ACE inhibitor use and the increased long-term risk of renal failure in diabetes.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
G J Navis
Publications and source records attributed to G J Navis.
Predictive capacity of pre-donation GFR and renal reserve capacity for donor renal function after living kidney donation.
Kidney transplantation from living donors is important to reduce organ shortage. Reliable pre-operative estimation of post-donation renal function is essential. We evaluated the predictive potential of pre-donation glomerular filtration rate (GFR) (iothalamate) and renal reserve capacity for post-donation GFR in kidney donors. GFR was measured in 125 consecutive donors (age 49 +/- 11 years; 36% male) 119 +/- 99 days before baseline GFR (GFRb) and 57 +/- 16 days after donation (GFRpost). Reserve capacity was assessed as GFR during stimulation by low-dose dopamine (GFRdopa), amino acids (GFRAA) and both (GFRmax). GFRb was 112 +/- 18, GFRdopa 124 +/- 22, GFRAA 127 +/- 19 and GFRmax 138 +/- 22 mL/min. After donation, GFR remained 64 +/- 7%. GFRpost was predicted by GFRb(R2 = 0.54), GFRdopa(R2 = 0.35), GFRAA(R2 = 0.56), GFRmax(R2 = 0.55)and age (R2 = -0.22; p < 0.001 for all). Linear regression provided the equation GFRpost = 20.01 + (0.46*GFRb). Multivariate analysis predicted GFRpost by GFRb, age and GFRmax(R2 = 0.61, p < 0.001). Post-donation renal function impairment (GFR < or = 60 mL/min/1.73 m2) occurred in 31 donors. On logistic regression, GFRb, body mass index (BMI) and age were independent predictors for renal function impairment, without added value of reserve capacity. GFR allows a relatively reliable prediction of post-donation GFR, improving by taking age and stimulated GFR into account. Long-term studies are needed to further assess the prognostic value of pre-donation characteristics and to prospectively identify subjects with higher risk for renal function loss.
Donor Selection↗
Obesity and renal hemodynamics.
Obesity is a risk factor for renal damage in native kidney disease and in renal transplant recipients. Obesity is associated with several renal risk factors such as hypertension and diabetes that may convey renal risk, but obesity is also associated with an unfavorable renal hemodynamic profile independent of these factors, and that may exert effects on renal damage as well. In animal models of obesity-associated renal damage, micro-puncture studies showed glomerular hypertension and hyperfiltration. In humans an elevated glomerular filtration rate has been demonstrated in several studies, sometimes associated with hyperperfusion as well, independent of blood pressure or the presence of diabetes. An elevated filtration fraction was found in several studies, consistent with glomerular hypertension. This renal hemodynamic profile resembles the hyperfiltration pattern in diabetes and is therefore assumed to be a pathogenetic factor in renal damage. Of note, the association between body mass index and renal hemodynamics is not limited to overt obesity or overweight, but is also present across the normal range, without a particular threshold. Multiple factors are assumed to contribute to these renal hemodynamic alterations, such as insulin resistance, the renin-angiotensin system and the tubulo-glomerular responses to increased proximal sodium reabsorption, and possibly also inappropriate activity of the sympathetic nervous system and increased leptin levels. Obesity has a high world-wide prevalence. On a population-basis, therefore, its contribution to long-term renal risk may be considerable, especially as it is usually clustered with risk factors like hypertension and insulin resistance. In short-term studies the renal hemodynamic alterations in obesity and the associated proteinuria were reversible by weight loss, and renin-angiotensin system-blockade, respectively. These interventions are therefore likely to have the potential to limit the renal risks of obesity.
Animals↗
[The guideline 'Diagnosis and treatment of peripheral artery disease of the lower extremities' of The Netherlands Surgical Society].
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Humans↗
Effect of dexamethasone on perioperative renal function impairment during cardiac surgery with cardiopulmonary bypass.
BACKGROUND: In cardiac surgery with cardiopulmonary bypass (CPB), corticosteroids are administered to attenuate the physiological changes caused by the systemic inflammatory response. The effects of corticosteroids on CPB-associated renal damage have not been documented. The purpose of this study was to evaluate the effects of dexamethasone on perioperative renal dysfunction in patients undergoing cardiac surgery with CPB. METHODS: Renal damage was prospectively studied in 20 patients without concomitant morbidity undergoing coronary artery surgery with CPB. Patients were randomized in a double-blind fashion to receive dexamethasone or placebo. Markers of glomerular function (creatinine clearance) and damage (microalbuminuria), and markers of tubular function (fractional excretion of sodium and free water clearance) and damage (N-acetyl-beta-D glucosaminidase (NAG)) were evaluated in addition to plasma and urinary glucose levels. Plasma and urinary specimens were obtained at the following time periods: (1) baseline, during the 12 h before surgery; (2) skin incision before heparinization; (3) from heparinization until the end of CPB; (4) during the 2 h following weaning from CPB; (5) in the intensive care unit from 2 to 6 h after weaning of CBP; (6) and from 36 to 60 h after weaning of CPB. RESULTS: CPB was associated with an increase in markers in the placebo group, which returned to baseline during the second postoperative day, demonstrating a transient impairment of glomerular and tubular renal function. Similar patterns were observed in patients treated with dexamethasone. While postoperative glycosuria was significantly higher in the dexamethasone-treated group, no other differences between groups were observed. CONCLUSION: Dexamethasone administration before CPB has no protective effect on perioperative renal dysfunction in low-risk cardiac surgical patients.
Aged↗
[Diabetic nephropathy: the role of blood pressure and extra-cellular volume in its pathogenesis and treatment].
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Diabetic Nephropathies↗
Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS-CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations.
Arteries↗
Renal ACE2 expression in human kidney disease.
Angiotensin-converting enzyme 2 (ACE2) is a recently discovered homologue of angiotensin-converting enzyme (ACE) that is thought to counterbalance ACE. ACE2 cleaves angiotensin I and angiotensin II into the inactive angiotensin 1-9, and the vasodilator and anti-proliferative angiotensin 1-7, respectively. ACE2 is known to be present in human kidney, but no data on renal disease are available to date. Renal biopsies from 58 patients with diverse primary and secondary renal diseases were studied (hypertensive nephropathy n = 5, IgA glomerulopathy n = 8, minimal change nephropathy n = 7, diabetic nephropathy n = 8, focal glomerulosclerosis n = 5, vasculitis n = 7, and membranous glomerulopathy n = 18) in addition to 17 renal transplants and 18 samples from normal renal tissue. Immunohistochemical staining for ACE2 was scored semi-quantitatively. In control kidneys, ACE2 was present in tubular and glomerular epithelium and in vascular smooth muscle cells and the endothelium of interlobular arteries. In all primary and secondary renal diseases, and renal transplants, neo-expression of ACE2 was found in glomerular and peritubular capillary endothelium. There were no differences between the various renal disorders, or between acute and chronic rejection and control transplants. ACE inhibitor treatment did not alter ACE2 expression. In primary and secondary renal disease, and in transplanted kidneys, neo-expression of ACE2 occurs in glomerular and peritubular capillary endothelium. Further studies should elucidate the possible protective mechanisms involved in the de novo expression of ACE2 in renal disease.
Angiotensin-Converting Enzyme 2↗
Sodium intake affects urinary albumin excretion especially in overweight subjects.
OBJECTIVES: To examine the relationship between sodium intake and urinary albumin excretion, being an established risk marker for later cardiovascular morbidity and mortality. DESIGN: Cross-sectional cohort study using linear regression analysis. Setting. University hospital outpatient clinic. SUBJECTS: A cohort drawn from the general population, consisting of 7850 subjects 28-75 years of age, all inhabitants of the city of Groningen, the Netherlands. The cohort is enriched for the presence of subjects with elevated urinary albumin concentration. RESULTS: The results show a positive relationship between dietary sodium intake and urinary albumin excretion. The association was independent of other cardiovascular risk factors (such as sex, age, blood pressure, body mass index (BMI), waist-to-hip ratio, serum cholesterol, plasma glucose and smoking) and other food constituents (calcium, potassium and protein). The relationship between sodium intake and urinary albumin excretion was steeper in subjects with a higher BMI compared with a lower BMI. CONCLUSIONS: Sodium intake is positively related to urinary albumin excretion. This relation is more pronounced in subjects with a higher BMI. These results suggest that high sodium intake may unfavourably influences cardiovascular prognosis especially in overweight and obese subjects.
Adult↗
The influence of the ACE ( I/D) polymorphism on systemic and renal vascular responses to angiotensins in normotensive, normoalbuminuric Type 1 diabetes mellitus.
AIM/HYPOTHESIS: The renin-angiotensin-aldosterone system is important in diabetic nephropathy, with the angiotensin-converting-enzyme DD-genotype being a renal risk factor. The D-allele is associated with higher ACE concentrations, but functional consequences in diabetes mellitus are not known. To analyse these consequences, we assessed renal and systemic responsiveness to angiotensin I infusion, with the response to angiotensin II as reference. METHODS: Uncomplicated Type 1 (insulin-dependent) diabetic patients with contrasting genotypes (11 II and 11 DD) were studied, during low (50 mmol/24 h) and liberal (200 mmol/24 h) sodium diet, during a euglycaemic clamp. Angiotensin I was infused at 4 and 8 ng.kg(-1).min(-1), 1 h each, followed by infusions of angiotensin II after a 2-h wash-out period. RESULTS: During low sodium, DD-homozygotes showed higher blood pressure sensitivity to angiotensin I ( DD 21+/-5% vs II 15+/-5%, p<0.01). With liberal sodium, no differences in blood pressure were detected, whereas angiotensin I induced a higher response of ERPF ( DD 40+/-5% vs II 35+/-4%, p<0.05) and RVR ( DD 105+/-20% and II 89+/-16% p<0.05) in DD-homozygotes. Differences were not explained by altered angiotensin II sensitivity. Multiple-linear regression analysis showed that angiotensin I induced responses of blood pressure and renal haemodynamics are higher in subjects carrying the DD-genotype. The magnitude of the responses was modulated by sodium intake and long-term glycaemic control. CONCLUSION/INTERPRETATION: This study showed that responses of blood pressure and renal haemodynamics to angiotensin I are increased in diabetic subjects carrying the DD-genotype. Genotype-associated differences in ACE concentrations could, under certain circumstances, have functional consequences in uncomplicated Type 1 diabetes mellitus.
Adolescent↗
Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats.
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Retraction Notice↗
Decreased cortisol production in male type 1 diabetic patients.
BACKGROUND: It is unclear whether cortisol production and the 11betaHSD-mediated cortisol to cortisone interconversion are different between type 1 diabetic patients and healthy subjects. MATERIALS AND METHODS: Fourteen male, nonobese, normotensive type 1 diabetic patients without severe complications (HbA1c < 8.5%) were studied twice during a daily sodium intake of 50 and 200 mmol, and were then compared with 14 individually matched healthy subjects. Cortisol production was assessed by the sum of urinary cortisol metabolite excretion. Urinary ratios of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydro-cortisone [(THF + allo-THF)/THE] and of free cortisol/free cortisone [UFF/UFE] were determined as parameters of 11betaHSD activity. RESULTS: Sum of urinary cortisol metabolite excretion during low- and high-salt diet was 7.4 +/- 2.5 vs. 7.7 +/- 2.3 nmol min-1 m-2 (NS) in diabetic patients and 9.7 +/- 2.1 vs. 11.2 +/- 4.1 nmol min-1 m-2 (NS) in healthy subjects, respectively (P < 0.05 vs. healthy subjects at both diets). The allo-THF excretion and allo-THF/THF ratios were lower in the diabetic than in the healthy males during both diets (P < 0.05). Urinary (THF + alloTHF)/THE and UFF/UFE were similar in both groups and remained unchanged after salt loading. CONCLUSIONS: The sum of urinary cortisol metabolite excretion as a measure of cortisol production is lower in nonobese, normotensive type 1 diabetic males with adequate glycaemic control and without severe complications, irrespective of sodium intake. We suggest that this is at least in part as result of diminished 5alpha reductase activity, resulting in a decreased cortisol metabolic clearance. In type 1 diabetic and in healthy males, the 11betaHSD setpoint is not affected by physiological variations in sodium intake.
11-beta-Hydroxysteroid Dehydrogenases↗
Low plasma aldosterone despite normal plasma renin activity in uncomplicated type 1 diabetes mellitus: effects of RAAS stimulation.
BACKGROUND: Data on levels and responsiveness of PRA and aldosterone in type 1 diabetes mellitus are conflicting. Earlier studies were not standardized with respect to the type of diabetes mellitus, the presence of diabetic complications or sodium intake. Therefore, we studied plasma renin activity and plasma aldosterone in uncomplicated type 1 diabetes mellitus by evaluating the effects of endogenous (sodium restriction) and exogenous (angiotensin I infusion) stimulation. DESIGN: Twenty-four type 1 diabetic patients and 24 matched healthy subjects were studied after 1 week of liberal sodium diet (200 mmol 24 h-1) and 1 week of low sodium diet (50 mmol 24 h-1). Angiotensin (Ang)I was infused at 4 and 8 ng kg-1 min-1 during both study days. RESULTS: During liberal and low sodium intake, plasma aldosterone was lower in type 1 diabetic patients compared with healthy subjects both at 08:00 h (P < 0.05) and after a 2-h euglycaemic clamp (P < 0.05), despite similar PRA levels. The correlations between changes in PRA and changes in plasma aldosterone when shifting sodium intake were similar in both groups. During liberal sodium intake, the aldosterone levels after AngI infusion were lower in type 1 diabetic patients, whereas during low sodium they were not different. CONCLUSIONS: Plasma aldosterone was deceased relative to PRA in uncomplicated type 1 diabetic patients, irrespective sodium intake. The responsiveness to sodium restriction was adequate and sodium restriction was able to overcome the decreased plasma aldosterone response to exogenous AngI, which was observed during liberal sodium in diabetic patients. The lower aldosterone is not secondary to diabetic complications and does not depend on the level of sodium intake.
Adult↗
Short-term moderate sodium restriction induces relative hyperfiltration in normotensive normoalbuminuric Type I diabetes mellitus.
AIMS/HYPOTHESIS: Type I (insulin-dependent) diabetes mellitus is associated with an increased extracellular volume. Sodium restriction might seem a logical form of treatment but data on its renal effects is conflicting. We therefore studied the effects of sodium restriction on renal haemodynamics in uncomplicated Type I diabetes mellitus. METHODS: Uncomplicated Type I diabetic patients ( n = 24) and matched control subjects ( n = 24) were studied twice in random order: after a week of 50 mmol or after 200 mmol sodium intake, respectively. The diabetic patients were studied under normoglycaemic clamp conditions. Glomerular filtration rate and effective renal plasma flow were measured as the clearances of iothalamate and hippuran, respectively. RESULTS: During liberal sodium intake, glomerular filtration, effective renal plasma flow and filtration fraction were similar between the diabetic patients and the control subjects. Sodium restriction decreased the effective renal plasma flow in both groups, whereas glomerular filtration rate only decreased in the control subjects. Consequently, in the diabetic patients, the filtration fraction was increased on low sodium (4.1 +/- 8.4 %, p < 0.05 vs liberal sodium). As a consequence, filtration fraction (24.0 +/- 2.6 vs 22.1 +/- 2.0 %, p < 0.05) and glomerular filtration (119 +/- 14 vs 110 +/- 13 ml/min, p < 0.05) were higher in the diabetic patients than in the control subjects during sodium restriction. CONCLUSION/INTERPRETATION: Short-term moderate sodium restriction induces relative hyperfiltration in uncomplicated Type I diabetes. This could indicate an increased intraglomerular pressure. Sodium restriction could be an unfavourable preventive approach in diabetes mellitus but its long-term effects are not known.
Adult↗
11beta-hydroxysteroid dehydrogenase activity in proteinuric patients and the effect of angiotensin-II receptor blockade.
BACKGROUND: It has been suggested that an altered setpoint of the 11betaHSD-mediated cortisol to cortisone interconversion towards cortisol contributes to sodium retention in nephrotic syndrome patients. We studied the parameters of 11betaHSD activity in proteinuric patients, in particular its activity at the kidney level. We also studied the effect of angiotensin-II receptor blockade on the parameters of 11betaHSD activity. MATERIALS AND METHODS: Serum cortisol/cortisone ratio and the urinary ratios of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone [(THF + allo-THF)/THE] and of urinary free cortisol/free cortisone (UFF/UFE) were measured in eight proteinuric patients and compared with eight matched, healthy subjects. Patients were subsequently studied after 4 weeks' treatment with losartan 50 mg day-1 and placebo, respectively. RESULTS: No significant differences between the proteinuric patients and the healthy subjects were observed in the serum cortisol, serum cortisone, serum cortisol to cortisone ratio, or in the urinary excretions of THF, allo-THF, THE, sum of cortisol metabolites, or the (THF + allo-THF)/THE ratio. Urinary free cortisol excretion and the UFF/UFE ratio were lower in the proteinuric patients than in the healthy subjects (56 +/- 21 vs. 85 +/- 24 pmol min-1, P < 0.05, and 0.39 +/- 0.07 vs. 0.63 +/- 0.28, P < 0.05, respectively). Mean arterial pressure and proteinuria were reduced significantly during losartan treatment, but without concomitant changes in peripheral cortisol metabolism. CONCLUSIONS: Increased renal inactivation of cortisol in proteinuric patients does not support the contention that altered 11betaHSD activity contributes to sodium retention in patients with nephrotic syndrome. Losartan 50 mg d.d. reduces mean arterial pressure and proteinuria, but does not exert a significant effect on the cortisol to cortisone interconversion.
11-beta-Hydroxysteroid Dehydrogenases↗
D2 -like receptor stimulation decreases effective renal plasma flow and glomerular filtration rate in spontaneously hypertensive rats.
In spontaneously hypertensive rats (SHRs) the dopaminergic D1-like renal vasodilator response is impaired. The renal vascular response to D2-like receptor stimulation in vivo is incompletely known. Therefore, renal hemodynamics were studied in conscious SHRs during continuous infusion of D2-like agonist N,N-Di-n-propyldopamine (DPDA) (10 microg/kg/min) with Wistar-Kyoto (WKY) rats as controls. As sodium status may affect dopaminergic responses, rats were studied during both low- and high-sodium diets. D2-like stimulation reduced mean arterial pressure and effective renal plasma flow and glomerular filtration rate (GFR) similarly in SHR and WKY rats. Renal vascular resistance increased significantly in both strains. The response to DPDA is modified by sodium status, with a more pronounced fall in blood pressure (in WKYs and SHRs) and GFR (in WKYs) during high-sodium conditions. The responses were blocked by co-infusion with D2 antagonist domperidone. Thus, D2-like renal vascular responses are normal in SHRs irrespective of sodium intake. The combination of a preserved D2-like renal vasoconstrictive and an impaired D1-like renal vasodilatory response may contribute to maintenance of hypertension in SHRs.
Animals↗
Does a low-salt diet exert a protective effect on endothelial function in normal rats?
Sodium restriction is often used as an adjunct in the treatment of conditions characterized by endothelial dysfunction, such as hypertension and heart or kidney disease. However, the effect of sodium restriction on endothelial function is not known. Therefore, male Wistar rats were studied after a fixed salt diet had been maintained (low-salt group: 0.05% NaCl, n = 10; normal-salt group: 0.3% NaCl, n = 10) for 6 weeks. Blood pressure and sodium excretion values were measured once a week. Subsequently the rats were killed, the aorta was removed, and rings were cut. Endothelium-independent (sodium nitrite [SN]) and endothelium-dependent (acetylcholine [ACh]) vasodilator responses were assessed in the presence of indomethacin (a cyclo-oxygenase inhibitor) and in the presence or absence of NG-monomethyl-L-arginine (L-NMMA; a competitive inhibitor of nitric oxide [NO] synthase). Endothelium-independent vasodilatation was not different for the two salt groups. Endothelium-dependent vasodilatation, on the other hand, was different. The response to ACh was almost completely abolished by L-NMMA in the normal-salt group, whereas vasodilatation was partially preserved during L-NMMA in the low-salt group. Accordingly, the L-NMMA-sensitive contribution to ACh-dependent vasodilatation was smaller in the low-salt group. Thus, salt restriction induced a non-NO and non-prostaglandin-dependent vasodilating pathway. By exclusion this could be endothelium-derived hyperpolarizing factor, a pathway of vasculoprotective potential. Accordingly, the relative contributions of the different vasoactive endothelial pathways were affected by salt intake. Further research will be needed to clarify the nature and importance of this non-NO, non-prostaglandin-dependent pathway in the clinical setting as well.
Acetylcholine↗
ACE inhibition preserves heparan sulfate proteoglycans in the glomerular basement membrane of rats with established adriamycin nephropathy.
The gradual onset of the antiproteinuric effects of ACE inhibition suggests that structural effects on the glomerular basement membrane (GBM) may be involved in their renoprotective action. To test this hypothesis, we studied the effects of lisinopril (5 mg/kg/24 h) on proteinuria, focal glomerulosclerosis (FGS) and glomerular heparan sulfate (HS) proteoglycan (HSPG) GBM staining in rats with established Adriamycin nephrosis. Treatment was started 6 weeks after disease induction. As expected, lisinopril reduced blood pressure, proteinuria and the FGS score. In control rats, Adriamycin nephrosis was associated with significantly impaired GBM staining for both HSPG core protein (assessed from BL-31 staining) and HS staining (assessed from JM-403 staining) 12 weeks after disease induction. In rats treated with lisinopril (5 mg/kg/24 h) GBM staining was significantly better preserved for HS as well as for HSPG core protein. These data suggest that structural effects on the GBM, improving glomerular permselectivity, may be involved in the renoprotective effects of ACE inhibition in proteinuria-induced renal damage.
Angiotensin-Converting Enzyme Inhibitors↗