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Viggiano D. Mechanisms of Diabetic Nephropathy Not Mediated by Hyperglycemia. J Clin Med 2023; 12:6848. [PMID: 37959313 PMCID: PMC10650633 DOI: 10.3390/jcm12216848] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 11/15/2023] Open
Abstract
Diabetes mellitus (DM) is characterized by the appearance of progressive kidney damage, which may progress to end-stage kidney disease. The control of hyperglycemia is usually not sufficient to halt this progression. The kidney damage is quantitatively and qualitatively different in the two forms of diabetes; the typical nodular fibrosis (Kimmelstiel Wilson nodules) appears mostly in type 1 DM, whereas glomerulomegaly is primarily present in type 2 obese DM. An analysis of the different metabolites and hormones in type 1 and type 2 DM and their differential pharmacological treatments might be helpful to advance the hypotheses on the different histopathological patterns of the kidneys and their responses to sodium/glucose transporter type 2 inhibitors (SGLT2i).
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Affiliation(s)
- Davide Viggiano
- Department of Translational Medical Sciences, University of Campania, 80131 Naples, Italy
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2
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Esposito P, Picciotto D, Cappadona F, Costigliolo F, Russo E, Macciò L, Viazzi F. Multifaceted relationship between diabetes and kidney diseases: Beyond diabetes. World J Diabetes 2023; 14:1450-1462. [PMID: 37970131 PMCID: PMC10642421 DOI: 10.4239/wjd.v14.i10.1450] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 10/09/2023] Open
Abstract
Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure. The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments, such as the vascular system and glomeruli. Glomerular alterations include thickening of the glomerular basement membrane, loss of podocytes, and segmental mesangiolysis, which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules. Beyond lesions directly related to diabetes, awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing. These nondiabetic lesions include focal segmental glomerulosclerosis, IgA nephropathy, and other primary or secondary renal disorders. Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches. However, the relationship between diabetes and the kidney is bidirectional; thus, new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases. Here, we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course, differential diagnosis, and therapeutic oppor-tunities offered by novel drugs.
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Affiliation(s)
- Pasquale Esposito
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa 16132, Italy
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Daniela Picciotto
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Francesca Cappadona
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Francesca Costigliolo
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Elisa Russo
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa 16132, Italy
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Lucia Macciò
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa 16132, Italy
| | - Francesca Viazzi
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa 16132, Italy
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
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Salman L, Martinez L, Faddoul G, Manning C, Ali K, Salman M, Vazquez-Padron R. Hyaluronan Inhibition as a Therapeutic Target for Diabetic Kidney Disease: What Is Next? KIDNEY360 2023; 4:e851-e860. [PMID: 37055910 PMCID: PMC10371374 DOI: 10.34067/kid.0000000000000126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/17/2023] [Indexed: 04/15/2023]
Abstract
Diabetic kidney disease (DKD) is the leading cause of CKD and ESKD in the United States and worldwide. Pharmacotherapy and lifestyle modifications for glycemia, dyslipidemia, and BP control have shown success in slowing the progression of DKD. Traditional treatments, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and more recently the use of sodium-glucose cotransporter 2 inhibitors, nonsteroidal selective mineralocorticoid receptor antagonists, such as finerenone, and glucagon-like peptide 1 receptor agonists, have led to added benefits on various outcomes. However, significant residual risk for DKD progression remains despite the current standard-of-care approaches. Arteriolar hyalinosis (AH) is among the key findings seen on kidney biopsies of patients with DKD. It results from the excessive accumulation of hyaluronan (HA) in the arterioles. AH has not been targeted specifically by any of the therapeutic methods currently being used. We discuss in this manuscript the potential use of a selective therapy targeting AH and the increased total renal HA deposits using a HA synthesis inhibitor in DKD.
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Affiliation(s)
- Loay Salman
- Division of Nephrology and Hypertension, Department of Medicine, Albany Med Health System, Albany, New York
| | - Laisel Martinez
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
| | - Geovani Faddoul
- Division of Nephrology and Hypertension, Department of Medicine, Albany Med Health System, Albany, New York
| | - Christina Manning
- Division of Nephrology and Hypertension, Department of Medicine, Albany Med Health System, Albany, New York
| | - Karim Ali
- Division of Nephrology and Hypertension, Department of Medicine, Albany Med Health System, Albany, New York
| | - Maya Salman
- Faculty of Medicine, Damascus University, Damascus, Syria
| | - Roberto Vazquez-Padron
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
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Kemec Z, Akgul F. Are patients with Covid-19 at risk of long-term chronic kidney disease? Niger J Clin Pract 2023; 26:341-346. [PMID: 37056110 DOI: 10.4103/njcp.njcp_382_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2023]
Abstract
Background The relationship between Coronavirus Disease 2019 (COVID-19) and acute kidney injury (AKI) is well-established. However, a comprehensive evaluation of kidney outcomes in the long-term course of COVID-19 is not yet been performed. The aim of this study is to investigate whether chronic kidney disease (CKD) develops within six months after hospital discharge in COVID-19 patients who did not have kidney damage at the time of admission to the hospital. Patients and Methods This single-center retrospective study investigated a total of 1008 participants selected from 7500 COVID-19 patients with real-time reverse transcription-polymerase chain reaction (RT-PCR) positivity. All patients had mild/moderate or severe COVID-19. Patients were randomly selected from inpatient and outpatient settings. Critical COVID-19 patients were not included. Results The mean age of the patients was 56.57 ± 16.30 years, and 69.9% of them were male. The comorbidity percentages of the participants were as follows; 19.5% coronary artery disease (CAD), 28.6% diabetes mellitus (DM), 36.2% hypertension (HT), 3.1% cerebrovascular obstruction (CVO), 1.7% malignancy, 2.6% chronic obstructive pulmonary disease (COPD), 9.4% asthma, % 1.7 dementia, 9.9% hyperlipidaemia, and 1.7% hepatitis B virus (HBV). Kidney function tests of these patients at first admission and 6 months later were compared to reveal the relationship between COVID-19 and CKD. Serum glucose, sodium estimated glomerular filtration rate (eGFR), and uric acid levels were found to be high in the post-COVID-19 period (P = 0.001). However, there were a decrease in serum albumin, potassium, alanine aminotransferase (ALT), C-reactive protein (CRP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT) levels (P = 0.001). The difference between the first measurement of serum urea and creatinine (Cr) levels and the measurement 6 months later was not statistically significant (P = 0.102 and P = 0.300, respectively). Conclusions Those who survived the mild/moderate and severe clinical manifestations of COVID-19 did not exhibit any risk of kidney outcomes after the acute phase of the disease, suggesting that the kidney can protect itself over a long period of time.
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Affiliation(s)
- Z Kemec
- Batman Training and Research Hospital, Department of Nephrology Clinic, Batman, Turkey
| | - F Akgul
- Batman Training and Research Hospital, Department of Infectious Diseases and Clinical Microbiology, Batman, Batman, Turkey
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Adeva-Andany MM, Adeva-Contreras L, Fernández-Fernández C, Carneiro-Freire N, Domínguez-Montero A. Histological Manifestations of Diabetic Kidney Disease and its Relationship with Insulin Resistance. Curr Diabetes Rev 2023; 19:50-70. [PMID: 35346008 DOI: 10.2174/1573399818666220328145046] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/18/2022] [Accepted: 02/08/2022] [Indexed: 11/22/2022]
Abstract
Histological manifestations of diabetic kidney disease (DKD) include mesangiolysis, mesangial matrix expansion, mesangial cell proliferation, thickening of the glomerular basement membrane, podocyte loss, foot process effacement, and hyalinosis of the glomerular arterioles, interstitial fibrosis, and tubular atrophy. Glomerulomegaly is a typical finding. Histological features of DKD may occur in the absence of clinical manifestations, having been documented in patients with normal urinary albumin excretion and normal glomerular filtration rate. Furthermore, the histological picture progresses over time, while clinical data may remain normal. Conversely, histological lesions of DKD improve with metabolic normalization following effective pancreas transplantation. Insulin resistance has been associated with the clinical manifestations of DKD (nephromegaly, glomerular hyperfiltration, albuminuria, and kidney failure). Likewise, insulin resistance may underlie the histological manifestations of DKD. Morphological changes of DKD are absent in newly diagnosed type 1 diabetes patients (with no insulin resistance) but appear afterward when insulin resistance develops. In contrast, structural lesions of DKD are typically present before the clinical diagnosis of type 2 diabetes. Several heterogeneous conditions that share the occurrence of insulin resistance, such as aging, obesity, acromegaly, lipodystrophy, cystic fibrosis, insulin receptor dysfunction, and Alström syndrome, also share both clinical and structural manifestations of kidney disease, including glomerulomegaly and other features of DKD, focal segmental glomerulosclerosis, and C3 glomerulopathy, which might be ascribed to the reduction in the synthesis of factor H binding sites (such as heparan sulfate) that leads to uncontrolled complement activation. Alström syndrome patients show systemic interstitial fibrosis markedly similar to that present in diabetes.
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Affiliation(s)
- María M Adeva-Andany
- Internal Medicine Department, Nephrology Division, Hospital General Juan Cardona c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Lucía Adeva-Contreras
- University of Santiago de Compostela Medical School, Santiago de Compostela, Acoruna, Spain
| | - Carlos Fernández-Fernández
- Internal Medicine Department, Nephrology Division, Hospital General Juan Cardona c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Natalia Carneiro-Freire
- Internal Medicine Department, Nephrology Division, Hospital General Juan Cardona c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Alberto Domínguez-Montero
- Internal Medicine Department, Nephrology Division, Hospital General Juan Cardona c/ Pardo Bazán s/n, 15406 Ferrol, Spain
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Lopez LN, Wang W, Loomba L, Afkarian M, Butani L. Diabetic kidney disease in children and adolescents: an update. Pediatr Nephrol 2022; 37:2583-2597. [PMID: 34913986 PMCID: PMC9489564 DOI: 10.1007/s00467-021-05347-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 12/15/2022]
Abstract
Diabetic kidney disease (DKD), previously encountered predominantly in adult patients, is rapidly gaining center stage as a childhood morbidity and one that pediatric nephrologists are likely to encounter with increasing frequency. This is in large part due to the obesity epidemic and the consequent rise in type 2 diabetes in children and adolescents, as well as the more aggressive diabetes phenotype in today's youth with more rapid β-cell decline and faster development and progression of diabetes-related complications along with lower responsiveness to the treatments used in adults. DKD, an end-organ complication of diabetes, is at the very least a marker of, and more likely a predisposing factor for, the development of adverse cardiovascular outcomes and premature mortality in children with diabetes. On an optimistic note, several new therapeutic approaches are now available for the management of diabetes in adults, such as GLP1 receptor agonists, SGLT2 inhibitors, and DPP4 inhibitors, that have also been shown to have a favorable impact on cardiorenal outcomes. Also promising is the success of very low-energy diets in inducing remission of diabetes in adults. However, the addition of these pharmacological and dietary approaches to the management toolbox of diabetes and DKD in children and adolescents awaits thorough assessment of their safety and efficacy in this population. This review outlines the scope of diabetes and DKD, and new developments that may favorably impact the management of children and young adults with diabetes and DKD.
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Affiliation(s)
- Lauren N. Lopez
- Division of Nephrology, Department of Internal Medicine, University of California, Davis, Sacramento, CA USA
| | - Weijie Wang
- University of California, Berkeley, Berkeley, CA USA
| | - Lindsey Loomba
- Division of Pediatric Endocrinology, Department of Pediatrics, University of California, Davis, Sacramento, CA USA
| | - Maryam Afkarian
- Division of Nephrology, Department of Internal Medicine, University of California, Davis, Sacramento, CA USA
| | - Lavjay Butani
- Division of Pediatric Nephrology, Department of Pediatrics, University of California, Davis, 2516 Stockton Blvd, Room 348, Sacramento, CA, 95817, USA.
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Di Vincenzo A, Bettini S, Russo L, Mazzocut S, Mauer M, Fioretto P. Renal structure in type 2 diabetes: facts and misconceptions. J Nephrol 2020; 33:901-907. [PMID: 32656750 PMCID: PMC7557481 DOI: 10.1007/s40620-020-00797-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/02/2020] [Indexed: 01/09/2023]
Abstract
The clinical manifestations of diabetic nephropathy are similar in type 1 and type 2 diabetes, while the renal lesions may differ. Indeed, diabetic glomerulopathy is the predominant renal lesion in type 1 diabetes, although also tubular, interstitial and arteriolar lesions are present in the advanced stages of renal disease. In contrast, in type 2 diabetes renal lesions are heterogeneous, and a substantial number of type 2 diabetic patients with diabetic kidney disease have mild or absent glomerulopathy with tubulointerstitial and/or arteriolar abnormalities. In addition, a high prevalence of non-diabetic renal diseases, isolated or superimposed on classic diabetic nephropathy lesions have been reported in patients with type 2 diabetes, often reflecting the bias of selecting patients for unusual clinical presentations for renal biopsy. This review focuses on renal structural changes in type 2 diabetes, emphasizing the contribution of research kidney biopsy studies to the understanding of the pathogenesis of DKD and of the structural lesions responsible for the different clinical phenotypes. Also, kidney biopsies could provide relevant information in terms of renal prognosis, and help to understand the different responses to different therapies, especially SGLT2 inhibitors, thus allowing personalized medicine.
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Affiliation(s)
- Angelo Di Vincenzo
- Department of Medicine, Clinica Medica 3, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - Silvia Bettini
- Department of Medicine, Clinica Medica 3, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - Lucia Russo
- Department of Medicine, Clinica Medica 3, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - Sara Mazzocut
- Department of Medicine, Clinica Medica 3, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
| | - Michael Mauer
- Department of Pediatrics and Medicine, University of Minnesota School of Medicine, Minneapolis, MN, USA
| | - Paola Fioretto
- Department of Medicine, Clinica Medica 3, University of Padova, Via Giustiniani 2, 35128, Padova, Italy.
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Sample Preparation and Stereological Methods for the Study of Glomerular Ultrastructure Using Electron Microscopy. Methods Mol Biol 2019. [PMID: 31701447 DOI: 10.1007/978-1-4939-9841-8_7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2023]
Abstract
In this chapter we describe conventional methods used for preparing renal tissue for transmission electron microscopy. We also describe a relatively new technique, serial block face scanning electron microscopy. Protocols are given for processing, sectioning, and imaging of tissue along with methods for obtaining quantitative data from the results.
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9
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Yamanouchi M, Furuichi K, Hoshino J, Toyama T, Hara A, Shimizu M, Kinowaki K, Fujii T, Ohashi K, Yuzawa Y, Kitamura H, Suzuki Y, Sato H, Uesugi N, Hisano S, Ueda Y, Nishi S, Yokoyama H, Nishino T, Samejima K, Kohagura K, Shibagaki Y, Mise K, Makino H, Matsuo S, Ubara Y, Wada T. Nonproteinuric Versus Proteinuric Phenotypes in Diabetic Kidney Disease: A Propensity Score-Matched Analysis of a Nationwide, Biopsy-Based Cohort Study. Diabetes Care 2019; 42:891-902. [PMID: 30833372 DOI: 10.2337/dc18-1320] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 02/04/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Clinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce. RESEARCH DESIGN AND METHODS We retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), who underwent clinical renal biopsy and had follow-up data, from Japan's nationwide multicenter renal biopsy registry. For comparative analyses, we derived one-to-two cohorts of those without proteinuria versus those with proteinuria using propensity score-matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ≥50%, or doubling of serum creatinine. The secondary end point was all-cause mortality. RESULTS Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR] <300 mg/g) had lower systolic blood pressure and less severe pathological lesions compared with 164 propensity score-matched patients with proteinuria (UACR ≥300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9-5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5-93.8) for the nonproteinuric group and 30.3% (95% CI 22.4-38.6) for the proteinuric group (log-rank test P < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test P = 0.005). CONCLUSIONS Patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality.
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Affiliation(s)
- Masayuki Yamanouchi
- Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan .,Nephrology Center, Toranomon Hospital, Tokyo, Japan.,Nephrology Center, Toranomon Hospital Kajigaya, Kanagawa, Japan.,Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Kengo Furuichi
- Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan
| | - Junichi Hoshino
- Nephrology Center, Toranomon Hospital, Tokyo, Japan.,Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Tadashi Toyama
- Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan
| | - Akinori Hara
- Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan
| | - Miho Shimizu
- Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan
| | | | - Takeshi Fujii
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
| | - Kenichi Ohashi
- Department of Pathology, Toranomon Hospital, Tokyo, Japan.,Department of Pathology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Yukio Yuzawa
- Department of Nephrology, Fujita Health University School of Medicine, Aichi, Japan
| | - Hiroshi Kitamura
- Department of Pathology, Clinical Research Center, National Hospital Organization Chiba-East National Hospital, Chiba, Japan
| | - Yoshiki Suzuki
- Health Administration Center, Niigata University, Niigata, Japan
| | - Hiroshi Sato
- Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Miyagi, Japan
| | - Noriko Uesugi
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Satoshi Hisano
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Yoshihiko Ueda
- Department of Pathology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan
| | - Shinichi Nishi
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Hitoshi Yokoyama
- Department of Nephrology, Kanazawa Medical University School of Medicine, Ishikawa, Japan
| | - Tomoya Nishino
- Department of Nephrology, Nagasaki University Hospital, Nagasaki, Japan
| | | | - Kentaro Kohagura
- Department of Cardiovascular Medicine, Nephrology and Neurology, University of the Ryukyus School of Medicine, Okinawa, Japan
| | - Yugo Shibagaki
- Division of Nephrology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Koki Mise
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hirofumi Makino
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Seiichi Matsuo
- Division of Nephrology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshifumi Ubara
- Nephrology Center, Toranomon Hospital Kajigaya, Kanagawa, Japan.,Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan .,Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan
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Liljedahl L, Pedersen MH, McGuire JN, James P. The impact of the glucagon-like peptide 1 receptor agonist liraglutide on the streptozotocin-induced diabetic mouse kidney proteome. Physiol Rep 2019; 7:e13994. [PMID: 30806030 PMCID: PMC6389751 DOI: 10.14814/phy2.13994] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 01/02/2019] [Indexed: 11/24/2022] Open
Abstract
In diabetes mellitus (DM), the kidneys are exposed to increased levels of hyperglycemia-induced oxidative stress. Elevated amounts of reactive oxygen species (ROS) are believed to provoke ultrastructural changes in kidney tissue and can eventually result in DM late complications such as diabetic nephropathy. While it is reported that glucagon-like peptide 1 receptors (GLP-1R) are present in the kidney vasculature, the effects of GLP-1 on the kidney proteome in DM is not well described. Thus, we set out to investigate potential effects on the proteomic level. Here the effects of GLP-1R agonism using the GLP-1 analogue liraglutide are studied in the kidneys of streptozotocin (STZ)-treated mice (n = 6/group) by label-free shotgun mass spectrometry (MS) and targeted MS. Unsupervised and supervised multivariate analyses are followed by one-way ANOVA. Shotgun MS data of vehicle and liraglutide-treated mouse groups are separated in the supervised multivariate analysis and separation is also achieved in the subsequent unsupervised multivariate analysis using targeted MS data. The mouse group receiving the GLP-1R agonist liraglutide has increased protein abundances of glutathione peroxidase-3 (GPX3) and catalase (CATA) while the abundances of neuroplastin (NPTN) and bifunctional glutamate/proline-tRNA ligase (SYEP) are decreased compared to the STZ vehicle mice. The data suggest that GLP-1R agonism mainly influences abundances of structurally involved proteins and proteins involved in oxidative stress responses in the STZ mouse kidney. The changes could be direct effects of GLP-1R agonism in the kidneys or indirectly caused by a systemic response to GLP-1R activation.
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Affiliation(s)
| | | | | | - Peter James
- Department of ImmunotechnologyLund UniversityLundSweden
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11
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Caramori ML. Should all patients with diabetes have a kidney biopsy? Nephrol Dial Transplant 2018; 32:3-5. [PMID: 28391311 DOI: 10.1093/ndt/gfw389] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 09/29/2016] [Indexed: 11/14/2022] Open
Affiliation(s)
- M Luiza Caramori
- Division of Endocrinology and Diabetes, Department of Medicine and Division of Pediatric Nephrology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
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12
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Hornung RJ, Reed PW, Mouat F, Jefferies C, Gunn AJ, Hofman PL. Angiotensin-converting enzyme-inhibitor therapy in adolescents with type 1 diabetes in a regional cohort: Auckland, New Zealand from 2006 to 2016. J Paediatr Child Health 2018; 54:493-498. [PMID: 29271523 DOI: 10.1111/jpc.13814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Revised: 09/25/2017] [Accepted: 10/23/2017] [Indexed: 11/28/2022]
Abstract
AIM To review indications and use of angiotensin-converting enzyme-inhibitor (ACEI) therapy for the treatment of persistent microalbuminuria (MA) and/or hypertension (HTN) in adolescents with type 1 diabetes mellitus (T1DM). METHODS Retrospective chart review of adolescent patients with T1DM seen within the paediatric diabetes service in Auckland, New Zealand, from 2006 to 2016. MA, HTN, patient demographic characteristics and ACEI prescribing and monitoring indices were examined. RESULTS Five hundred adolescents with T1DM were included. There were 26 patients (5%) with MA and/or HTN. MA alone was present in 16, HTN alone in 3 and both HTN and MA in 7. The 5-year MA/HTN-free rate was 98%, and the 10-year MA/HTN-free rate was 93%. Longer disease duration and earlier diagnosis were predictors of MA/HTN. There was no significant difference in standard clinical indices between study patients and others. ACEI was prescribed for 17 of 26 patients for either HTN or MA. Within 6 weeks of ACEI commencement, less than half of the subjects had repeat serum creatinine and MA screens and no record of repeat blood pressure measurement. Despite this, all patients had 3-monthly reviews within outpatient clinics where adjustments of ACEI doses were made. CONCLUSION In our regional adolescent population with T1DM, there were low rates of both MA and/or HTN. In those who required treatment with ACEI, clinical monitoring post-commencement of therapy was inconsistent. Local consensus guidelines for the management of persistent MA in children and adolescents with diabetes mellitus were developed in response to this study.
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Affiliation(s)
- Rosalie J Hornung
- Paediatric Diabetes and Endocrinology Service, Starship Children's Health, Auckland, New Zealand
| | - Peter W Reed
- Starship Children's Health Children's Research Centre, Auckland District Health Board, Auckland, New Zealand
| | - Fran Mouat
- Paediatric Diabetes and Endocrinology Service, Starship Children's Health, Auckland, New Zealand
| | - Craig Jefferies
- Paediatric Diabetes and Endocrinology Service, Starship Children's Health, Auckland, New Zealand
| | - Alistair J Gunn
- Paediatric Diabetes and Endocrinology Service, Starship Children's Health, Auckland, New Zealand.,Department of Physiology,, University of Auckland, Auckland, New Zealand
| | - Paul L Hofman
- Paediatric Diabetes and Endocrinology Service, Starship Children's Health, Auckland, New Zealand.,Liggins Institute, University of Auckland, Auckland, New Zealand
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Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy. Am J Physiol Renal Physiol 2017; 312:F1101-F1111. [PMID: 28228399 DOI: 10.1152/ajprenal.00020.2017] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 02/07/2017] [Accepted: 02/17/2017] [Indexed: 12/12/2022] Open
Abstract
Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918 biopsies with DN revealed strong evidence that these mechanisms are connected to each other, wherein excess GBM components fail to undergo degradation and are deposited in the mesangium. These data do not exclude that mesangial cells also synthesize components that contribute to the accumulation of matrix in the mesangium. Light, electron microscopic, immunofluorescence, and in situ hybridization studies clearly show that the thickening of the GBM is due not only to overproduction of components of the mature GBM (α3 and α5 chains of collagen IV and agrin) by podocytes but also to resumed increased synthesis of the α1 chain of collagen IV and of perlecan by endothelial cells usually seen during embryonic development. We hypothesize that these abnormal production mechanisms are caused by different processes: overproduction of mature GBM-components by the diabetic milieu and regression of endothelial cells to an embryonic production mode by decreased availability of mediators from podocytes.
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Affiliation(s)
- Wilhelm Kriz
- Department of Neuroanatomy, Medical Faculty Mannheim, University Heidelberg, Germany;
| | - Jana Löwen
- Department of Neuroanatomy, Medical Faculty Mannheim, University Heidelberg, Germany.,Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and
| | - Giuseppina Federico
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and
| | - Jacob van den Born
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Elisabeth Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and
| | - Hermann Josef Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and
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14
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Bhatti AB, Usman M. Drug Targets for Oxidative Podocyte Injury in Diabetic Nephropathy. Cureus 2015; 7:e393. [PMID: 26798569 PMCID: PMC4699926 DOI: 10.7759/cureus.393] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 11/30/2015] [Indexed: 12/19/2022] Open
Abstract
Diabetic nephropathy (DN) is one the most prevalent chronic complications of diabetes mellitus that affects as much as one-third of diabetic patients irrespective of the type of diabetes. Hyperglycemia is the key trigger for DN that initiates a number of microscopic and ultramicroscopic changes in kidney architecture. Microscopic changes include thickening of the glomerular basement membrane (GBM), tubular basement membrane (TBM), mesangial proliferation, arteriosclerosis, and glomerulotubular junction abnormalities (GTJA). Among the ultramicroscopic changes, effacement of podocytes and decrease in their density seem to be the centerpiece of DN pathogenesis. These changes in kidney architecture then produce functional deficits, such as microalbuminuria and decreased glomerular filtration rate (GFR). Among several mechanisms involved in inflicting damage to podocytes, injuries sustained by increased oxidative stress turns out to be the most important mechanism. Different variables that are included in increased production of reactive oxygen species (ROS) include a hyperglycemia-induced reduction in glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation via hyperglycemia, advanced glycation end products (AGEs), protein kinase C (PKC), and renin-angiotensin-aldosterone system (RAAS). Unfortunately, control of podocyte injury hasn't received much attention as a treatment approach for DN. Therefore, this review article is mainly concerned with the exploration of various treatment options that might help in decreasing the podocyte injury, mainly by reducing the level of NADPH oxidase-mediated generation of ROS. This article concludes with a view that certain NADPH oxidase inhibitors, RAAS inhibitors, statins, antidiabetic drugs, and antioxidant vitamins might be useful in decreasing podocyte injury and resultant structural and functional kidney impairments in DN.
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Affiliation(s)
- Adnan Bashir Bhatti
- Department of Medicine, Capital Development Authority Hospital, Islamabad, Pakistan
| | - Muhammad Usman
- Department of Medicine, Jinnah Hospital Lahore (JHL)/Allama Iqbal Medical College (AIMC), Lahore, Pakistan
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15
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Early-onset diabetic E1-DN mice develop albuminuria and glomerular injury typical of diabetic nephropathy. BIOMED RESEARCH INTERNATIONAL 2015; 2015:102969. [PMID: 26000279 PMCID: PMC4426768 DOI: 10.1155/2015/102969] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 09/26/2014] [Accepted: 09/29/2014] [Indexed: 11/18/2022]
Abstract
The transgenic E1-DN mice express a kinase-negative epidermal growth factor receptor in their pancreatic islets and are diabetic from two weeks of age due to impaired postnatal growth of β-cell mass. Here, we characterize the development of hyperglycaemia-induced renal injury in the E1-DN mice. Homozygous mice showed increased albumin excretion rate (AER) at the age of 10 weeks; the albuminuria increased over time and correlated with blood glucose. Morphometric analysis of PAS-stained histological sections and electron microscopy images revealed mesangial expansion in homozygous E1-DN mice, and glomerular sclerosis was observed in the most hyperglycaemic mice. The albuminuric homozygous mice developed also other structural changes in the glomeruli, including thickening of the glomerular basement membrane and widening of podocyte foot processes that are typical for diabetic nephropathy. Increased apoptosis of podocytes was identified as one mechanism contributing to glomerular injury. In addition, nephrin expression was reduced in the podocytes of albuminuric homozygous E1-DN mice. Tubular changes included altered epithelial cell morphology and increased proliferation. In conclusion, hyperglycaemic E1-DN mice develop albuminuria and glomerular and tubular injury typical of human diabetic nephropathy and can serve as a new model to study the mechanisms leading to the development of diabetic nephropathy.
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16
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Afkarian M. Diabetic kidney disease in children and adolescents. Pediatr Nephrol 2015; 30:65-74; quiz 70-1. [PMID: 24643739 PMCID: PMC4169353 DOI: 10.1007/s00467-014-2796-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Revised: 02/18/2014] [Accepted: 02/19/2014] [Indexed: 12/21/2022]
Abstract
Diabetes, more frequently type 1, but increasingly also type 2, commonly occurs in childhood. While more advanced diabetic kidney disease (DKD), e.g., loss of glomerular filtration rate (GFR), does not occur until adulthood, kidney biopsies show DKD structural changes as early as 1.5-5 years after the onset of type 1 diabetes. Earliest clinical sign of DKD, increased urine albumin excretion, commonly appears during childhood and adolescence and presents an important opportunity to detect and intervene in early DKD, perhaps more successfully than later in the disease course. Longitudinal studies of type 1 diabetes have enriched our understanding of the DKD natural history and modifiable risk factors for DKD progression. These studies have also shown that the presence of DKD marks a subset of people with diabetes who are at the highest risk of early mortality, supporting an enhanced focus on DKD detection, prevention, and treatment. Early studies suggest that youth-onset type 2 diabetes is associated with a higher prevalence of comorbidities and risk factors and follows a more aggressive natural history. A deeper understanding of the natural history, risk factors, underlying mechanisms and therapeutic options for DKD in young-onset type 2 diabetes awaits further studies.
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Affiliation(s)
- Maryam Afkarian
- University of Washington, Medicine, 325 9th Avenue, Box 359606, Seattle, WA, 98104, USA,
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17
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Alicic RZ, Tuttle KR. Novel therapies for diabetic kidney disease. Adv Chronic Kidney Dis 2014; 21:121-33. [PMID: 24602462 DOI: 10.1053/j.ackd.2014.01.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 01/13/2014] [Accepted: 01/15/2014] [Indexed: 02/07/2023]
Abstract
The number of people diagnosed with diabetes is rising throughout the world, which in turn drives upward the global frequency of diabetic kidney disease (DKD). Individuals with DKD are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Current treatments concentrate on controlling hyperglycemia and hypertension with the specific use of renin-angiotensin system inhibitors. Although such measures reduce the risk of progressive kidney disease, DKD remains the leading cause of ESRD and the major risk amplifier for death in this population. Therefore, novel therapeutic approaches are urgently needed. Ideas for novel targets for therapy are founded on recent advances in understanding DKD mechanisms that are based on experimental models and human observations. The purpose of this review is to describe the epidemiology and present knowledge of DKD pathophysiology as the basis for novel therapies including inhibitors of Janus kinases (JAK), protein kinase C, fibrosis, advanced glycation end products treatments, and endothelin.
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18
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19
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White KE. Research into the structure of the kidney glomerulus--making it count. Micron 2012; 43:1001-9. [PMID: 22607953 DOI: 10.1016/j.micron.2012.04.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 04/20/2012] [Accepted: 04/23/2012] [Indexed: 11/26/2022]
Abstract
The renal glomerulus and its components have been intensively studied using microscopy - both light and electron - for decades and much has been learnt about their role in the pathogenesis of chronic kidney diseases such as diabetic nephropathy. In order to get more than purely qualitative information from the images, stereological tools have been applied to obtain unbiased quantitative data and thus allow structural-functional relationships to be explored. These techniques are likely to continue to be used in the coming decades in order to provide vital information about the disease process, complementing knowledge obtained from molecular techniques.
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Affiliation(s)
- Kathryn E White
- EM Research Services, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 2DU, UK.
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20
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Perrin NESS, Torbjörnsdotter T, Jaremko GA, Berg UB. Risk markers of future microalbuminuria and hypertension based on clinical and morphological parameters in young type 1 diabetes patients. Pediatr Diabetes 2010; 11:305-13. [PMID: 19761528 DOI: 10.1111/j.1399-5448.2009.00595.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Nephropathy is a severe complication of type 1 diabetes and develops in 30% of patients. Currently, it is not possible to identify young patients at risk prior to the development of microalbuminuria (MA) and/or hypertension (HT). OBJECTIVE To study predictors of MA and/or HT in young normoalbuminuric (NA) patients with type 1 diabetes. SUBJECTS AND METHODS Forty-six NA and normotensive (NT) type 1 diabetes patients, regularly followed since onset with checks on metabolic control, kidney function, and MA, were investigated with kidney biopsies and 24-h ambulatory blood pressure measurements (ABPMs) after 10.6 yr of diabetes. The patients were followed another six and a half years with regard to the development of MA and HT. RESULTS Fifteen patients developed MA and/or HT during follow-up. The strongest risk markers were poor metabolic control after puberty, high day-time systolic blood pressure (BP), and increased BMT at 10 yr, which explained 62% of the outcome for MA and/or HT at 17 yr duration with 77% sensitivity and 65% specificity. The threshold values were long-term postpubertal HbA(1c) > 8.2%, day-time systolic BP > 130 mmHg, and BMT > 490 nm/1.73 m(2). CONCLUSIONS Normoalbuminuric and NT patients at risk of developing MA and HT could be identified and might benefit from an early start of antihypertensive therapy and improvement of metabolic control.
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Affiliation(s)
- Nina E S S Perrin
- Division of Pediatrics, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
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21
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Mogensen CE. Mistakes, misunderstandings and controversies in diabetes: A review and personal account. J Diabetes Investig 2010; 1:97-100. [PMID: 24843414 PMCID: PMC4008022 DOI: 10.1111/j.2040-1124.2010.00012.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
A number of controversies in diabetes have had too little attention. I discuss the following issues: (i) drug therapy; (ii) genetics; (iii) antihypertensive treatment in patients with normoalbuminuria and with abnormal albuminuria; (iv) insulin analogs; (v) cancer in diabetes; (vi) hypophysectomy; (vii) renal biopsy; (viii) low protein diet; and (ix) glycated hemoglobin. A closer look at these items is required in order to have a more realistic picture of diabetes research. A scheme of other controversies is also provided. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00012.x, 2010)
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Affiliation(s)
- Carl Erik Mogensen
- Medical Department M, Aarhus Sygehus and University of Aarhus, Aarhus, Denmark
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22
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Kamenetsky I, Rangayyan RM, Benediktsson H. Analysis of the glomerular basement membrane in images of renal biopsies using the split-and-merge method: a pilot study. J Digit Imaging 2009; 23:463-74. [PMID: 19760293 DOI: 10.1007/s10278-009-9233-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Revised: 06/16/2009] [Accepted: 08/05/2009] [Indexed: 11/30/2022] Open
Abstract
Abnormal thinning, thickening, or variation in the thickness of the glomerular basement membrane (GBM) are caused by familial hematuria, diabetes mellitus, and Alport syndrome, respectively. We propose a semi-automated procedure for the segmentation and analysis of the thickness of the GBM in images of renal biopsy samples obtained by using a transmission electron microscope (TEM). The procedure includes the split-and-merge algorithm, morphological image processing, skeletonization, and statistical analysis of the width of the GBM. The procedure was tested with 34 TEM images of six patients. The mean and standard deviation of the GBM width for a patient with normal GBM were estimated to be 368 +/- 177 nm, those for a patient with thin GBM associated with familial hematuria were 216 +/- 95 nm, and those for a patient with thick GBM due to diabetic nephropathy were 1,094 +/- 361 nm. Comparative analysis of the results of image processing with manual measurements by an experienced renal pathologist indicated low error in the range of 12 +/- 9 nm.
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Affiliation(s)
- Ilya Kamenetsky
- Department of Electrical & Computer Engineering, Schulich School of Engineering, University of Calgary, Calgary, AB, T2N 1N4, Canada
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23
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24
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Kamenetsky I, Rangayyan RM, Benediktsson H. Segmentation and analysis of the glomerular basement membrane using the split and merge method. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2009; 2008:3064-7. [PMID: 19163353 DOI: 10.1109/iembs.2008.4649850] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Certain renal diseases are characterized by alterations in the thickness of the glomerular basement membrane (GBM), as visualized by images of biopsy samples obtained by using a transmission electron microscope (TEM). Abnormal thinning, thickening, or variation in thickness can occur in familial hematuria, diabetes mellitus, and Alport syndrome, respectively. We propose image processing methods for the segmentation and measurement of the GBM. The methods include the split and merge algorithm, morphological image processing, skeletonization, and statistical analysis of the width of the GBM. The proposed methods were applied to 34 TEM images of six patients. The mean and standard deviation of normal GBM were estimated to be 368 +/- 177 nm; those of thin GBMs associated with familial hematuria were 216 +/- 95 nm; and those of thick GBM due to diabetic nephropathy were 1094 +/- 361 nm. Comparative analysis of the results of image processing with manual measurements by an experienced renal pathologist indicated low error in the range of 12 +/- 9 nm.
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Affiliation(s)
- Ilya Kamenetsky
- Department of Electrical & Computer Engineering, Schulich School of Engineering, University of Calgary, AB, Canada
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25
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Rangayyan RM, Kamenetsky I, Benediktsson H. Segmentation and analysis of the glomerular basement membrane in renal biopsy samples using active contours: a pilot study. J Digit Imaging 2009; 23:323-31. [PMID: 19225841 DOI: 10.1007/s10278-009-9188-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2008] [Revised: 01/13/2009] [Accepted: 01/21/2009] [Indexed: 01/23/2023] Open
Abstract
Some renal diseases cause changes in the structure of the glomerular basement membranes (GBM). Measurement of the thickness of the GBM can be performed on transmission electron microscopy (TEM) images of renal biopsy samples. Increased thickness of the GBM is observed in patients with diabetic nephropathy. Abnormally thin GBMs are associated with hematuria. We propose image processing methods for the detection and measurement of the GBM. The methods include edge detection, morphological image processing, active contour modeling, skeletonization, and statistical analysis of the width of the GBM. In the present pilot study, the methods were tested with 34 TEM images of six patients. The estimated mean and standard deviation of the GBM width for a patient with normal GBM were 348 +/- 135 nm; those for a patient with thin GBMs due to hematuria were 227 +/- 94 nm; and those for a patient with diabetic nephropathy were 1,152 +/- 411 nm. Comparison with manual measurements by an experienced renal pathologist indicated low error in the range of 36 +/- 11 nm.
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Affiliation(s)
- Rangaraj M Rangayyan
- Department of Electrical and Computer Engineering, Schulich School of Engineering, University of Calgary, Calgary, AB, Canada.
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26
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Mason RM. Connective tissue growth factor(CCN2), a pathogenic factor in diabetic nephropathy. What does it do? How does it do it? J Cell Commun Signal 2009; 3:95-104. [PMID: 19214781 PMCID: PMC2721079 DOI: 10.1007/s12079-009-0038-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2009] [Accepted: 01/26/2009] [Indexed: 01/15/2023] Open
Abstract
Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of matricellular proteins. Its expression is induced by a number of factors including TGF-β. It has been associated with fibrosis in various tissues including the kidney. Diabetic nephropathy (DN) develops in about 30% of patients with diabetes and is characterized by thickening of renal basement membranes, fibrosis in the glomerulus (glomerulosclerosis), tubular atrophy and interstitial fibrosis, all of which compromise kidney function. This review examines changes in CTGF expression in the kidney in DN, the effects they have on glomerular mesangial and podocyte cells and the tubulointerstitium, and how these contribute to driving fibrotic changes in the disease. CTGF can bind to several other growth factors modifying their function. CTGF is also able to interact with receptors on cells, including integrins, tyrosine receptor kinase A (TrkA), low density lipoprotein receptor-related protein (LRP) and heparan sulphate proteoglycans. These interactions, the intracellular signalling pathways they activate, and the cellular responses evoked are reviewed. CTGF also induces the expression of chemokines which themselves have pharmacological actions on cells. CTGF may prompt some responses by acting through several different mechanisms, possibly simultaneously. For example, CTGF is often described as an effector of TGF-β. It can promote TGF-β signalling by binding directly to the growth factor, promoting its interaction with the TGF-β receptor; by triggering intracellular signalling on binding the TrkA receptor, which leads to the transcriptional repression of Smad7, an inhibitor of the TGF-β signalling pathway; and by binding to BMP-7 whose own signalling pathway opposing TGF-β is inhibited, leading to enhanced TGF-β signalling.
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Affiliation(s)
- Roger M Mason
- Division of Medicine, Imperial College London, London, W12 ONN, UK,
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27
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Najafian B, Mauer M. Progression of diabetic nephropathy in type 1 diabetic patients. Diabetes Res Clin Pract 2009; 83:1-8. [PMID: 19070384 DOI: 10.1016/j.diabres.2008.08.024] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Revised: 06/19/2008] [Accepted: 08/18/2008] [Indexed: 11/18/2022]
Abstract
Understanding pathogenetic mechanisms of diabetic nephropathy progression risk factors is important. Structural-functional relationship studies have increased our understanding of the glomerular, vascular and tubulointerstitial lesions evolution at various stages of diabetic nephropathy. Classical and more recently described lesions of diabetic nephropathy are discussed. Structural changes associated with progression toward proteinuria and GFR loss are summarized. The relationships of renal structure and function in diabetic nephropathy are best described by non-linear models which mimic the natural history of the disease, i.e., renal pathology develops in clinical silence but, once established, leads to proteinuria and GFR decline.
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Affiliation(s)
- Behzad Najafian
- MMC 76 Mayo, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
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28
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Fioretto P, Caramori ML, Mauer M. The kidney in diabetes: dynamic pathways of injury and repair. The Camillo Golgi Lecture 2007. Diabetologia 2008; 51:1347-55. [PMID: 18528679 DOI: 10.1007/s00125-008-1051-7] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2008] [Accepted: 04/17/2008] [Indexed: 11/29/2022]
Abstract
Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD). The natural history of diabetic nephropathy has changed over the last decades, as a consequence of better metabolic and blood pressure management. Thus, it may now be possible to delay or halt the progression towards ESRD in patients with overt diabetic nephropathy, and the decline of renal function is not always inexorable and unavoidable. Also, the rate of progression from microalbuminuria to overt nephropathy is much lower than originally estimated in the early 80s. Furthermore, there is now evidence that it is possible, in humans, to obtain reversal of the established lesions of diabetic nephropathy. This review focuses on the contribution of kidney biopsy studies to the understanding of the pathogenesis and natural history of diabetic nephropathy and the identification of patients at high risk of progression to ESRD. The classic lesions of diabetic nephropathy and the well-established structural-functional relationships in type 1 diabetes will be briefly summarised and the renal lesions leading to renal dysfunction in type 2 diabetes will be described. The relevance of these biopsy studies to diabetic nephropathy pathogenesis will be outlined. Finally, the evidence and the possible significance of reversibility of diabetic renal lesions will be discussed, as well as future directions for research in this field.
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Affiliation(s)
- P Fioretto
- Department of Medical and Surgical Sciences, University of Padua, Via Giustininiani n.2, 35128, Padua, Italy.
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29
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Bogdanović R. Diabetic nephropathy in children and adolescents. Pediatr Nephrol 2008; 23:507-25. [PMID: 17940807 DOI: 10.1007/s00467-007-0583-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2007] [Revised: 07/09/2007] [Accepted: 07/12/2007] [Indexed: 12/12/2022]
Abstract
Type 1 diabetes mellitus (T1DM) commonly occurs in childhood or adolescence, although the rising prevalence of type 2 diabetes mellitus (T2DM) in these age groups is now being seen worldwide. Diabetic nephropathy (DN) develops in 15-20% of subjects with T1DM and in similar or higher percentage of T2DM patients, causing increased morbidity and premature mortality. Although overt DN or kidney failure caused by either type of diabetes are very uncommon during childhood or adolescence, diabetic kidney disease in susceptible patients almost certainly begins soon after disease onset and may accelerate during adolescence, leading to microalbuminuria or incipient DN. Therefore, all diabetics warrant ongoing assessment of kidney function and screening for the earliest manifestations of renal injury. Pediatric health care professionals ought to understand about risk factors, strategy for prevention, method for screening, and treatment of early DN. This review considers each form of diabetes separately, including natural history, risk factors for development, screening for early manifestations, and strategy recommended for prevention and treatment of DN in children and adolescents.
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Affiliation(s)
- Radovan Bogdanović
- The Institute of Mother and Child Healthcare of Serbia Dr Vukan Cupic, Belgrade, Serbia.
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30
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Fioretto P, Bruseghin M, Barzon I, Arboit M, Dalla Vestra M. Diabetic nephropathy: An update on renal structure. ACTA ACUST UNITED AC 2007. [DOI: 10.1016/j.ics.2007.03.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
The clinical manifestations of diabetic nephropathy, proteinuria, increased blood pressure, and decreased glomerular filtration rate, are similar in type 1 and type 2 diabetes; however, the renal lesions underlying renal dysfunction in the 2 conditions may differ. Indeed, although tubular, interstitial, and arteriolar lesions are ultimately present in type 1 diabetes, as the disease progresses, the most important structural changes involve the glomerulus. In contrast, a substantial subset of type 2 diabetic patients, despite the presence of microalbuminuria or proteinuria, have normal glomerular structure with or without tubulointerstitial and/or arteriolar abnormalities. The clinical manifestations of diabetic nephropathy are strongly related with the structural changes, especially with the degree of mesangial expansion in both type 1 and type 2 diabetes. However, several other important structural changes are involved. Previous studies, using light and electron microscopic morphometric analysis, have described the renal structural changes and the structural-functional relationships of diabetic nephropathy. This review focuses on these topics, emphasizing the contribution of research kidney biopsy studies to the understanding of the pathogenesis of diabetic nephropathy and the identification of patients with a higher risk of progression to end-stage renal disease. Finally, evidence is presented that the reversal of established lesions of diabetic nephropathy is possible.
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Affiliation(s)
- Paola Fioretto
- Department of Medical and Surgical Sciences, University of Padova Medical School, Via Giustiniana 2, 35128 Padua, Italy.
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32
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33
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Hohenstein B, Hausknecht B, Boehmer K, Riess R, Brekken RA, Hugo CPM. Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int 2006; 69:1654-61. [PMID: 16541023 DOI: 10.1038/sj.ki.5000294] [Citation(s) in RCA: 132] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Several studies have implicated the angiogenic cytokine vascular endothelial growth factor (VEGF) in the development of diabetic nephropathy, but no data are available about its local activity during human disease. Glomeruli from 52 archival biopsies from type II diabetics were evaluated and compared to 10 renal biopsies without kidney disease (controls). Glomerulosclerosis, capillary rarefaction, glomerular and endothelial cell proliferation, apoptosis, VEGF expression, as well as receptor-bound VEGF indicating local VEGF activity, and phosphorylation of the signal transduction molecule Akt were investigated. Owing to substantial heterogeneity of glomerular lesions in individual biopsies, these parameters were correlated with the degree of injury in individual glomeruli rather than biopsies. Severe glomerular capillary rarefaction was linked to the degree of glomerulosclerosis. While cellular apoptosis was detected independent of the stage of injury, endothelial cell proliferation indicating capillary repair was markedly increased only in mildly/moderately injured glomeruli. In controls, VEGF was predominantly expressed in podocytes, whereas receptor-bound VEGF was confined to the glomerular endothelium. VEGF expression was increased in all diabetic glomeruli by many different cell types. In contrast, VEGF receptor activation was increased predominantly in the endothelium of only mildly injured glomeruli, but significantly decreased in more severely injured glomeruli. Diabetic nephropathy is associated with glomerular capillary rarefaction. Despite overall increased glomerular VEGF, the decreased receptor-bound VEGF on the endothelium may be an indicator of an insufficient capillary repair reaction.
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Affiliation(s)
- B Hohenstein
- Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Erlangen, Germany
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Marquez B, Zouvani I, Karagrigoriou A, Anastasiades E, Pierides A, Kyriacou K. A Simplified Method for Measuring the Thickness of Glomerular Basement Membranes. Ultrastruct Pathol 2003. [DOI: 10.1080/01913120390248728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Okada M, Takemura T, Yanagida H, Yoshioka K. Response of mesangial cells to low-density lipoprotein and angiotensin II in diabetic (OLETF) rats. Kidney Int 2002; 61:113-24. [PMID: 11786091 DOI: 10.1046/j.1523-1755.2002.00107.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Progression of diabetic nephropathy is closely associated with morphological changes in glomeruli, such as thickening of the glomerular basement membrane, mesangial expansion, and glomerulosclerosis. To elucidate early glomerular events, we compared the mitogenic activity and extracellular matrix production in mesangial cells (MC) isolated from diabetic rats prior to the manifestation of nephropathy and those showing overt nephropathy. This study may help to clarify the mechanisms underlying diabetic nephropathy and provide clues about early therapeutic interventions for preventing or slowing this process. METHODS Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a chronic model for human type 2 diabetes mellitus, and age-matched control (LETO) rats were used. Glomerular cell numbers, expression of immediate early genes (c-Fos and c-Myc) and proliferating cell nuclear antigen (PCNA), and low-density lipoprotein (LDL) deposition were determined in renal tissue sections from rats aged 15 to 75 weeks. Mesangial cells (MCs) from OLETF rats at two different stages of the disease, that is, young (12- to 14-week-old) OLETF rats (y-OLETF) prior to the manifestation of nephropathy and old (48- to 50-week-old) OLETF rats (o-OLETF) showing nephropathy, were isolated and cultured. After stimulation with native (n-) or oxidized (ox-) LDL or angiotensin II (Ang II), DNA synthesis and extracellular matrix (ECM) production were examined. Cellular expression of LDL/scavenger receptors was analyzed using fluorescence-labeled LDL and binding to 125I-labeled-LDL. RESULTS The number of cells per glomerular cross section was significantly higher in OLETF rats than in LETO rats between 25 and 65 weeks of age. In OLETF glomeruli, c-Fos, c-Myc, and PCNA were transiently expressed in the early phase. Glomerular LDL deposition increased with the age of OLETF rats. Addition of a low dose of n-LDL (10 microg/mL) to the culture medium significantly stimulated DNA synthesis of y-OLETF MCs, as compared with o-OLETF MCs and LETO MCs (P < 0.05). A high dose of n-LDL (100 microg/mL) caused cytotoxic effects in all cells. Exposure to ox-LDL minimally affected DNA synthesis of OLETF or LETO MCs. LDL receptors and scavenger receptors were predominant in y-OLETF and o-OLETF, respectively. After stimulation with n-LDL and ox-LDL, expression of type I and type III collagen, along with transforming growth factor-beta (TGF-beta), was higher in o-OLETF MCs that in y-OLETF MCs or LETO MCs. Exposure to Ang II markedly induced DNA synthesis and ECM mRNA expression in y-OLETF MCs and o-OLETF MCs, respectively. CONCLUSIONS These findings indicate that the cell proliferation process precedes the evolution of diabetic glomerulopathy. The responses of OLETF MCs to n-LDL/ox-LDL and Ang II differed depending on the stage of diabetes. In the early phase, MCs were prone to proliferate, whereas in the late stage, MCs, which expressed higher levels of TGF-beta, tended to synthesize ECM. A functional switch in MCs may contribute to the development of glomerulosclerosis in diabetic nephropathy.
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Affiliation(s)
- Mitsuru Okada
- Department of Pediatrics, Kinki University School of Medicine, Osaka-Sayama, Japan
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Abstract
Altered growth of renal cells is one of the early abnormalities detected after the onset of diabetes. Cell culture studies whereby renal cells are exposed to high glucose concentrations have provided a considerable amount of insight into mechanisms of growth. In the glomerular compartment, there is a very early and self-limited proliferation of mesangial cells with subsequent hypertrophy, whereas proximal tubular cells primarily undergo hypertrophy. There is overwhelming evidence from in vivo and cell culture studies that induction of the transforming growth factor-beta (TGF-beta) system mediates the actions of high ambient glucose and that this system is pivotal for the hypertrophy of mesangial and tubular cells. Other factors such as hemodynamic forces, protein glycation products, and several mediators (for example, angiotensin II, endothelin-1, thromboxane, and platelet-derived growth factor) may further amplify the synthesis of TGF-beta and/or the expression of its receptors in the diabetic state. Cellular hypertrophy can be characterized by cell cycle arrest in the G1 phase. The molecular mechanism arresting mesangial cells in the G1 phase of the cell cycle is the induction of cyclin-dependent kinase (CdK) inhibitors such as p27Kip1 and p21, which bind to and inactivate cyclin-CdK complexes responsible for G1-phase exit. High-glucose-induced activation of protein kinase C and stimulated TGF-beta expression appear to be essential for stimulated expression of p27Kip1. In addition, a decreased turnover of protein caused by the inhibition of proteases contributes to hypertrophy. The development of irreversible renal changes in diabetes mellitus such as glomerulosclerosis and tubulointerstitial fibrosis is always preceded by the early hypertrophic processes in the glomerular and the tubular compartments. It may still be debated whether diabetic renal hypertrophy will inevitably lead to irreversible fibrotic changes in the absence of other factors such as altered intraglomerular hemodynamics and genetic predisposition. Nevertheless, understanding cellular growth on a molecular level may help design a novel therapeutic approach to prevent or treat diabetic nephropathy effectively.
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Affiliation(s)
- G Wolf
- Department of Medicine, University of Hamburg, Germany
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Nielsen B, Grønbaek H, Osterby R, Flyvbjerg A. Effect of the calcium channel blocker nitrendipine in normotensive and spontaneously hypertensive, diabetic rats on kidney morphology and urinary albumin excretion. J Hypertens 1999; 17:973-81. [PMID: 10419071 DOI: 10.1097/00004872-199917070-00014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To investigate the effect of nitrendipine on the development of renal changes in experimental diabetes. DESIGN Streptozotocin (STZ)-induced diabetic normotensive Wistar rats (WIS) and spontaneously hypertensive rats (SHR) were randomly allocated to nitrendipine treatment (250 mg/kg fodder) or placebo treatment for 6 months. METHODS Blood pressure was assessed by the tail-cuff method, urinary albumin excretion (UAE) was determined, and glomerular basement membrane (GBM) thickness, mesangial volume, and mean glomerular volume (MGV) were estimated by morphometric measurements. RESULTS In diabetic WIS, nitrendipine significantly reduced UAE after 2 months of treatment (P< 0.05), while no effect was was seen after 4-6 months. In diabetic SHR, no effect on UAE was seen at any time. Nitrendipine was unable to inhibit the renal and glomerular enlargement in diabetic WIS and SHR. Diabetes plus hypertension was associated with significant increase in GBM thickness, while diabetes or hypertension alone showed no significant increase in GBM. Nitrendipine treatment was unable to prevent increased GBM in diabetic SHR. CONCLUSION Nitrendipine inhibits an early increase in UAE in normotensive, diabetic rats, but fails to sustain this effect in long-term diabetes. No effect of nitrendipine was observed in SHR.
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Affiliation(s)
- B Nielsen
- Institute of Experimental Clinical Research, Medical Research Laboratory, Aarhus University Hospital, Denmark.
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Marquez B, Stavrou F, Zouvani I, Anastasiades E, Patsias C, Pierides A, Kyriacou K. Thin glomerular basement membranes in patients with hematuria and minimal change disease. Ultrastruct Pathol 1999; 23:149-56. [PMID: 10445281 DOI: 10.1080/019131299281644] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
A detailed morphometric analysis of glomerular basement membrane (GBM) thickness was carried out on biopsies from 16 patients exhibiting normal histology and unremarkable immunofluorescence. Eleven of these patients presented with proteinuria, 8 in the nephrotic syndrome range, while 5 had hematuria as well. The remaining 5 patients presented with hematuria only. Eight patients had an initial diagnosis of minimal change disease, 4 were diagnosed as thin-membrane nephropathy, 2 had Alport syndrome, and the remaining 2 had hypertensive nephropathy. Quantitative morphometric analysis of GBM identified 3 subsets of patients. The first subset consisted of 6 patients: 5 adults, with an average GBM width of 361 +/- 34 nm, and 1 child. The second subset included 8 patients with thin GBMs and a mean thickness of 253 +/- 15 nm. The last subset comprised 2 patients with Alport syndrome showing marked variability in GBM thickness. This study has confirmed the presence of thin GBMs in hematurics, but has also revealed GBM thinning in 50% of patients with a diagnosis of minimal change disease.
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Affiliation(s)
- B Marquez
- Department of Electron Microscopy and Molecular Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Abstract
Stereologic methods are used to obtain quantitative information about three-dimensional structures based on observations from section planes or--to a limited degree--projections. Stereologic methods, which are used in biologic research and especially in the research of normal and pathologic kidneys, will be discussed in this review. Special emphasis will be placed on modern stereologic methods, free of assumptions of the structure, size, and shape, etc., so-called UFAPP (unbiased for all practical purposes) stereologic methods. The basic foundation of all stereology, sampling, will be reviewed in relation to most of the methods discussed. Estimation of error variances and some of the basic problems in stereology will be reviewed briefly. Finally, a few comments will be made about the future directions for stereology in kidney research.
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Affiliation(s)
- J R Nyengaard
- Stereological Research Laboratory, University Institute of Pathology, University of Aarhus, Denmark.
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Abstract
Chronic complications of diabetes are dominated by disorders of the vascular system. They are a much larger burden on both diabetic patients and overall medical costs than diabetes itself. Large vessel problems are far more frequent than microvascular disorders. Loss of arterial elasticity alters arterial flow patterns and increases microcirculatory peak flow rates. Hyperglycemia may directly disrupt elastin formation. Diabetic leg artery disease may be generated by nerve damage, reversing this interactive contribution sequence. The major anatomic feature of microangiopathy in long-term diabetes is an unevenly distributed thickening of the intima of smaller arterioles. The thickening is primarily due to accumulation of type IV (basement membrane) collagen. Arterioles change local vessel diameter to adjust blood distribution to meet current needs. The thickening compromises the maximum local blood flow that may be achieved by this means. Compromise of maximal arteriolar dilatation does not disrupt exercising muscle but in the kidney, retina, and possibly in nerve, local circumstances can generate serious damage. Each of these system's responses has unique features that mediate its vulnerability, but all these organs show arteriolar hyalinization. The increased arteriolar accumulation of type IV collagen appears to be a response to the tangential force generated by flow over local endothelial cells. An increase in peak arteriolar wall force is mediated by a diabetes-specific doubling of erythrocyte membrane curvature change resistance. Red cell aggregation rate determines the rate of damage. The same nonspecific burden may also predispose to heart disease and stroke. Intensive metabolic control improves red cell deformability and protects against arteriolar damage. Therapies that address the rheologic problem more directly may add to the effectiveness of good diabetes control in the future.
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Terentyeva EA, Hayakawa K, Tanae A, Katsumata N, Tanaka T, Hibi I. Urinary biotinidase and alanine excretion in patients with insulin-dependent diabetes mellitus. EUROPEAN JOURNAL OF CLINICAL CHEMISTRY AND CLINICAL BIOCHEMISTRY : JOURNAL OF THE FORUM OF EUROPEAN CLINICAL CHEMISTRY SOCIETIES 1997; 35:21-4. [PMID: 9156561 DOI: 10.1515/cclm.1997.35.1.21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Twenty-four-hour urine specimens from 21 juvenile insulin-dependent diabetics and 10 healthy controls were compared with respect to biotinidase activity and alanine content. Urinary biotinidase activity was analysed by a newly developed high-performance liquid chromatography (HPLC) method. It was found that the excretion of biotinidase in urine was elevated in diabetics (7.02 mU/d; p < 0.005) as compared with controls (not detectable). Alanine excretion was also found to increase (p < 0.01) in diabetics. Biotinidase excretion in diabetics was correlated with alanine excretion (rS = 0.667; p < 0.01), but not with protein, albumin or N-acetyl-beta-glucosaminidase excretion. The simultaneous elevation of urinary biotinidase and alanine excretion in juvenile diabetics suggests that changes in kidney metabolism arise in the early stages of diabetes.
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Affiliation(s)
- E A Terentyeva
- Endocrine and Metabolism Research Laboratory, National Children's Medical Research Center, Tokyo, Japan
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Jonas E, Jäckle-Meyer I, Szukics B, Stolte H. Urinary fibronectin excretion in streptozotocin-diabetic rats. EUROPEAN JOURNAL OF CLINICAL CHEMISTRY AND CLINICAL BIOCHEMISTRY : JOURNAL OF THE FORUM OF EUROPEAN CLINICAL CHEMISTRY SOCIETIES 1996; 34:485-92. [PMID: 8831050 DOI: 10.1515/cclm.1996.34.6.485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Previous investigations performed in human diabetics demonstrate an increase in their urinary fibronectin excretion which was already present in subjects without microalbuminuria and which was elevated prior to functional restrictions. The present study was performed to examine whether in an experimental model these data obtained in men can be confirmed using an animal experimental model, and to further study pathomechanisms of diabetic nephropathy in rats. Fibronectin levels in serum and urine, and renal functional properties such as creatinine clearance, urinary albumin and protein excretion were studied in rats rendered diabetic with streptozotocin and compared with values of control and insulin treated animals for 5 months. Diabetic animals demonstrated the same creatinine clearance, but slightly decreased albumin and total protein excretion rates compared to controls and insulin "treated", euglycaemic animals. Diabetic rats showed a significantly increased excretion following day 42 compared to controls and insulin "treated" group. Concerning serum fibronectin, there was no significant difference between control, diabetic and insulin "treated" animals. The urinary fragment pattern of fibronectin was analyzed qualitatively by immunoblotting pattern and consisted of two main bands (M(r) 66,000 and 45,000). These bands were not altered in controls, insulin "treated" and diabetic rats, independent of the stage of renal involvement in diabetes. Present data provide evidence that fibronectin excretion is elevated in diabetic animals prior to functional restrictions, confirming results obtained in human diabetics. Therefore, determination of urinary fibronectin can serve as a more sensitive indicator for renal involvement in diabetes mellitus than microalbuminuria or changes in glomerular filtration rate. Urinary excretion may therefore serve as an early marker for the renal involvement in diabetes before the onset of clinical symptoms.
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Affiliation(s)
- E Jonas
- Abteilung für Nephrologie, Medizinische Hochschule Hannover, Germany
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43
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Shostak A, Gotloib L. Increased peritoneal permeability to albumin in streptozotocin diabetic rats. Kidney Int 1996; 49:705-14. [PMID: 8648911 DOI: 10.1038/ki.1996.99] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The mechanism behind the increased peritoneal permeability to albumin in diabetics is still unclear. In this study, streptozotocin diabetic rats developed albuminuria and significantly increased D/P of albumin after the fourth week of disease, reaching peak levels at the end of the 24 week period of follow-up. Coincidentally, extravasation of albumin to the interstitial tissue was evaluated with the Evans-blue method. Age-matched control rats showed Evans-blue concentrations of 0.023 +/- 0.013 micrograms/100 mg of dry tissue, whereas in diabetics the numbers were 1.22 +/- 0.719 micrograms (P < 0.001). Perfusion with Ruthenium-Red (RR) done in control at zero time, and in age-matched intact as well as in diabetic rats after 24 weeks of disease showed that the density distribution of capillary subendothelial anionic sites was significantly lower for diabetics (13 +/- 3/microns basement membrane vs. 31 +/- 3 and 34 +/- 4 in control groups; P < 0.001). Similar findings were made on the mesenteric submesothelial basement membrane. Mean density of RR decorated anionic sites was 12 +/- 2/microns basement membrane in diabetics, whereas those observed in both control groups were 31 +/- 2 and 31 +/- 3/microns (P < 0.001). Therefore, this reduced density of microvascular and submesothelial negative charges, equivalent to that induced by diabetes in other capillary beds, appears to be at the origin of the decreased permselectivity of the diabetic peritoneum for anionic serum albumin.
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Affiliation(s)
- A Shostak
- Department of Nephrology, Central Emek Hospital, Afula, Israel
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Yamamoto M, Fukui M, Kuramoto T, Kabuki K, Tomino Y. Effects of antiplatelet drug dilazep dihydrochloride on anionic sites and extracellular matrix (ECM) components in glomerular basement membrane of STZ-induced diabetic rats. J Clin Lab Anal 1995; 9:380-6. [PMID: 8587006 DOI: 10.1002/jcla.1860090608] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
A study of anionic sites in the glomerular basement membrane (GBM) of streptozotocin (STZ)-induced diabetic rats with or without treatment by an antiplatelet drug, dilazep dihydrochloride, is described. Expression of glomerular extracellular matrix (ECM) components was examined by immunofluorescence. Renal specimens were immersed in polyethyleneimine (PEI) as a cationic probe and then examined by electron microscopy. Renal specimens were also incubated with rabbit antirat type IV collagen, laminin, and fibronectin antisera and then stained with fluorescein isothiocyanate (FITC)-labeled goat antirabbit IgG antiserum. Mean values of proteinuria in the dilazep-treated diabetic rats were significantly decreased compared with those in nontreated diabetic rats. There was no significant correlation between the levels of proteinuria and those of creatinine clearance (CCr). Number of anionic sites on the GBM in the dilazep-treated diabetic rats were greater than those in diabetic rats. There was no significant difference in the staining of such ECM components between both rat groups. The authors concluded that the dilazep dihydrochloride might prevent anionic charges on the GBM and decrease the urinary excretion of proteins in STZ-induced diabetic rats.
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Affiliation(s)
- M Yamamoto
- Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan
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45
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Affiliation(s)
- S M Mauer
- University of Minnesota Medical School, Minneapolis
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46
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Lane P, Steffes MW, Mauer SM. Structural-functional relationships in type I insulin-dependent diabetes mellitus in humans. THE JOURNAL OF DIABETIC COMPLICATIONS 1991; 5:69-71. [PMID: 1770056 DOI: 10.1016/0891-6632(91)90021-g] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The major renal pathologic changes of diabetes include thickening of all renal extracellular basement membranes and mesangial matrix and, to a lesser extent, mesangial cell expansion. Two renal lesions appear critical in diabetic nephropathy. Mesangial expansion out of proportion to the size of the glomerulus is closely and inversely related to measures of peripheral capillary wall filtration surface and to clinical features of proteinuria, hypertension, and decreasing glomerular filtration rate (GFR). Arteriolar hyalinosis is related to global glomerulosclerosis, and both are correlated with the clinical features of nephropathy. These lesions are markedly advanced by the time renal dysfunction is clinically detectable. Relationships of structure and function early in the course of the diabetes have not been examined satisfactorily.
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Affiliation(s)
- P Lane
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis 55455
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47
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Renal Pathology in Insulin Dependent (IDDM) and Noninsulin Dependent Diabetes Mellitus (NIDDM). Nephrology (Carlton) 1991. [DOI: 10.1007/978-3-662-35158-1_137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Bilous RW, Mauer SM, Sutherland DE, Najarian JS, Goetz FC, Steffes MW. The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 1989; 321:80-5. [PMID: 2659996 DOI: 10.1056/nejm198907133210204] [Citation(s) in RCA: 194] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The microvascular complications of diabetes mellitus may be caused, in part, by poor glycemic control. Diabetic patients who have received renal allografts may have new glomerular lesions that are manifested structurally by increases in mesangial and glomerular volume. Successful pancreas transplantation produces long-term normoglycemia and provides a unique opportunity to evaluate the impact of the normalization of the blood glucose level on the development of the renal lesions typical of diabetes mellitus in transplanted kidneys. We obtained biopsy specimens from the functioning renal allografts of 12 patients with insulin-dependent (Type I) diabetes before successful pancreas transplantation (performed one to seven years after renal transplantation) and repeated the biopsy at least 1.9 years later. In renal biopsy specimens obtained before pancreas transplantation, the mesangial volume was normal or modestly increased and the glomerular basement membrane was moderately thickened. At follow-up, no progression could be detected in any structural measure in the glomerulus. Furthermore, the recipients of pancreas transplants had smaller glomerular volumes than 13 matched diabetic patients who were recipients of renal allografts but who did not undergo pancreas transplantation (mean +/- SD, 1.80 +/- 0.55 vs. 2.47 +/- 0.73 x 10(6) microns 3; P = 0.02) and showed markedly less mesangial expansion (mesangial-volume fraction, 0.19 +/- 0.07 vs. 0.31 +/- 0.10 microns 3 per cubic micrometer; P = 0.004). We conclude that successful pancreas transplantation is associated with significantly less severe diabetic glomerulopathy in kidneys previously transplanted into diabetic patients. These data support the hypothesis that normoglycemia can prevent the progression of diabetic glomerulopathy in humans.
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Affiliation(s)
- R W Bilous
- Department of Laboratory Medicine, University of Minnesota Medical School, Minneapolis
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Sutherland CG, Fisher BM, Frier BM, Dargie HJ, More IA, Lindop GB. Endomyocardial biopsy pathology in insulin-dependent diabetic patients with abnormal ventricular function. Histopathology 1989; 14:593-602. [PMID: 2759556 DOI: 10.1111/j.1365-2559.1989.tb02200.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
We have previously shown impaired ventricular function in asymptomatic middle-aged type 1 (insulin-dependent) diabetic patients who had no evidence of coronary artery disease. The diabetic patients had normal coronary angiograms but reduced ventricular ejection fraction on exercise. To examine the possible contribution of small vessel disease to this functional abnormality, we compared endomyocardial biopsies from seven symptom-free type 1 diabetic patients with biopsies from seven age- and sex-matched non-diabetic subjects. Interstitial fibrosis was present in three diabetic patients, arteriolar hyalinization in three patients and arteriolar thickening was observed in five patients. Morphometry performed on electron micrographs showed no significant difference in the thickness of the capillary basal lamina between diabetics and controls. While the functional significance of the abnormalities on light microscopy is unclear, our findings indicate that the abnormality of cardiac function described in diabetes is not associated with thickening of the myocardial capillary basal lamina.
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Affiliation(s)
- C G Sutherland
- Department of Pathology, Royal Infirmary, Glasgow, Scotland
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Stribling D, Armstrong FM, Harrison HE. Aldose reductase in the etiology of diabetic complications: 2. Nephropathy. THE JOURNAL OF DIABETIC COMPLICATIONS 1989; 3:70-6. [PMID: 2526143 DOI: 10.1016/0891-6632(89)90015-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The progression of diabetic nephropathy can be arrested by an improvement in diabetic control. High glucose concentrations increase the flux through the aldose reductase pathway, and it has been proposed that this may contribute to renal damage. Aldose reductase is present in both the glomerulus and the renal tubule. Biochemical changes associated with increased sorbitol production have been demonstrated in animal models, including myo-inositol depletion, reduced Na+-K+ ATPase activity, and activation of the pentose phosphate and glucuronate-xylose pathways. Selective inhibition of aldose reductase reverses these biochemical changes and prevents some of the structural and functional abnormalities in diabetic rats. The potential beneficial effects of aldose reductase inhibitors on diabetic kidney disease in man are at present being investigated.
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Affiliation(s)
- D Stribling
- Bioscience II, ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, England
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