Effects of chronic volume expansion and enalapril on chronic cyclosporine nephropathy

1990 ◽  
Vol 258 (4) ◽  
pp. F934-F939
Author(s):  
D. M. Gillum ◽  
L. Truong
Keyword(s):  
Drinking Water ◽  
Interstitial Fibrosis ◽  
Renin Angiotensin System ◽  
Juxtaglomerular Apparatus ◽  
Prolonged Treatment ◽  
Renal Lesion ◽  
Tubular Atrophy ◽  
Renal Vasoconstriction ◽  
Volume Contraction ◽  
Tubulointerstitial Lesion

Prolonged treatment with cyclosporine (CS) results in an irreversible renal lesion consisting of interstitial fibrosis and tubular atrophy, as well as prominent hyperplasia of the juxtaglomerular apparatus (JGA). Ischemia to the tubulointerstitial compartment caused by intense CS-mediated renal vasoconstriction may contribute significantly to the development of this lesion. To explore the potential role of volume contraction and activation of the renin-angiotensin system (RAS) in the genesis of this lesion, we have employed a recently described rodent model of chronic cyclosporine nephropathy (CCN). Over 28 days of CS therapy, animals received plain drinking water, 1% saline, or enalapril (ENAL), 50 mg/l in drinking water. At the end of 28 days, Na+ balance in saline-treated animals was markedly positive, and plasma volume was increased; however, glomerular filtration rate (GFR) did not change, and the tubulointerstitial lesion and JGA hyperplasia as evaluated by morphometric techniques were unaffected. Enalapril-treated animals were relatively hypotensive with lower GFR than CS controls. Enalapril conferred no protection against the development of tubulointerstitial disease and exacerbated the development of JGA hyperplasia and hyperkalemia. We conclude that volume contraction is not an important contributor to the reduced GFR, tubulointerstitial lesion, or JGA hyperplasia associated with long-term CS treatment. Blockade of the RAS also conferred no protection against the development of tubulointerstitial disease but resulted in worsening of JGA hyperplasia and hyperkalemia.

scholarly journals Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252758
Author(s):  
Nicholas A. Maksimowski ◽  
James W. Scholey ◽  
Vanessa R. Williams ◽  
Keyword(s):  
Kidney Disease ◽  
Focal Segmental Glomerulosclerosis ◽  
Current Knowledge ◽  
Interstitial Fibrosis ◽  
Linear Regression Analysis ◽  
Renin Angiotensin System ◽  
Multiple Linear Regression Analysis ◽  
Tubular Atrophy ◽  
Kidney Fibrosis ◽  
Segmental Glomerulosclerosis

Background Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge. Methods We studied renal tubulointerstitial microarray data and clinical variables from subjects with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) study. We compared relationships between ACE2 expression and age, estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), interstitial fibrosis, tubular atrophy, and genes implicated in inflammation and fibrosis in male and female subjects. Results ACE2 mRNA expression was lower in the tubulointerstitium of males compared to females (P = 0.0026). Multiple linear regression analysis showed that ACE2 expression was related to sex and eGFR but not to age or treatment with renin angiotensin system blockade. ACE2 expression is also related to interstitial fibrosis, and tubular atrophy, in males but not in females. Genes involved in inflammation (CCL2 and TNF) correlated with ACE2 expression in males (TNF: r = -0.65, P < 0.0001; CCL2: r = -0.60, P < 0.0001) but not in females. TGFB1, a gene implicated in fibrosis correlated with ACE2 in both sexes. Conclusions Sex is an important determinant of ACE2 expression in the tubulointerstitium of the kidney in FSGS. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.

Immunoglobulin A-nephropathy in Russian population: clinical and morphological presentation and long-term prognosis

2019 ◽  
Vol 23 (6) ◽  
pp. 45-60
Author(s):  
V. A. Dobronravov ◽  
T. O. Muzhetskaya ◽  
D. I. Lin ◽  
Z. Sh. Kochoyan
Keyword(s):  
Iga Nephropathy ◽  
Cox Regression ◽  
Interstitial Fibrosis ◽  
Immunoglobulin A ◽  
Renin Angiotensin System ◽  
Composite Endpoint ◽  
Russian Population ◽  
Progression Rate ◽  
Tubular Atrophy ◽  
Lower Egfr

 AIM. The analysis of incidence, clinical and morphological manifestations, and the prognosis of IgA nephropathy in the Russian population.PATIENTS AND METHODS. Six hundred cases with primary IgA nephropathy (IgAN) from 1999 to 2019 were enrolled in the single-center retrospective study. Demographic and clinical parameters, morphrology data, and the treatment were analyzed. Three hundred forty seven patients were included in follow-up study. The following outcomes were evaluated: the occurrence of complete (PR) or partial remission (CR), death from all causes, the need for renal replacement therapy (RRT). The composite endpoint (RRT or eGFR decrease ≥ 50 % from the time of biopsy) was used to evaluate the risk of IgAN progression and associated factors.RESULTS. The period-average incidence of IgAN cases was 20.5 % of all indication biopsies and 31.7 % of primary immune glomerulopathies (with gradual increase to 41,5 % in last 5 years). At the time of the kidney biopsy, the proteinuria was 2.20 (1.10; 4.40) g/24h, eGFR – 69 ± 32 ml / min / 1.73 m2. Proportions of cases with arterial hypertension and with eGFR <60 ml / min / 1.73 m2 were 75 % and 36 %, respectively. The prevalence of histological changes in accordance with the MEST-C classification was as follows: M1 – 40.5 %, E1 -22.9 %, S1-70.2 %, T1-22 %, T2 – 9 %, C1-16.7 %, C2 – 4.4 %. Combined deposits of IgA and IgM (71.1 % of cases) were more frequent compared to IgA and IgG (9,6 %). In the followup period (27 (11; 61) month), 6 deaths from all causes were registered (1.7 %). The 10-year cumulative renal survival was 75 % (by dialysis) and 55 % (by composite endpoint). PR registered in 26 % of cases, CR – 24 %. PR / CR was more frequent in patients who received immunosuppression compared with patients on renin-angiotensin system blockers only (60 % vs. 40 %, p = 0.001). In multivariable Cox regression the independent factors associated with the risk of IgAN progression were: male gender, a younger age, higher blood pressure and hematuria, lower eGFR, interstitial fibrosis/ tubular atrophy (≥50 %), peritubular capillaritis and the presence of any crescents. Compared to the cohorts of other ethnic or geographical affiliation, analyzed IgAN cases were found to have more severe clinical and morphological presentations and faster progression rate.CONCLUSION. While being the most common glomerulopathy, IgAN in the Russian population has more pronounced clinical and morphological presentations and an unfavorable prognosis.

Regulation of angiotensin II AT1 and AT2 receptors in neonatal ureteral obstruction

1997 ◽  
Vol 273 (2) ◽  
pp. R503-R509 ◽  
Author(s):  
K. H. Yoo ◽  
V. F. Norwood ◽  
S. S. el-Dahr ◽  
I. Yosipiv ◽  
R. L. Chevalier
Keyword(s):  
Angiotensin Ii ◽  
Receptor Binding ◽  
Ureteral Obstruction ◽  
Interstitial Fibrosis ◽  
Renin Angiotensin System ◽  
Sham Operation ◽  
At2 Receptor ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Renal Vasoconstriction

Chronic unilateral ureteral obstruction (UUO) in early development activates the intrarenal renin-angiotensin system and leads to profound renal vasoconstriction, renal growth arrest, and interstitial fibrosis. To investigate the response of the AT1 and AT2 subtypes of the angiotensin II (ANG II) receptors to UUO, Sprague-Dawley rats underwent UUO or control sham operation in the first 48 h of life and were studied 1-28 days later. Renal mRNA for renin, AT1 and AT2 receptor, and receptor binding and distribution were determined. In contrast to controls, renin mRNA increased from 14 to 28 days in the obstructed kidney. After ipsilateral UUO, AT1 mRNA was suppressed at 1 day, but had increased compared with controls at 28 days. AT2 receptor mRNA fell rapidly in all kidneys from 1 to 3 days of age, after which it remained undetectable. Compared with the intact opposite kidney, AT2 mRNA was suppressed in the obstructed kidney 1 day after UUO. Compared with controls, AT1 and AT2 receptor binding was decreased by ipsilateral UUO at 1 day, whereas AT1 binding was increased at 28 days. Renal ANG II content was increased in the obstructed compared with the intact opposite kidney 28 days after UUO. In view of the increase in renal renin and angiotensin II production resulting from UUO, increased renal AT1 mRNA and receptor binding are likely to contribute to the vasoconstriction and interstitial fibrosis of the neonatal kidney after prolonged UUO.

Identifying patients with CKD risk at the time of nephrectomy: When to initiate nephrology consult

2021 ◽  
pp. 239936932110319
Author(s):  
Yihe Yang ◽  
Zachary Kozel ◽  
Purva Sharma ◽  
Oksana Yaskiv ◽  
Jose Torres ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Radical Nephrectomy ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Interstitial Fibrosis ◽  
Kidney Neoplasm ◽  
Tubular Atrophy ◽  
Independent Risk Factors

Introduction: The prevalence of chronic kidney disease (CKD) is high among kidney neoplasm patients because of the overlapping risk factors. Our purpose is to identify kidney cancer survivors with higher CKD risk. Methods: We studied a retrospective cohort of 361 kidney tumor patients with partial or radical nephrectomy. Linear mixed model was performed. Results: Of patients with follow-up >3 months, 84% were identified retrospectively to fulfill criteria for CKD diagnosis, although CKD was documented in only 15%. Urinalysis was performed in 205 (57%) patients at the time of nephrectomy. Multivariate analysis showed interstitial fibrosis and tubular atrophy (IFTA) >25% ( p = 0.005), severe arteriolar sclerosis ( p = 0.013), female gender ( p = 0.024), older age ( p = 0.012), BMI ⩾ 25 kg/m2 ( p < 0.001), documented CKD ( p < 0.001), baseline eGFR ⩽ 60 ml/min/1.73 m2 ( p < 0.001), and radical nephrectomy ( p < 0.001) were independent risk factors of lower eGFR at baseline and during follow-up. Average eGFR decreased within 3 months post nephrectomy. However, patients with different risk levels showed different eGFR time trend pattern at longer follow-ups. Multivariate analysis of time × risk factor interaction showed BMI, radical nephrectomy and baseline eGFR had time-dependent impact. BMI ⩾ 25 kg/m2 and radical nephrectomy were associated with steeper eGFR decrease slope. In baseline eGFR > 90 ml/min/1.73 m2 group, eGFR rebounded to pre-nephrectomy levels during extended follow-up. In partial nephrectomy patients with baseline eGFR ⩾ 90 ml/min/1.73 m2 ( n = 61), proteinuria ( p < 0.001) and BMI ( p < 0.001) were independent risk factors of decreased eGFR during follow up. Conclusions: As have been suggested by others and confirmed by our study, proteinuria and CKD are greatly under-recognized. Although self-evident as a minimum workup for nephrectomy patients to include SCr, eGFR, urinalysis, and proteinuria, the need for uniform applications of this practice should be reinforced. Non-neoplastic histology evaluation is valuable and should include an estimate of global sclerosis% (GS) and IFTA%. Patients with any proteinuria and/or eGFR ⩽ 60 at the time of nephrectomy or in follow-up with urologists, and/or >25% GS or IFTA, should be referred for early nephrology consultation.

scholarly journals Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

2013 ◽  
Vol 304 (7) ◽  
pp. C591-C603 ◽  
Author(s):  
Gabriela Campanholle ◽  
Giovanni Ligresti ◽  
Sina A. Gharib ◽  
Jeremy S. Duffield
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Innate Immune ◽  
Cellular Mechanisms ◽  
Tubular Atrophy ◽  
Kidney Fibrosis ◽  
Capillary Rarefaction ◽  
Peritubular Capillaries

Chronic kidney disease, defined as loss of kidney function for more than three months, is characterized pathologically by glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary rarefaction, and inflammation. Recent studies have identified a previously poorly appreciated, yet extensive population of mesenchymal cells, called either pericytes when attached to peritubular capillaries or resident fibroblasts when embedded in matrix, as the progenitors of scar-forming cells known as myofibroblasts. In response to sustained kidney injury, pericytes detach from the vasculature and differentiate into myofibroblasts, a process not only causing fibrosis, but also directly contributing to capillary rarefaction and inflammation. The interrelationship of these three detrimental processes makes myofibroblasts and their pericyte progenitors an attractive target in chronic kidney disease. In this review, we describe current understanding of the mechanisms of pericyte-to-myofibroblast differentiation during chronic kidney disease, draw parallels with disease processes in the glomerulus, and highlight promising new therapeutic strategies that target pericytes or myofibroblasts. In addition, we describe the critical paracrine roles of epithelial, endothelial, and innate immune cells in the fibrogenic process.

Early Urinary CCL2 is Associated With the Later Development of Interstitial Fibrosis and Tubular Atrophy in Renal Allografts

2010 ◽  
Vol 90 (4) ◽  
pp. 394-400 ◽  
Author(s):  
Julie Ho ◽  
David N. Rush ◽  
Ian W. Gibson ◽  
Martin Karpinski ◽  
Leroy Storsley ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Tubular Atrophy ◽  
Renal Allografts

scholarly journals Is mycophenolate mofetil combined with low-dose prednisone a treatment option for advanced IgA nephropathy? A 10-year follow-up case and brief literature review

2018 ◽  
Vol 16 ◽  
pp. 205873921880268
Author(s):  
Qijun Wan ◽  
Yongcheng He ◽  
Hongtao Chen ◽  
Hongping Liu ◽  
Saodong Luan ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Iga Nephropathy ◽  
Treatment Option ◽  
Low Dose ◽  
Interstitial Fibrosis ◽  
Immunosuppressive Treatment ◽  
Channel Blockers ◽  
Tubular Atrophy ◽  
Dose Prednisone

IgA nephropathy (IgAN) is now widely recognized as the most common primary glomerulonephritis worldwide, especially in China. The immunosuppressive treatment option for IgAN is still controversial. Previously, we proved that mycophenolate mofetil (MMF; Shanghai Roche, China) combined with low-dose prednisone was an effective and safe option for biopsy-proven mild to moderate IgAN patients in a short term of follow-up. This article we first reported the safety and efficacy of this regimen in a 42-year-old male biopsy-proven advanced 10-year follow-up IgAN case (Lee’s Class V; the patient was biopsied 10 years ago, so the Oxford Mesangial hypercellularity Endocapillary hypercellularity Segmental glomerulosclerosis Tubular atrophy/interstitial fibrosis (MEST) classification was not used). The mycophenolate and prednisone were only given for a limited time. The other main medications included calcium channel blockers and antiplatelet agents. Clinical and laboratory indexes were aperiodic assessed during the 10-year follow-up. The serum creatinine decreased from 356 to around 210 μmol/L and urine excretion protein reduced from 3.4 g/d to about 0.5 g/d after 6 months of the initiation of this regimen, respectively. These perfect treatment effects could maintain well during the whole follow-up period. No obvious complications were observed.

Prevention of experimental cyclosporin-induced interstitial fibrosis by losartan and enalapril

1995 ◽  
Vol 269 (4) ◽  
pp. F491-F499 ◽  
Author(s):  
E. A. Burdmann ◽  
T. F. Andoh ◽  
C. C. Nast ◽  
A. Evan ◽  
B. A. Connors ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Renal Scarring ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Tubular Dysfunction ◽  
Angiotensin System ◽  
Salt Diet ◽  
Renin Angiotensin ◽  
Dependent Model ◽  
Angiotensin Blockade

The pathogenesis of renal scarring in chronic cyclosporin nephropathy is unknown. In this study, we evaluated the effects of renin-angiotensin system blockade by enalapril and losartan in a salt-dependent model of cyclosporin-associated chronic tubulointerstitial fibrosis (TIF). Rats kept on normal or low-salt diet were given cyclosporin, cyclosporin+enalapril, cyclosporin+losartan, cyclosporin+enalapril#losartan, or vehicle for 14 and 28 days. Cyclosporin reduced glomerular filtration rate (GFR) in rats fed either diet, but only salt-depleted animals developed significant TIF. Cyclosporin also impaired renal concentrating ability and caused tubular enzymuria. Renin-angiotensin system blockade decreased blood pressure (BP) and promoted afferent arteriolar vasodilatation. Losartan reduced plasma renin activity and prevented cyclosporin-induced increment of cortical alpha 1(I) procollagen mRNA. Renin-angiotensin blockade did not improve GFR and tubular function; however, it strikingly prevented TIF development, even in presence of very low BP. Rats treated with cyclosporin, hydralazine, and furosemide achieved BP values similar to losartan or enalapril groups, but there was no protection against interstitial fibrosis development. These results suggest that cyclosporin-related chronic interstitial injury is mediated by angiotensin II and that the mechanisms promoting the interstitial scarring can be dissociated from glomerular and tubular dysfunction in cyclosporin nephropathy.

scholarly journals In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes

2021 ◽  
pp. ASN.2020081181 ◽  
Author(s):  
Aishwarya Ravindran ◽  
Marta Casal Moura ◽  
Fernando C. Fervenza ◽  
Samih H. Nasr ◽  
Mariam P. Alexander ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Kidney Biopsy ◽  
Interstitial Fibrosis ◽  
Study Cohort ◽  
Lower Serum ◽  
Tubular Atrophy ◽  
Novel Proteins ◽  
Biopsy Specimens ◽  
Membranous Lupus Nephritis

BackgroundIn patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis.MethodsWe conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared.ResultsOur study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger (P=0.01), had significantly lower serum creatinine levels (P=0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h (P=0.009), and had significantly less chronicity features (glomerulosclerosis, P=0.001 or interstitial fibrosis and tubular atrophy, P<0.001) on kidney biopsy. Clinical follow-up data were available for 160 patients, of which 64 (40%) biopsy results were EXT1/EXT2-positive and 96 (60%) were EXT1/EXT2-negative. The proportion of patients with class 3/4 lupus nephritis coexisting with membranous lupus nephritis was not different between the EXT1/EXT2-positive and EXT1/EXT2-negative groups (25.0% versus 32.3%; P=0.32). The patients who were EXT1/EXT2-negative evolved to ESKD faster and more frequently compared with EXT1/EXT2-positive patients (18.8% versus 3.1%; P=0.003).ConclusionsThe prevalence of EXT1/EXT2 positivity was 32.6% in our cohort of membranous lupus nephritis. Compared with EXT1/EXT2-negative membranous lupus nephritis, EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices. Cases of membranous lupus nephritis that are EXT1/EXT2-negative are more likely to progress to ESKD compared with those that are EXT1/EXT2-positive.

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