scholarly journals Peritubular Capillary Rarefaction: An Underappreciated Regulator of CKD Progression

2020 ◽  
Vol 21 (21) ◽  
pp. 8255
Author(s):  
Yujiro Kida
Keyword(s):  
Molecular Mechanisms ◽  
Significant Contribution ◽  
Basic Research ◽  
Peritubular Capillary ◽  
Ckd Progression ◽  
Hypertensive Nephrosclerosis ◽  
Capillary Rarefaction ◽  
Major Factors ◽  
Stage Renal Disease ◽  
End Stage

Peritubular capillary (PTC) rarefaction is commonly detected in chronic kidney disease (CKD) such as hypertensive nephrosclerosis and diabetic nephropathy. Moreover, PTC rarefaction prominently correlates with impaired kidney function and predicts the future development of end-stage renal disease in patients with CKD. However, it is still underappreciated that PTC rarefaction is a pivotal regulator of CKD progression, primarily because the molecular mechanisms of PTC rarefaction have not been well-elucidated. In addition to the established mechanisms (reduced proangiogenic factors and increased anti-angiogenic factors), recent studies discovered significant contribution of the following elements to PTC loss: (1) prompt susceptibility of PTC to injury, (2) impaired proliferation of PTC, (3) apoptosis/senescence of PTC, and (4) pericyte detachment from PTC. Mainly based on the recent and novel findings in basic research and clinical study, this review describes the roles of the above-mentioned elements in PTC loss and focuses on the major factors regulating PTC angiogenesis, the assessment of PTC rarefaction and its surrogate markers, and an overview of the possible therapeutic agents to mitigate PTC rarefaction during CKD progression. PTC rarefaction is not only a prominent histological characteristic of CKD but also a central driving force of CKD progression.

Abstract MP30: Chronic Kidney Disease Progression and Risk of End-Stage Renal Disease: The Use of Change in Novel Kidney Filtration Markers

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Casey M Rebholz ◽  
Kunihiro Matsushita ◽  
Elizabeth Selvin ◽  
Morgan E Grams ◽  
Josef Coresh
Keyword(s):  
Chronic Kidney Disease ◽  
Clinical Trials ◽  
Kidney Disease ◽  
Cystatin C ◽  
End Stage Renal Disease ◽  
Ckd Progression ◽  
Percent Change ◽  
Stage Renal Disease ◽  
End Stage

Introduction: Chronic kidney disease (CKD) progression assessed by estimated GFR from creatinine (eGFR-Cr) is a risk factor for cardiovascular disease and end-stage renal disease (ESRD) and has been proposed as a surrogate endpoint for clinical trials. It is unclear if CKD progression assessed by change in different filtration markers has similar risk associations with ESRD. Hypothesis: We hypothesized that percent change in novel kidney filtration markers (β 2 -microglobulin and cystatin C) over a 6-year period would be independently associated with increased risk of ESRD during 15 years of follow-up, similar to the risk seen with change in eGFR-Cr. Methods: We conducted prospective analyses of the ARIC study (N=9,703). β 2 -microglobulin, cystatin C, and creatinine were measured at study visits 1 (1990-92) and 2 (1996-98). Incident ESRD (kidney dialysis or transplant) was defined as entry into the U.S. Renal Data System registry between study visit 2 and September 30, 2011. Cox proportional hazards regression was used to estimate the association between percent change in filtration marker and incident ESRD, adjusting for demographics, kidney disease risk factors, and 1 st measurement of the filtration marker. Results: During a median follow-up of 13.1 years, there were 142 incident ESRD cases. Median eGFR-Cr was 97.3 mL/min/1.73 m 2 at 1 st measurement and 89.0 mL/min/1.73 m 2 at 2 nd measurement. Percent change in eGFR-Cr was moderately correlated with percent change in the inverse of β 2 -microglobulin (r = 0.34) and the inverse of cystatin C (r = 0.36). Progression of CKD (10-25% and >25% decline in filtration function) was associated with increased ESRD risk, with novel markers (β 2 -microglobulin, cystatin C) showing an association at least as strong as the creatinine and eGFR-Cr estimates (Table). Conclusions: CKD progression assessed using novel filtration markers is independently associated with ESRD risk, suggesting the potential utility of measuring change in β 2 -microglobulin and cystatin C in clinical trials.

scholarly journals The Key Role of Epithelial to Mesenchymal Transition (EMT) in Hypertensive Kidney Disease

2019 ◽  
Vol 20 (14) ◽  
pp. 3567 ◽  
Author(s):  
Teresa Seccia ◽  
Brasilina Caroccia ◽  
Maria Piazza ◽  
Gian Paolo Rossi
Keyword(s):  
Kidney Disease ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Renal Diseases ◽  
Hypertensive Nephropathy ◽  
Mesenchymal Transition ◽  
Afferent Arterioles ◽  
Stage Renal Disease ◽  
End Stage

Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the ‘classic’ view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.

scholarly journals Capillary rarefaction is more closely associated with CKD progression after cisplatin, rhabdomyolysis, and ischemia-reperfusion-induced AKI than renal fibrosis

2019 ◽  
Vol 317 (5) ◽  
pp. F1383-F1397 ◽  
Author(s):  
Anna Menshikh ◽  
Lauren Scarfe ◽  
Rachel Delgado ◽  
Charlene Finney ◽  
Yuantee Zhu ◽  
...  
Keyword(s):  
Renal Function ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Capillary Density ◽  
Repeat Dose ◽  
Peritubular Capillary ◽  
Ckd Progression ◽  
Capillary Rarefaction

Acute kidney injury (AKI) is a strong independent predictor of mortality and often results in incomplete recovery of renal function, leading to progressive chronic kidney disease (CKD). Many clinical trials have been conducted on the basis of promising preclinical data, but no therapeutic interventions have been shown to improve long-term outcomes after AKI. This is partly due to the failure of preclinical studies to accurately model clinically relevant injury and long-term outcomes on CKD progression. Here, we evaluated the long-term effects of AKI on CKD progression in three animal models reflecting diverse etiologies of AKI: repeat-dose cisplatin, rhabdomyolysis, and ischemia-reperfusion injury. Using transdermal measurement of glomerular filtration rate as a clinically relevant measure of kidney function and quantification of peritubular capillary density to measure capillary rarefaction, we showed that repeat-dose cisplatin caused capillary rarefaction and decreased renal function in mice without a significant increase in interstitial fibrosis, whereas rhabdomyolysis-induced AKI led to severe interstitial fibrosis, but renal function and peritubular capillary density were preserved. Furthermore, long-term experiments in mice with unilateral ischemia-reperfusion injury showed that restoration of renal function 12 wk after a contralateral nephrectomy was associated with increasing fibrosis, but a reversal of capillary rarefaction was seen at 4 wk. These data demonstrate that clear dissociation between kidney function and fibrosis in these models of AKI to CKD progression and suggest that peritubular capillary rarefaction is more strongly associated with CKD progression than renal fibrosis.

Effect of intensive blood pressure on the progression of non-diabetic chronic kidney disease at varying degrees of proteinuria

2021 ◽  
pp. jim-2020-001702
Author(s):  
Paul J Der Mesropian ◽  
Gulvahid Shaikh ◽  
Kelly H Beers ◽  
Swati Mehta ◽  
Mauricio R Monrroy Prado ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Pooled Analysis ◽  
Ckd Progression ◽  
Glomerular Filtration Rate Decline ◽  
Multivariable Regression ◽  
Stage Renal Disease ◽  
End Stage

The ideal blood pressure (BP) target for renoprotection is uncertain in patients with non-diabetic chronic kidney disease (CKD), especially considering the influence exerted by pre-existing proteinuria. In this pooled analysis of landmark trials, we coalesced individual data from 5001 such subjects randomized to intensive versus standard BP targets. We employed multivariable regression to evaluate the relationship between follow-up systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CKD progression (defined as glomerular filtration rate decline by 50% or end-stage renal disease), focusing on the potential for effect modification by baseline proteinuria or albuminuria. The median follow-up was 3.2 years. We found that SBP rather than DBP was the primary predictor of renal outcomes. The optimal SBP target was 110–129 mm Hg. We observed a strong interaction between SBP and proteinuria such that lower SBP ranges were significantly linked with progressively lower CKD risk in grade A3 albuminuria or ≥0.5–1 g/day proteinuria (relative to SBP 110–119 mm Hg, the adjusted HR for SBP 120–129 mm Hg, 130–139 mm Hg, and 140–149 mm Hg was 1.5, 2.3, and 3.3, respectively; all p<0.05). In grade A2 microalbuminuria or proteinuria near 0.5 g/day, a non-significant but possible connection was seen between tighter BP and decreased CKD (aforementioned HRs all <2; all p>0.05), while in grade A1 albuminuria or proteinuria <0.2 g/day no significant association was apparent (HRs all <1.5; all p>0.1). We conclude that in non-diabetic CKD, stricter BP targets <130 mm Hg may help limit CKD progression as proteinuria rises.

scholarly journals Interleukin-22 mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury

2020 ◽  
Author(s):  
Wei Chen ◽  
Yilan Shen ◽  
Jiajun Fan ◽  
Xian Zeng ◽  
Xuyao Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Kidney Damage ◽  
Metabolic Reprogramming ◽  
Protective Effects ◽  
Interleukin 22 ◽  
Renal Tubular ◽  
Stage Renal Disease ◽  
End Stage

AbstractKidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end-stage renal disease (ESTD). Interleukin 22 (IL-22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here we first provide evidence that IL-22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL-22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL-22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL-22 are certificated in cisplatin induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL-22 on kidney and highlight the therapeutic opportunities of IL-22 and the involved metabolic regulators in various kidney diseases.

The effect of hypertension on renal vasculature and structure

2015 ◽  
Author(s):  
Ulrich Wenzel ◽  
Thorsten Wiech ◽  
Udo Helmchen
Keyword(s):  
Blood Pressure ◽  
Great Increase ◽  
Vascular Lesions ◽  
Blood Vessel Wall ◽  
Renal Vasculature ◽  
Experimental Conditions ◽  
Humoral Factors ◽  
Hypertensive Nephrosclerosis ◽  
Stage Renal Disease ◽  
End Stage

The concept of hypertensive nephrosclerosis was introduced by Volhard and Fahr in 1914 and has been extensively used in the literature since then, but its existence is controversial. While it is indisputable that malignant hypertension is a cause of end-stage renal disease (ESRD), there remains controversy as to whether the so-called benign nephrosclerosis can also lead to ESRD.Pressure, if it is great enough, will eventually disrupt any structure. Obviously, this is also true of blood pressure. It is therefore not surprising that an experimentally induced great increase in pressure disrupts the integrity of the blood-vessel wall. Such vascular lesions may be caused or at least influenced by several factors: humoral factors such as angiotensin II, catecholamines, mineralocorticoids, and vasopressin may increase vascular permeability, thereby damaging the vessel walls independently of, or superimposed upon, elevated blood pressure.Nephrosclerosis (literally, hardening of the kidney, Greek derivation: nephros, kidney; sclerosis, hardening) refers to diseases with predominant pathological changes occurring in the pre-glomerular vasculature and secondary changes involving the glomeruli and interstitium. Therefore, it is appropriate to describe first those vascular lesions, which, at least under defined experimental conditions, are believed to be caused solely by the presence of hypertension.

scholarly journals Transcription and translation of APOL1 variants

2017 ◽  
Vol 37 (5) ◽  
Author(s):  
Samina Ejaz
Keyword(s):  
Trypanosoma Brucei ◽  
Genetic Variants ◽  
End Stage Renal Disease ◽  
Molecular Mechanisms ◽  
Genetic Mutations ◽  
Major Focus ◽  
Molecular Alterations ◽  
Stage Renal Disease ◽  
End Stage

It is highly important to document the molecular alterations existing in normal cells prior to the onset of any disease. Knowledge of genetic mutations and associated molecular mechanisms will be helpful for better diagnosis and management of disease. The major focus of this commentary on providing understanding about the apolipoprotein 1 (APOL1) gene, the protein encoded by this gene (apoL1) and the mechanistic details regarding the role of apoL1 in the lysis of Trypanosoma brucei. Information about APOL1 genetic variants, APOL1G1 and APOL1G2, is provided along with the association of these variants with hypertension-attributed end-stage renal disease (ESRD) and focal segmental glomerulosclerosis (FSGS). Moreover, this commentary presents a brief overview of how the authors of a recent Bioscience Reports article [Haque et al (2017) 37, BSR20160531, doi: 10.1042/BSR20160531] have evaluated the functional impact of G1 and G2 alleles on the transcription and translation of APOL1 mRNA.

Pleiotropy of microRNA-192 in the kidney

2012 ◽  
Vol 40 (4) ◽  
pp. 762-767 ◽  
Author(s):  
Robert H. Jenkins ◽  
John Martin ◽  
Aled O. Phillips ◽  
Timothy Bowen ◽  
Donald J. Fraser
Keyword(s):  
End Stage Renal Disease ◽  
Molecular Mechanisms ◽  
Global Gene Expression ◽  
Transcriptional Level ◽  
Matrix Deposition ◽  
Fibrotic Process ◽  
E Box ◽  
Extracellular Matrix Deposition ◽  
Stage Renal Disease ◽  
End Stage

Diverse aetiologies result in significant deviation from homoeostasis in the kidney, leading to CKD (chronic kidney disease). CKD progresses to end-stage renal disease principally as a result of renal fibrosis, although the molecular mechanisms underlying this fibrotic process are still poorly understood. miRNAs (microRNAs) are a recently discovered family of endogenous short single-stranded RNAs that regulate global gene expression at the post-transcriptional level. The recent findings from our laboratory and others discussed in the present review outline pleiotropic roles for miR-192 in renal homoeostasis and in the fibrotic kidney. We describe miR-192-driven anti-and pro-fibrotic effects via the repression of ZEB1 and ZEB2 (zinc finger E-box-binding homeobox proteins 1 and 2), resulting in changes in extracellular matrix deposition and cell differentiation.

scholarly journals Special Issue “Diabetic Nephropathy: Diagnosis, Prevention and Treatment”

2020 ◽  
Vol 9 (3) ◽  
pp. 813 ◽  
Author(s):  
Marta Ruiz-Ortega ◽  
Raul R. Rodrigues-Diez ◽  
Carolina Lavoz ◽  
Sandra Rayego-Mateos
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Damage ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Clinical Medicine ◽  
Histopathological Changes ◽  
Special Issue ◽  
Genetic And Environmental Factors ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is the main cause of end-stage renal disease. DN is a complex disease mediated by genetic and environmental factors, and many cellular and molecular mechanisms are involved in renal damage in diabetes. There are no biomarkers that reflect the severity of the underlying renal histopathological changes and can effectively predict the progression of renal damage and stratify the risk of DN among individuals with diabetes mellitus. Current therapeutic strategies are based on the strict control of glucose and blood pressure levels and, although there are new anti-diabetic drugs, these treatments only retard renal damage progression, being necessary novel therapies. In this Special Issue, there are several comprehensive reviews and interesting original papers covering all these topics, which would be of interest to the growing number of readers of the Journal of Clinical Medicine.

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