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      Progression of Diabetic Nephropathy

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          Abstract

          Nephropathy in patients with type I and II diabetes mellitus is a rapidly increasing problem worldwide. Studies using both glomerular and tubular cells have delineated some of the consequences induced by acute hyperglycemia. In vitro studies have clearly demonstrated that exposure of cultured renal cells, such as glomerular mesangial cells and proximal tubular epithelial cells, to elevated glucose concentrations, may alter cell proliferation and/or extracellular matrix turnover. The latter is effected both directly and indirectly by the alteration of cytokine generation. Furthermore, these in vitro studies have allowed detailed examination of the mechanisms by which exposure of these cells to high ambient glucose concentrations may alter cell function. Extension of these studies to the experimental in vivo situation has confirmed most of the in vitro findings. Important insights gained from models of type I diabetes (i.e. streptocotocin–induced diabetes) as well as type II diabetes (i.e. Goto–Kakizaki (GK) rats and obese Zucker rats) include: (1) The demonstration that increased glomerular cell proliferation and renal matrix accumulation, driven by TGF–β and/or PDGF, occur in streptocotocin–induced diabetes, yet that nephropathy in these rats does not progress to renal failure. (2) The demonstration that prolonged mild type II diabetes does induce morphological changes characteristic of pre–clinical diabetic nephropathy in GK–rats but does not result in albuminuria or progressive renal disease. (3) The demonstration that the association of type II diabetes with hyperlipidemia in obese Zucker rats results in early podocyte damage and subsequent progression to glomerulosclerosis, tubulointerstitial damage, and renal insufficiency. Identification of the mediators involved in the above processes and in particular of the conditions that will determine progression of subclinical morphological changes to overt nephropathy and renal failure will likely result in future novel therapeutic approaches to diabetic nephropathy.

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          Most cited references 5

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          The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus.

          A cause-and-effect relation between blood glucose concentrations and microvascular complications in patients with insulin-dependent diabetes mellitus has not been established. We randomly assigned 102 patients with insulin-dependent diabetes mellitus, nonproliferative retinopathy, normal serum creatinine concentrations, and unsatisfactory blood glucose control to intensified insulin treatment (48 patients) or standard insulin treatment (54 patients). We then evaluated them for microvascular complications after 18 months and 3, 5, and 7.5 years. Mean (+/- SD) glycosylated hemoglobin values were reduced from 9.5 +/- 1.3 percent to 7.1 +/- 0.7 percent in the group receiving intensified treatment and from 9.4 +/- 1.4 percent to 8.5 +/- 0.7 percent in the group receiving standard treatment (P = 0.001). In 12 of the patients receiving intensified treatment (27 percent of those included in the analysis) and 27 of those receiving standard treatment (52 percent), serious retinopathy requiring photocoagulation developed (P = 0.01). Visual acuity decreased in 6 patients receiving intensified treatment (14 percent) and in 18 receiving standard treatment (35 percent) (P = 0.02). Nephropathy (urinary albumin excretion, > 200 micrograms per minute) developed in one patient in the group receiving intensified treatment, as compared with nine patients in the group receiving standard treatment (P = 0.01). No patient in the intensified-treatment group had nephropathy with subnormal glomerular filtration rates, as compared with six patients in the standard-treatment group (P = 0.02). The conduction velocities of the ulnar, tibial, peroneal, and sural nerves decreased significantly more in the standard-treatment group than in the intensified-treatment group. The odds ratio for serious retinopathy was 0.4 (95 percent confidence interval, 0.2 to 1.0; P = 0.04) in the intensified-treatment group as compared with the standard-treatment group. The corresponding odds ratio for nephropathy was 0.1 (95 percent confidence interval, 0 to 0.8; P = 0.04). Long-term intensified insulin treatment, as compared with standard treatment, retards the development of microvascular complications in patients with insulin-dependent diabetes mellitus.
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            Reversal of lesions of diabetic nephropathy after pancreas transplantation.

            In patients with type I diabetes mellitus who do not have uremia and have not received a kidney transplant, pancreas transplantation does not ameliorate established lesions of diabetic nephropathy within five years after transplantation, but the effects of longer periods of normoglycemia are unknown. We studied kidney function and performed renal biopsies before pancreas transplantation and 5 and 10 years thereafter in eight patients with type I diabetes but without uremia who had mild to advanced lesions of diabetic nephropathy at the time of transplantation. The biopsy samples were analyzed morphometrically. All patients had persistently normal glycosylated hemoglobin values after transplantation. The median urinary albumin excretion rate was 103 mg per day before transplantation, 30 mg per day 5 years after transplantation, and 20 mg per day 10 years after transplantation (P=0.07 for the comparison of values at base line and at 5 years; P=0.11 for the comparison between base line and 10 years). The mean (+/-SD) creatinine clearance rate declined from 108+/-20 ml per minute per 1.73 m2 of body-surface area at base line to 74+/-16 ml per minute per 1.73 m2 at 5 years (P<0.001) and 74+/-14 ml per minute per 1.73 m2 at 10 years (P<0.001). The thickness of the glomerular and tubular basement membranes was similar at 5 years (570+/-64 and 928+/-173 nm, respectively) and at base line (594+/-81 and 911+/-133 nm, respectively) but had decreased by 10 years (to 404+/-38 and 690+/-111 nm, respectively; P<0.001 and P=0.004 for the comparisons with the base-line values). The mesangial fractional volume (the proportion of the glomerulus occupied by the mesangium) increased from base line (0.33+/-0.07) to 5 years (0.39+/-0.10, P=0.02) but had decreased at 10 years (0.27+/-0.02, P=0.05 for the comparison with the baseline value and P=0.006 for the comparison with the value at 5 years), mostly because of a reduction in mesangial matrix. Pancreas transplantation can reverse the lesions of diabetic nephropathy, but reversal requires more than five years of normoglycemia.
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              Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy.

              The relationship between hyperglycemia, measured by glycosylated hemoglobin at the initial examination, and the four-year incidence and progression of diabetic retinopathy was examined in a population-based study in Wisconsin. Younger- (n = 891) and older-onset (n = 987) persons participating in baseline and follow-up examinations were included. Glycosylated hemoglobin was measured by microcolumn. Retinopathy was determined from stereoscopic fundus photographs. In the younger-onset group, comparing the highest with the lowest quartile of glycosylated hemoglobin, the relative risk for developing any diabetic retinopathy was 1.9; for proliferative retinopathy, 21.8; and for progression, 4.0. Among older-onset persons taking insulin, the corresponding relative risks were 1.9, 4.0, and 2.1. Among older-onset persons not taking insulin, relative risks were 4.0 for any retinopathy and 6.2 for progression. A positive relationship between incidence and progression of retinopathy and glycosylated hemoglobin remained after controlling for duration of diabetes, age, sex, and baseline retinopathy. These data suggest a strong and consistent relationship between hyperglycemia and incidence and progression of retinopathy.
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                978-3-8055-6876-0
                978-3-318-00155-6
                1420-4096
                1423-0143
                1999
                1999
                18 May 1999
                : 22
                : 1-2
                : 81-97
                Affiliations
                aInstitute of Nephrology, Cardiff Royal Infirmary, Cardiff, UK; bDivision of Nephrology, Medizinische Hochschule, Hannover, Germany
                Article
                25912 Kidney Blood Press Res 1999;22:81–97
                10.1159/000025912
                10352411
                © 1999 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 13, Tables: 2, References: 127, Pages: 17
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/25912
                Categories
                Paper

                Cardiovascular Medicine, Nephrology

                Mesangial cell, Podocyte, Tubular cells, Diabetes mellitus, Matrix

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