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Part 5: PD in Pediatric, Elderly, and Diabetic Patients |
Division of Nephrology and Department of Internal Medicine, Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Korea
Correspondence to: Y.L. Kim, Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, 50 Samduk-dong 2Ga, Jung-gu, Daegu 700-721 Korea. ylkim{at}knu.ac.kr
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ABSTRACT |
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 TOP ABSTRACT RISKS FOR CVD DURING...SURVIVAL OF DIABETIC PD...CONCLUSIONSREFERENCES |
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Although the survival of diabetic peritoneal dialysis (PD) patients has
improved, it is still much worse than the survival of nondiabetic patients.
Diabetes has its own risks for cardiovascular disease (CVD), such as increased
levels of advanced glycation end-products, carbonyl and oxidative stress, and
low-grade inflammation. An independent, graded association has been observed
between a reduced glomerular filtration rate and the risk of CVD events in
chronic kidney disease (CKD). Both CKD and diabetes synergistically lead to a
high risk of CVD. It seems that the poor survival of diabetic PD patients is
predestined at the initiation of dialysis because of multiple pre-existing
risk factors and comorbid diseases, particularly CVD.
Recently, several trials were successful in improving the survival of
patients with diabetic CKD. Tight control of glucose, blood pressure
management using angiotensin converting-enzyme inhibitors or angiotensin II
receptor blockers, and use of statins, antioxidants, or peroxisome
proliferator-activated receptor gamma agonists may improve the survival of
diabetic PD patients. However, simple correction of a single CVD risk factor
is not likely to be effective. New PD solutions such as those low in glucose
degradation products or those with icodextrin may also be effective in
reducing the risk of CVD in diabetic PD patients. Therefore, multifactorial
interventions—including diet control, early referral, and choice of an
optimal PD solution—may improve the survival of diabetic PD
patients.
KEY WORDS: Diabetes; survival; cardiovascular disease.
The prevalence of type 2 diabetes mellitus is now exploding in most populations. European countries still have a low prevalence (2% in Britain and Germany). A high prevalence is seen in urban Taiwan (12%), in India (12%), and among the Pima Indians (50%) in the United States (1).
Diabetes is the most important cause of end-stage kidney disease (ESRD) in most countries. During the last several years, the survival of diabetic patients with ESRD has improved; however, that survival is still much worse than the survival of nondiabetic ESRD patients (2). Diabetic ESRD patients have multiple comorbid conditions. Cardiac diseases including congestive heart failure, ischemic heart disease, and myocardial infarction (MI) are more common in diabetic ESRD patients than in nondiabetic ESRD patients. Stroke and peripheral vascular diseases are also more common in diabetic ESRD patients. Cardiovascular events including MI, cardiac arrest, and stoke are the most common causes of death in this population, followed by infection (3).
In a large community-based population, an independent graded association was observed between reduced estimated glomerular filtration rate and the risk of death and cardiovascular events (4). According to a multinational study by the World Health Organization, cardiovascular disease (CVD) accounts for about 50% of deaths in type 2 diabetes (5). Therefore, the combination of CKD and diabetes synergistically leads to the development of a high risk for CVD.
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RISKS FOR CVD DURING THE PRE-DIALYSIS PERIOD AND TRIALS TO MITIGATE THOSE RISKS |
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TOPABSTRACTRISKS FOR CVD DURING...SURVIVAL OF DIABETIC PD...CONCLUSIONSREFERENCES |
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For example, intracellular AGE precursors damage vascular cells. First, the intracellular protein modified by AGE alters cell function. Second, the extracellular matrix component modified by AGE precursors interacts abnormally with other matrix components and with the receptors for matrix protein on cells. Third, the plasma protein modified by AGE precursors binds to AGE receptors on endothelial cells and macrophages and induces receptor-mediated production of ROS. The AGE receptor ligation activates nuclear factor kappa B, causing pathologic changes in gene expression (7). Levels of plasma AGE–modified low-density lipoproteins (LDLs) are increased in diabetes. The increase is more profound in ESRD and is highest in patients with diabetes and ESRD. The AGE-modified LDLs contribute to dyslipidemia in diabetic ESRD patients (8).
Plasma carbonyl stress is also elevated in diabetes. This increase is more profound in diabetic patients on dialysis (9).
Markers of inflammation such as C-reactive protein (CRP) and interleukin-6 (IL-6) increase in patients with nephropathy related to type 1 diabetes, suggesting that low-grade inflammation is associated with that condition (10).
Strict sugar control has been shown to reduce CVD in patients with type 1 diabetes. The Diabetes Control and Complications Trial (DCCT) assessed the carotid intima media thickness (IMT) in patients with type 1 diabetes after 6 years. That study showed that intensive glucose control resulted in lesser progression of IMT (11).
In an extended long-term follow-up of DCCT, intensive sugar control reduced CVD in patients with type 1 diabetes during a mean follow-up of 17 years. As compared with conventional treatment, intensive sugar control reduced the risk of CVD by 57% (12).
Although not as well established as for patients with type 1 diabetes, reduced risk of CVD through intensive glucose control in patients with type 2 diabetes is beginning to accumulate evidence. The U.K. Prospective Diabetes Study (13) showed that intensive glucose control reduces the risk of microvascular complications, retinopathy, and microalbuminuria in type 2 diabetes. It reduced the risk of MI by 16%. However, the statistical power for these results was borderline (p = 0.05).
The Atherosclerosis Risk In Communities study, a community-based cohort study of nearly 16 000 people aged 45–64 years, showed that HbA1c levels had a graded association with IMT. In patients diagnosed with diabetes, the highest HbA1c quartile was significantly associated with a thickened intima media (14).
Oomichi et al. performed a 7-year observational study evaluating
the impact of glucose control on survival in diabetic dialysis patients
(23;
Table 1). The cumulative
survival of the group with poor HbA1c values (
8.0%) was significantly
lower than that of the groups with good values (<6.5%) and fair values
(6.5%–7.9%).
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The cumulative death rate from the onset of diabetic nephropathy in type 1 diabetes has improved with effective antihypertensive therapy (25). The Heart Outcomes Prevention Evaluation study reported on the effect of ramipril on CVD in patients with diabetes. Ramipril reduced the risk of combined primary outcomes (MI, stroke, cardiovascular death) by 25%, MI alone by 22%, stroke alone by 33%, and cardiovascular death alone by 37% (26).
The Reduction of Endpoints in NIDDM (non-insulin dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial were the first to specifically recruit patients with type 2 diabetes and overt nephropathy. Those studies evaluated the effects of angiotensin II receptor blockers (ARBs). In both studies, the ARB reduced the risks for the primary endpoint (composite of doubling of serum creatinine, ESRD, and all-cause mortality), but could not reduce the risk of all-cause mortality alone (15,16). However, in a subgroup analysis of the RENAAL study (19), the ARB losartan reduced the risk for cardiovascular events in patients with left ventricular hypertrophy.
Peroxisome proliferator-activated receptor gamma (PPARG) agonists are promising drugs for improving the survival of diabetic ESRD patients. The receptor is expressed in many tissues, including adipose tissue, liver, skeletal muscle, pancreas, and kidney. The agonists may increase lipogenesis in adipose tissue and insulin sensitivity in muscles and liver, reduce free fatty acids, and increase adiponectin. Also, PPARG agonists have been shown to reduce the levels of markers of CVD and vascular inflammation, including matrix metalloproteinase-9, IL-6, CRP, and plasminogen activator inhibitor type 1 (27).
The Prospective Pioglitazone Clinical Trial in Macrovascular Events reported the results of secondary prevention of macrovascular events in patients with type 2 diabetes taking PPARG agonists. The study was prematurely stopped because of a significant reduction in the composite endpoint for all-cause mortality, MI, and stroke in the pioglitazone group (28). Wong et al. reported the effects of rosiglitazone in type 2 diabetic PD patients. Systolic and diastolic blood pressure and serum levels of high-sensitivity CRP (hs-CRP) were both decreased with PPARG agonists (20).
The lipid-lowering statins are another promising group of drugs for reducing CVD. In a trial in which the primary outcome was time to fatal coronary, nonfatal MI, and coronary revascularization (21), pravastatin was shown to reduce the relative risk of this composite primary outcome by 25% in patients with CKD (stage 2 or 3) and diabetes. However, atorvastatin had no significant effect on the primary composite endpoint of cardiovascular death, nonfatal MI, and stroke in patients with type 2 diabetes on hemodialysis (HD) (22).
Antioxidants may also help to reduce cardiovascular risk. Vitamin E supplements administered for 3 months reduced inflammatory markers such as hs-CRP and IL-6 in patients with diabetes, with or without macrovascular complication (29). In the Secondary Prevention with Antioxidants of CVD in ESRD trial, high doses of vitamin E reduced the CVD endpoint and MI in ESRD patients with preexisting CVD (30). The antioxidant acetylcysteine was shown to reduce CVD events in patients on HD (31). The Steno-2 study demonstrated that multifactorial interventions including tight control of blood sugar, blood pressure, and lipid profile with the use of aspirin and ACE inhibitors reduced the risk of CVD in patients with type 2 diabetes and microalbuminuria (17).
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SURVIVAL OF DIABETIC PD PATIENTS DURING THE POST-DIALYSIS PERIOD |
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TOPABSTRACTRISKS FOR CVD DURING...SURVIVAL OF DIABETIC PD...CONCLUSIONSREFERENCES |
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In vivo and in vitro studies have demonstrated a negative impact of glucose degradation products (GDPs) in PD solution. These compounds enter the systemic circulation from the peritoneal cavity and increase plasma AGEs (36). They may induce renal tubular epithelial cell apoptosis and hasten deterioration of residual renal function (37). In diabetic ESRD, carbonyl stress increases because of increased substrate in diabetes and reduced renal clearances in ESRD. The GDPs in PD solution may aggravate carbonyl stress. The carbonyl intermediate can form AGEs and induce oxidative stress, which may ultimately cause diabetic complications (38). In the Euro-Balance Trial, use of PD solution with low GDP content reduced circulating AGE levels (39).
In a large-scale observational study, the survival of diabetic patients treated with low-GDP solution was better than that of diabetic patients treated with conventional solution (23). Icodextrin solution improves the fluid status of PD patients. Icodextrin solution has been shown to reduce total body water and extracellular fluid volume (40) which may lead to a decrease in left ventricular mass (41). Icodextrin solution appears to improve abnormal adipokine metabolism. With the use of icodextrin solution, adiponectin levels increased, and leptin levels decreased. These results suggest that the use of icodextrin-based PD solution may be useful in preventing atherosclerosis in PD patients (42). Several reports have shown that the use of icodextrin leads to better blood sugar control (43).
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CONCLUSIONS |
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TOPABSTRACTRISKS FOR CVD DURING...SURVIVAL OF DIABETIC PD...CONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTRISKS FOR CVD DURING...SURVIVAL OF DIABETIC PD...CONCLUSIONSREFERENCES |
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