UMLS:C0033687 - FACTA Search

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Query: UMLS:C0033687 (proteinuria)
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The most important factor that prevents the progression of renal damage in diabetes mellitus, beside the improvement of blood glucose control, is tight BP control. The tenet of tight BP control may be defined as the lowest BP level one can accomplish using antihypertensive therapy that is at the same time compatible with the absence of untoward side effects. In fact, both the Framingham Heart Study in nondiabetic normal subjects and the United Kingdom Prospective Diabetes Study in type 2 diabetic patients showed that systolic values as low as 108 to 111 mmHg and diastolic values as low as 70 to 71 mmHg are significantly associated with decreased cardiovascular mortality and morbidity. However, 45 to 50% of the patients with type 2 diabetes mellitus and hypertension have systolic BP levels above 140 mmHg during antihypertensive therapy, particularly when using monotherapy. Thus the issue regarding the choice of which drugs one should use to treat hypertension became critical from a clinical point of view. Pharmaceutical compounds, which inhibit the renin-angiotensin system, have become the first-choice treatment in patients with diabetes mellitus and incipient and advanced renal complications. The present brief review analyzes the effects of calcium channel blockers (CCB) on cardiovascular and renal complications in diabetes mellitus. The review discussed those studies that directly and blindly compared CCB with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin II AT(1) receptor blockers (ARB). Furthermore, size of the population recruited in each trial was used as a criterion of priority in the selection of the reports from the available literature. From the point of view of cardiovascular complications, the results of these studies showed a slightly better benefit of CCB on stroke, whereas ACE inhibitors better prevented the occurrence of myocardial infarction and congestive heart failure. On the other hand, recent observations demonstrated that also ACE inhibitors and ARB are effective in the primary and secondary prevention of stroke, although these studies did not directly compare these compounds with CCB. With regard to the outcome of renal complications, both ARB and ACE inhibitors more effectively prevented the progression of renal damage among the patients with overt nephropathy than CCB. On the contrary, both CCB and ACE inhibitors were equally effective on blunting the decay of GFR in diabetic patients who do not have overt proteinuria. However, ACE inhibitors and ARB more markedly decreased the rate of albumin excretion rate in the range of both microalbuminuria and macroalbuminuria. Recent advances in the understanding of the pathogenesis of abnormalities of albumin excretion rate and of atherosclerosis are also discussed. Both mechanical stress, mainly secondary to systolic hypertension, and elevated circulating and tissue levels of angiotensin II, partially independent from each other, cause excessive generation of superoxide compounds. This chain reaction of events in turn leads to disorders of structural components of glomerular filter and to damage of the vascular wall. Systolic BP control (<130 mmHg) is not adequately accomplished in the majority of the patients treated only with ACE inhibitors and ARB, even in association with diuretics. Poor BP control may lead to excessive systemic mechanical stress at the vascular level despite satisfactory inhibition of angiotensin II effects. In conclusion, one can suggest that CCB are useful and often indispensable pharmaceutical compounds, beside ACE inhibitors and ARB, to accomplish tight BP control (<130/85 mmHg), a target that is unlikely to be successfully maintained in the overall population of type 2 diabetic patients only by ACE inhibitors or ARB, as monotherapy. However, ACE inhibitors and ARB might be considered first-choice drugs in the treatment of hypertension in diabetes mellitus, mainly because of a better renoprotection.
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PMID:Cardiovascular and renal protection in type 2 diabetes mellitus: the role of calcium channel blockers. 1246 17

Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT(1)-receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide, prompting the search for improved renoprotective strategies. In spite of proven efficacy at group level, the long-term renoprotective effect of RAAS blockade displays a marked between-patient heterogeneity, which is closely linked to between-patient differences in the intermediate parameters of blood pressure, proteinuria and renal haemodynamics. Of note, the between-patient differences by far exceed the between-regimen differences, and thus may provide a novel target for exploration and intervention. The responsiveness to RAAS blockade appears to be an individual characteristic as demonstrated by studies applying a rotation-schedule design. The type and severity of renal disease, obesity, insulin-resistance, glycaemic control, and genetic factors may all be involved in individual differences in responsiveness, as well as dietary factors, such as dietary sodium and protein intake. Several strategies, such as dietary sodium restriction and diuretic therapy, dose-titration for proteinuria, and dual RAAS blockade with ACE-I and ARB, can improve the response to therapy at a group level. However, when analysed for their effect in individuals, it appears that these measures do not allow poor responders to catch up with the good responders, i.e. in spite of their efficacy at group level, the available measures are usually not sufficient to overcome individual resistance to RAAS blockade. We conclude that between-patient differences in responsiveness to renoprotective intervention should get specific attention as a target for intervention. Unravelling of the underlying mechanisms may allow development of specific intervention. Based on the currently available data, we propose that response-based treatment schedules, with a multidrug approach titrated and adapted at individual responses rather than fixed treatment schedules, may provide a fruitful strategy for more effective renoprotection.
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PMID:Between-patient differences in the renal response to renin-angiotensin system intervention: clue to optimising renoprotective therapy? 1258 64

Although the angiotensin receptor antagonist (ARB) shares the angiotensin-II-blocking activity with the angiotensin-converting enzyme inhibitor (ACE-I), pharmacological mechanisms of action of these agents differ. We evaluated the temporal profiles of action of ACE-I and ARB on urinary protein excretion and nitrate/nitrate (NO(x)) excretion in hypertensive (140 and/or 90 mmHg) patients with chronic renal disease (serum creatinine < 265 (range, 44-265) micromol/l or creatinine clearance > 30 (range, 30-121) ml/min). Patients with mild (<1 g/day; range, 0.4-1.0) and moderate proteinuria (>1 g/day; range, 1.1-6.9) were randomly assigned to ACE-I- and ARB-treated groups, and were treated with ACE-I (trandolapril or perindopril) or ARB(losartan or candesartan) for 48 weeks. In all groups, treatment with ACE-I or ARB decreased blood pressure to the same level, but had no effect on creatinine clearance. In patients with mild proteinuria, neither ACE-I nor ARB altered urinary protein excretion. In patients with moderate proteinuria, ACE-I caused 44 +/- 6% reduction in proteinuria (from 2.7 +/- 0.5 to 1.5 +/- 0.4 g/day, n = 14) at 12 weeks, and this beneficial effect persisted throughout the protocol (48 weeks, 1.2 +/- 0.2 g/day). In contrast, ARB did not produce a significant decrease in proteinuria at 12 weeks (23 +/- 8%, n = 13), but a 41 +/- 6% reduction in proteinuria was observed at 48 weeks. Similarly, although early (12 weeks) increases in urinary NO(x) excretion were observed with ACE-I (from 257 +/- 70 to 1111 +/- 160 micromol/day) and ARB (from 280 +/- 82 to 723 +/- 86 micromol/day), the ARB-induced increase in NO(x) excretion was smaller than that by ACE-I (P < 0.05). In conclusion, although both ACE-I and ARB reduce blood pressure similarly, the effect of these agents on proteinuria differs in chronic renal disease with moderate proteinuria. Relatively early onset of the proteinuria-reducing effect was observed with ACE-I, which paralleled the increase in urinary NO(x) excretion. Conversely, ARB decreased proteinuria and increased urinary NO(x) excretion gradually. These time course-dependent changes in proteinuria and urinary NO(x) may reflect the pharmacological property of ACE-I and ARB, with regard to the action on bradykinin.
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PMID:Distinct time courses of renal protective action of angiotensin receptor antagonists and ACE inhibitors in chronic renal disease. 1269 72

Combination therapy with angiotensin receptor antagonist(ARB) plus angiotensin converting enzyme inhibitor(ACE-I) (ARB/ACE-I) was efficacious in reducing proteinuria in patients with progressive renal disease. However, this therapy may be associated with the worsening of anemia and hyperkalemia. The present study addressed whether or not triple therapy with low-dose ARB, low-dose diuretic (D) and calcium channel blocker(CCB) (ARB/D/CCB) is as effective as therapy with low-dose ARB/ACE-I in retarding the progression of overt diabetic nephropathy. In the triple therapy, the patients were initially subjected to monotherapy with CCB for 24 weeks. Low-dose ARB and low-dose D were added to the treatment for an additional 24-week period. In parallel, patients undergoing double therapy were initially treated with low-dose ACE-I alone for 24 weeks, and then low-dose ARB was added for an additional 24-week period. The results were as follows: 1) In the triple therapy, blood pressure was reduced by 9 mmHg in systole and 5 mmHg in diastole (not significant) compared to monotherapy with CCB. There was a significant decline in proteinuria (3.3 +/- 1.2 g/day in the CCB-treated period vs. 2.1 +/- 1.0 g/day in the ARB/D/CCB-treated period, n = 12, p = 0.0143). Furthermore, a significant improvement in the slope of reciprocal serum creatinine concentration(1/Cr) was found in response to triple therapy(1/Cr: -0.0118 +/- 0.0009 in the CCB-treated vs. -0.0035 +/- 0.0028(I/mg/dl/month) in the ARB/D/CCB-treated period, n = 12, p < 0.001). There was neither a worsening of anemia nor an increase in the serum potassium(K) concentration. 2) In the double therapy, blood pressure was reduced by 12 mmHg in systole(p = 0.0079, n = 11) and 6 mmHg in diastole(n = 11, p = 0.0037) compared to the monotherapy with ACE-I. A significant improvement in the slope of 1/Cr was found in the double therapy(1/Cr: -0.0095 +/- 0.0052 in the ACE-I treated period vs. -0.0029 +/- 0.0028(I/mg/dl/month) in the ARB/ACE-I, n = 11, p < 0.001). In addition, there was a substantial reduction in hematocrit and increase in serum K concentration. The present result suggests that triple therapy consisting of ARB/D/CCB is as efficacious as double therapy with ARB/ACE-I in protecting the kidney from the progression in patients with diabetic overt nephropathy. The former may be expected to have less adverse effects.
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PMID:[Renoprotective effect of triple therapy with low-dose angiotensin receptor blocker, low-dose diuretic and Ca-antagonist in hypertensive type 2 diabetic patients with overt nephropathy]. 1280 73

The lengthy course of IgA nephropathy and the possibility of good outcomes without therapy suggest nontoxic therapies such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs.) Among patients with IgA nephropathy, both ACE inhibitors and ARBs reduce the transglomerular passage of large, but not small, molecules, reducing proteinuria. The antiproteinuric effects of ACE inhibitors and ARBs are probably equivalent. Dual ACE inhibitor-ARB therapy reduces proteinuria by 54% to 73% and is more effective than either agent alone. To determine whether ACE inhibitors or ARBs preserve renal function long-term, one must rely on trials studying nondiabetic, proteinuric renal diseases rather than on trials specific to IgA nephropathy. Among this group of patients, several randomized, controlled trials, including the AIPRI trial, the REIN trial, and a metaanalysis of 11 randomized, controlled trials, have established clearly that the ACE inhibitors preserve renal function. There is no reason to believe that this information is not applicable to IgA nephropathy. The COOPERATE trial, in which 50% of the subjects had IgA nephropathy, established that ACE inhibitors and ARBs preserve renal function equally, and that dual ACE inhibitor-ARB therapy preserves renal function more effectively than either therapy alone. These data suggest that most individuals with proteinuric renal diseases, including IgA nephropathy, should be treated with ACE inhibitors and ARBs, ideally in combination. Polymorphisms of the angiotensinogen gene, the ACE gene, and the angiotensin II type I receptor gene have, so far, failed to predict either susceptibility to or progression of IgA nephropathy. However, the D allele of the ID polymorphism, particularly the DD genotype, could predict a favorable response to renin-angiotensin blockade.
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PMID:Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for IgA nephropathy. 1515 27

We report three cases of focal glomerular sclerosis (FGS) with proteinuria that improved with the administration of angiotensin type 1 receptor blocker (ARB, losartan or valsartan). These three patients were a 41-year-old male (case 1), a 22-year-old male (case 2) and a 47-year-old male (case 3), who showed proteinuria, renal dysfunction, and hyperlipidemia. In case 1, proteinuria and renal dysfunction were improved by losartan administration and low protein diet therapy. In case 2, losartan with steroid and immunosuppressant led to the complete remission of proteinuria, improvement of renal dysfunction and reduction of the glomerular injury score from repeat biopsy specimen by approximately 20%. In case 3, proteinuria was reduced by valsartan administration with steroid and immunosuppressant therapy. ARB treatment with steroid and immunosuppressant might be more effective on the reduction of proteinuria in FGS patients.
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PMID:[Angiotensin type 1 receptor blocker reduced proteinuria in patients of focal glomerular sclerosis]. 1544

Diabetic nephropathy affects both type 1 and type 2 diabetic patients with a frequency of 20-30%. The first sign is microalbuminuria within a range of 30-300 mg/24h, frequently evolving towards frank proteinuria and renal failure. Tight glucose control, control of arterial hypertension with the use of ACEi or ARB can retard progression. Once renal failure is established, kidney transplantation can be considered for type 1 and type 2 diabetic patients. Quality of life and survival are improved with this procedure. In type 1 diabetes, simultaneous grafting of a kidney and pancreas considerably improves quality of life and diabetic complications. Surgical and infectious complications are sporadic drawbacks of this procedure. Pancreas transplantation alone (PTA) remains controversial, since a retrospective study in 2003 by Venstrom concluded that survival for PTA patients is worse than for comparable patients remaining on the waiting list. PTA can be considered for type 1 diabetic patients without advanced renal failure with severe and frequent metabolic instability (hypoglycaemia, ketoacidosis). Islet transplantation is still an experimental but promising procedure in highly selected patients, avoiding major abdominal surgery.
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PMID:Transplantation as a therapeutic option for diabetic nephropathy. 1546 8

Large, placebo-controlled RCTs that involve only diabetic patients who have hypertension have not been performed. Subgroup analyses of hyper-tension control from several recent RCTs un-equivocally demonstrated greater benefit in diabetic populations (see Table 3) with ACE inhibitors, TDs, and CCBs. Treatment with fBs(atenolol) also was beneficial in diabetic patients who had hypertension in the actively-controlled UKPDS. The results of three RCTs support intensive BP control in diabetic patients (see Table 4). In these trials, diabetic patients gained more benefit than nondiabetic patients. Such an effect is consistent with the fact that diabetics are at higher risk for CV events. Although there are limited data from RCTs with head-to-head comparison of newer agents (eg,ACE inhibitors, ARBs, CCBs) to show that these drugs are better than diuretics and betaBs in reducing CV events by treating hypertension in the diabetic population, the available data support ACE inhibitors (and ARBs if ACE inhibitors are not tolerated) as an initial drug of choice in diabetic,hypertensive patients (see Table 5). Most diabetic patients require three or four drugs to control their BP to target range; as such, it is not necessary to justify the choice of any single class of drug. Tight BP control is cost-effective and is more rewarding than hyperglycemic control in diabetic,hypertensive patients. The optimal goal in diabetics should be to achieve BP that is less than 130/80 mm Hg. Appropriate action should be taken if BP is greater than 140/85 mm Hg. In subjects who have diabetes and renal insufficiency,the BP should be decreased to less than 125/75 mm Hg to delay the progression of renal failure. Limited data suggest that an ACE inhibitor or an ARB is the agent of choice, especially in patients who have proteinuria or renal insufficiency. betaBs can be the first-line agent in diabetics who have CAD. TDs and CCBs are the second line drugs.AAAs should be avoided. Most hypertensive patients require more than one agent to adequately control their BP. There is no evidence to support one combination regimen over the others, nevertheless, the combination of an ACE inhibitor with a TD or a fPB may be more beneficial and cost effective than other combinations in the diabetic population. Large outcome studies that compare different combination therapies in hypertensive,diabetic patients are needed.
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PMID:Diabetes and hypertension, the deadly duet: importance, therapeutic strategy, and selection of drug therapy. 1569 43

The renin-angiotensin-aldosterone system (RAAS) blockade is currently the best-documented treatment strategy to delay the progression of chronic nephropathies. Angiotensin-converting enzyme inhibitors (CEIs) or angiotensin II type 1 receptor antagonists (ARBs) should be used in every normotensive and hypertensive patient with chronic proteinuric nephropathy of both diabetic and non-diabetic origin. The therapy should be initiated as early as possible, bearing in mind that the renoprotection is more effective if used before overt proteinuria or a reduction in kidney function is present. The therapy should be offered to all patients, regardless of renal function, as well as to subjects with severely impaired glomerular filtration. CEIs and ARBs should be administered in therapeutic doses as high as possible to achieve maximal possible proteinuria reduction and systemic blood pressure target <130/80 mm Hg, and 125/75 mm Hg in those subjects with renal insufficiency who present with proteinuria above 1 g/24 h. The combined therapy with the concomitant use of CEIs and ARBs should be offered to all patients with proteinuric non-diabetic chronic nephropathies who do not achieve full and persistent remission of proteinuria with CEI or ARB alone. The article reviews an evidence-based approach on the use of RAAS-inhibiting agents in kidney diseases, considers treatment strategies in different clinical situations and discusses some perspectives related to the implementation of the RAAS blockade in renal protection.
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PMID:Renal protective effects of the renin-angiotensin-aldosterone system blockade: from evidence-based approach to perspectives. 1612 80

Blood pressure and genetic factors are important factors for diabetic nephropathy. We investigated the relationship between the efficacy of renin angiotensin system (RAS) inhibitors and angiotensin-converting enzyme (ACE) genotypes. Patients with type 2 diabetes without proteinuria, were treated with RAS inhibitors, the first being an ACE inhibitor (ACEI) and the second, an angiotensin II (ATII) receptor blocker (ARB) for 8 weeks each. There was no significant difference (except serum ACE activity) between the two treatments. However, by analysis segregated with ACE gene polymorphism, ARB significantly decreased transforming growth factor-beta1 (TGF-beta) compared to ACEI in patients with the I/I genotype but not in patients with the D/I+D/D genotype. DeltaATII and DeltaTGF-beta have a negative correlation with the I/I genotype and a positive correlation with the D/I+D/D genotypes. These correlation coefficients are significantly different. We suggest that in I/I patients, TGF-beta was reduced by ARB via effects on (ATII) type 2 receptors (AT2). In our experiments, the effect of ARB on TGF-beta reduction was only detected by segregation of ACE genotypes. This indicates that the selection of medicine in light of a patient's genotype is important in treating diabetic nephropathy.
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PMID:Differential effects of RAS inhibitors associated with ACE gene polymorphisms in type 2 diabetic nephropathy. 1629 Jan 23

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