital from July 2014 to December 2020. Sixty patients were included in this study and underwent Anderson-Hynes (A-H) dismembered pyeloplasty for PUJ obstruction. All patients were evaluated with diuretic 99mTc-DTPA renogoam before and at 3 and 6 months after pyeloplasty. Improvement of renal function was evaluated by comparing preoperative and postoperative differential renal function (DRF) and glomerular filtration rate (GFR).
 Results: Sixty patients (34 male and 26 female) with unilateral HDN due to PUJ obstruction were included in this study with mean age of 15.6 years (ranged from 3 – 38 years). Out of 60 patients, 56.7% had left sided HDN and 43.3% had right sided HDN. The mean preoperative DRF was 16.72 ± 8.35% at baseline which increased to 26.03 ± 7.08% at the end of 3rd month and 28.15 ± 5.84% at the end of 6th month. The mean preoperative GFR was 14.29 ± 6.73 ml/min/1.73 m2 at baseline which increased to 24.13 ± 5.31ml/min/1.73 m2 at the end of 3rd month and 27.38 ± 4.78 ml/min/1.73 m2 at the end of 6th month.
 Conclusion: The result demonstrates that, after pyeloplasty renal function improves. Highest recovery of renal function noted in patients with poor pre-operative DRF and GFR.
 BIRDEM Med J 2022; 12(2): 142-146

Effects of preoperative high-oral protein loading on short- and long-term renal outcomes following cardiac surgery: a cohort study

BackgroundPost-cardiac surgery acute kidney injury (AKI) is associated with increased mortality. A high-protein meal enhances the renal blood flow and glomerular filtration rate (GFR) and might protect the kidneys from acute ischemic insults. Hence, we assessed the effect of a preoperative high-oral protein load on post-cardiac surgery renal function and used experimental models to elucidate mechanisms by which protein might stimulate kidney-protective effects.MethodsThe prospective “Preoperative Renal Functional Reserve Predicts Risk of AKI after Cardiac Operation” study follow-up was extended to postoperative 12 months for 109 patients. A 1:2 ratio propensity score matching method was used to identify a control group (n = 214) to comparatively evaluate the effects of a preoperative protein load and standard care. The primary endpoints were AKI development and postoperative estimated GFR (eGFR) loss at 3 and 12 months. We also assessed the secretion of tissue inhibitor of metalloproteases-2 (TIMP-2) and insulin-like growth factor–binding protein 7 (IGFBP7), biomarkers implicated in mediating kidney-protective mechanisms in human kidney tubular cells that we exposed to varying protein concentrations.ResultsThe AKI rate did not differ between the protein loading and control groups (13.6 vs. 12.3%; p = 0.5). However, the mean eGFR loss was lower in the former after 3 months (0.1 [95% CI − 1.4, − 1.7] vs. − 3.3 [95% CI − 4.4, − 2.2] ml/min/1.73 m2) and 12 months (− 2.7 [95% CI − 4.2, − 1.2] vs − 10.2 [95% CI − 11.3, − 9.1] ml/min/1.73 m2; p < 0.001 for both). On stratification based on AKI development, the eGFR loss after 12 months was also found to be lower in the former (− 8.0 [95% CI − 14.1, − 1.9] vs. − 18.6 [95% CI − 23.3, − 14.0] ml/min/1.73 m2; p = 0.008). A dose–response analysis of the protein treatment of the primary human proximal and distal tubule epithelial cells in culture showed significantly increased IGFBP7 and TIMP-2 expression.ConclusionsA preoperative high-oral protein load did not reduce AKI development but was associated with greater renal function preservation in patients with and without AKI at 12 months post-cardiac surgery. The potential mechanisms of action by which protein loading may induce a kidney-protective response might include cell cycle inhibition of renal tubular epithelial cells.Clinical trial registration ClinicalTrials.gov: NCT03102541 (retrospectively registered on April 5, 2017) and ClinicalTrials.gov: NCT03092947 (retrospectively registered on March 28, 2017).

MO271: A Single Dose of Lithium Protects Against Renal Injury Following Bilateral Ureteral Obstruction

Abstract BACKGROUND AND AIMS Obstructive nephropathy decreases renal blood flow (RBF) and glomerular filtration rate (GFR). Glycogen synthase kinase 3β (GSK3 β), an apoptotic enzyme, is increased in a model of unilateral obstruction. Treatment with a single dose of lithium, a selective inhibitor of GSK3β, accelerated recovery of renal function in models of cisplatin and ischemia-reperfusion induced acute kidney injury (AKI). The aim of this study was to evaluate the efficacy of a single dose of lithium in the treatment of AKI induced by bilateral ureteral obstruction (BUO) METHOD Adult male Wistar rats were divided in four groups: (i) sham (sham operated); (ii) lithium: rats treated with lithium chloride 80 mg/Kg BW Intraperitonially (IP); (iii) BUO during 24 h; (iv) BUO during 24 h and treated with the same dose immediately after ureteral desobstruction. The rats were anesthetized 48 h after desobstruction to measure inulin clearance and renal blood flow. At the end of the clearance experiments, the rats were euthanized and the kidneys were removed to measure GSK3 β renal expression. RESULTS As described in the Table 1, BUO showed markedly reduction of GFR and RBF associated with an increase of GSK3β. A single dose of lithium administration ameliorated all these alterations. CONCLUSION Lithium treatment attenuated renal dysfunction in this model of BUO-associated AKI by improving inulin clearance. These therapeutic effects were due to an inhibition of renal expression of GSK3β. This may be a new therapeutic approach for BUO-induced AKI.

MO608: INV-202, A CB1 Receptor Blocker, Reduces Renal Injury in A Murine Model of Streptozotocin (STZ)-Induced Type-1 Diabetes

Abstract BACKGROUND AND AIMS Renal diseases remain a burden for Public Health and chronic kidney disease (CKD) affects several millions of individuals worldwide. Diabetic Nephropathy (DN) is the most frequent consequence of diabetes and is characterized by an increase in urinary albumin excretion and progressive loss of renal function associated with glomerular basement membrane thickening, mesangial expansion, nodular glomerular sclerosis and tubulointerstitial fibrosis. To date, there are few treatments that can prevent its progression. Indeed, current therapeutic approaches including RAAS blockers, SGLT2 inhibitors or both approaches combined do not fully abrogate DN progression. A growing body of experimental evidence suggests that modulation of the endocannabinoid system, and in particular its type 1 receptor (CB1R), may be a therapeutic tool in the management of CKD and more particularly DN. CB1R blockade represents a potential therapeutic modality in the fight against obesity, diabetes and their metabolic sequelae. In kidney, CB1R inhibition promotes a reduction in albuminuria, renal fibrosis and preserves renal function in both obesity-induced and diabetic nephropathy in mice mainly through a direct action of CB1R in podocytes and/or proximal tubules. INV-202 is a peripherally acting Cannabinoid receptor-1 (CB1r) inverse agonist that is under clinical development for the treatment of diseases associated with diabetes and metabolic syndrome. Here we report the effects of INV-202 on renal function and associated parameters in a preclinical model of diabetic nephropathy. METHOD Twelve weeks after the initiation of diabetes using streptozotocin, C57BL6/J mice (8 per treatment group) were randomized to receive a daily oral dose of INV-202, 0.3 mg/kg and 3 mg/kg or vehicle for 4 weeks. Five mice not treated with STZ were used as a nondiabetic control. At the end of treatment, animals were sacrificed. Urinary albumin-to-creatinine ratio (ACR), renal matrix remodelling, glomerular filtration and interstitial fibrosis were assessed in addition to glucose levels, body weight and organ weights. RESULTS After 28 days of treatment, there was no significant effect on hyperglycemia or body weight with either dose of INV-202. Renal and hepatic weights were reduced while heart weight was unaffected. This remained true when normalizing for tibial length. Compared with vehicle-treated diabetic mice, INV-202-challenged mice displayed a marked decrease in many clinical features of DN such as albuminuria, albumin-to-creatinine ratio, urinary urea, loss of glomerular filtration rate and renal hypertrophy. Interestingly, we also found an improvement in both podocyte and proximal tubular cells morphology and health markers that were likely responsible for the improvement previously mentioned. In addition, INV-202 led to a downregulation of the angiotensin II receptor expression as well as a reduced urinary excretion, suggesting an inhibitory effect of this compound on the angiotensin II-mediated renal dysfunction in the context of DN. Furthermore, INV-202 also led to a drastic reduction in renal inflammation and oxidative stress markers that are known to be highly involved in the pathogenesis of DN. Finally, despite the limitation of our model in regard to interstitial fibrosis development, we could observe a marked anti-fibrotic effect of INV-202. CONCLUSION Treatment with INV-202 reduced the progression of nephropathy in STZ-induced diabetic mice. Improvements in kidney size, function and histology, with corresponding gene expression, were noted with both doses of INV-202. Further work to explore the effect of INV-202 in humans is warranted.

FC014: Target Deconvolution from Phenotypic Screens—Identification of Ataxia Telangiectasia Mutated as a Potential Therapeutic Target for Podocyte Protection

Abstract BACKGROUND AND AIMS As part of the renal filtration barrier, podocytes are critical to the function of kidney glomeruli. Their loss is one of the hallmarks of chronic kidney disease, including diabetic kidney disease (DKD). Indeed, many drug discovery efforts focus on preventing podocyte apoptosis triggered by diabetic stressors to delay kidney disease progression. In order to discover and characterize new therapeutic agents, phenotypic screens are a powerful tool to directly screen for the desired cellular outcome. These need to be complemented by target-centric assays to support the chemical optimization of compounds. Generally, the deconvolution and confirmation of molecular targets are considered challenging, but necessary in the follow-up of phenotype-based drug discovery programmes to allow progression towards the clinic. We have combined novel technologies like high-throughput next-generation sequencing (NGS) and Cell Painting [1] to develop an unbiased approach for deconvolution of targets from phenotypic screens. As an outcome, we identified a small molecule compound that can protect conditionally immortalized human podocytes (CIHP) from apoptosis in vitro. In a second step, we were able to identify the target responsible for this effect. METHOD Phenotypic screen: CIHP [2] were treated with high glucose and palmitate, a common DKD injury model, as the main driver for apoptosis as evaluated by caspase 3/7 activation [3]. Potentially protective agents were screened against apoptosis from a library of 50 000 small molecules. We selected a hit compound (CpdX) for subsequent target deconvolution to identify the target causing the protective effect. Target deconvolution and compound profiling: We compared the molecular signatures triggered by CpdX treatment to those of a reference panel of known, bio-annotated compounds (#L3500; Selleckchem). Dimensional reduction based on UMAP and PCA applied to transcriptomic data (NGS) as well as Cell Painting fingerprints were used to identify known compounds exhibiting a similar transcriptomic and morphological profile as the CpdX. We hypothesized that the molecular targets of these compounds also constitute likely targets for the new CpdX. RESULTS We developed a screening cascade (Figure 1A) to identify novel targets for kidney disease. A first-pass phenotypic podocyte apoptosis screen delivered a potent compound, able to rescue CIHP from a diabetic challenge in vitro (Figure 1B, C). Integrated analysis and alignment of cellular changes in transcriptomic profile and morphology following CpdX or reference compound treatment enabled us to identify the serine/threonine-protein kinase Ataxia Telangiectasia Mutated (ATM) as one of the putative targets of the orphan compound. Both KU-60019, a known inhibitor of ATM [4] (Figure 1D) and CpdX showed remarkably similar effects in NGS and Cell Painting (Figure 2A, B) and were also equally protecting the cells from apoptosis in vitro (Figure 1B). From this data, we inferred that ATM is a likely effector of CpdX treatment. CONCLUSION The initial lack of specific target candidates following primary phenotypic screens is a widespread problem in drug discovery. In the absence of a target deconvolution strategy, many potential candidates cannot be progressed easily to optimization. Here, we demonstrated that a combination of state-of-the-art technologies used to benchmark hit compounds from phenotypic screens versus known bio-annotated compound libraries represent a viable approach to perform target deconvolution of hits from phenotypic screening approaches. In this work, a phenotypic screen and subsequent deconvolution identified a novel target in combination with a novel compound, making a suitable starting point for progression into a potential kidney therapeutic agent.

Elastin Insufficiency Accelerates Age‐Related Impairment of Renal Hemodynamics

Gradual loss of functional elastin fibers during aging leads to increased arterial stiffening and decreased compliance. Elastin insufficiency in mice and humans has been shown to be associated with arteriopathy and the development of hypertension. However, it is unclear whether elastin insufficiency in the resistance vasculature, as occurs in the renal vascular bed, contributes to age‐related decline in renal function. We hypothesized that elastin insufficiency exacerbates age‐related impairment of renal hemodynamics by accelerating functional and structural changes of the renal microvasculature. We assessed renal hemodynamics in anesthetized young (4‐6‐month‐old) and old (14–16‐month‐old) female wild‐type (WT) and elastin heterozygous (Eln+/‐) mice. Renal autoregulation was assessed by a stepwise increase in renal perfusion pressure (RPP) by simultaneously occluding the superior mesenteric and celiac arteries. Autonomic activity was clamped by continuous infusion of a cocktail containing vasoactive hormones. Baseline systolic blood pressure (SBP; 91.1±4.2 vs 90.1±3.1mmHg) and renal vascular resistance (RVR; 13.1±2.4 vs 10.0±1.5 mmHg/μL/min/g left kidney weight) were elevated in old versus young WT mice. Renal blood flow (RBF; 7.3±1.7 vs 9.8±1.4 μL/min/g left kidney weight), renal plasma flow (RPF; 5±1.2 vs 6±1mL/min/g left kidney weight) and glomerular filtration rate (GFR), all trended lower in old WT mice compared to young WT mice. However, in Eln+/‐mice, SBP was lower in old mice (78.2±9.4 vs 104.6±4.9mmHg), while RVR (13.5± 2.6 vs 14.4±1.1), RBF (6.7±1.2 vs 7.5±0.6), RPF (4.2±0.7 vs 4.5±0.3) and GFR were all similar between young and old mice. Increasing RPP caused a robust RVR and RPF response in young vs old WT mice. In contrast, the maximal changes in RBF (5.8±0.6 vs 5.5±1 μL/min/g left kidney weight), RVR (23.8±2.5 vs 21.8±7.0 mmHg/μL/min/g left kidney weight) were less robust and similar between young and old Eln+/‐mice. Autoregulatory index average values were closer to 0 in young and old Eln+/‐and old WT miceindicating greater impairment of renal autoregulation compared to young WT mice. Correlation analysis between pulse pressure and RBF showed that a high pulse pressure was more positively correlated to high RBF in young and old Eln+/‐mice as well as old WT mice. Together, our data demonstrate that elastin insufficiency accelerates age‐related impairment of renal hemodynamics and autoregulation likely mediated by functional and structural remodeling of the renal microvasculature.

Postinjury Inhibition of Endothelin‐1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis‐Induced Acute Kidney Injury

Rhabdomyolysis is a life‐threatening condition resulting from the breakdown of skeletal muscle fibers leading to the release of myoglobin into the blood. Increased circulating myoglobin can cause kidney damage, and acute kidney injury (AKI) occurs in 33‐50% of patients with myoglobinuria. Persistent constriction of the renal microvessels, which reduces renal blood flow (RBF) and glomerular filtration rate (GFR), contributes to rhabdomyolysis‐induced AKI. Since activation of G‐protein‐coupled receptors (GPCR) and ion channels regulate renal vascular resistance (RVR), rhabdomyolysis may likely modulate RVR via GPCR and vascular ion channel mechanisms. Pretreatment of rats with an endothelin receptor antagonist has been shown to alleviate rhabdomyolysis‐induced AKI. However, the downstream and upstream links between rhabdomyolysis and increased ET‐1 synthesis are unknown. The downstream effectors of ET‐1‐induced vasoconstriction are smooth muscle cell (SMC) Ca2+‐permeable ion channels. Yet, the ion channel mechanisms that trigger renal vasoconstriction in rhabdomyolysis‐induced AKI remain unknown. Also, most cases of rhabdomyolysis‐induced AKI cannot be predicted. Whether post‐injury inhibition of the vascular mechanisms of ET‐1 ameliorates, rhabdomyolysis‐induced AKI is unknown. This study investigates post‐injury renal production and vascular regulation of the ET system in rhabdomyolysis‐induced AKI. Six h of rhabdomyolysis increased peptidase endothelin converting enzyme (ECE‐1)‐dependent biosynthesis of ET‐1 in the kidneys. Rhabdomyolysis‐induced AKI was not sex‐dependent. At 24 h, rhabdomyolysis also increased renal reactive oxygen species (ROS), ECE‐1, and ET‐1 levels. Furthermore, ET‐1 activated rat renal vascular smooth muscle cell TRPC3 leading to a reduction in RBF and increased RVR. Protein expression levels of the ET receptors (ETA and ETB) and TRPC3 channels in renal microvessels were unaltered. However, postinjury inhibition of ECE1, ET Receptors, and TRPC3 mitigated rhabdomyolysis‐induced GFR impairment, renal hypoperfusion, AKI biomarker elevation, and morphological kidney damage. To further explore the role of TRPC3 ion channels in rhabdomyolysis‐induced AKI, we subjected TRPC3 knock‐out (KO) rats to rhabdomyolysis. Compared to their wild‐type counterparts, KO rats show protection against rhabdomyolysis‐induced AKI. Our findings suggest that ECE‐driven proteolytic ET‐1 production contributes to rhabdomyolysis‐induced AKI. Downstream, ET‐derived DAG activates renal vascular smooth muscle cell TRPC3 channels leading to extracellular calcium entry, vasoconstriction, increased RVR, and reduced GFR.

Profil Klirens Kreatinin pada Pasien Penyakit Ginjal di RSUD Dr. Doris Sylvanus Kota Palangka Raya

Kidney disease is the loss of kidney function. This results in salt retention, nitrogen wastewater, and a decrease in urine volume. Kidney disorders are characterized by structural or functional abnormalities of the kidneys that last more than three months. Indicators to see the ability of renal glomerular filtration can be done by checking creatinine clearance. Creatinine clearance is the number of millimeters of plasma cleared of creatinine by the kidneys in one minute. This study aimed to determine the level of creatinine clearance in patients with kidney disease in RSUD dr. Doris Sylvanus City of Palangka Raya. This research was conducted by quantitative descriptive method, with the number of research samples as many as 15 outpatient kidney disease patients who had not performed hemodialysis at the Clinical Pathology Laboratory of RSUD dr. Doris Sylvanus Palangka Raya, with a sampling technique in the form of Accidental Sampling. The examination method used is the measurement of creatinine clearance as a marker of the glomerular filtration rate (GFR) using the Cockroft-Gault formula. The results showed that based on the value of normal creatinine clearance, as much as 7%, and the decreased value of creatinine clearance, as much as 93%.

Synthesis, Renal Clearance, and Photothermal Therapy Based on the Self-Assembly of a Nanomedicine Consisting of Quaterrylene Bisimide and Glycocluster Conjugates.

Renal-clearable nanomedicines are considered the next generation of nanomedicines, and show potential application for future clinical translations. However, it is important to determine whether self-assembly can form large aggregates that accrue in tumors and then tailor the size of these assemblies to be excreted renally. In this paper, a renal-clearable nanomedicine based on quanterrylene bisimide-mannose conjugates (QDI-Man) was developed. QDI-Man showed a high renal clearance efficiency of 80.31 ± 2.85% in mice. We confirmed that the self-assembly of QDI-Man exhibited a dynamic adjustment process through the renal filtration thresholds, that is, "aggregation → self-regulating the aggregate size through the renal filtration thresholds → reaggregating into aggregates". Benefiting from the modification of mannose-based glycoclusters, QDI-Man showed selective photothermal therapy because of the mannose receptors overexpressed in breast cancer cells, and showed good photothermal therapy in mice. This paper developed a dynamic adjustment theory for effective renal clearance based on organic self-assembly.

Three-Dimensional Super-Resolved Imaging of Paraffin-Embedded Kidney Samples.

Diseases of the glomeruli, the renal filtration units, are a leading cause of progressive kidney disease. Assessment of the ultrastructure of podocytes at the glomerular filtration barrier is essential for diagnosing diverse disease entities, providing insight into the disease pathogenesis, and monitoring treatment responses. Here we apply previously published sample preparation methods together with stimulated emission depletion and confocal microscopy for resolving nanoscale podocyte substructure. The protocols are modified and optimized in order to be applied to formalin-fixed paraffin-embedded (FFPE) samples. We successfully modified our protocols to allow for deep three-dimensional stimulated emission depletion and confocal imaging of FFPE kidney tissue with similar staining and image quality compared with our previous approaches. We further show that quantitative analysis can be applied to extract morphometrics from healthy and diseased samples from both mice and humans. The results from this study could increase the feasibility of implementing optical kidney imaging protocols in clinical routines because FFPE is the gold-standard method for storage of patient samples.

Effect of Age and Acute-Moderate Intensity Exercise on Biomarkers of Renal Health and Filtration.

Simple SummaryIn this research manuscript, the authors demonstrate that when assessing renal health and filtration after an acute bout of moderate-intensity aerobic exercise in healthy individuals of varying ages, only renal function is altered via contemporary biomarker cystatin C, indicating actual changes in renal filtration are not solely due to concentration changes seen in traditional markers of renal function. The clinical application of this study is understanding the value that maintaining good health through the middle-age years offers in the prevention of renal decline. Additionally, healthy individuals appear to have a limit on how high renal health and filtration can be obtained, and in the absence of cardiometabolic diseases, exercise minimally influences renal health and filtration.Aerobic exercise elicits a multitude of physiological improvements in both healthy and diseased populations. However, acute changes in renal health and filtration with aerobic exercise remain difficult to quantify by traditional biomarkers to estimate glomerular filtration rate (eGFR). This study aimed to determine if an acute bout of moderate-intensity aerobic exercise transiently improves non-traditional biomarkers when compared to traditional biomarkers of renal health and filtration in individuals without cardiometabolic diseases. Thirty-nine participants (n = 18 men; n = 21 women; age 32.5 + 12.6 yr; height 171.1 + 11.4 cm; weight 78.7 + 15.6 kg; BMI 27.1 + 5.8) completed a single bout of moderate-intensity (50–60% HRR) aerobic exercise. Blood and urine samples were collected and compared before and post-exercise. Serum creatinine, urine epidermal growth factor (uEGF), uEGF/urine creatinine ratio (uEGFR), and cystatin C (CyC) were measured. In addition, eGFR-MDRD and the CKD-epidemiology equations were used to analyze renal clearance. Relative to pre-exercise measures: serum creatinine (p = 0.26), uEGF (p = 0.35), and uEGFR (p = 0.09) remained unchanged, whereas cystatin C (p = 0.00) significantly increased post-exercise. CyC eGFR was the only estimator of renal filtration to significantly change (p = 0.04). In conclusion, CyC is the only biomarker of renal health and filtration to significantly increase after aerobic exercise. Further investigation focused on sampling time and exercise-intensity is needed to solidify the current understanding of renal health and filtration.

Increased intrarenal post-glomerular blood flow is a key condition for the development of calcineurin inhibitor-induced renal tubular acidosis in kidney transplant recipients.

Hyperchloremic metabolic acidosis (HCMA) from renal tubular acidosis (RTA) is common in kidney transplant (KT) recipients. Calcineurin inhibitors (CNIs) are a potential cause of RTA, and whether HCMA is a determinant of poor graft prognosis is controversial. The subjects were living-donor KT recipients (LDKTRs, n=47) and matched donors (n=43). All cases of rejection, extrarenal causes, and respiratory disorders were excluded. HCMA was defined as having a [Na+]-[Cl- ] value of ≤34 or starting alkalization. We determined the potential causes of HCMA in LDKTRs at 3 months (m) and 1 year (y) post-KT. We examined renal hemodynamic parameters in 26 LDKTRs at 1 y post-KT: namely, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction (FF; GFR/RPF) and pre-/post-glomerular vascular resistance (pre-/postVR). The HCMA incidence in the 3-m post-KT LDKTR group was higher than that of the donors (51.0%vs. 6.9%, p<0.001, adjusted odds ratio: 6.7-15.7). Among adjusted factors, the most dominant HCMA contributor was low hemoglobin concentration (Hb≤12g/dl). Compared to non-HCMA cases, HCMA patients had low FF and low post-VR (p=0.008, 0.003, respectively) suggesting increased intrarenal post-glomerular blood flow. The high pathological score of alternative arteriolar hyalinosis (aah) ≥2 was a significant HCMA risk. The tacrolimus trough level was not high in HCMA but was significantly high in HCMA in the low post-VR setting (p=0.002). Among LDKTRs, low hemoglobin level is an important contributor to the manifestation of HCMA in the induction period, and increased intrarenal post-glomerular blood flow is a key condition for the development of CNI-induced RTA.

Hepatorenal syndrome: criteria and problems of diagnosis (part II)

Hepatorenal syndrome, the extreme manifestation of renal impairment in patients with cirrhosis, is characterized by reduction in renal blood flow and glomerular filtration rate. Hepatorenal syndrome is diagnosed when kidney function is reduced but evidence of intrinsic kidney disease is absent. Unlike other causes of kidney injury, hepatorenal syndrome results from functional changes in the renal circulation and is potentially reversible. An analysis of literature reviews, clinical studies, experimental research, clinical recommendations from PubMed / Medline and ELIBRARY databases was carried out for 7 keywords according to the review topic.

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease.

Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association prevents renal filtration due to the formation of a higher molecular weight complex. In the circulation, RBP4 binds to specific membrane receptors, thereby delivering retinol to target cells, rendering liver-secreted RBP4 the major mechanism to distribute hepatic vitamin A stores to extrahepatic tissues. In particular, binding of RBP4 to ‘stimulated by retinoic acid 6’ (STRA6) is required to balance tissue retinoid responses in a highly homeostatic manner. Consequently, defects/mutations in RBP4 can cause a variety of conditions and diseases due to dysregulated retinoid homeostasis and cover embryonic development, vision, metabolism, and cardiovascular diseases. Aside from the effects related to retinol transport, non-canonical functions of RBP4 have also been reported. In this review, we summarize the current knowledge on the regulation and function of RBP4 in health and disease derived from murine models and human mutations.

Risk of heart failure depending on the state of renal filtration function in patients with uncomplicated hypertension

Aim. To assess the risk of heart failure (HF) depending on the state of renal filtration function in patients with uncomplicated hypertension (HTN) without kidney dysfunction.Material and methods. This cross-sectional screening clinical trial consecutively included 176 outpatients with uncomplicated HTN and without chronic kidney disease (CKD). To assess the HF risk, the blood concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) was determined. To assess the renal filtration function, the blood serum concentration of creatinine and cystatin C was determined, followed by glomerular filtration rate (GFR) estimation using the CKDEPI equation with both parameters. Echocardiography was performed to assess the cardiac structural and functional state.Results. Correlation analysis revealed a moderate direct relationship between NT-proBNP and blood cystatin C concentration (r=0,370; p&lt;0,005), as well as a moderate inverse relationship with GFR (CKD-EPIcre) and GFR (CKD-EPIcys) (r= -0,321; p&lt;0,05 and r=-0,360; p&lt;0,005, respectively). ROC curve for all available values of blood cystatin C revealed the most optimal cut-off threshold of 1016 ng/ml (AUC=0,726, p&lt;0,001), which ensures the sensitivity of 72,2% (p&lt;0,001) and specificity of 62,0% (p&lt;0,001). ROC curve for all available GFR values (CKD-EPIcys) revealed a cut-off threshold of 74 ml/min/1,73 m2 (AUC=0,702, p=0,002) with a sensitivity and specificity of 55,6% and 74,7%, respectively (p=0,001 and p=0,001, respectively). Taking into account the cut-off points for cystatin C and GFRcys, the first group consisted of 73 (41,48%) patients with cystatin C ≥1016 ng/ml and GFR (CKD-EPIcys) ≤74 ml/min/1,73 m2, while the second one — 103 (58,52%) patients with cystatin C &lt;1016 pg/ml and GFR (CKDEPIcys) &gt;74 ml/min/1,73 m2. The presence of impaired glucose tolerance, left ventricular diastolic dysfunction (LV DD), LV hypertrophy and left atrial enlargement leads to an additional increase in HF risk in patients with uncomplicated HNT without CKD.Conclusion. The ROC analysis showed that cystatin C and cystatin C-based GFR (CKD-EPIcys) can be used as markers of HF risk in patients with uncomplicated HTN without CKD. With an increase in cystatin C ≥1016 ng/ml, the relative risk of HF is 2,99, while with a decrease in GFR (CKD-EPIcys) ≤74 ml/min/1,73 m2 — 1,26. The presence of impaired glucose tolerance, LV DD, LV hypertrophy and left atrial enlargement in patients with uncomplicated HTN without CKD with a cystatin C increase ≥1016 ng/ml and a decrease in GFR (CKD-EPIcys) ≤74 ml/min/1,73 m2 and below further increases the risk of developing CHF.

Quality of life and cognitive assessment in healthy older Asian people with early and moderate chronic kidney disease: The NAHSIT 2013-2016 and validation study.

Taiwan has the highest prevalence of chronic kidney disease (CKD). Impaired cognition and quality of life are significant phenomena in the late stages of CKD. We sought to obtain an overview and the attributable effect of impaired glomerular filtration on multiple domains in cognition and dimensions of quality of life for community-based healthy older adults in Taiwan. The study was derived from the Nutrition and Health Survey in Taiwan (NAHSIT) 2013-2016, a nationwide cross-sectional study conducted to sample healthy, community-based older adults aged ≥65 years in Taiwan. Participants were categorized into four CKD groups: CKD stage 1, stage 2, stages 3a and 3b, and stages 4-5. The Mini-Mental State Examination (MMSE) and the QoL questionnaire derived from the 12-item Short Form Health Survey (SF-12) were measured. Generalized linear mixed models (GLMMs) and principal component regressions were employed for the analysis and validation, respectively. Participants with moderate CKD (stages 3a and 3b) showed deficits in global MMSE, domain orientation to time, calculation, complex commands, and role-physical and vitality in QoL questionnaires. In GLMMs, impaired eGFR per 30 mL/min/1.73 m² was associated with lower global MMSE scores (β = -0.807, standard error [SE] = 0.235, P = 0.0007), domain orientation to time (β = -0.155, SE = 0.047, P = 0.0011), calculation (β = -0.338, SE = 0.109, P = 0.0020), complex commands (β = -0.156, SE = 0.079, P = 0.0494), and role-physical (β = -2.219, SE = 0.779, P = 0.0046) dimensions of QoL. Elderly Han Chinese adults with moderately impaired renal filtration could manifest cognitive deficits in orientation to time, calculation, and impaired quality of life in physical role functioning.

The nephropathy of sickle cell trait and sickle cell disease.

Sickle cell syndromes, including sickle cell disease (SCD) and sickle cell trait, are associated with multiple kidney abnormalities. Young patients with SCD have elevated effective renal plasma flow and glomerular filtration rates, which decrease to normal ranges in young adulthood and subnormal levels with advancing age. The pathophysiology of SCD-related nephropathy is multifactorial - oxidative stress, hyperfiltration and glomerular hypertension are all contributing factors. Albuminuria, which is an early clinical manifestation of glomerular damage, is common in individuals with SCD. Kidney function declines more rapidly in individuals with SCD than in those with sickle cell trait or in healthy individuals. Multiple genetic modifiers, including APOL1, HMOX1, HBA1 and HBA2 variants are also implicated in the development and progression of SCD-related nephropathy. Chronic kidney disease and rapid decline in estimated glomerular filtration rate are associated with increased mortality in adults with SCD. Renin-angiotensin-aldosterone system inhibitors are the standard of care treatment for albuminuria in SCD, despite a lack of controlled studies demonstrating their long-term efficacy. Multiple studies of novel therapeutic agents are ongoing, and patients with SCD and kidney failure should be evaluated for kidney transplantation. Given the high prevalence and severe consequences of kidney disease, additional studies are needed to elucidate the pathophysiology, natural history and treatment of SCD-related nephropathy.

Markers of structural and cellular renal damage in localized renal cell carcinoma before treatment

Purpose of the study. The purpose of the study was to analyze parameters of molecular markers of structural and cellular renal damage in localized renal cell carcinoma (RCC) with determining the nature of the initial abnormalities in the kidney functional state before the treatment.Patients and methods. The study included 46 patients receiving elective surgical treatment for localized renal cancer in the Department of Oncourology, National Medical Research Centre for Oncology. The comparison group included the clinical and laboratory data of 13 healthy people comparable with the RCC patients in terms of age and gender. Cystatin C, IL‑18, KIM‑1, L-FABP, NGAL were determined in blood and urine in all patients.Results. Evaluation of the kidney functional state of RCC patients showed that the initial values of serum creatinine and the glomerular filtration rate were similar to the reference levels in healthy people, but statistically significant differences were found in the ratios of cystatin C concentrations in the blood and urine in all patients, compared with normal values. Determination of L-FABP indices in RCC patients showed that their levels were 2.5 times higher than normal values, and the urine concentration of IL‑18 was 1.7 times higher than normal values (p &lt; 0.05). Blood and urine levels of NGAL and KIM‑1 did not differ significantly from the comparison group.Conclusions. The development of localized RCC is accompanied by the formation of tubulointerstitial dysfunction with impaired renal filtration capacity. All RCC patients showed elevated endogenous markers of structural and cellular renal damage – cystatin C, L-FABP, and IL‑18.