sparing solutions, such as those with amino acids or icodextrin, could ... In a transversal study with 27 CAPD patients, utilization of icodextrin during the long ...
Metabolic Impact of Peritoneal Dialysis Thyago Proença de Moraes, MD Pontifícia Universidade Católica do Paraná/ Fundação Pró Renal
ABSTRACT Carbohydrate metabolism disturbances are known factors potentially associated with cardiovascular complications in patients with chronic kidney disease (CKD). Disorders of lipids and glucose metabolism are commonly found in the early stages of CKD and aggravate with the progression of kidney dysfunction. Recent reports suggest that the relationship between hyperglycemia and cardiovascular disease (CVD) may extend below the limits currently defined as diabetes: higher levels of glycosylated hemoglobin (HbA1c) has been identified as independent predictors of mortality in general population and nondiabetic CKD patients [1-3]. Insulin resistance was also identified as an independent predictor of cardiovascular events and mortality in general and CKD patients [4, 5]. The initiation of peritoneal dialysis (PD) revert some factors presented since the early stages of renal insufficiency and implicated in the pathogenesis of insulin resistance, however it’s also provides an additional risk due to the absorption of glucose contained in the dialysate, which potentially intensifies carbohydrate disturbances [6]. In fact, patients with no previous history of glucose intolerance are more likely to develop hyperglycemia and de novo diabetes after the initiation of PD therapy as described in previous studies [7, 8]. Such high glucose load offered during PD therapy can also contribute to insulin resistance and worsening of dislipidemia. The use of glucose sparing solutions is an interesting approach aiming to reduce glucose load and its consequences. In summary carbohydrate and lipids abnormalities are common in PD patients with an important impact in cardiovascular outcomes. Glucose sparing solutions could have a potential benefit upon these metabolic disturbances and future studies will clarify their real efficiency. New therapeutic measures are needed in order to improve metabolic disturbances reducing cardiovascular events.
CARDIOVASCULAR MORTALITY IS THE MAIN CAUSE OF DEATH IN END-STAGE RENAL DISEASE
RISK FACTORS FOR CARDIOVASCULAR DISEASE
Peritoneal dialysis (PD) patients are at high risk of developing cardiovascular disease, resulting from both traditional and nontraditional cardiovascular risk factors, including factors related to uremia and dialysis. In fact, disorders of lipids and glucose metabolism are commonly found even in the early stages of CKD, aggravate with the progression of kidney dysfunction manifestations
and are
their insulin
most
common
resistance
and
dyslipidemia, known factors in the pathogenesis of hypertension and atherosclerosis.
RISK FACTORS ASSOCIATED TO INITIATION OF PERITONEAL DIALYSIS
The initiation of peritoneal dialysis (PD) provides an additional risk due to the absorption of glucose contained in the dialysate, which potentially intensifies carbohydrate disturbances. Fast transporters are particularly exposed to a higher glucose load: their large effective peritoneal surface area and/or higher intrinsic membrane permeability lead to a large absorption of glucose into the circulation which can reach up to 400g/day. These complex metabolic disturbances in glucose/lipid metabolism are extremely important among these risk factors as they permeate all stages of the kidney-cardiovascular interaction, from the generation of diabetic nephropathy through the genesis of uremic insulin resistance and metabolic disorders.
CHRONIC EXPOSURE TO A HIGH GLUCOSE LOAD Prolonged exposure of the peritoneum to hypertonic glucose solutions can damage the peritoneal tissue, inducing histologic and functional changes in the membrane. Prolonged exposure of the peritoneum to hypertonic glucose solutions can damage the peritoneal tissue, inducing histologic and functional changes in the membrane. The peritoneal membrane of fast transporters present a large effective peritoneal surface area or higher intrinsic membrane permeability, and these patients are therefore prone to lose the osmotic gradient required for sustained ultrafiltration capacity. In addition, fast transporters absorb large quantities of glucose to the circulation.
. The metabolic alterations induced by fast transport potentially play a role in the development of CV disease in PD patients with a high peritoneal transport status. Indeed, the association between metabolic syndrome and peritoneal solute clearance and transport rate has been recently reported. Chen HY, Kao TW, Huang JW, Chu TS, Wu KD. Correlation of metabolic syndrome with residual renal function, solute transport rate and peritoneal solute clearance in chronic peritoneal dialysis patients. Blood Purif 2008; 26:138–44
HYPERGLYCEMIA AND MORTALITY`
Hyperglycemia is associated with poor prognosis in the general population, even in non-diabetics. Several prospective, randomized controlled clinical trials have demonstrated that intensive therapy aimed at lower levels of glycemia results in decreased rates of retinopathy, nephropathy, and neuropathy improving outcomes.
GLYCEMIC EFFECT OF ORAL AND INTRAPERITONEAL DEXTROSE The use of hypertonic dextrose solutions to enhance ultrafiltration is at a high metabolic cost. This is illustrated by a study by Delarue et al which evaluated the metabolic impact of intraperitoneal (i.p.) dextrose relative to an equivalent oral dose in 9 chronically uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). As shown on this slide, both oral and i.p. dextrose were associated with an acute hyperglycemic response. Glycemia increased similarly following i.p. and oral dextrose administration, with peak values noted at 60 minutes. Glycemia decreased more progressively after the i.p. load; glycemia remained significantly higher after the i.p. load from 180 to 360 minutes. This effect may be explained by persistent glucose absorption through the peritoneum, which contrasts a more rapid absorption profile following oral administration. This study also demonstrated that i.p. glucose is oxidized and contributes significantly to energy metabolism. The amount of glucose oxidized over the 6-hour study period was similar across routes of delivery.
NEW ONSET HYPERGLYCEMIA Bergstron et al, in 1993, has estimated that PD patients derive about 20% of their total daily energy intake from the glucose in dialysate (Kidney Int 44:1048-1057, 1993). The chronic exposure to this high glucose load could probably be involved in the development of de novo hyperglycemia. In fact, Szeto et al investigating 252 non-diabetic PD patients at initiation of their therapy found that 4.4% developed a fasting glucose higher than 200 mg/dl and another 19% between 126 and 200mg/dl/. In this study even a minor degree of hyperglycemia was an important prognostic factor, the Cox Proportional Hazard model utilized by the author found that each increase of 10mg/dl in fasting glucose model was associated with 16% increase in mortality rates (American Journal of Kidney Diseases, Vol 49, No 4 (April), 2007: pp 524-532).
INSULIN RESISTANCE IN CKD
Insulin resistance was described in the uremic setting more than 30 years ago when DeFronzo, comparing insulin tissue sensitivity by euglycemic insulin clamp technique in 17 chronically uremic and 36 normal subjects, concluded that the possible mechanisms involved with uremic insulin resistance include increased hepatic gluconeogenesis, hepatic and/or skeletal muscle glucose uptake and impaired intracellular glucose metabolism.
PARTIAL REVERSION OF INSULIN RESISTANCE WITH INITIATION OF DIALYSIS Initiation of peritoneal dialysis therapy partially revert the insulin resistance ESRD
observed patients.
in
nondialytic
However,
such
improvement appears to be lower than that observed when the initial therapy is the hemodialysis, probably due the high glucose load exposure in PD patients.
METABOLIC EFFECT OF GLUCOSE SPARING SOLUTIONS Improved glycemic control has the potential to reduce complications and improve outcomes. Glucosesparing solutions, such as those with amino acids or icodextrin, could potentially benefit both diabetic and nondiabetic PD patients by improving disturbances in carbohydrate metabolism.
EFFECT ON INSULIN RESISTANCE In a transversal study with 27 CAPD patients, utilization of icodextrin during the long dwell reduced fasting insulin levels and improved insulin sensitivity.
CONCLUSION
In conclusion carbohydrate abnormalities are common in PD patients with an important impact in cardiovascular outcomes. Glucose based PD solutions remains as the most common osmotic agent and the prolonged exposure to high glucose concentration generates a series of consequences that varies from hyperglycemia and insulin resistance to dislipidemia and obesity. Glucose sparing solutions could have a potential benefit upon carbohydrate metabolism and future studies will clarify their real efficiency. New therapeutic measures are needed in order to improve metabolic disturbances reducing cardiovascular events.
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