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Effects of Salt Supplementation on the Albuminuric Response to Telmisartan With or Without Hydrochlorothiazide Therapy in Hypertensive Patients With Type 2 Diabetes Are Modulated by Habitual Dietary Salt Intake

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Elif I Ekinci at University of Melbourne
Elif I Ekinci
Georgina Thomas
Georgina Thomas
Georgina Thomas
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David Thomas
David Thomas
David Thomas
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Cameron Johnson
Cameron Johnson
Cameron Johnson
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OBJECTIVE This prospective randomized double-blind placebo-controlled crossover study examined the effects of sodium chloride (NaCl) supplementation on the antialbuminuric action of telmisartan with or without hydrochlorothiazide (HCT) in hypertensive patients with type 2 diabetes, increased albumin excretion rate (AER), and habitual low dietary salt intake (LDS; <100 mmol sodium/24 h on two of three consecutive occasions) or high dietary salt intake (HDS; >200 mmol sodium/24 h on two of three consecutive occasions). RESEARCH DESIGN AND METHODS Following a washout period, subjects (n = 32) received 40 mg/day telmisartan for 4 weeks followed by 40 mg telmisartan plus 12.5 mg/day HCT for 4 weeks. For the last 2 weeks of each treatment period, patients received either 100 mmol/day NaCl or placebo capsules. After a second washout, the regimen was repeated with supplements in reverse order. AER and ambulatory blood pressure were measured at weeks 0, 4, 8, 14, 18, and 22. RESULTS In LDS, NaCl supplementation reduced the anti-albuminuric effect of telmisartan with or without HCT from 42.3% (placebo) to 9.5% (P = 0.004). By contrast, in HDS, NaCl supplementation did not reduce the AER response to telmisartan with or without HCT (placebo 30.9%, NaCl 28.1%, P = 0.7). Changes in AER were independent of changes in blood pressure. CONCLUSIONS The AER response to telmisartan with or without HCT under habitual low salt intake can be blunted by NaCl supplementation. By contrast, when there is already a suppressed renin angiotensin aldosterone system under habitual high dietary salt intake, the additional NaCl does not alter the AER response.
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Effects of Salt Supplementation on the Albuminuric Response to Telmisartan With or Without Hydrochlorothiazide Therapy in Hypertensive Patients With Type 2 Diabetes Are Modulated by Habitual Dietary Salt Inta
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... Altered dietary salt intake is noted to prevent and treat CKD (Lankhorst et al., 2016;Mcmahon et al., 2021). A high-salt diet (HSD) leads to increased biomarkers of renal tubular damage, not associated with hypertension (Hosohata, 2017;Washino et al., 2018), and such a diet may interfere with drugs' effectiveness (Ekinci et al., 2009;Slagman et al., 2011;Juncos et al., 2012;Kwakernaak et al., 2014). Although the relationship between kidney damage and salt intake is well known, the underlying mechanism is not fully clear and needs to be clarified, especially in type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). ...
... Although the relationship between kidney damage and salt intake is well known, the underlying mechanism is not fully clear and needs to be clarified, especially in type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Previous studies have suggested that fatty acid metabolism is a main energy source of proximal tubular epithelial cells (PTEC) (Ekinci et al., 2009;Slagman et al., 2011;Juncos et al., 2012;Kwakernaak et al., 2014). In humans and animal models with renal fibrosis, fatty acid oxidation (FAO) was decreaed (Kang et al., 2015;Chung et al., 2018). ...
High-Salt Attenuates the Efficacy of Dapagliflozin in Tubular Protection by Impairing Fatty Acid Metabolism in Diabetic Kidney Disease
Article
Full-text available
  • Dec 2021
High-salt intake leads to kidney damage and even limits the effectiveness of drugs. However, it is unclear whether excessive intake of salt affects renal tubular energy metabolism and the efficacy of dapagliflozin on renal function in diabetic kidney disease (DKD). In this study, we enrolled 350 DKD patients and examined the correlation between sodium level and renal function, and analyzed influencing factors. The results demonstrated that patients with macroalbuminuria have higher 24 h urinary sodium levels. After establishment of type 2 diabetes mellitus model, the animals received a high-salt diet or normal-salt diet. In the presence of high-salt diet, the renal fibrosis was aggravated with fatty acid metabolism dysregulation. Furthermore, Na+/K+-ATPase expression was up-regulated in the renal tubules of diabetic mice, while the fatty acid metabolism was improved by inhibiting Na+/K+-ATPase of renal tubular epithelial cells. Of note, the administration with dapagliflozin improved renal fibrosis and enhanced fatty acid metabolism. But high salt weakened the above-mentioned renal protective effects of dapagliflozin in DKD. Similar results were recapitulated in vitro after incubating proximal tubular epithelial cells in high-glucose and high-salt medium. In conclusion, our results indicate that high salt can lead to fatty acid metabolism disorders by increasing Na+/K+-ATPase expression in the renal tubules of DKD. High salt intake diminishes the reno-protective effect of dapagliflozin in DKD.
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... One article [26] provided the following 24-h urine protein data: 0.79 (0.1-1.39) mg/24 h for the low-sodium group; and 1.14 (0.1-5.06) mg/24 h for the high-sodium diet group was. Another article [27] provided the ACR data. When using losartan, the urine protein in the low-sodium diets decreased by 29% (CI 50-8.5%), and the urine protein in the regular sodium diet group increased by 14% (CI 19.4-47.9%). ...
... Although most of the included studies were published in high-impact journals, most of the included studies were crossover randomized controlled studies, and there was still an individual risk of bias. In addition, many studies did not observe the effect of a salt-limited diet alone but instead observed the effect of a salt-limited diet combined with other drugs to reduce urinary protein and blood pressure [20,27,[36][37][38][39][40]. Most of the studies were open-label designs because dietary education may introduce some biases. ...
Effect of a sodium restriction diet on albuminuria and blood pressure in diabetic kidney disease patients: a meta-analysis
Article
Full-text available
  • Jun 2022
  • INT UROL NEPHROL
Background A sodium restriction diet is a key component of chronic kidney disease (CKD) management. However, the efficacy of its use in patients with diabetic kidney disease (DKD) is uncertain. The present meta-analysis explored the effects of restricting sodium intake on albuminuria and blood pressure in DKD patients with albuminuria. Methods We searched the Cochrane Central Register of Controlled Trials, Web of Science, MEDLINE, and EMBASE for randomized controlled trials, and we reviewed the references of all searched articles to avoid omitting other relevant articles. Our primary endpoints were blood pressure, albumin excretion rate, and plasma renin activity. We assessed pooled data using a random-effects model. Results Of the 661 articles identified, a total of 12 articles were included in the meta-analysis. The random-effects model indicated that salt-restriction diet interventions led to a poled − 4.72 mmHg (95% CI − 6.71, − 2.73) difference in systolic blood pressure and that the intervention resulted in a 2.33 mmHg lower diastolic blood pressure (95% CI − 3.61, − 1.05). In patients with microalbuminuria, restricted sodium intake decreased the albumin excretion rate (AER) by 12.62 mg/min (95% CI − 19.64, − 5.60). Furthermore, the AER was 127.69 mg/min lower in patients with macroalbuminuria (95% CI − 189.07, − 66.32). Conclusion Moderate sodium restriction diets reduce urinary albumin excretion and decrease the level of blood pressure, especially for patients with macro-albuminuria. Thus, it is necessary to strengthen the intervention and health education as well as to provide individualized dietary advice.
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... Another clinical benefit of reducing sodium intake in CKD patients is the potentiation of the BP and albuminuria responses to blockers of the renin-angiotensin system (RAS) in both diabetic and non-diabetic nephropathy [13][14][15]. In this respect, reducing salt intake was more effective than combining two RAS blockers [15] and also potentiated the antiproteinuric effect of hydrochlorothiazide [14] and diltiazem, but not nifedipine [16]. ...
... Another clinical benefit of reducing sodium intake in CKD patients is the potentiation of the BP and albuminuria responses to blockers of the renin-angiotensin system (RAS) in both diabetic and non-diabetic nephropathy [13][14][15]. In this respect, reducing salt intake was more effective than combining two RAS blockers [15] and also potentiated the antiproteinuric effect of hydrochlorothiazide [14] and diltiazem, but not nifedipine [16]. In a post hoc analysis of the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan and Irbesartan Diabetic Nephropathy Trial, Lambers Heerspink et al. [13] reported a significant reduction of the risk of renal and cardiovascular events in CKD patients belonging to the lower tertiles of sodium intake. ...
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... Fifteen relevant studies were identified comparing low-salt versus normal-salt diets in several groups (Supplementary Tables S17-S20 [290][291][292][293][294][295][296][297][298][299][300][301][302][303][304][305] ). All studies contained small numbers of patients and examined surrogate outcomes, with the quality of the evidence being low due to risk of bias and inconsistency or imprecision. ...
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... It has been reported that TZD combined with losartan attenuates glomerular overload and albuminuria, indicating that this dual therapy may provide glomerular protection in patients with elevated glomerular pressure without causing prolonged damage to the kidney [16]. Moreover, dual concomitant use of telmisartan and TZD resulted in a significantly greater decrease in albuminuria, which is independent of BP, compared with telmisartan alone [17]. Furthermore, it has been reported that HCTZ has direct vascular relaxant effects through modulation of the opening of Caactivated potassium channels [18]. ...
Triple combination therapy with telmisartan, amlodipine, and hydrochlorothiazide ameliorates albuminuria in a normotensive rat remnant kidney model
Article
Full-text available
  • Dec 2021
Background Some types of antihypertensive drugs may have pleiotropic effects in patients with chronic kidney disease (CKD). However, whether triple combination therapy with angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide diuretics (TZD) confer renoprotective effects in normotensive CKD remains unknown. Thus, we explored this issue using a normotensive rat remnant kidney model. Methods Sprague-Dawley rats were randomly allocated into four groups: sham ( n = 10), 5/6 nephrectomy (NTx) ( n = 9), NTx treated with telmisartan and amlodipine (dual) ( n = 8), and NTx treated with telmisartan, amlodipine, and hydrochlorothiazide (triple) ( n = 7), and followed for 4 weeks. Blood pressure (BP), blood chemistry including renal function, urinary albumin excretion (UAE), and renal pathology were evaluated in all groups. Results There was no significant change in systolic BP among the four groups during the study period. Serum blood urea nitrogen (BUN) was significantly higher, and 24-h creatinine clearance (Ccr) was lower in all NTx groups ( p < 0.001). Dual therapy further increased the glomerular diameter in NTx rats ( p < 0.001), which was significantly ameliorated by triple therapy ( p < 0.001). Triple therapy, but not dual therapy, significantly reduced NTx-induced UAE levels ( p < 0.05), whereas BUN, 24-h Ccr, and tubulointerstitial injury scores were comparable among all the NTx groups. Conclusions Our results suggest that triple combination therapy with telmisartan, amlodipine, and hydrochlorothiazide could ameliorate glomerular hypertrophy and albuminuria in normotensive CKD rats in a BP-lowering independent manner.
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... Legumes, dried beans, nuts, seeds: 100 g (0.5 cup) cooked = 7-10 g protein Whole grains, cereals: 100 g (0.5 cup) cooked = 3-6 g protein Starchy vegetables, breads: 2-4 g protein c h a p t e r 3 www.kidney-international.org S50 Fifteen relevant studies were identified comparing low-salt versus normal-salt diets in several groups (Supplementary Tables S13-S16 [186][187][188][189][190][191][192][193][194][195][196][197][198][199][200] ). All studies contained small numbers of patients and examined surrogate outcomes, with the quality of the evidence being low due to risk of bias and inconsistency or imprecision. ...
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Sodium Management in Kidney Disease: Old Stories, New Tricks
Article
  • Mar 2023
  • SEMIN NEPHROL
Excessive dietary sodium intake is associated with an increased risk of hypertension, especially in the setting of chronic kidney disease (CKD). Although implementation of a low-sodium diet in patients with CKD generally is recommended, data supporting the efficacy of this practice is mostly opinion-based. Few controlled studies have investigated the specific association of dietary sodium intake and cardiovascular events and mortality in CKD. Furthermore, in epidemiologic studies, the association of sodium intake with CKD progression, cardiovascular risk, and mortality is not homogeneous, and both low- and high-sodium intake has been associated with adverse health outcomes in different studies. In general, the adverse effects of high dietary sodium intake are more apparent in the setting of advanced CKD. However, there is no established definitive target level of dietary sodium intake in different CKD stages based on glomerular filtration rate and albuminuria/proteinuria. This review discusses the current challenges regarding the rationale of sodium restriction, target levels and assessment of sodium intake, and interventions for sodium restrictions in CKD in relation to clinical outcomes.
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Altered dietary salt intake for preventing diabetic kidney disease and its progression
Article
  • Jan 2023
Background: There is strong evidence that our current consumption of salt is a major factor in the development of increased blood pressure (BP) and that a reduction in our salt intake lowers BP, whether BP levels are normal or raised initially. Effective control of BP in people with diabetes lowers the risk of strokes, heart attacks and heart failure and slows the progression of chronic kidney disease (CKD) in people with diabetes. This is an update of a review first published in 2010. Objectives: To evaluate the effect of altered salt intake on BP and markers of cardiovascular disease and of CKD in people with diabetes. Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 31 March 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria: We included randomised controlled trials (RCTs) of altered salt intake in individuals with type 1 and type 2 diabetes. Studies were included when there was a difference between low and high sodium intakes of at least 34 mmol/day. Data collection and analysis: Two authors independently assessed studies and resolved differences by discussion. We calculated mean effect sizes as mean difference (MD) and 95% confidence intervals (CI) using the random-effects model. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results: Thirteen RCTs (313 participants), including 21 comparisons (studies), met our inclusion criteria. One RCT (two studies) was added to this review update. Participants included 99 individuals with type 1 diabetes and 214 individuals with type 2 diabetes. Two RCTs (four studies) included some participants with reduced overall kidney function. The remaining studies either reported that participants with reduced glomerular filtration rate (GFR) were excluded from the study or only included participants with microalbuminuria and normal GFR. Five studies used a parallel study design, and 16 used a cross-over design. Studies were at high risk of bias for most criteria. Random sequence generation and allocation concealment were adequate in only three and two studies, respectively. One study was at low risk of bias for blinding of participants and outcome assessment, but no studies were at low risk for selective reporting. Twelve studies reported non-commercial funding sources, three reported conflicts of interest, and eight reported adequate washout between interventions in cross-over studies. The median net reduction in 24-hour urine sodium excretion (24-hour UNa) in seven long-term studies (treatment duration four to 12 weeks) was 76 mmol (range 51 to 124 mmol), and in 10 short-term studies (treatment duration five to seven days) was 187 mmol (range 86 to 337 mmol). Data were only available graphically in four studies. In long-term studies, reduced sodium intake may lower systolic BP (SBP) by 6.15 mm Hg (7 studies: 95% CI -9.27 to -3.03; I² = 12%), diastolic BP (DBP) by 3.41 mm Hg (7 studies: 95% CI -5.56 to -1.27; I² = 41%) and mean arterial pressure (MAP) by 4.60 mm Hg (4 studies: 95% CI -7.26 to -1.94; I² = 28%). In short-term studies, low sodium intake may reduce SBP by 8.43 mm Hg (5 studies: 95% CI -14.37 to -2.48; I² = 88%), DBP by 2.95 mm Hg (5 studies: 95% CI -4.96 to -0.94; I² = 70%) and MAP by 2.37 mm Hg (9 studies: 95% CI -4.75 to -0.01; I² = 65%). There was considerable heterogeneity in most analyses but particularly among short-term studies. All analyses were considered to be of low certainty evidence. SBP, DBP and MAP reductions may not differ between hypertensive and normotensive participants or between individuals with type 1 or type 2 diabetes. In hypertensive participants, SBP, DBP and MAP may be reduced by 6.45, 3.15 and 4.88 mm Hg, respectively, while in normotensive participants, they may be reduced by 8.43, 2.95 and 2.15 mm Hg, respectively (all low certainty evidence). SBP, DBP and MAP may be reduced by 7.35, 3.04 and 4.30 mm Hg, respectively, in participants with type 2 diabetes and by 7.35, 3.20, and 0.08 mm Hg, respectively, in participants with type 1 diabetes (all low certainty evidence). Eight studies provided measures of urinary protein excretion before and after salt restriction; four reported a reduction in urinary albumin excretion with salt restriction. Pooled analyses showed no changes in GFR (12 studies: MD -1.87 mL/min/1.73 m², 95% CI -5.05 to 1.31; I² = 32%) or HbA1c (6 studies: MD -0.62, 95% CI -1.49 to 0.26; I² = 95%) with salt restriction (low certainty evidence). Body weight was reduced in studies lasting one to two weeks but not in studies lasting for longer periods (low certainty evidence). Adverse effects were reported in only one study; 11% and 21% developed postural hypotension on the low-salt diet and the low-salt diet combined with hydrochlorothiazide, respectively. Authors' conclusions: This systematic review shows an important reduction in SBP and DBP in people with diabetes with normal GFR during short periods of salt restriction, similar to that obtained with single drug therapy for hypertension. These data support the international recommendations that people with diabetes with or without hypertension or evidence of kidney disease should reduce salt intake to less than 5 g/day (2 g sodium).
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Secondary Diseases of the Kidney: Diabetic Nephropathy
Chapter
  • Nov 2022
Modern nomenclature has favored the term diabetic kidney disease (DKD) over diabetic nephropathy as this is more representative of the coexistent obesity‐induced, vascular, and hypertensive kidney injury that is likely to be over‐represented in patients with type 2 DM. Diabetes is recognized as the world's fastest growing non communicable chronic disease. Hyperglycemia is considered a key driver of DKD. Vascular and glomerular lesions contribute to hypoxia, which further exacerbates oxidative stress in both the glomerulus and tubules. Lifestyle interventions such as reduced salt intake, weight loss, physical exercise, and supplementation with polyunsaturated fats have been shown to improve glycemic control, lower blood pressure, reduce albuminuria, and change metabolic risk profiles in the general population as well as in individuals with diabetes and chronic kidney failure (CKD). Dipeptidyl peptidase inhibitors are increasingly used in the CKD population to achieve optimal glycemic control.
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The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide
Article
Full-text available
  • Jul 1998
  • NEPHROL DIAL TRANSPL
Background: Dietary sodium restriction enhances the antiproteinuric and blood pressure lowering effect of ACE inhibition. In clinical practice, however, long-term compliance to a low-sodium diet may be difficult to obtain. We therefore investigated whether the blunting of the antiproteinuric and blood pressure lowering efficacy of ACE inhibition by high sodium intake can be restored by the addition of a diuretic. Patients and methods: Seven proteinuric patients with non-diabetic renal disease on chronic ACE inhibition were studied during three consecutive 4-week periods: low sodium (50 mmol/day), high sodium (200 mmol/day) and high sodium plus hydrochlorothiazide (50 mg o.i.d.). Results: During low sodium intake proteinuria was 3.1 (0.7-5.2) g/day, during high sodium intake proteinuria increased to 4.5 (1.6-9.2) g/day (P < 0.05). Interestingly, addition of hydrochlorothiazide again reduced proteinuria to 2.8 (0.6-5.8) g/day (P < 0.05). Mean arterial blood pressure was 89 (84-96), 98 (91-104) and 89 (83-94) mmHg (P < 0.05) during the three periods, respectively. Conclusion: Addition of hydrochlorothiazide can overcome the blunting of the therapeutic efficacy of ACE inhibition on proteinuria and blood pressure by a high sodium intake.
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INTERSALT: an international study of electrolyte excretion and blood pressure. Results for 24h urinary sodium and potassium excretion. INTERSALT Cooperative Research Group. BMJ. 1988;297:319–328
Article
  • Jul 1988
  • Br Med J
The Intersalt Cooperative Research Group, together with Laaser U Intersalt: An International Study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion.
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Glomerular Hyperfiltration and the Salt Paradox in Early Type 1 Diabetes Mellitus: A Tubulo-Centric View
Article
  • Feb 2003
Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review proposes a “tubulo-centric” view of glomerular function in early type I diabetes mellitus. The following are particularly discussed (1) the primary role of an increase in reabsorption by the proximal tubule in early glomerular hyperfiltration, (2) the role of sodium-glucose cotransport and tubular growth under these conditions, and (3) the primary role of reabsorption by the proximal tubule for the paradoxical relationship between dietary salt and glomerular filtration rate. Finally, an outline is presented of potential therapeutic implications for the prevention of diabetic kidney disease. E-mail: volker.vallon@uni-tuebingen.de
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Dietary Salt, Blood Pressure, and Microalbuminuria
Article
  • Nov 2004
The relationship between dietary salt, blood pressure, and risk for cardiovascular disease has been debated for decades. Microalbuminuria is a biomarker for both cardiovascular and kidney disease. The presence of microalbuminuria correlates directly with the risk for myocardial infarction and stroke and indicates individuals at risk for the development of progressive kidney disease. Since patients with the metabolic syndrome, diabetes, or chronic kidney disease often are blood pressure salt sensitive, and it is well known that increasing dietary salt may offset both the antihypertensive and antiproteinuric effects of renin-angiotensin system blocking drugs, physicians must consider increased salt intake as a potential modifiable risk factor for progression of chronic kidney disease and possibly even cardiovascular disease.
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Comparative effects of converting enzyme inhibition and conventional therapy in hypertensive non-insulin dependent diabetics with normal renal function
Article
  • Jan 1992
The effects of long-term reduction in blood pressure by the angiotensin converting enzyme inhibitor captopril, as single therapy or in combination with hydrochlorothiazide (HCTZ), were compared with those of metoprolol and/or hydrochlorothiazide in 91 hypertensive non insulin-dependent diabetics with normal renal function. Following a single-blind placebo run-in period of 4 weeks, treatments were assigned randomly in a double-blind fashion. During the study, weight and glycosylated hemoglobin remained elevated. After 9 months of treatment, blood pressure fell significantly (p less than 0.0001) in all treatment groups, with most patients achieving goal supine diastolic blood pressure of less than or equal to 85 mmHg. Whereas urinary albumin excretion (UAE) did not change in patients given metoprolol and/or HCTZ, captopril monotherapy (p = 0.0021) or captopril given in combination with HCTZ (p = 0.0002) decreased UAE without affecting glomerular filtration rate. These data are in favour of a renal beneficial effect of angiotensin converting enzyme inhibitors distinct from their effects on systemic blood pressure. Further studies are needed to determine whether this effect persists with longer treatment, and whether it would lead to better preservation of kidney function than other antihypertensive agents.
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Glomerular Filtration Rate in Streptozocin-Induced Diabetic Rats: Role of Exchangeable Sodium, Vasoactive Hormones, and Insulin Therapy
Article
  • Nov 1990
  • DIABETES
The interrelationships of sodium and volume status, atrial natriuretic peptide (ANP), plasma renin activity (PRA), insulinlike growth factor I (IGF-I), and kidney weight and their influence on glomerular filtration rate (GFR) were investigated in rats during the first 4 wk of streptozocin-induced diabetes (STZ-D). In each of three experiments, untreated diabetic rats were compared with nondiabetic control rats and rats with varying degrees of glycemic control during insulin therapy. The first experiment evaluated exchangeable sodium, plasma volume, and GFR. In untreated diabetic rats, exchangeable sodium and plasma volume, but not GFR, were increased by approximately 25% compared with control rats. Insulin-treated diabetic rats with plasma glucose levels ranging from 12 to 30 mM had increased GFR, whereas exchangeable sodium and plasma volume were reduced toward control values. Daily insulin therapy, titrated to maintain euglycemia, further reduced exchangeable sodium and plasma volume and decreased but did not normalize GFR. The second experiment evaluated the relationship between vasoactive hormones and GFR. In untreated diabetic rats, plasma ANP levels increased 89% and urinary cyclic GMP (cGMP) excretion increased 94%, with an 85% decrease in PRA, whereas GFR was unchanged. Moderate hyperglycemia (plasma glucose 12-30 mM) was associated with normalized plasma ANP levels and urinary cGMP excretion, a 52% decrease in PRA, and a 13% increase in GFR. The third experiment studied serial changes in food and water intake and vasoactive hormones and end-point measurement of kidney weight, GFR, and plasma IGF-I. In the untreated diabetic group, urinary cGMP excretion was significantly elevated after 3 wk, whereas the reduction in PRA levels was apparent after 1 wk.(ABSTRACT TRUNCATED AT 250 WORDS)
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Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril
Article
  • Sep 1989
We studied the efficacy of the ACE inhibitor lisinopril in treating overt proteinuria in comparison with the NSAID indomethacin, and evaluated some of the conditions that could influence this antiproteinuric effect. In 12 patients with a proteinuria varying from 3.2 to 10.5 g/24 hr, a diastolic BP ranging from 64 to 105 mm Hg, and a GFR varying from 34 to 127 ml/min, the effect of different lisinopril doses and of changing dietary sodium intake was evaluated. Proteinuria fell by 27 +/- 20% from 6.1 +/- 2.1 to 4.5 +/- 1.9 g/24 hr on a low dose (median 5 mg/day) lisinopril and by 50 +/- 17% to 3.1 +/- 1.4 g/24 hr on a higher dose (median 10 mg/day), irrespective of initial proteinuria, BP, or GFR. This antiproteinuric effect was abolished by increasing salt intake from 50 to 200 mmol/day, and was recovered again by re-instituting the sodium restricted diet. The antiproteinuric effect of 10 mg/day lisinopril was comparable to the reduction in proteinuria (by 57 +/- 21% to 2.8 +/- 2.0 g/24 hr) on 150 mg/day indomethacin, while adverse effects were less and renal hemodynamic effects were more favorable during lisinopril. In some patients it took several weeks before the effect of the ACE inhibitor on proteinuria was stabilized. Thus, the antiproteinuric effect of the ACE inhibitor lisinopril appears to be dose and time related, and is strongly dependent on dietary sodium restriction, whereas it does not depend on initial proteinuria, BP, or GFR. The effect is comparable to that of indomethacin, while adverse effects are less.
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Body sodium-blood volume state in nonazotemic diabetes mellitus
Article
  • Feb 1982
Total exchangeable sodium and blood volume were measured in 126 diabetic patients without renal or heart failure, in 52 patients with essential hypertension and in 99 normal subjects. Both body constituents were judged using the body surface area as the frame of reference. Exchangeable sodium (ExNa) was significantly increased in diabetics as compared to normal subjects (110 vs. 100%), regardless of age, sex or body habitus. ExNa averaged 108% in the 63 diabetics with normal blood pressure, 111% in the 63 hypertensive diabetics and 99% in essential hypertension. Blood volume (BV) was normal or sometimes slightly low in the diabetics with normal or high blood pressure and in essential hypertension. In normal subjects, ExNa or BV were unrelated to age or systolic or diastolic blood pressure. In the diabetic population, ExNa correlated with the systolic blood pressure (r = 0.25; p less than 0.005) but not with the diastolic blood pressure or age; BV was unrelated to blood pressure. The correlation between ExNa and systolic blood pressure was closer in the diabetics with high blood pressure (r = 0.47; p less than 0.001); this relationship could not be explained by a concomitant influence of age or plasma creatinine (rp = 0.34; p less than 0.05). These findings indicate that an increased ExNa associated with a normal circulatory volume is a common abnormality in patients with nonazotemic diabetes mellitus. Excess body sodium may play an important pathogenetic role in the maintenance of diabetes-associated hypertension.
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Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats: Effect of sodium and salt restriction
Article
  • May 1995
Six weeks after the onset of insulin-treated streptozotocin diabetes (STZ) in Munich-Wistar rats, the effect of a low-sodium (LNa) and a low-salt (LNaCl) diet on renal function and on plasma and kidney tissue angiotensin II (AIIp, AIIk) was tested. Clearance experiments were performed in anesthetized rats 7 days after starting on LNa or LNaCl. On a control diet, STZ exhibited an increase in GFR, RBF, and kidney weight (KW) and a reduction in renal vascular resistance (RVR) and AIIk, but no change in AIIp, compared with nondiabetic normal rats (CON). Although sodium restriction reduced and salt restriction increased AIIk in CON, both diets increased AIIp without affecting renal hemodynamics or KW. In diabetic rats, both salt and sodium restriction further increased GFR and RBF by reducing RVR, increased KW, and changed AIIk and AIIp in a similar pattern, but at significantly lower values compared with CON. Daily treatment of STZ-LNa with the AII-receptor blocker losartan (20 mg/L, in drinking water) did not affect the reduction in RVR and the increase in KW but slightly reduced RBF because of a decrease in mean arterial blood pressure and further increased GFR. It was concluded that (1) AIIk but not AIIp is affected differently by LNa compared with LNaCl in both CON and STZ; (2) LNaCl and LNa change AIIp and AIIk in a similar pattern but at significant lower values in STZ compared with CON; and (3) with regard to renal hemodynamics and KW, the response to LNa and LNaCl is different in CON compared with rats 6 wk after the onset of diabetes mellitus, the latter exhibiting a further increase in renal hyperfiltration and KW by a mechanism that is not directly AII receptor dependent.
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