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Biomedical subjects

M E Cooper

Publications and source records attributed to M E Cooper.

At least 127 records · Page 7Linked to original sources
PubMed1997

Rat amylin mediates a pressor response in the anaesthetised rat: implications for the association between hypertension and diabetes mellitus.

Amylin (or islet amyloid polypeptide) has been reported to have binding sites in the central nervous system and the kidney and has been shown to activate plasma renin. It has been postulated that this peptide may be an important mechanistic link between hypertension and diabetes in the insulin resistance syndrome. To explore this issue, the effects of rat amylin on mean arterial blood pressure were investigated in anaesthetised rats. Amylin elicited a pressor response of approximately 10 mmHg (maximal at 100 pmol.kg-1) which was apparent within 30-60 s and persisted over 15 min. At higher concentrations amylin elicited a hypotensive response (negative log IC50 8.52 mol.kg-1). The novel amylin receptor antagonist AC413 (12 nmol.kg-1.min-1) reduced the pressor response but not the hypotensive effects of amylin. The peptide antagonist calcitonin gene-related peptide (CGRP)8-37 (12 nmol.kg-1.min-1) reduced the pressor response elicited by amylin and also antagonized the hypotensive effect of amylin. Pre-treatment of animals with the ganglion blocker mecamylamine (3 mg.kg-1 s.c.) reduced the pressor effect of amylin. Following the administration of the angiotensin converting enzyme inhibitor ramiprilat (300 nmol.kg-1 i.v.) the pressor response to amylin was reduced. Salmon calcitonin also elevated blood pressure in the anaesthetised rat; doses of amylin and salmon calcitonin associated with a pressor effect were associated with increases in plasma renin activity. We conclude that amylin may act centrally to elevate blood pressure in the anaesthetised rat, possibly through activation of the renin angiotensin system.

Amino Acid Sequence↗
PubMed1997

Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury.

Advanced glycation end products (AGEs) are believed to play an important role in the development of diabetic complications. AGEs are increased in experimental diabetes and treatment with the inhibitor of advanced glycation end products, aminoguanidine, has been shown to attenuate the level of these products in tissues undergoing complications. Recently, an AGE-binding protein has been isolated from bovine lung endothelial cells and termed the receptor for advanced glycated end products (RAGE). The present study sought to determine the distribution of AGE and RAGE in tissues susceptible to the long-term complications of diabetes including the kidney, eye, nerve, arteries as well as in a tissue resistant to such complications, the lung. Using polyclonal antisera both AGE and RAGE were found to co-localize in the renal glomerulus. AGE staining was clearly increased with age and was further increased by diabetes. Aminoguanidine treatment reduced AGE accumulation in the kidney. Co-localisation of AGE and RAGE was demonstrated in the inner plexiform layer and the inner limiting membrane of the retina and in nerve bundles from mesenteric arteries. In the aorta, both AGE and RAGE were found in the intima, media and adventitia. Medial staining was increased in diabetes and was reduced by aminoguanidine treatment. A similar pattern was observed for RAGE in the aorta. In the lung, RAGE was found widely distributed throughout the lung whereas the distribution of AGE staining was more limited, primarily localising to macrophages. The co-localisation of AGEs and RAGE in sites of diabetic microvascular injury suggests that this ligand-receptor interaction may represent an important mechanism in the genesis of diabetic complications.

Animals↗
PubMed1997

Increased epidermal growth factor in experimental diabetes related kidney growth in rats.

Renal enlargement is a characteristic feature of human and experimental diabetes mellitus that may be predictive of subsequent nephropathy. In the streptozotocin diabetic rat kidney growth rapidly follows the induction of experimental diabetes but the mechanisms responsible for this growth are poorly understood. Epidermal growth factor (EGF) is a potent mitogen for renal tubular cells. Thirty one male Sprague-Dawley rats aged 13 weeks were randomised to receive either streptozotocin (diabetic, n = 20) or buffer (control, n = 11). Animals were studied on days 1, 3, 5 and 7 following streptozotocin. Diabetes was associated with a 3-fold increase in urinary EGF excretion (223 +/- 15 vs 59 +/- 5 ng/day, mean +/- SEM, diabetic vs control, p < 0.0001) and 3-6 fold increase in renal EGF mRNA relative to controls (p < 0.001). A transient rise in kidney EGF protein was noted on day 1. There was no difference between diabetic and control animals with regard to intrarenal sites of EGF expression or in plasma EGF. These data suggest that the increased urinary EGF excretion in diabetic animals is the result of enhanced local production and that EGF is not stored for a prolonged period within renal tubular cells but is released following its synthesis. In the context of the known intrarenal actions of EGF this growth factor may play a role in the pathogenesis of diabetes related kidney growth.

Animals↗
PubMed1997

Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats.

Advanced glycation end products (AGEs) have previously been shown to be increased in the diabetic kidney. Aminoguanidine, an inhibitor of advanced glycation, has been shown to attenuate the development of AGEs as well as the progression of renal disease in experimental diabetes. However, the precise mechanisms through which aminoguanidine acts remain to be elucidated since it is also able to act as an inhibitor of nitric oxide synthase (NOS). This study has therefore compared the effects of aminoguanidine with the effects of two other inhibitors of NOS, L-NAME and methylguanidine, on the development of experimental diabetic nephropathy. Diabetic rats were randomised to receive no treatment, aminoguanidine (1 g/l in drinking water), L-NAME (5 mg/l in drinking water) or methylguanidine (1 g/l in drinking water). Diabetic rats had increased levels of albuminuria and urinary nitrite/nitrate excretion when compared to control rats. Renal AGEs measured by fluorescence as well as by a carboxymethyllysine reactive radioimmunoassay, were elevated in diabetic rats. No changes in inducible NOS (iNOS) protein expression were detected in experimental diabetes nor did aminoguanidine affect iNOS expression. Aminoguanidine did not affect blood glucose or HbA1c but it did prevent increases in albuminuria, urinary nitrites/nitrates and renal AGE levels as measured by fluorescence and radioimmunoassay. L-NAME and methylguanidine did not retard the development of albuminuria, nor did they prevent increases in renal AGE levels, as assessed by fluorescence. However, these treatments did prevent increases in AGEs, as measured by radioimmunoassay. This study indicates that the renoprotective effect of aminoguanidine in experimental diabetes cannot be reproduced by L-NAME or methylguanidine. It is likely that the effect of aminoguanidine is mediated predominantly by decreased AGE formation rather than via NOS inhibition. It also raises the possibility that inhibition of fluorescent AGE formation may be more renoprotective than inhibition of the formation of carboxymethyllysine-containing AGEs.

Administration, Oral↗
PubMed1997

Transforming growth factor beta 1 and renal injury following subtotal nephrectomy in the rat: role of the renin-angiotensin system.

Transforming growth factor-beta (TGF-beta) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of chronic renal disease. The present experiment investigated the chronology of TGF-beta 1 gene expression following subtotal nephrectomy (STNx) in the rat and the effect of blocking the RAS by angiotensin converting enzyme (ACE) inhibition or by angiotensin II receptor (AT1) antagonism. Rats that had undergone subtotal nephrectomy developed hypertension, proteinuria, renal impairement, glomerulosclerosis, tubulointerstitial fibrosis and mononuclear cell infiltration. These changes were associated with a 2.5-fold increase in TGF-beta 1 gene expression during a 16-week time course. In situ hybridization localized TGF-beta 1 mRNA to sclerotic glomeruli, areas of tubuloin-terstitial injury and sites of mononuclear cell infiltration. Administration of the ACE inhibitor ramipril and the AT1 receptor blocker valsartan blunted the increase in TGF-beta 1 mRNA, and attenuated the structural and functional manifestations of injury. These data suggest an interaction between the intrarenal RAS and TGF-beta in the pathogenesis of the glomerular and tubulointerstitial fibrosis that follow a major reduction in renal mass.

Angiotensin II↗
PubMed1997

Renal amylin binding in normotensive and hypertensive rats: effects of angiotensin converting enzyme inhibition with perindopril.

OBJECTIVES: To investigate the effect of angiotensin converting enzyme inhibition with perindopril on the binding density of [125I]-rat amylin in the renal cortex in normotensive Sprague-Dawley rats, renally ablated hypertensive rats and spontaneously hypertensive rats. DESIGN: Sprague-Dawley rats, renally ablated hypertensive rats and spontaneously hypertensive rats were administered either the angiotensin converting enzyme inhibitor perindopril or no treatment. METHODS: The density of [125I]-rat amylin binding was measured in the renal cortex using autoradiography in vitro. The systolic blood pressure was measured by indirect tail-cuff plethysmography. The plasma renin activity was measured by radioimmunoassay. RESULTS: The density of [125I]-amylin binding was reduced by approximately 50% in Sprague-Dawley and subtotally nephrectomized Sprague-Dawley rats after treatment with perindopril. These changes were associated with a reduction in systolic blood pressure and an increase in plasma renin activity. In contrast, amylin binding in the perindopril-treated spontaneously hypertensive rats was not reduced, despite the prevention of a rise in systolic blood pressure and an increase in plasma renin activity. CONCLUSIONS: These findings provide further evidence for the hypothesis that there is an association among renal amylin binding, the renin-angiotensin system and blood pressure for rats of the Sprague-Dawley strain. In contrast, the lack of an effect of angiotensin converting enzyme inhibition on renal amylin binding for rats of the spontaneously hypertensive rat strain is consistent with previous findings that the changes in amylin binding in rats of this strain are not linked directly to the prevailing systemic blood pressure but may be associated with a developmental abnormality in the kidney of these rats.

Amyloid↗
PubMed1997

Amylin stimulates proximal tubular sodium transport and cell proliferation in the rat kidney.

In autoradiographic studies in anesthetized rats, 125I-labeled amylin binding was associated with proximal convoluted tubules but not distal tubules, interstitium, or glomeruli in the renal cortex. Split-drop micropuncture experiments showed that perfusion of the peritubular capillaries with amylin (10(-9) M) stimulated proximal tubular fluid absorption by 28%. This effect was inhibited by luminal addition of ethylisopropylamiloride, indicating mediation by a brush-border Na+/H+ exchanger. Intravenous infusion of an amylin binding antagonist, AC-187, reduced proximal fluid reabsorption (22%) in anesthetized rats, indicating a role for endogenous amylin in salt homeostasis. In primary cultures of rat proximal tubule cells, amylin (10(-7) M) stimulated proliferation with a potency equal to epidermal growth factor. Peptide antagonists (AC-187, AC-413, and AC-512) of the amylin binding sites in the renal cortex blocked the mitogenic action of amylin. We conclude that amylin acts on renal proximal tubules to promote sodium and water reabsorption and cell proliferation. These novel actions may have implications for the development of hypertension for example in non-insulin-dependent diabetes mellitus and obesity in which hyperamylinemia has been observed.

Absorption↗
PubMed1997

Increased density of renal amylin binding sites in experimental hypertension.

High-affinity binding sites for the pancreatic beta-cell hormone amylin have been reported in the kidney, and it has been postulated that these sites may be involved in the genesis of hypertension. In the present study, we have used in vivo injection of 125I-amylin and in vitro autoradiographic techniques to assess renal amylin binding in both a genetic and a surgically induced model of hypertension. In the spontaneously hypertensive rat (SHR) at 6 weeks of age, before the rise in systolic blood pressure, there was a 36% increase in density of amylin binding compared with their normotensive counterpart, the Wistar-Kyoto rat (WKY). In SHR, there was a further increase in the density of amylin binding (to 53% greater) as the systolic blood pressure rose between 6 and 12 weeks of age. Histological examination of kidneys from SHR at 12 weeks of age revealed staining for a brush border glycoprotein, normally restricted to the proximal tubules, extending from the urinary pole into half of the epithelial lining of the glomerular capsule. In contrast to WKY, these cells also bound 125I-amylin with high density in SHR. In a rat model of renal ablation and hypertension, systolic blood pressure correlated with the density of 125I-amylin binding in the renal cortex (r=.54, P=.003, n=28). The changes in amylin binding reported here suggest a possible role for this peptide and/or activation of its receptor in the genesis as well as the maintenance of hypertension.

Amyloid↗
PubMed1997

Secreted protein acidic and rich in cysteine expression after subtotal nephrectomy and blockade of the renin-angiotensin system.

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix-associated protein with antiadhesive, antiproliferative, and matrix remodeling properties. SPARC gene and protein expression were investigated after subtotal nephrectomy (STNx), a model of noninflammatory progressive renal injury. In addition, the effect of blockade of the renin-angiotensin system by the angiotensin-converting enzyme inhibitor ramipril or by the angiotensin II receptor antagonist valsartan was examined. The STNx rats developed hypertension, proteinuria, and renal impairment. These changes were associated with a 2.4-fold increase in SPARC gene expression in STNx compared with SHAM kidneys (P < 0.001). In situ hybridization revealed increased SPARC mRNA in glomeruli and interstitial cells, as well as de novo expression by tubular epithelial cells at sites of renal injury. Immunofluorescence studies confirmed concordant changes in SPARC protein. Both ramipril and valsartan ameliorated renal injury and significantly reduced SPARC overexpression in the STNx animals. The findings of the present study suggest that SPARC, in the context of its known biological actions, may influence some of the pathological features associated with significant renal mass reduction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Salt restriction reduces hyperfiltration, renal enlargement, and albuminuria in experimental diabetes.

The effects of dietary salt restriction on the renin-angiotensin system, glomerular filtration rate (GFR), renal size, and albuminuria were assessed in streptozotocin diabetic rats. Two series of experiments were performed: one short-term with severe salt restriction and the second long-term with moderate salt restriction. The first studied the effect of a very-low-salt diet for 4 weeks on GFR, renal size, and plasma angiotensin II concentration in diabetic and control rats. Diabetic and control male Sprague-Dawley rats received either a very-low-salt (0.005% NaCl) or a normal-salt (0.4% NaCl) diet. Diabetes was associated with a 49% increase in GFR, a 34% increase in kidney weight, and an 85% reduction in plasma angiotensin II when compared with control rats (P < 0.001). Sodium restriction in diabetic rats reduced GFR, restored plasma angiotensin II to control values, and retarded kidney growth when compared with diabetic rats receiving a normal sodium diet. GFR correlated negatively with plasma angiotensin II (r = -0.65, P < 0.001) and positively with kidney weight (r = 0.66, P < 0.001). In the second experiment, serial measurements of albuminuria and GFR were performed in control, diabetic, and salt-restricted (0.05% NaCl) control and diabetic rats over 24 weeks. Albuminuria showed a continuous rise in the diabetic rats when compared with control rats. Salt restriction attenuated the increase in albuminuria over the whole study period as well as reducing blood pressure and kidney weight in the diabetic rats. In conclusion, sodium restriction was associated with a lower GFR and kidney weight after 4 weeks and reduced levels of albuminuria, kidney weight, and blood pressure after 24 weeks in diabetic rats. Salt restriction may have an important role in the prevention and treatment of diabetic nephropathy.

Albuminuria↗
PubMed1997

Role of angiotensin II and bradykinin in experimental diabetic nephropathy. Functional and structural studies.

We explored the relative roles of the suppression of angiotensin II and the prevention of bradykinin degradation in mediating the renoprotective effects of ACE inhibitors in experimental diabetic nephropathy. Over a 24-week period, we studied male Sprague-Dawley diabetic and control rats and Sprague-Dawley diabetic rats treated with the ACE inhibitor ramipril, the angiotensin II-AT1 receptor antagonist valsartan, the bradykinin-B2 receptor antagonist HOE 140 (icatibant), and a combination of ramipril and icatibant. Serial measurements of urinary albumin excretion, blood pressure, and glycated hemoglobin were performed monthly. After 6 months, the animals were killed for the measurement of kidney weight and the assessment of glomerular ultrastructure. Over 24 weeks, urinary albumin excretion showed a continuous rise in the untreated diabetic rats. Both ramipril and valsartan, which were equihypotensive, prevented the increase in urinary albumin excretion over the whole study period. Icatibant therapy did not attenuate the antialbuminuric effect of the ACE inhibitor, nor did it have any effect as the sole therapy. Diabetes was associated with increased glomerular basement membrane thickness, glomerular volume, and total mesangial volume. Both ACE inhibition and angiotensin II receptor antagonism attenuated the glomerular ultrastructural changes to a similar degree. Icatibant did not attenuate the effects of ramipril on glomerular morphology. ACE inhibitors and angiotensin II-AT1 receptor blockers appear to confer similar benefits in experimental diabetic nephropathy, and bradykinin-B2 receptor blockers do not influence this effect. These findings suggest that the blockade of angiotensin II is the major pathway responsible for renoprotection afforded by ACE inhibition in experimental diabetic nephropathy.

Albuminuria↗
PubMed1997

Macrophage and myofibroblast proliferation in remnant kidney: role of angiotensin II.

Local macrophage proliferation has been shown to be a major mechanism of macrophage accumulation in several immunologically-induced animal models of renal diseases. This study has explored whether local proliferation of macrophages and myofibroblasts contribute to their accumulation in rat remnant kidney model and investigated the role of angiotensin II (Ang II) in these cellular pathological events by blocking the angiotensin II activity with ramipril, and angiotensin converting enzyme (ACE) inhibitor, or valsartan, an Ang II type 1 receptor antagonist. There was local proliferation of macrophages and myofibroblasts within renal parenchyma following renal ablation, contributing significantly to macrophage and myofibroblasts accumulation, renal dysfunction and fibrosis. Both treatment resulted in inhibition of local proliferation of macrophages and myofibroblasts and this was associated with attenuation of renal injury. In conclusion, inhibition of local macrophage and myofibroblast proliferation may be an important mechanism by which Ang II blockade attenuated renal injury following renal ablation.

Angiotensin II↗
PubMed1996

Contemporary practice of coronary revascularization in U.S. hospitals and hospitals participating in the bypass angioplasty revascularization investigation (BARI).

OBJECTIVES: To assess generalizability of the Bypass Angioplasty Revascularization Investigation (BARI), we conducted a separate study comparing revascularization in U.S. and BARI hospitals. BACKGROUND: The BARI trial is a multicenter investigation comparing initial revascularization with percutaneous transluminal coronary angioplasty and coronary bypass graft surgery in patients with symptomatic multivessel coronary disease. METHODS: All revascularization procedures during 5 consecutive workdays were surveyed at 75 U.S. hospitals offering coronary angioplasty and bypass surgery and at all BARI hospitals. Data collected were demographics, extent of disease and type of current and previous revascularization. RESULTS: At both U.S. and BARI hospitals, 57% of all revascularization procedures were coronary angioplasty and 43% were bypass surgery. The U.S. hospitals had more patients with single-vessel disease, acute myocardial infarction and primary procedures. Other characteristics were similar. The majority of revascularization procedures were angioplasty for single-vessel disease (U.S. 32% vs. BARI 25%) and bypass surgery for triple-vessel disease (U.S. 31% vs. BARI 31%). Overall, the choice between bypass surgery and angioplasty was similar in BARI and U.S. hospitals (adjusted odds ratio [OR] 1.0, p = 0.914). However, older patients were more likely and younger patients less likely to undergo bypass surgery in BARI versus U.S. hospitals (older patients: adjusted OR 1.6, p = 0.031; younger patients: adjusted OR 0.6, p = 0.028). The BARI protocol would have excluded 65% of all candidates for revascularization, for whom indications already exist for angioplasty or bypass surgery, and another 23%, for whom angioplasty would be contraindicated for individual lesions. CONCLUSIONS: Patients undergoing coronary revascularization in BARI and U.S. hospitals were generally similar, as was the choice between types of revascularization. Results from the BARI trial apply to approximately 300 (12%) candidates for coronary revascularization/workday.

Aged↗
PubMed1996

Vascular hypertrophy and albumin permeability in a rat model combining hypertension and diabetes mellitus. Effects of calcium antagonism, angiotensin converting enzyme inhibition, and angiotensin II-AT1-receptor blockade.

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats. There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.

Analysis of Variance↗
PubMed1996

Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment.

It has been postulated that the accumulation of advanced glycation end products (AGEs) in the kidney is important in the pathogenesis of diabetic nephropathy. Previously, aminoguanidine has been shown to inhibit the accumulation of renal AGEs and to retard the development of experimental diabetic nephropathy. The present study serially assessed the accumulation of AGEs in the aorta and kidney, as well as renal functional and structural parameters over 32 weeks of experimental diabetes in the absence and presence of aminoguanidine. In addition, it was determined if aminoguanidine was more effective if administered earlier or later in the evolution of diabetic nephropathy by treating diabetic rats with aminoguanidine in the first or second half of the 32-week study period. In the serial studies, glomerular and renal tubular fluorescence increased over the 32 week period and this increase was attenuated by aminoguanidine treatment. Concomitant with the effects of aminoguanidine on fluorescence, there was a retardation in the rise in urinary albumin excretion and prevention of mesangial expansion. Early or late administration of aminoguanidine in diabetic rats reduced tissue fluorescence in glomeruli and renal tubules. At 32 weeks, renal AGEs were increased in diabetic rats as assessed by tissue fluorescence. Using a specific RIA, renal AGEs were increased in diabetic rats and decreased by aminoguanidine treatment, administered over the entire 32 weeks or in the first or latter half of the 32-week study period. Aminoguanidine therapy for the entire 32-week study period retarded the rise in albuminuria in the diabetic rats and was more effective than 16 weeks of treatment either in the first or second half of the study. Early and late aminoguanidine administration were similar in their capacity to retard the development of albuminuria in diabetic rats. Similar effects were observed on mesangial expansion. The increased glomerular basement thickness in diabetic rats was not affected by aminoguanidine, irrespective of duration or timing of therapy. This study confirms that in vivo generation of AGEs in the kidney is time dependent and closely linked to the development of experimental diabetic nephropathy. The renoprotective effects of aminoguanidine in diabetes appear to be related to the duration but not to the timing of treatment.

Animals↗
PubMed1996

Serum total renin is increased before microalbuminuria in diabetes.

Serum prorenin is increased in patients with insulin dependent diabetes mellitus (IDDM) with microvascular complications. The present longitudinal study investigated whether increases in serum total renin concentration (TRC, active+prorenin) can predict the development of microalbuminuria in IDDM patients over a 10 year period. TRC and albumin excretion rates (AER) were determined in 78 IDDM patients who were followed longitudinally for 10.4 +/- 0.2 (mean +/- SE) years. Twelve patients had progressively increasing albuminuria (progressors), and these were compared to 66 patients in whom albuminuria did not rise (non-progressors). The two groups had similar duration of diabetes, age, follow-up, glycemic control and blood pressure at the start of the study. Serum TRC was increased in progressors [350 (1.1) mIU/liter, geometric mean (tolerance factor)] compared to non-progressors [189 (1.2)] after 5 to 10 years duration of diabetes, and continued to rise in this group, reaching a mean of 923 mIU/liter (normal range 131 to 170) after 20 years of diabetes. When serial measurements of TRC and AER were compared in individual progressors, a significant increase in TRC was apparent up to five years before the onset of microalbuminuria. Microalbuminuria in patients with IDDM is preceded by a substantial increase in serum TRC, suggesting that serum TRC may predict the subsequent development of incipient nephropathy.

Adolescent↗