Chronic Renal Changes After a Single Ischemic Event in an Experimental Model of Feline Chronic Kidney Disease

Previous work demonstrated renal fibrosis 70 days after a single unilateral in vivo renal ischemic event, but changes associated with a single episode of renal ischemia past this time are unknown. In this study, we evaluated renal function and structural changes 6 months after a 90-minute in vivo unilateral renal ischemic event. Six adult female cats underwent unilateral renal ischemia and renal function was followed for 6 months, at which time the kidneys were evaluated by histology and histomorphometry. Over time, there was a significant reduction in the glomerular filtration rate and an elevation of serum creatinine of 31% and 42%, respectively. All cats had tubulointerstitial lesions characterized by segmental interstitial inflammation, tubular atrophy, and interstitial fibrosis. Unlike short-term studies, ischemic kidneys had variable numbers of obsolescent glomeruli, consistent with the development of atubular glomeruli and subsequent ischemic glomerulosclerosis. Chronic changes associated with acute renal ischemia may include loss of function and glomerulosclerosis.

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The Benefit of Anti-Inflammatory and Renal-Protective Dietary Ingredients on the Biological Processes of Aging in the Kidney

Biology ◽

10.3390/biology7040045 ◽

2018 ◽

Vol 7 (4) ◽

pp. 45 ◽

Cited By ~ 2

Author(s):

Kiran Panickar ◽

Dennis Jewell

Keyword(s):

Oxidative Stress ◽

Renal Function ◽

Kidney Function ◽

Structural Changes ◽

Dietary Intervention ◽

Interstitial Fibrosis ◽

Tubular Atrophy ◽

Functional Changes ◽

General Decline ◽

Organ Systems

One of the significant organ systems which decline in aging is the kidney. While the causes of age-associated decline in renal function are likely multifactorial, oxidative stress and inflammation are hypothesized to play important roles in the structural and functional changes of the kidney. During aging there is a general decline in the glomerular filtration rate (GFR), a primary measurement used to assess kidney function. Inflammation and oxidative stress have been hypothesized to have a significant detrimental effect on renal function in aging and this may be attenuated by renal protective dietary ingredients. These dietary ingredients may affect renal function directly or through a microbiome-mediated secondary product. Likewise, structural changes including renal tubular atrophy, interstitial fibrosis, and glomerulosclerosis have all been described in aging. Such detrimental changes may benefit from dietary ingredients that may delay or attenuate the occurrence of such changes. This review will describe the physiology and pathophysiology of aging in renal function with an emphasis on dogs and cats that develop a decline in kidney function naturally. In addition, the varying biomarkers of health and renal dysfunction will be discussed. Finally, we will evaluate the aid in the management of this normal decline through dietary intervention in animal models.

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Renal circulatory occlusion and local cooling

Journal of Applied Physiology ◽

10.1152/jappl.1959.14.2.227 ◽

1959 ◽

Vol 14 (2) ◽

pp. 227-232 ◽

Cited By ~ 35

Author(s):

S. Birkeland ◽

A. Vogt ◽

J. Krog ◽

C. Semb

Keyword(s):

Renal Function ◽

Body Temperature ◽

Renal Artery ◽

Clinical Application ◽

Renal Ischemia ◽

Local Cooling ◽

Experimental Procedure ◽

Reversible Lesion ◽

Initial Depression

A method was developed for local kidney cooling in vivo, evaluated in dogs and applied clinically. In dogs a reversible lesion was not obtained if renal ischemia lasted beyond 1 hour at 37℃. Application of local cooling (10±5℃) extended the tolerance time to 7 hours, with clamping of the entire renal pedicle, and to 12 hours with occlusion of the renal artery alone. Exposure of the same kidney to a second occlusion period (up to 9 hr.) resulted in a reversible lesion. Renal function studies (CU, CIn, CPAH and TmPAH) showed the same pattern (initial depression and course of recovery) as after renal ischemia at body temperature. Initial depression was roughly paralleling the duration of clamping. Preischemic function values were, in most instances, reached 3 months following the experimental procedure. Physiological aspects of ‘local cooling’ are discussed and the advantages over general hypothermia are pointed out. The technique used for clinical application is described. Submitted on April 25, 1958

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Kidney aging.Geriatric view

Russian Journal of Geriatric Medicine ◽

10.37586/2686-8636-1-2021-76-81 ◽

2021 ◽

pp. 76-81

Author(s):

L. I. Merkusheva ◽

N. K. Runikhina ◽

O. N. Tkacheva

Keyword(s):

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Structural Changes ◽

Water Soluble ◽

Older Age ◽

Sodium Reabsorption ◽

Tubular Atrophy ◽

Age Related ◽

Population Demographic

Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging. Senescence or normal physiologic aging portrays the expected age-related changes in the kidney as compared to chronic kidney disease (CKD) in some individuals. The microanatomical structural changes of the kidney with older age include a decreased number of functional glomeruli from an increased prevalence of nephrosclerosis (arteriosclerosis, glomerulosclerosis, and tubular atrophy with interstitialﬁbrosis), and to some extent, compensatory hypertrophy of remaining nephrons. Among the macroanatomical structural changes, older age associates with smaller cortical volume. There is reason to be concerned that the elderly are being misdiagnosed with CKD. In addition to the structural changes in the kidney associated with aging, physiological changes in renal function are also found in older adults, such as decreased glomerular ﬁltration rate, vascular dysautonomia, altered tubular handling of creatinine, reduction in sodium reabsorption and potassium secretion, and diminished renal reserve. These alterations make aged individuals susceptible to the development of clinical conditions in response to usual stimuli that would otherwise be compensated for in younger individuals, including acute kidney injury, volume depletion and overload, disorders of serum sodium and potassium concentration, and toxic reactions to water -soluble drugs excreted by the kidneys. Additionally, the preservation with aging of a normal urinalysis, normal serum urea and creatinine values, erythropoietin synthesis, and normal phosphorus, calcium and magnesium tubular handling distinguishes decreased GFR due to normal aging from that due to chronic kidney disease.

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Gene of the month: GLIS1-3

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-206859 ◽

2020 ◽

Vol 73 (9) ◽

pp. 527-530

Author(s):

Karen Pinto ◽

Runjan Chetty

Keyword(s):

Autosomal Recessive ◽

Interstitial Fibrosis ◽

Neonatal Diabetes ◽

Diagnostic Value ◽

Cystic Kidney Disease ◽

Cystic Kidney ◽

Facial Dysmorphism ◽

Loss Of Function ◽

Tubular Atrophy ◽

Colon Cancers

The GLIS 1–3 genes belong to a family of transcription factors, the Krüppel-like zinc finger proteins. The GLIS proteins function primarily as activators of transcription (GLIS 1 and 3), while GLIS 2 functions as a repressor. Collectively, the GLIS proteins are involved in a variety of diseases in several organs ranging from Alzheimer’s disease, facial dysmorphism, neonatal diabetes mellitus, breast and colon cancers and leukaemia. In particular, loss-of-function mutations in GLIS2 are responsible for an autosomal recessive cystic kidney disease called nephronophthisis, which is characterised by tubular atrophy, interstitial fibrosis and corticomedullary cysts.Of diagnostic value in current practice are the presence of GLIS 3 and 1 fusions with PAX8 in almost 100% of hyalinising trabecular tumours of the thyroid gland. This enables its separation from papillary thyroid cancer.

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Microcirculation: nexus of comorbidities in diabetes

AJP Renal Physiology ◽

10.1152/ajprenal.00503.2006 ◽

2007 ◽

Vol 293 (2) ◽

pp. F486-F493 ◽

Cited By ~ 14

Author(s):

Constance Temm ◽

Jesus H. Dominguez

Keyword(s):

Metabolic Syndrome ◽

Large Scale ◽

Interstitial Fibrosis ◽

Peritubular Capillary ◽

Tubular Atrophy ◽

The Metabolic Syndrome ◽

Peritubular Capillaries ◽

Obese Rats ◽

Capillary Dysfunction

Generalized capillary dysfunction is a morbid element in the metabolic syndrome, and it is likely involved in its complications. We tested the hypothesis that vast amounts of serum albumin previously observed in kidneys of rats with the metabolic syndrome were caused, in part, by leakage from renal peritubular capillaries. We report herein large scale leaks of plasma fluid in peritubular capillaries of rats with the metabolic syndrome. This finding was directly demonstrated in vivo, and the presence of leftover albumin residue confirmed the leak in postmortem kidney specimens. Moreover, renal interstitial fibrosis and tubular atrophy were found in a distribution similar to the leaked renal albumin in obese rats. We suggest that there is an important link between peritubular capillary damage and interstitial fibrosis, represented as tubulointerstitial disease in the metabolic syndrome. We propose that maintenance of the peritubular microcirculation may improve renal outcomes in diabetes and the metabolic syndrome.

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Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis

Frontiers in Immunology ◽

10.3389/fimmu.2021.737708 ◽

2021 ◽

Vol 12 ◽

Author(s):

Samy Hakroush ◽

Désirée Tampe ◽

Philipp Ströbel ◽

Peter Korsten ◽

Björn Tampe

Keyword(s):

Mononuclear Cell ◽

Plasma Cells ◽

Immune Cell ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Tubular Atrophy ◽

Interstitial Inflammation ◽

Tubulointerstitial Lesions ◽

Mononuclear Cell Infiltrates ◽

Immune Cell Infiltrates

BackgroundAcute kidney injury (AKI) is a common and severe complication of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), potentially leading to chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response with intrarenal immune cell infiltration resulting in a pauci-immune necrotizing and crescentic glomerulonephritis (GN). However, a systematic analysis of intrarenal immune cell subtypes concerning neutrophils, eosinophils, plasma cells, and mononuclear cell infiltrates (macrophages, lymphocytes) in ANCA GN remains elusive. Therefore, we aimed to compare distinct immune cell infiltrates in association with clinicopathological findings in ANCA GN.MethodsA total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively analyzed. Histological infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the total area of inflammation.ResultsNeutrophilic infiltrates were associated with glomerular necrosis and severe kidney injury in ANCA GN. Among tubulointerstitial lesions, intrarenal neutrophils correlated with interstitial inflammation, tubulitis, and inflammation in areas of interstitial fibrosis/tubular atrophy (IFTA), representing active inflammatory lesions. Concerning eosinophils, infiltrates were associated with severe kidney injury, interstitial inflammation, and cellular casts independent of glomerular lesions, implicating a distinct role in inflammation and damage in ANCA GN. Plasma cell infiltrates correlated with tubulitis and interstitial fibrosis and were associated with renal replacement therapy during the short-term disease course. Finally, mononuclear cell infiltrates correlated with severe kidney injury and active histopathological lesions (glomerular crescents, interstitial inflammation, tubulitis, inflammation, and tubulitis in areas of IFTA) besides chronic lesions (interstitial fibrosis and tubular atrophy) in ANCA GN. Interestingly, intrarenal subtypes of immune cell infiltrates differed in MPO-ANCA versus PR3-ANCA GN and were associated with distinct glomerular and tubulointerstitial lesions, implicating different pathogenic mechanisms of kidney injury in ANCA subtypes.ConclusionOur observations imply distinct pathomechanisms contributing to inflammation and renal injury in MPO vs. PR3-associated ANCA GN and potentially contribute to new therapeutic targets in specific ANCA subtypes.

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Biomarkers of Chronic Renal Tubulointerstitial Injury

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155419861092 ◽

2019 ◽

Vol 67 (9) ◽

pp. 633-641 ◽

Cited By ~ 1

Author(s):

Serena M. Bagnasco ◽

Avi Z. Rosenberg

Keyword(s):

Interstitial Fibrosis ◽

Renal Tissue ◽

Experimental Models ◽

Renal Outcome ◽

Tubulointerstitial Injury ◽

Tubular Atrophy ◽

Non Invasive ◽

Diagnosis And Prognosis

Progression of renal parenchyma injury is characterized by increasing interstitial fibrosis and tubular atrophy, irrespective of the cause. Histopathologic assessment of renal tissue obtained by biopsy remains the gold standard for determining the presence and extent of tubulointerstitial scarring. Discovery of robust non-invasive means for capturing a snapshot and for longitudinal monitoring of parenchymal deterioration has been the focus of intense multimodal effort by investigators within the renal community and beyond. Research in this field has included the use of in vitro and in vivo experimental models and has fostered the development and evaluation of tissue and biofluid assays for novel analytes with potential translation to the diagnosis and prognosis of kidney disease. Here, we examine recent advances in the search of “biomarkers” for detection of renal tubulointerstitial scarring and prediction of renal outcome in human renal disease.

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Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

AJP Renal Physiology ◽

10.1152/ajprenal.00189.2014 ◽

2014 ◽

Vol 307 (4) ◽

pp. F471-F484 ◽

Cited By ~ 20

Author(s):

Florin L. Craciun ◽

Amrendra K. Ajay ◽

Dana Hoffmann ◽

Janani Saikumar ◽

Steven L. Fabian ◽

...

Keyword(s):

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Wild Type ◽

Tubular Atrophy ◽

Kidney Fibrosis ◽

Surface Receptors ◽

Fibrotic Disorders ◽

Vehicle Treated Control

Fibrinogen (Fg) has been implicated in the pathogenesis of several fibrotic disorders by acting as a profibrotic ligand for a variety of cellular surface receptors and by modulating the provisional fibrin matrix formed after injury. We demonstrated increased renal Fg expression after unilateral ureteral obstruction and folic acid (FA) nephropathy in mice, respectively. Urinary Fg excretion was also increased in FA nephropathy. Using in vitro and in vivo approaches, our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated (p)STAT3 binds to Fgα, Fgβ, and Fgγ promoters in the kidney to regulate their transcription. Genetically modified Fg heterozygous mice (∼75% of normal plasma Fg levels) exhibited only 3% kidney interstitial fibrosis and tubular atrophy after FA nephropathy compared with 24% for wild-type mice. Fibrinogenolysis through Ancrod administration after FA reduced interstitial fibrosis more than threefold compared with vehicle-treated control mice. Mechanistically, we show that Fg acts synergistically with transforming growth factor (TGF)-β1 to induce fibroblast proliferation and activates TGF-β1/pSMAD2 signaling. This study offers increased understanding of Fg expression and molecular interactions with TGF-β1 in the progression to kidney fibrosis and, importantly, indicates that fibrinogenolytics like Ancrod present a treatment opportunity for a yet intractable disease.

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A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion

AJP Renal Physiology ◽

10.1152/ajprenal.00185.2003 ◽

2004 ◽

Vol 286 (2) ◽

pp. F298-F306 ◽

Cited By ~ 104

Author(s):

H. Thomas Lee ◽

Hua Xu ◽

Samih H. Nasr ◽

Jurgen Schnermann ◽

Charles W. Emala

Keyword(s):

Renal Function ◽

Knockout Mice ◽

Adenosine Receptor ◽

Renal Injury ◽

Renal Ischemia ◽

Myeloperoxidase Activity ◽

Ischemia And Reperfusion ◽

Wild Type Littermate ◽

Renal Histology

Controversy exists regarding the effect of A1 adenosine receptor (AR) activation in the kidney during ischemia and reperfusion (I/R) injury. We sought to further characterize the role of A1 ARs in modulating renal function after I/R renal injury using both pharmacological and gene deletion approaches in mice. A1 AR knockout mice (A1KO) or their wild-type littermate controls (A1WT) were subjected to 30 min of renal ischemia. Some A1WT mice were subjected to 30 min of renal ischemia with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or 2-chrolo-cyclopentyladenosine (CCPA), selective A1 AR antagonist and agonist, respectively. Plasma creatinine and renal histology were compared 24 h after renal injury. A1KO mice exhibited significantly higher creatinines and worsened renal histology compared with A1WT controls following renal I/R injury. A1WT mice pretreated with the A1 AR antagonist or agonist demonstrated significantly worsened or improved renal function, respectively, after I/R injury. In addition, A1WT mice pretreated with DPCPX or CCPA showed significantly increased or reduced markers of renal inflammation, respectively (renal myeloperoxidase activity, renal tubular neutrophil infiltration, ICAM-1, TNF-α, and IL-1β mRNA expression), while demonstrating no differences in indicators of apoptosis. In conclusion, we demonstrate that endogenous or exogenous preischemic activation of A1 ARs protects against renal I/R injury in vivo via mechanisms leading to decreased necrosis and inflammation.

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Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy

BMC Nephrology ◽

10.1186/s12882-021-02510-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Miho Shimizu ◽

Kengo Furuichi ◽

Shinji Kitajima ◽

Tadashi Toyama ◽

Megumi Oshima ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Interstitial Fibrosis ◽

Long Term Outcomes ◽

Renal Interstitial Fibrosis ◽

Tubular Atrophy ◽

Tubulointerstitial Lesions ◽

The Impact

Abstract Background Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. Methods A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. Results At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. Conclusions Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

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