Progressive Deterioration Of Kidney Function Research Articles

Extracellular Vesicles Derived from Human Liver Stem Cells Counteract Chronic Kidney Disease Development and Cardiac Dysfunction in Remnant Kidney Murine Model: The Possible Involvement of Proteases

Fibrosis is a marker of chronic kidney disease (CKD) and consists of the accumulation of the extracellular matrix (ECM) components, causing the progressive deterioration of kidney function. Human liver stem cells (HLSCs) have anti-fibrotic activity, and HLSC-derived extracellular vesicles (EVs) mediate this effect. Herein, we evaluated the ability of HLSC-EVs to reverse renal and cardiac alterations in a murine model of partial nephrectomy (PNx) that mimics human CKD development. Furthermore, we investigated the contribution of extracellular matrix remodeling-related proteases to the anti-fibrotic effect of HLSC-EVs. PNx was performed by ligation of both poles of the left kidney, followed one week later by the removal of the right kidney. EV treatment started 4 weeks after the nephrectomy, when renal and cardiac alternations were already established, and mice were sacrificed at week eight. HLSC-EV treatment improved renal function and morphology, significantly decreasing interstitial fibrosis, glomerular sclerosis, and capillary rarefaction. This improvement was confirmed by the decreased expression of pro-fibrotic genes. Moreover, EV treatment improved cardiac function and reduced cardiac fibrosis. HLSC-EVs shuttled different proteases with ECM remodeling activity, and matrix metalloproteinase 1 (MMP-1) was involved in their anti-fibrotic effect on renal tissue. HLSC-EV treatment interferes with CKD development and ameliorates cardiomyopathy in PNx mice.

Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant

Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes.Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present.In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.

Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant

Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes.Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present.In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.

Indoxyl sulfate impairs erythropoiesis at BFU-E stage in chronic kidney disease

Chronic kidney disease (CKD) is a global health condition characterized by a progressive deterioration of kidney function. It is associated with high serum levels of uremic toxins (UT), such as Indoxyl Sulfate (IS), which may participate in the genesis of several uremic complications. Anemia is one of the major complications in CKD patients that contribute to cardiovascular disease, increase morbi-mortality, and is associated with a deterioration of kidney failure in these patients. Our study aimed to characterize the impact of IS on CKD-related erythropoiesis. Using cellular and pre-clinical models, we studied cellular and molecular effects of IS on the growth and differentiation of erythroid cells. First, we examined the effect of clinically relevant concentrations of IS (up to 250 μM) in the UT7/EPO cell line. IS at 250 μM increased apoptosis of UT7/EPO cells at 48 h compared to the control condition. We confirmed this apoptotic effect of IS in erythropoiesis in human primary CD34+ cells during the later stages of erythropoiesis. Then, in IS-treated human primary CD34+ cells and in a (5/6 Nx) mice model, a blockage at the burst-forming unit-erythroid (BFU-E) stage of erythropoiesis was also observed. Finally, IS deregulates a number of erythropoietic related genes such as GATA-1, Erythropoietin-Receptor (EPO-R), and β-globin. Our findings suggest that IS could affect cell viability and differentiation of erythroid progenitors by altering erythropoiesis and contributing to the development of anemia in CKD.

PENGARUH DOSIS HEMODIALISIS TERHADAP KEJADIAN ASCITES PADA PASIEN GAGAL GINJAL KRONIS YANG MENJALANI HEMODIALISIS DI RST dr. SOEDJONO MAGELANG

Chronic renal failure is a progressive and continuous destruction of kidney structures. Chronic renal failure occurs in susceptible individuals, analgesic nephropathy, destruction of renal papillae associated with daily use of analgesic drugs for years. Whatever the cause, there is a progressive deterioration of kidney function which is characterized by a progressive decrease in the Glomelurus Filter Rate (GFR) (Corwin, 2009). Chronic kidney failure is a failure of kidney function to maintain metabolism and fluid and electrolyte balance due to progressive destruction of kidney structures with manifestations of accumulation of residual metabolites (uremic toxicants) in the blood (Muttaqin & Sari, 2011). as well as electrolytes and acid-base composition of body fluids, removing metabolic wastes that are no longer needed by the body, regulating blood pressure and hormonal function. Chronic Kidney Disease (CKD) is the final stage of chronic kidney failure where GFR <15 ml/min/1.73m2 so that the body fails to maintain metabolism and fluid and electrolyte balance, causing uremia, namely retention of urea and other nitrogenous wastes in the blood (Smeltzer et al. al, 2008; National Kidney Foundation in Kallenbach, et al, 2005). With the increasingly real decline in kidney function or worsening of symptoms of uremia, renal replacement therapy is required for survival, namely dialysis and organ transplantation. There are two methods of dialysis, one of which is Hemodialysis (Potter, 2005; Smelzer, 2008).

MO454A NEW AKI TO CKD PROGRESSION IN VIVO EXPERIMENTAL MODEL

Abstract Background and Aims Chronic kidney disease (CKD) represents an enormous problem for healthcare systems. It is estimated that in USA more than 37 million people suffer from this disease. Risk factors include hypertension, diabetes mellitus, older age, proteinuria and previous episodes of acute kidney injury (AKI). Indeed, several studies have shown that AKI increases the risk of CKD, independently of other risk factors, especially when the episode is severe or recurrent. Under these circumstances, maladaptive responses may occur leading to structural and functional abnormalities. Renal fibrosis is the hallmark for maladaptive repair and is considered the final common outcome of progressive kidney disease. We hypothesized that after multiple renal insults, the mechanisms of adaptive repair could be less effective generating a progressive accumulation of extracellular matrix and a progressive deterioration of kidney function. Method We used 8 weeks old male Wistar rats and we analyse their evolution during 9 months. Animals were subdivided into 4 experimental groups: Control group: SHAM operated rats, saline solution, i.p.; “CDDP5-I/R60-I/R60” group: 5 mg/kg cisplatin i.p., after renal function normalization, 60-minute ischemia-reperfusion (I/R60) on left kidney, and 2 weeks later 60-minute ischemia-reperfusion (I/R60) on right kidney; “5/6 RMR” group: 5/6 renal mass reduction; “UNX” group: nephrectomy. Blood and urine were collected at: day 0 (basal); day 4 (AKI development); day 8 (normalized renal function after AKI and induction of renal ischemia); day 9 (1 day after ischemia); day 13, day 20 and monthly thereafter. Renal function was analyzed by sCr, creatinine clearance, blood urea nitrogen and proteinuria determination using colorimetric methods. Tissue samples were stained with Masson´s trichrome and Sirius Red at days 13, 20, 56, 165 and 270 and renal fibrosis was quantified using Image J program. Results The addition of several AKI episodes induces a progressive accumulation of extracellular matrix. In addition, the “CDDP5-I/R60-I/R60” group presented an initial reduction in renal function that remained stable in the last 6 months of the study. On the contrary, we observed a spontaneous and progressive decline of kidney function in the “5/6 RMR” group, which nevertheless presented a significant lower degree of interstitial fibrosis than the “CDDP5-I/R60-I/R60” group. Conclusion We have generated a new in vivo experimental model of AKI to CKD transition combining nephrotoxic and ischemic AKI. We demonstrate that after recurrent episodes of AKI, kidneys show progressive interstitial fibrosis which however does not correlate with a progressive decline of renal function.

Urinary biomarkers as point-of-care tests for predicting progressive deterioration of kidney function in congenital anomalies of kidney and urinary tract: trefoil family factors (TFFs) as theemerging biomarkers.

Children with congenital anomalies of kidney and urinary tract (CAKUT) are at high risk of progressive deterioration of kidney function and further developing stage5 chronic kidney disease (CKD5), even after a successful surgery. This prospective study was designed to determine whether urinary biomarkers can predict progressive deterioration of kidney function in children with CAKUT. The study included 50 consecutive children, aged < 14 years, who were diagnosed with congenital uropathies (PUV, VUR, and PUJO) and 20 age-matched controls. Examination of four urinary biomarkers, i.e., trefoil family factors (TFF) 1 and 3, neutrophil gelatinase-associated lipocalin (NGAL) and microalbuminuria (MALB) was done at the beginning of follow-up. Kidney function was assessed, at the beginning and after 12-months of follow-up, by technetium-99m diethylene triamine pentaacetic acid (DTPA) and technetium-99m dimercaptosuccinic acid (DMSA) scans. Progressive deterioration in the kidney function was defined as a fall in the GFR from ≥ 60 to < 60 ml/min/1.73 m2 on comparing the baseline and latest DTPA scans; and/or new-onset cortical scar/scars or increase in the size of previous scar/scars on serial DMSA scans. Group 1 and group 2 included children without and with progressive functional deterioration respectively. The median (IQR) age of children with CAKUT and controls was 3 (1.5-5) and 2.3 (1.2-3.6) years, respectively, and showed no significant difference (p = 0.29). Median concentrations of TFF1, TFF3, NGAL, and microalbumin in patients were 44.5, 176.5, 281.2, and 15.5 mcg/gCr, respectively, and were significantly elevated as compared to controls (p < 0.05). Children belonging to group 2 had significantly higher concentration of biomarkers as compared to those in group 1. TFF3 was found have the highest AUC (0.9198) on ROC curve for predicting progressive functional deterioration. Urinary TFFs, NGAL, and microalbumin significantly correlate with progressive deterioration of kidney function in children harboring CAKUT. TFF3, with the strongest prediction of functional deterioration, is an emerging peptide showing sufficient potential to be included in the biomarker panel. Graphical abstract.

English

BACKGROUND Kidneys are vital organs for excretory and many other biochemical functions in the human body. Most chronic diseases end up damaging the kidneys, acute to chronic, based on the cause and duration. Chronic kidney disease is a sequence of damages to the renal cells and parenchyma leading to progressive deterioration of kidney function, which eventually develops into terminal stage of chronic kidney failure. Chronic renal failure leads to a pro-oxidant state, which leads to damage to the renal cells and parenchyma and the amount of intracellular oxidative stress or extracellular oxidative stress has a relation to the severity of renal failure either directly or indirectly. The study aimed to find the correlation between high sensitivity c-reactive protein (hs-CRP) to lipid peroxidation product, malondialdehyde (MDA). METHODS This prospective study was designed and conducted from January 2018 to December 2019 in the Department of Biochemistry, Government Medical College, Ananthapuramu. The study comprised a total of 70 subjects in the age group of 35 - 65 years. The subjects of the approved study plan were divided into two groups; 35 subjects were healthy controls (group-1), and 35 subjects were chronic renal failure (CRF) patients. A blood sample was collected in Government General Hospital, Anantapuramu. RESULTS The sample was analysed for estimation of blood urea, plasma glucose, serum creatinine, Malondialdehyde (MDA) and C-reactive protein (CRP). The mean value of blood urea, serum creatinine, serum hs-CRP, serum MDA was higher in CRF (group-2) patients when compared to healthy controls (group-1) (p &lt; 0.0001). We observed a positive correlation between serum MDA and serum creatinine (r = 0.46832), hs-CRP (r = 0.0234). CONCLUSIONS In CRF, oxidative stress is obviously evident, but the inflammation induced oxidative stress which can be corrected if detected early will reduce oxidative damage. Our study shows that there is an elevation in hs-CRP and MDA which confirms the presence of oxidative damage, inflammation and probably inflammation induced oxidative damage. KEYWORDS CRF, Oxidative Stress, MDA, Serum Creatinine, hs-CRP

Spectrum of red blood cell parameters in chronic kidney disease in a tertiary care centre

Background: Chronic Kidney Disease (CKD) is an emerging public health problem worldwide. The increasing cost of healthcare, particularly in developing nations like India, is a social and economic burden. Slow but progressive deterioration in kidney function leads to numerous hematological and biochemical changes. The aim of the present study is to study various changes in red cell parameters that occur in the CKD patients. Materials and Method: 50 patients with CKD were included in this study. Age, gender, RBC count; hemoglobin (Hb); hematocrit; mean corpuscular volume (MCV); mean corpuscular hemoglobin (MCH); MCH concentration (MCHC); and peripheral smears were studied. Results were analyzed using SPSS 20.0 version. Results: Of the 50 CKD patients on maintenance HD, the most common group sampled were male patients (72%) with the mean age of 54 (±15) years. The study revealed that Hemoglobin (Hb), Packed Cell Volume (PCV), Red Blood Cells (RBC) were low in CKD patients. The most common type of anemia was normocytic normochromic anemia, followed by dimorphic anemia. Fragmented RBCs and Spherocytes were 42% and 32% respectively. Conclusion: CKD is associated with different degrees of abnormality in hematological parameters that needs careful evaluation and management. From the CBC and peripheral smear findings the type of anemia, the degree of hemolysis can be analysed and the patients can be evaluated for the underlying cause and treated appropriately. The present study might help clinicians understand haematological profile and take necessary steps in the management.

Relationship between GFR, intact PTH, oxidized PTH, non‐oxidized PTH as well as FGF23 in patients with CKD

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are regulators of renal phosphate excretion and vitamin D metabolism. In chronic kidney disease (CKD), circulating FGF23 and PTH concentrations progressively increase as renal function declines. Oxidation of PTH at two methionine residues (positions 8 and 18) causes a loss of function. The impact of n-oxPTH and oxPTH on FGF23 synthesis, however, and how n-oxPTH and oxPTH concentrations are affected by CKD, is yet unknown. The effects of oxidized and non-oxidized PTH 1-34 on Fgf23 gene expression were analyzed in UMR106 osteoblast-like cells. Furthermore, we investigated the relationship between n-oxPTH and oxPTH, respectively, with FGF23 in two independent patients' cohorts (620 children with CKD and 600 kidney transplant recipients). While n-oxPTH stimulated Fgf23 mRNA synthesis in vitro, oxidation of PTH in particular at Met8 led to a markedly weaker stimulation of Fgf23. The effect was even stronger when both Met8 and Met18 were oxidized. In both clinical cohorts, n-oxPTH-but not oxPTH-was significantly associated with FGF23 concentrations, independent of known confounding factors. Moreover, with progressive deterioration of kidney function, intact PTH (iPTH) and oxPTH increased substantially, whereas n-oxPTH increased only moderately. In conclusion, n-oxPTH, but not oxPTH, stimulates Fgf23 gene expression. The increase in PTH with decreasing GFR is mainly due to an increase in oxPTH in more advanced stages of CKD.

Specificity of anemic syndrome in geriatric patients with chronic kidney disease.

Anemic syndrome is detected in 10-25% of geriatric patients, and with increasing age, there is a tendency to increase the incidence of the disease. Among the diseases that lead to the development of anemia, kidney pathology plays an important role. Progressive deterioration of kidney function in old age is associated with an increased risk of fractures, sarcopenia, and the development of cognitive impairment. Also, nephrogenic anemia aggravates the prognosis in patients with cardiovascular diseases, which is associated with an increase in myocardial ischemia, an increase in tissue hypoxia, a progression of left ventricular hypertrophy, and a decrease in left ventricular systolic function.

Chronic kidney disease in children: problems of arterial hypertension

The review contains materials on the course of chronic kidney disease (CKD) in children with arterial hypertension (AH). The relationship between CKD and AH was shown, where hastening of CKD progression to end-stage renal failure in the presence of AH was established. The regulation of AH in children is necessary for the treatment of CKD, because AH is not established on time, is not well controlled and is often masked. Impaired vascular regulation, fluid overload, increased cardiac output, and peripheral vascular resistance, alone or in combination, can lead to hypertension in CKD. The use of modern methods for monitoring and controlling blood pressure is crucial to improve the management of AH and prevent damage to target organs in children. 24-hour blood pressure measurements are an important tool in determining the prognosis and treatment of children with CKD. To identify impaired renal function in CKD, a large number of biomarkers are used. Glomerular filtration rate (GFR), serum creatinine and cystatin C are currently used as biomarkers for renal failure. Recently, biomarkers, including KIM-1, LFABP, NGAL, and IL-18 have been proposed as markers of acute kidney injury, and they may be useful in the future for early detection of CKD progression in children. In newborns and children of early and older age, hypertension occurs due to renovascular and parenchymal diseases.AH is considered a marker of CKD severity and is a risk factor for progressive deterioration of kidney function, as well as thedevelopment of cardiovascular diseases. Sympathetic hyperactivity, excessive formation of free radicals, reduced bioavailability of nitric oxide (NO) and excessive production of angiotensin II leads to an increase in blood pressure. Obesity or an increase in body mass index (BMI) is currently considered as a risk factor not only for cardiovascular diseases and diabetes but also for CKD. Hyperuricemia and CKD are closely related, as the accumulation of uric acid is associated with hypertension, metabolic syndrome and microalbuminuria, which are also risk factors for the progression of CKD. AH has a detrimental effect on target organs, including the kidneys, eyes, and heart. Lifestyle modifications, weight control, healthy eating, reduced sodium intake, maintenance exercises and basic drug therapy using angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers can slow the progression of CKD in children.

The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD.

Hyperuricaemia is common among patients with chronic kidney disease (CKD), and increases in severity with the deterioration of kidney function. Although existing guidelines for CKD management do not recommend testing for or treatment of hyperuricaemia in the absence of a diagnosis of gout or urate nephrolithiasis, an emerging body of evidence supports a direct causal relationship between serum urate levels and the development of CKD. Here, we review randomized clinical trials that have evaluated the effect of urate-lowering therapy (ULT) on the rate of CKD progression. Among trials in which individuals in the control arm experienced progressive deterioration of kidney function (which we define as ≥4 ml/min/1.73 m² over the course of the study - typically 6 months to 2 years), treatment with ULT conferred consistent clinical benefits. In contrast, among trials where clinical progression was not observed in the control arm, treatment with ULT was ineffective, but this finding should not be used as an argument against the use of uric acid-lowering therapy. Although additional studies are needed to identify threshold values of serum urate for treatment initiation and to confirm optimal target levels, we believe that sufficient evidence exists to recommend routine measurement of serum urate levels in patients withCKD and consider initiation of ULT among those who are hyperuricaemic with evidence of deteriorating renal function, unless specific contraindications exist.

Study of serum leptin levels in patients with chronic kidney disease

Background and objectives: Chronic kidney disease is a global threat to health in general and for developing countries. It is characterized by progressive deterioration of kidney function which develops eventually into a terminal stage of chronic kidney failure. Leptin is an adipose tissue-derived hormone shown to be related to several metabolic, inflammatory, and hemostatic factors related to chronic kidney disease. The objective of the study is to understand the role of serum Leptin in chronic kidney disease. Material and Methods: A case control study was done with 87 patients divided into 2 groups. 43 healthy individuals were served as controls and 44 chronic kidney disease patients were served as cases. Serum Leptin was estimated by ELISA method. Blood urea was estimated by urease method and serum creatinine by modified Jaffe‟s method. BMI was calculated. Data was analysed by using graph pad prism 7.0. Results: In the present study, patients with chronic kidney disease had significant higher levels of serum Leptin (55.88 ± 31.59),blood urea (75.23 ± 30.91), serum creatinine is (4.09 ± 1.90) and BMI is (24.66 ± 2.667) when compared to healthy individuals serum Leptin levels is (7.91 ± 8.24), blood urea (27.53 ± 8.03), serum creatinine is (1.28 ± and BMI is (23.33 ± 2.45) with a p value < 0.001. Conclusion: Serum Leptin levels were high in patients with chronic kidney disease when compared to healthy individuals even the BMI was in normal range in both patients and healthy individuals. The study concludes that serum Leptin is associated with chronic kidney disease and can be used as a marker for diagnosis and prognosis in chronic kidney disease.

Asymptomatic proteinuria in Indonesian adolescent students.

Proteinuria is one of the common manifestations of kidney disease that has a serious impact on the progressive deterioration of kidney function. In developed countries, school screening for asymptomatic proteinuria is routinely performed, especially in adolescent students, to detect early stage of chronic kidney disease. This study aimed to find out the prevalence of asymptomatic persistent proteinuria in adolescent students. This was a multi-assessment study. Screening for proteinuria was conducted on five junior high schools across Jakarta, Indonesia, in April-June 2015. Healthy students aged 12-14 years whose parents provided informed consent were selected randomly. Urine collections were performed thrice. We used dipstick tests and protein-to-creatinine ratio to measure protein in the urine. From 536 students, 485 were eligible and recruited for this study. They were more female and well-nourished students. Hypertension constituted 12.9% of students. Proteinuria accounted for 7.42%. Transient, orthostatic, and persistent proteinuria were found in 5.77%, 1.03%, and 0.62% of students, respectively. The prevalence of asymptomatic persistent proteinuria among adolescent students in Jakarta is higher than that in other populations in Asia. Consequently, a routine screening to detect proteinuria should be considered in Indonesia to detect chronic kidney disease in children.

Dietary management of hyperphosphatemia in chronic kidney disease

Progressive deterioration of kidney function in chronic kidney disease (CKD) leads to retention of many substances, including phosphorus, that are normally excreted by the kidney. Serum phosphorous concentration, however, is usually maintained within the normal range by a variety of compensatory mechanisms until renal disease has progressed to approximately CKD-Stage 5. The challenge is to provide appropriate nutrition while maintaining phosphorus content within recommended limits. During dietary counseling of patients with CKD, the absolute dietary phosphorous content as well as the phosphorous-to-protein ratio in foods should be addressed. This study focuses on dietary management of hyperphosphatemia in CKD.

Estimation of Serum Vitamin D, Calcium and Phosphorus in Chronic Kidney Disease

Introduction: Abnormalities in mineral metabolism are invariable with progressive deterioration of kidney function in chronic kidney disease (CKD). These abnormalities are documented in CKD on dialysis in our population but not on pre dialysis. So, present study aims to estimate serum vitamin D, calcium and phosphorus in CKD stage 3-5ND. Methods: It was a cross sectional study of established new CKD patients not on dialysis, vitamin D, calcium, phosphate binders and corticosteroids therapy. Blood sample was drawn for estimation of serum vitamin D, creatinine, calcium, phosphorus and albumin and CKD staging done by KDIGO (2012) criteria. SPSS software version 19 was used for data analysis and chi-squared and ANOVA test was applied as the test of significance.Results: Sixty six (51 male and 15 female) CKD patients with a mean age of 54.3±14.8 years were studied. Hypovitaminosis D (&lt;30 ng/ml) was present in 84.8%, with deficiency (&lt;20 ng/ml) in 50% and insufficiency (20-30) ng/ml in 34.8%. Other abnormalities observed were hypocalcemia (60.6%), hypercalcemia (1.5%) and hyperphosphatemia (63.6%) with no difference of corrected calcium, significant difference of serum phosphorus (p&lt;0.001) with hyperphosphatemia in stage 4 and 5 CKD and vitamin D insufficiency in stage 3b, deficiency in stage 3a, 4 and 5 CKD. There was no correlation of serum vitamin D with calcium and phosphorus in different stages of CKD.Conclusion: Present study concludes that hypovitaminosis D, hypocalcemia and hyperphosphatemia is common in our pre-dialysis CKD patients and serum phosphorus raises more with reduction of GFR.

The Role of Angiotensin II in Parietal Epithelial Cell Proliferation and Crescent Formation in Glomerular Diseases

Crescentic glomerulonephritis (GN) is a devastating disease with rapidly progressive deterioration in kidney function, which, histologically, manifests as crescent formation in most glomeruli. We previously found that crescents derive from the aberrant proliferation and migration of parietal epithelial cells (PECs)/progenitor cells, and that the angiotensin (ang) II/ang II type-1 (AT1) receptor pathway may participate, together with the stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor 4 axis, in the development of those lesions. Herein, we elucidated sequential events and cellular and molecular interactions occurring during crescentic lesion onset and evolution. By analyzing kidney biopsy specimens of patients with extracapillary GN, divided according to the grade of glomerular lesions, we found that the accumulation of macrophages expressing matrix metalloproteinase-12 started manifesting in glomeruli affected by early-stage lesions, whereas AT1 receptor expression could not be detected. In glomeruli with advanced lesions, AT1 receptor expression increased markedly, and the up-regulation of SDF-1, and its receptor C-X-C chemokine receptor 7, was documented on podocytes and PECs, respectively. Invitro studies were instrumental to demonstrating the role of ang II in inducing podocyte SDF-1 production, which ultimately activates PECs. The present findings support the possibility that angiotensin-converting enzyme inhibitor treatment might limit PEC activation and reduce the frequency and extension of crescents in extracapillary GN.

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Protects Against Acute Kidney Injury-Mediated Chronic Kidney Disease: Role of Oxidative Stress.

Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 hours), 18 rats were divided into sham, bilateral renal ischemia of 25 minutes, and rats that received 3 doses of finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4 months), 23 rats were divided into sham, rats that underwent 45 minutes of bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour before IR. We found that after 24 hours of reperfusion, the untreated IR rats presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin mRNA levels were increased. In contrast, the rats treated with finerenone displayed normal kidney function and significantly lesser tubular injury and kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin levels. After 4 months, the IR rats developed chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-β and collagen-I mRNA. The transition from acute kidney injury to chronic kidney disease was fully prevented by finerenone. Altogether, our data show that in the rat, finerenone is able to prevent acute kidney injury induced by IR and the chronic and progressive deterioration of kidney function and structure.

Abstract P298: Finerenone Protects Against the Acute and Chronic Consequences of Renal Ischemia/reperfusion Injury

Introduction: One of the most common causes of acute kidney injury (AKI) is renal ischemia/reperfusion (IR). Mineralocorticoid receptor (MR) antagonism has shown beneficial effects against renal IR consequences. The potential benefit of novel non-steroidal MR antagonists such as finerenone has not been explored. Objective: Evaluate the efficacy of finerenone to prevent the acute and chronic consequences of ischemic AKI. Methods: For the acute study (24 hours), 18 rats were divided in: sham, rats subjected to bilateral renal ischemia of 25 min and rats that received three doses of finerenone at -48 h, -24 h and -1 h before the ischemia. For the chronic study (4 months), 21 rats were divided in: sham, rats with 45 min of bilateral ischemia and rats treated with Finerenone at day -2, -1 and 1h before IR. The left kidney was used for histology and the right kidney for molecular analysis. Results: After 24 h of reperfusion, the untreated IR rats presented a 3-fold increase in plasma creatinine, accompanied by 40% of tubules presenting cell detachment and casts. Kim-1 and NGAL mRNA levels were induced by 30-fold. In contrast, the rats that received finerenone presented normal creatinine and significantly fewer injured tubules (11%) and a less pronounced induction of kim-1 and NGAL (8-fold). After 4 months, the untreated IR rats developed chronic kidney disease (CKD), evidenced by kidney dysfunction, increased proteinuria (121.6 vs. 14.3 mg/24h in sham) and renal vascular resistance (16.8 vs. 11.4 mmHg/mL in sham). Tubular dilation, extensive tubule-interstitial fibrosis and an increase in kidney TGF-β and Collagen-I mRNA levels also characterized CKD. The transition from AKI to CKD was fully prevented by finerenone administration at the time of IR. Conclusion: Altogether, our data shows that finerenone is able to prevent AKI induced by IR as well as the chronic and progressive deterioration of kidney function and structure.