Abstract 161: Identification of Genetic Variants Associated with Kidney Injury That Leads to Increased Blood Pressure

Hypertension, diabetes and obesity, along with genetic predisposition, contribute to the growing number of chronic kidney disease patients. Our novel congenic model [S.SHR(11)] was developed through genetic modification of the Dahl salt-sensitive (S) rat, a model of hypertension related renal disease. The S.SHR(11) strain exhibits accelerated kidney injury compared to the already highly susceptible S rat. On either a low or high-salt diet, the S.SHR(11) model predominately exhibited more tubulointerstitial fibrosis compared to the S rat (17.1±1.29% vs. 12.9±1.22%). Increased α-SMA and macrophage infiltration was also observed. The S and S.SHR(11) had similar blood pressure (week 12), despite an early reduction in renal function in the S.SHR(11); however at an advanced age the S.SHR(11) demonstrated significantly higher blood pressure than the S (215±6.6 mm Hg vs. 183±5.9, respectively). This suggests that increased kidney injury is driving the development of hypertension later in life. Since these two animal models are identical with exception of chromosome 11, the causative genetic variants contributing to decreased renal function must reside within this region. The Dahl S and SHR genomes have been sequenced; this data provides a catalog of all the genetic variants between the two models. The 95% confidence interval of the genomic locus contains 28 non-synonymous SNP, with 15 of these SNP occurring within only three genes: Retnlg , Trat1 and Myh15. Two of these genes, Retnlg and Trat1, are known to play a role in immune response leading to our hypothesis that genetic variants in these genes alter protein function and lead to an increased immune response. Bone marrow transplant studies have been initiated to test our hypothesis and preliminary data shows that S rats who receive S.SHR(11) bone marrow have kidney function measurements similar to the S.SHR(11). The sequencing information has also lead to the development of nine new, more refined congenic strains. Through functional analysis of these new congenic animals, identification of the causative genetic variations will be expedited. In summary, we are employing a model of accelerated kidney disease to identify genes or genetic variants responsible for reduced kidney function and hypertension.

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Complications of Polycystic Kidney Disease and Relation With Disease Progression: An Observational Retrospective Study

10.21203/rs.3.rs-122413/v1 ◽

2020 ◽

Author(s):

Mònica Pérez-Mir ◽

Laura Carreras-Planella ◽

Francesc Borràs ◽

Josep Bonet ◽

Maribel Troya

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Retrospective Study ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Kidney Function ◽

High Blood Pressure ◽

Inherited Disease ◽

Polycystic Kidney ◽

Renal Complication

Abstract Background: Autosomal dominant polycystic kidney disease (ADPKD) is a renal inherited disease characterized by the growth of bilateral renal cysts that lead to deterioration in renal function and end-stage renal disease (ESRD). These patients frequently present complications like urinary tract infection, acute pyelonephritis, acute or chronic pain, renal lithiasis or high blood pressure (HBP). The aim of this study is to compare the renal evolution in ADPKD patients with renal complications and/or HBP compared to those without complications nor HBP.Methods: Observational retrospective study of 29 ADPKD patients with normal renal function and <70 years followed up in our center. Clinical and analytical information of 2010, 2015 and 2017 were determined.Results: 29 patients were enrolled with a median age of 41 years [34-54], eighteen women (62,1%) and eleven men. Median of estimation of glomerular function rate (eGFR) was 85.8ml/min [70.7-115.6] in 2010, 76.0 ml/min [57.0-99.9] in 2015 and 63.1ml/min [45.0-95.8] in 2017. Eight patients (27.6%) have never had kidney complication nor HBP. Nine patients (31.0%) have normal blood pressure, 6 others (20.7%) have well controlled high blood pressure (HBP) and 14 (48.3%) have badly controlled HBP. When patients were divided between those who have never presented a complication (C-) and those who present renal complication and/or HBP (C+), the first group presented better kidney function. When patients were segregated into those who have never presented complication or well-controlled HBP (CHBP-) and those with renal complication and/or badly-controlled HBP (CHBP+) no differences were found at the initial eGFR, but a faster worsening of kidney function in CHBP+ group.Conclusions: In ADPKD patients, the decrease in eGFR is significantly important in individuals showing complications (including HBP) compared to those who did not present complications. Individuals with complications and badly-controlled HBP show even greater differences in kidney function decrease compared with patients without complications or well controlled HBP.

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Abstract 517: The Use of Congenic Strains, Comparative Genome Hybridization, and Whole Genome Sequencing to Dissect the Genetic Basis of Chronic Kidney Disease in the Dahl S Rat

Hypertension ◽

10.1161/hyp.62.suppl_1.a517 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Ashley C Johnson ◽

Zibiao Guo ◽

Patrick B Kyle ◽

Michael R Garrett

Keyword(s):

Chronic Kidney Disease ◽

Genetic Variation ◽

Kidney Disease ◽

Kidney Function ◽

Spontaneously Hypertensive Rat ◽

Kidney Injury ◽

Comparative Genome Hybridization ◽

Genomic Locus ◽

Comparative Genome ◽

Congenic Strains

Chronic kidney disease is a major health issue, with hypertension playing a significant role in progression of kidney injury and decline in kidney function. Previously, genetic studies utilized the Dahl salt-sensitive (S) rat, a model of hypertensive related kidney disease and the spontaneously hypertensive rat (hypertensive, but resistant to kidney injury) to identify genomic regions associated with kidney injury. To confirm identified genomic intervals, congenic strains were developed for several chromosomes (RNO) by transfer of SHR genome to the genetic background of the S, including RNO2, 6, 8, 9, 10, 11, 13 and 19. Several of these congenic strains, with the exception of RNO6 and 19 have been extensively investigated. Here, we report that S.SHR(6) and (19) demonstrate significantly improved proteinuria (53±2.5 and 54±2.5 mg/24hr, respectively) compared to control S (116±7.2) and improved measures of kidney function (BUN= 24.3±0.6 and 24.6±0.6 vs. 28±1.3 mg/dl). To facilitate the identification of genetic variants that underlie each genomic region, especially on RNO6 and RNO19, comparative genome hybridization (CGH) was performed (NimbleGen and Agilent) to identify copy number variation (CNV) between the S and SHR. CNV was identified on RNO6 and RNO19 (as well as other chromosomes) which could be linked to the development of kidney injury. In addition, recent sequencing of the entire genomes of the S and SHR has identified essentially all genetic variation (SNP and INDEL) between the two inbred models. The 95% confidence interval of each causative locus spans ~10 Mb. The region on RNO6 contains 54 annotated genes (24 nonsynonymous SNP) and RNO19 contains 101 genes and/or miRNA (68 nonsynonymous SNP). The majority of SNP (>95%) are within intergenic or intronic regions, regardless of the genomic locus. A modest number of SNP (~5%) fall within the putative promoter region of genes which could impact gene expression. In summary, CGH and high quality genome sequence analysis will help guide upcoming congenic substrain analysis to expedite identification of the causative genetic variation(s) that underlie each genomic locus.

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Shroom3, a gene associated with chronic kidney disease, modulates epithelial recovery after acute kidney injury

Kidney360 ◽

10.34067/kid.0003802021 ◽

2021 ◽

pp. 10.34067/KID.0003802021

Author(s):

Aihua Li ◽

Joanna Cunanan ◽

Hadiseh Khalili ◽

Timothy Plageman ◽

Kjetil Ask ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Kidney Disease ◽

Kidney Function ◽

Genetic Variants ◽

Association Studies ◽

Kidney Injury ◽

Tubular Damage ◽

Genome Wide Association Studies ◽

Cellular Mechanisms

Background: Ischemia induced acute kidney injury (AKI) resulting in tubular damage can often progress to chronic kidney disease (CKD) and is a common cause of nephrology consultation. Following renal tubular epithelial damage, molecular and cellular mechanisms are activated to repair and regenerate the damaged epithelium. If these mechanisms are impaired, AKI can progress to CKD. Even in patients whose kidney function returns to normal baseline are more likely to develop CKD. Genome-wide association studies have provided robust evidence that genetic variants in SHROOM3, which encodes an actin-associated protein, are associated with CKD and poor outcomes in transplanted kidneys. Here, we sought to further understand the associations of Shroom3 in CKD. Methods: Kidney ischemia was induced in wild-type and Shroom3 heterozygous null mice (Shroom3Gt/+) and the mechanisms of cellular recovery and repair were examined. Results: A 28-minute bilateral ischemia in Shroom3Gt/+ mice resulted in 100% mortality within 24 hours. After 22-minute ischemic injury, Shroom3Gt/+ mice had a 16% increased mortality, worsened kidney function, and significantly worse histopathology, apoptosis, proliferation, inflammation, and fibrosis after injury. The cortical tubular damage in Shroom3Gt/+ was associated with disrupted epithelial redifferentiation, disrupted Rho-kinase/myosin signaling, and disorganized apical F-actin. Analysis of Madin Darby Canine Kidney Cells showed the levels of Shroom3 are directly correlated to apical organization of actin and actomyosin regulators. Conclusion: These findings establish that Shroom3 is required for epithelial repair and redifferentiation through the organization of actomyosin regulators and could explain why genetic variants in Shroom3 are associated with CKD and allograft rejection.

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FC 042IRF8 IN CDC1 IS PROTECTIVE IN POST-ISCHEMIC ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab119.002 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Li Na ◽

Stefanie Steiger ◽

Lingyan Fei ◽

Chenyu Li ◽

Chongxu Shi ◽

...

Keyword(s):

Bone Marrow ◽

Kidney Disease ◽

Kidney Function ◽

Ischemia Reperfusion ◽

Expression Patterns ◽

Kidney Injury ◽

Mononuclear Phagocytes ◽

Moderate Increase ◽

Acute Kidney Disease

Abstract Background and Aims Post-ischemic acute tubular necrosis is a common cause of acute kidney disease (AKD) and subsequent chronic kidney disease. In AKD, mononuclear phagocytes (MPCs) including conventional dendritic cells (cDCs) are present during the different phases of kidney injury, repair and regeneration. The contribution of cDCs to AKD is still poorly understood. Hence, we hypothesized that transcription factor interferon regulatory factor 8 (IRF8)-specific cDCs regulate the immune response in AKD. Method AKD was induced by unilateral ischemia reperfusion injury in IRF8-deficient Clec9a-specific DCs (IRF8fl/fl Clec9acre/cre or cre/wt) and wild type C57BL/6 mice. Immune phenotyping of leukocytes in kidney and spleen and mRNA expression profiling were performed, as well as kidney function evaluated. For in vitro studies, IRF8 small interfering RNA transfection technology on bone marrow-derived DCs was used. Results In the healthy kidney and lymphoid organ (e.g., spleen and kidney draining lymph node), we identified four MPC subsets according to the diverse expression patterns of CD11b and CD11c. Of which, IRF8 was specifically expressed in the CD11blow CD11chigh R4 subset (containing mainly cDC1). During AKD, IRF8 deficiency in cDCs reduced the number of MHCII+ DCs accumulating among tubulointerstium space without affecting cDC2 or CD64+ DCs, while completely abolished cDC1 in post-ischemic kidney (See Figure). This was accompanied with a decrease in the surface expression of chemokine receptor CCR7 and CCR9, reduction in the number of kidney CD4- CD8+ T cells and Tregs, but a moderate increase in TH1-related and pro-inflammatory cytokines and infiltrating neutrophils in the kidney of mice with IRF8-deficient cDCs. This was in line with reduced kidney function, marked by aggravated GFR loss, elevated plasma BUN level, kidney atrophy, pathological tubular injury and living proximal tubule loss. In vitro, bone marrow-derived IRF8-deficient DCs showed an impaired ability to repair “artificially injured” tubular epithelial cells (TECs), accompanied with less phagocytosis capacity and maturation capacity under necrotic TECs soup or histone stimulation. Conclusion Our data show that the restricted depletion of IRF8 in cDCs reduces the number of infiltrating kidney cDC1, which drives tissue inflammation and damage, and ultimately aggravates post-ischemic AKD. Thus, cDC1s are having a protective role in AKD.

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Increased susceptibility to kidney injury by transfer of genomic segment from SHR onto Dahl S genetic background

Physiological Genomics ◽

10.1152/physiolgenomics.00015.2012 ◽

2012 ◽

Vol 44 (12) ◽

pp. 629-637 ◽

Cited By ~ 11

Author(s):

Kevin R. Regner ◽

Ashlyn C. Harmon ◽

Jan M. Williams ◽

Cary Stelloh ◽

Ashley C. Johnson ◽

...

Keyword(s):

Blood Pressure ◽

Kidney Function ◽

Immune Cell ◽

Spontaneously Hypertensive Rat ◽

Kidney Injury ◽

Significant Decline ◽

High Salt ◽

Genomic Segment ◽

Chromosome 11 ◽

Low Salt

The Dahl salt-sensitive (S) rat is a widely studied model of salt-sensitive hypertension and develops proteinuria, glomerulosclerosis, and renal interstitial fibrosis. An earlier genetic analysis using a population derived from the S and spontaneously hypertensive rat (SHR) identified eight genomic regions linked to renal injury in the S rat and one protective locus on chromosome 11. The “protective” locus in the S rat was replaced with the SHR genomic segment conferring “susceptibility” to kidney injury. The progression of kidney injury in the S.SHR( 11 ) congenic strain was characterized in the present study. Groups of S and S.SHR( 11 ) rats were followed for 12 wk on either a low-salt (0.3% NaCl) or high-salt (2% NaCl) diet. By week 12 (low-salt), S.SHR( 11 ) demonstrated a significant decline in kidney function compared with the S. Blood pressure was significantly elevated in both strains on high salt. Despite similar blood pressure, the S.SHR( 11 ) exhibited a more significant decline in kidney function compared with the S. The decline in S.SHR( 11 ) kidney function was associated with more severe kidney injury including tubular loss, immune cell infiltration, and tubulointerstitial fibrosis compared with the S. Most prominently, the S.SHR( 11 ) exhibited a high degree of medullary fibrosis and a significant increase in renal vascular medial hypertrophy. In summary, genetic modification of the S rat generated a model of accelerated renal disease that may provide a better system to study progression to renal failure as well as lead to the identification of genetic variants involved in kidney injury.

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Systemic delivery of human bone-marrow derived extracellular vesicles ameliorates kidney injury and inflammation in an accelerated diabetic kidney disease mouse model

Cytotherapy ◽

10.1016/s1465324921004448 ◽

2021 ◽

Vol 23 (5) ◽

pp. S109

Author(s):

S.M. Conley ◽

X. Bian ◽

C. C. Gowan ◽

Z.K. Snow ◽

A.L. Smith ◽

...

Keyword(s):

Bone Marrow ◽

Kidney Disease ◽

Mouse Model ◽

Extracellular Vesicles ◽

Diabetic Kidney Disease ◽

Kidney Injury ◽

Human Bone ◽

Human Bone Marrow ◽

Systemic Delivery ◽

Diabetic Kidney

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Assessment of Kidney Function After Transcatheter Aortic Valve Replacement

Canadian Journal of Kidney Health and Disease ◽

10.1177/20543581211018029 ◽

2021 ◽

Vol 8 ◽

pp. 205435812110180

Author(s):

Orit Kliuk-Ben Bassat ◽

Sapir Sadon ◽

Svetlana Sirota ◽

Arie Steinvil ◽

Maayan Konigstein ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Kidney Function ◽

Transcatheter Aortic Valve Replacement ◽

Kidney Injury ◽

Single Center ◽

Transcatheter Aortic Valve ◽

Single Center Study ◽

Center Study

Background: Transcatheter aortic valve replacement (TAVR), although associated with an increased risk for acute kidney injury (AKI), may also result in improvement in renal function. Objective: The aim of this study is to evaluate the magnitude of kidney function improvement (KFI) after TAVR and to assess its significance on long-term mortality. Design: This is a prospective single center study. Setting: The study was conducted in cardiology department, interventional unit, in a tertiary hospital. Patients: The cohort included 1321 patients who underwent TAVR. Measurements: Serum creatinine level was measured at baseline, before the procedure, and over the next 7 days or until discharge. Methods: Kidney function improvement was defined as the mirror image of AKI, a reduction in pre-procedural to post-procedural minimal creatinine of more than 0.3 mg/dL, or a ratio of post-procedural minimal creatinine to pre-procedural creatinine of less than 0.66, up to 7 days after the procedure. Patients were categorized and compared for clinical endpoints according to post-procedural renal function change into 3 groups: KFI, AKI, or preserved kidney function (PKF). The primary endpoint was long-term all-cause mortality. Results: The incidence of KFI was 5%. In 55 out of 66 patients patients, the improvement in kidney function was minor and of unclear clinical significance. Acute kidney injury occurred in 19.1%. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 was a predictor of KFI after multivariable analysis (odds ratio = 0.93 to develop KFI; confidence interval [95% CI]: 0.91-0.95, P < .001). Patients in the KFI group had a higher Society of Thoracic Surgery (STS) score than other groups. Mortality rate did not differ between KFI group and PKF group (43.9% in KFI group and 33.8% in PKF group) but was significantly higher in the AKI group (60.7%, P < .001). Limitations: The following are the limitations: heterozygous definitions of KFI within different studies and a single center study. Although data were collected prospectively, analysis plan was defined after data collection. Conclusions: Improvement in kidney function following TAVR was not a common phenomenon in our cohort and did not reduce overall mortality rate.

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Histomorphometry of Feline Chronic Kidney Disease and Correlation With Markers of Renal Dysfunction

Veterinary Pathology ◽

10.1177/0300985812453176 ◽

2012 ◽

Vol 50 (1) ◽

pp. 147-155 ◽

Cited By ~ 79

Author(s):

S. Chakrabarti ◽

H. M. Syme ◽

C. A. Brown ◽

J. Elliott

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Image Analysis ◽

Renal Function ◽

Kidney Disease ◽

Renal Dysfunction ◽

Interstitial Fibrosis ◽

Glomerular Hypertrophy ◽

Renal Lesions ◽

Postmortem Examinations

Chronic kidney disease is common in geriatric cats, but most cases have nonspecific renal lesions, and few studies have correlated these lesions with clinicopathological markers of renal dysfunction. The aim of this study was to identify the lesions best correlated with renal function and likely mediators of disease progression in cats with chronic kidney disease. Cats were recruited through 2 first-opinion practices between 1992 and 2010. When postmortem examinations were authorized, renal tissues were preserved in formalin. Sections were evaluated by a pathologist masked to all clinicopathological data. They were scored semiquantitatively for the severity of glomerulosclerosis, interstitial inflammation, and fibrosis. Glomerular volume was measured using image analysis; the percentage of glomeruli that were obsolescent was recorded. Sections were assessed for hyperplastic arteriolosclerosis and tubular mineralization. Kidneys from 80 cats with plasma biochemical data from the last 2 months of life were included in the study. Multivariable linear regression ( P < .05) was used to assess the association of lesions with clinicopathological data obtained close to death. Interstitial fibrosis was the lesion best correlated with the severity of azotemia, hyperphosphatemia, and anemia. Proteinuria was associated with interstitial fibrosis and glomerular hypertrophy, whereas higher time-averaged systolic blood pressure was associated with glomerulosclerosis and hyperplastic arteriolosclerosis.

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Spontaneous one-kidney rats are more susceptible to develop hypertension by DOCA-NaCl and subsequent kidney injury compared with uninephrectomized rats

AJP Renal Physiology ◽

10.1152/ajprenal.00555.2015 ◽

2016 ◽

Vol 310 (10) ◽

pp. F1054-F1064 ◽

Cited By ~ 9

Author(s):

Xuexiang Wang ◽

Ashley C. Johnson ◽

Jennifer M. Sasser ◽

Jan M. Williams ◽

Leah C. Solberg Woods ◽

...

Keyword(s):

Blood Pressure ◽

Kidney Function ◽

Time Course ◽

Kidney Injury ◽

Solitary Kidney ◽

Course Evaluation ◽

Significant Rise ◽

Kidney Weight ◽

Unilateral Renal Agenesis ◽

Single Kidney

There is little clinical data of how hypertension may influence individuals with nephron deficiency in the context of being born with a single kidney. We recently developed a new rat model (the heterogeneous stock-derived model of unilateral renal agenesis rat) that is born with a single kidney and exhibits progressive kidney injury and decline in kidney function with age. We hypothesized that DOCA-salt would induce a greater increase in blood pressure and therefore accelerate the progression of kidney injury in rats born with a solitary kidney compared with rats that have undergone unilateral nephrectomy. Time course evaluation of blood pressure, kidney injury, and renal hemodynamics was performed in the following six groups of animals from weeks 13 to 18: 1) DOCA-treated rats with a solitary kidney (DOCA+S group), 2) placebo-treated rats with a solitary kidney, 3) DOCA-treated control rats with two kidneys (DOCA+C group), 4) placebo-treated control rats with two kidneys, 5) DOCA-treated rats with two kidneys that underwent uninephrectomy (DOCA+UNX8 group), and 6) placebo-treated rats with two kidneys that underwent uninephrectomy. DOCA+S rats demonstrated a significant rise ( P < 0.05) in blood pressure (192 ± 4 mmHg), proteinuria (205 ± 31 mg/24 h), and a decline in glomerular filtration rate (600 ± 42 μl·min−1·g kidney weight−1) relative to the DOCA+UNX8 (173 ± 3 mmHg, 76 ± 26 mg/24 h, and 963 ± 36 μl·min−1·g kidney weight−1) and DOCA+C (154 ± 2 mmHg, 7 ± 1 mg/24 h, and 1,484 ± 121 μl·min−1·g kidney weight−1) groups. Placebo-treated groups showed no significant change among the three groups. An assessment of renal injury markers via real-time PCR/Western blot analysis and histological analysis was concordant with the measured physiological parameters. In summary, congenital solitary kidney rats are highly susceptible to the induction of hypertension compared with uninephrectomized rats, suggesting that low nephron endowment is an important driver of elevated blood pressure, hastening nephron injury through the transmission of elevated systemic blood pressure and thereby accelerating decline in kidney function.

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