Glycemic Control in PD
Diabetes Mellitus (DM) is a potent cardiovascular risk factor in the general population as well as in those undergoing maintenance dialysis (1–5). Glycemic control, as measured by glycosylated hemoglobin (A1c) is a predictor of cardiovascular complications, including myocardial infarctions and hospitalizations for coronary artery disease (6,7). Clinical trials have shown that tight glycemic control decreases the risk of developing retinopathy, nephropathy, and neuropathy in the general population. However, there are limited studies that have investigated the impact of glycemic control in diabetic patients especially on peritoneal dialysis (PD) (8–10). Nonetheless, it has been shown that diabetes mellitus (DM) is a significant cause of kidney failure (11). Expert groups have recommended that diabetic dialysis patients should follow the American Diabetes Association guidelines; however, there is no consistent evidence to support these recommendations for patients with end-stage renal disease (ESRD), and the data for patients treated with peritoneal dialysis (PD) are even more limited (11–13).
Measures of glycemic control in PD patients
Current parameters used to assess glycemic control in diabetic patients include, but are not limited to, blood or capillary plasma glucose, glycated hemoglobin (HbA1c) and glycated albumin (14,15). Hemoglobin A1c (HbA1c) is the standard measure for glucose monitoring in patients without kidney impairment. According to NKF-KDOQI guidelines, currently recommended HbA1c targets in the setting of CKD are no different from those for the general diabetic population; that is, <7.0%, although the seminal glycemic control trials in type 1 and type 2 diabetes have excluded patients with significantly decreased kidney function (11). There are several issues unique to the dialysis population that mandates a separate examination of the glycemic control on outcomes in this population. Chronic kidney disease is associated with insulin resistance and, in advanced kidney disease, decreased insulin degradation (16). Moreover, it is difficult to accurately assess glycemic control in the ESRD population due to alterations in insulin metabolism and changes in red blood cell survival that lead to competing effects on measurements of glycemic control (16,17).
Importance of glycemic control
Duong et al. examined mortality and its predictability in 2,798 diabetic peritoneal dialysis patients by measuring HbA1c levels (9). They determined that poor glycemic control was associated with higher mortality in peritoneal dialysis patients, and that moderate to severe hyperglycemia was associated with a higher death risk. Data from Yoo and colleagues support these results (10). Peritoneal dialysis can result in a large amount of glucose absorption from the dialysate; therefore, strict glycemic control may be difficult in PD patients (22,23). Concerning peritoneal dialysis associated infections, poor glycemic control has not been established as a specific risk factor; however, it is known to increase the risk of infections in the general DM population (24). Recurrent peritonitis and inflammatory processes can increase peritoneal transport rates and cause rapid absorption of glucose from the peritoneal cavity which may, in turn, cause deterioration of glycemic control (25). This could lead to reduced ultrafiltration, requiring administration of increasingly hypertonic peritoneal dialysis solutions and, consequently, the perpetuation of hyperglycemia. It is suggested that glycemic control, measured by HbA1c, is not associated with preservation of residual renal function in diabetic peritoneal dialysis patients, at least in the first year on PD as reported in a study by Sung et al (26). However, this study included only 89 patients and was not sufficiently powered to detect a difference. Based on the currently available evidence from clinical studies, it is not known if better glycemic control preserves residual function (20). Regular and frequent monitoring of blood glucose, frequent and effective adjustment of therapy, and early diagnosis and treatment of concurrent conditions are essential.
Recommendations for glycemic control in PD
The KDOQI guidelines recommend that hyperglycemia be managed in diabetic patients regardless of kidney function status (11). Intensive treatment of hyperglycemia can help to prevent or delay kidney disease (11). The KDOQI workgroup suggests maintaining pre–prandial capillary glucose levels within 90-130 mg/dL (5.0-7.2 mmol/L), with postprandial sugars below 180 mg/dL (10 mmol/L) and an HbA1c of approximately 7%, which is consistent with the American Diabetes Association (ADA) guidelines (14). The ADA also recommends that blood sugar monitoring be conducted at least three times per day, before meals and at bedtime.
When compared to diabetic hemodialysis patients, diabetic peritoneal dialysis patients demonstrated better outcomes in a study by Lin et al. (27). However, Vonesh et al. showed that peritoneal dialysis was favored in younger diabetic patients while hemodialysis was favored in older diabetic patients (28). These studies demonstrate that any given dialysis therapy is not necessarily recommended over another and must be tailored to each individual patient. In order to achieve osmotic removal of retained fluid, peritoneal dialysis fluids contain supraphysiological concentrations of glucose. Time coupled with progressive loss of diuresis from the failing kidneys results in the average glucose concentration of the peritoneal dialysis prescription being increased. The potential for this glucose load to cause problems such as obesity, hyperlipidemia, potential worsening of insulin resistance, and blood glucose level fluctuations has led to the production of biocompatible alternatives PD solutions (29).
Biocompatible solutions have been shown to alleviate undesirable local and/or systemic effects while providing necessary therapy (30,31). Some biocompatible PD solutions use a glucose polymer, or amino acids as the alternative osmotic agent instead of glucose, thus preventing or minimizing glucose absorption during treatment (32,33). Two randomized clinical studies with at least 1 year of follow-up using a polyglucose-based PD solution in diabetic patients showed significant improvements in glycemic control and reduced insulin requirements (34,35). However, no effect on survival or mortality was found in several randomized controlled trials (36,37).
Glycemic control through pharmaceutical intervention is a part of therapy in diabetic peritoneal dialysis patients (25,38–47). Doses and regimens tend to vary and should be adjusted based on frequent monitoring by the physician, with the aim of achieving target goals of glycemic control. The presence of insulin resistance is a prevalent metabolic feature in chronic kidney disease (CKD) and it should be considered when evaluating therapy (48). The clinical impacts of insulin resistance in this setting are numerous, including endothelial dysfunction, increased cardiovascular mortality, muscle wasting, and possibly initiation and progression of CKD (49). Regarding intraperitoneal (IP) versus subcutaneous (SC) insulin administration, a meta-analysis of three studies found that glycemic control, as determined by HbA1c in diabetic CAPD patients, was comparable or better with IP versus SC insulin ; however, the dose required was more than two-fold higher in the IP treatment (45).
Overall, therapy for glycemic control in peritoneal dialysis patients should be individualized according to patient preference, compliance, peritoneal transport status, and coexisting co-morbid conditions.
- Diabetes Control and Complications Trial Research Group, Nathan, D. M., Genuth, S., Lachin, J., Cleary, P., Crofford, O., Davis, M., Rand, L., Siebert, C. The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. N. Engl. J. Med. 329, 977–986 (1993). www.ncbi.nlm.gov/pubmed/8366922
- UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet352, 837–53 (1998). www.ncbi.nlm.gov/pubmed/9742976
- Ohkubo, Y., Kishikawa, H., Araki, E., Miyata, T., Isami, S., Motoyoshi, S., Kojima, Y., Furuyoshi, N., Shichiri, M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res. Clin. Pract.28, 103–17 (1995). www.ncbi.nlm.gov/pubmed/7587918
- Wei, M., Gaskill, S. P., Haffner, S. M., Stern, M. P. Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study.Diabetes Care21, 1167–72 (1998). www.ncbi.nlm.gov/pubmed/9653614
- Selvin, E., Marinopoulos, S., Berkenblit, G., Rami, T., Brancati, F. L., Powe, N. R., Golden, S. H. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus.Ann. Intern. Med.141, 421–31 (2004). www.ncbi.nlm.gov/pubmed/15381515
- Chaturvedi, N., Fuller, J. H. Glycosylated hemoglobin and the risk of microalbuminuria in insulin-dependent diabetes mellitus. EURODIAB IDDM Complications Study Group.N. Engl. J. Med.333, 940–941 (1995). www.ncbi.nlm.gov/pubmed/7666888
- Gaede, P., Vedel, P., Larsen, N., Jensen, G. V. H., Parving, H.-H., Pedersen, O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N. Engl. J. Med.348, 383–393 (2003). www.ncbi.nlm.gov/pubmed/12556541
- Wu, M. S., Yu, C. C., Wu, C. H., Haung, J. Y., Leu, M. L., Huang, C. C. Pre-dialysis glycemic control is an independent predictor of mortality in type II diabetic patients on continuous ambulatory peritoneal dialysis.Perit. Dial. Int.19 Suppl 2, S179-83 (1999). www.ncbi.nlm.gov/pubmed/10406515
- Duong, U., Mehrotra, R., Molnar, M. Z., Noori, N., Kovesdy, C. P., Nissenson, A. R., Kalantar-Zadeh, K. Glycemic control and survival in peritoneal dialysis patients with diabetes mellitus.Clin. J. Am. Soc. Nephrol.6, 1041–8 (2011). www.ncbi.nlm.gov/pubmed/21511838
- Yoo, D. E., Park, J. T., Oh, H. J., Kim, S. J., Lee, M. J., Shin, D. H., Han, S. H., Yoo, T.-H., Choi, K. H., Kang, S.-W. Good glycemic control is associated with better survival in diabetic patients on peritoneal dialysis: a prospective observational study.PLoS One7, e30072 (2012). www.ncbi.nlm.gov/pubmed/22291903
- National Kidney Foundation. K/DOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update.Am. J. Kidney Dis.60, 850–86 (2012). www.ncbi.nlm.gov/pubmed/23067652
- Introduction: <em>Standards of Medical Care in Diabetes—2020</em>Diabetes Care43, S1 LP-S2 (2020).
- Isakova, T., Nickolas, T. L., Denburg, M., Yarlagadda, S., Weiner, D. E., Gutiérrez, O. M., Bansal, V., Rosas, S. E., Nigwekar, S., Yee, J.,et al.KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Am. J. Kidney Dis. 70, 737–751 (2017). www.ncbi.nlm.gov/pubmed/28941764
- Chamberlain, J. J., Rhinehart, A. S., Shaefer, C. F., Neuman, A. Diagnosis and Management of Diabetes: Synopsis of the 2016 American Diabetes Association Standards of Medical Care in Diabetes.Ann. Intern. Med.164, 542 (2016). www.ncbi.nlm.gov/pubmed/26928912
- Rhee, C. M., Leung, A. M., Kovesdy, C. P., Lynch, K. E., Brent, G. A., Kalantar-Zadeh, K. Updates on the management of diabetes in dialysis patients.Semin. Dial.27, 135–145 (2014).
- Rubenstein, A. H., Mako, M. E., Horwitz, D. L. Insulin and the kidney.Nephron15, 306–326 (1975). www.ncbi.nlm.gov/pubmed/1101090
- Ly, J., Marticorena, R., Donnelly, S. Red blood cell survival in chronic renal failure.Am. J. Kidney Dis.44, 715–9 (2004). www.ncbi.nlm.gov/pubmed/15384023
- Drechsler, C., Krane, V., Ritz, E., März, W., Wanner, C. Glycemic control and cardiovascular events in diabetic hemodialysis patients.Circulation120, 2421–8 (2009). www.ncbi.nlm.gov/pubmed/19948978
- Joy, M. S., Cefalu, W. T., Hogan, S. L., Nachman, P. H. Long-term glycemic control measurements in diabetic patients receiving hemodialysis.Am. J. Kidney Dis.39, 297–307 (2002). www.ncbi.nlm.gov/pubmed/11840370
- Inaba, M., Okuno, S., Kumeda, Y., Yamada, S., Imanishi, Y., Tabata, T., Okamura, M., Okada, S., Yamakawa, T., Ishimura, E.,et al.Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J. Am. Soc. Nephrol. 18, 896–903 (2007). www.ncbi.nlm.gov/pubmed/17267743
- Watanabe, Y., Ohno, Y., Inoue, T., Takane, H., Okada, H., Suzuki, H. Blood glucose levels in peritoneal dialysis are better reflected by HbA1c than by glycated albumin.Adv. Perit. Dial.30, 75–82 (2014). www.ncbi.nlm.gov/pubmed/25338425
- Fortes, P. C., Mendes, J. G., Sesiuk, K., Marcondes, L. B., Aita, C. A. M., Riella, M. C., Pecoits-Filho, R. Glycemic and lipidic profile in diabetic patients undergoing dialysis.Arq. Bras. Endocrinol. Metabol.54, 793–800 (2010). www.ncbi.nlm.gov/pubmed/21340171
- Tzamaloukas, A. H., Friedman, E. A. inHandb. Dial.(eds. Daugirdas, J., Blake, P. G. & Ing, T.) 490–507 (Lippincott Williams & Wilkins, 2007).
- Rodriguez-Carmona, A., Perez-Fontan, M., López-Muñiz, A., Ferreiro-Hermida, T., García-Falcón, T. Correlation between glycemic control and the incidence of peritoneal and catheter tunnel and exit-site infections in diabetic patients undergoing peritoneal dialysis.Perit. Dial. Int.(2013). doi:10.3747/pdi.2012.00185 www.ncbi.nlm.gov/pubmed/23818005
- Davies, S. J., Mushahar, L., Yu, Z., Lambie, M. Determinants of peritoneal membrane function over time.Semin. Nephrol.31, 172–82 (2011). www.ncbi.nlm.gov/pubmed/21439431
- Sung, S.-A., Hwang, Y.-H., Kim, S., Kim, S. G., Oh, J., Chung, W., Lee, S.-Y., Ahn, C., Oh, K.-H. Loss of residual renal function was not associated with glycemic control in patients on peritoneal dialysis.Perit. Dial. Int.31, 154–9 (2011). www.ncbi.nlm.gov/pubmed/21282376
- Lin, T.-C., Kao, M.-T., Lai, M.-N., Huang, C.-C. Mortality difference by dialysis modality among new ESRD patients with and without diabetes mellitus.Dial. Transplant.35, 234–244 (2006).
- Vonesh, E. F., Snyder, J. J., Foley, R. N., Collins, A. J. Mortality studies comparing peritoneal dialysis and hemodialysis: what do they tell us?Kidney Int. Suppl.S3-11 (2006). doi:10.1038/sj.ki.5001910 www.ncbi.nlm.gov/pubmed/17080109
- Mujais, S., Vonesh, E. E. F. Profiling of peritoneal ultrafiltration.Kidney Int. Suppl.62, S17–S22 (2002). www.ncbi.nlm.gov/pubmed/12230478
- Williams, D. F.The Williams Dictionary of Biomaterials. (Liverpool University Press, 1999).
- DF, W. Revisiting the definition of biocompatibility.Med. Device Technol.14, (2003).
- Chan, T., Yung, S. Studying the effects of new peritoneal dialysis solutions on the peritoneum.Perit Dial Inter27, S87–S93 (2007).
- Ho-dac-Pannekeet, M. M., Schouten, N., Langendijk, M. J., Hiralall, J. K., de Waart, D. R., Struijk, D. G., Krediet, R. T. Peritoneal transport characteristics with glucose polymer based dialysate.Kidney Int.50, 979–86 (1996). www.ncbi.nlm.gov/pubmed/8872974
- Paniagua, R., Ventura, M.-J., Avila-Díaz, M., Cisneros, A., Vicenté-Martínez, M., Furlong, M.-D.-C., García-González, Z., Villanueva, D., Orihuela, O., Prado-Uribe, M.-D.-C.,et al.Icodextrin improves metabolic and fluid management in high and high-average transport diabetic patients. Perit. Dial. Int. 29, 422–32 (2009). www.ncbi.nlm.gov/pubmed/19602608
- Li, P. K. T., Culleton, B. F., Ariza, A., Do, J.-Y., Johnson, D. W., Sanabria, M., Shockley, T. R., Story, K., Vatazin, A., Verrelli, M.,et al.Randomized, controlled trial of glucose-sparing peritoneal dialysis in diabetic patients. J. Am. Soc. Nephrol. 24, 1889–900 (2013). www.ncbi.nlm.gov/pubmed/23949801
- Chow, K. M., Szeto, C. C., Kwan, B. C. H., Pang, W. F., Ma, T., Leung, C. B., Law, M. C., Li, P. K.-T. Randomized controlled study of icodextrin on the treatment of peritoneal dialysis patients during acute peritonitis.Nephrol. Dial. Transplant29, 1438–43 (2014). www.ncbi.nlm.gov/pubmed/24578470
- Cho, Y., Johnson, D. W., Badve, S., Craig, J. C., Strippoli, G. F. K., Wiggins, K. J. Impact of icodextrin on clinical outcomes in peritoneal dialysis: a systematic review of randomized controlled trials.Nephrol. Dial. Transplant28, 1899–907 (2013). www.ncbi.nlm.gov/pubmed/23493329
- Khalili, K., Lan, F. P., Hanbidge, A. E., Muradali, D., Oreopoulos, D. G., Wanless, I. R. Hepatic subcapsular steatosis in response to intraperitoneal insulin delivery: CT findings and prevalence.AJR. Am. J. Roentgenol.180, 1601–4 (2003). www.ncbi.nlm.gov/pubmed/12760927
- Ito, H., Mifune, M., Matsuyama, E., Furusho, M., Omoto, T., Shinozaki, M., Nishio, S., Antoku, S., Abe, M., Togane, M.,et al.Vildagliptin is Effective for Glycemic Control in Diabetic Patients Undergoing either Hemodialysis or Peritoneal Dialysis. Diabetes Ther. 4, 321–9 (2013). www.ncbi.nlm.gov/pubmed/23801219
- Torun, D., Oguzkurt, L., Sezer, S., Zumrutdal, A., Singan, M., Adam, F. U., Ozdemir, F. N., Haberal, M. Hepatic subcapsular steatosis as a complication associated with intraperitoneal insulin treatment in diabetic peritoneal dialysis patients.Perit. Dial. Int.25, 596–600 (2005). www.ncbi.nlm.gov/pubmed/16411528
- Thorp, M. L., Wilks, T. S. Three diabetic peritoneal dialysis patients receiving intraperitoneal insulin with dosage adjustment based on capillary glucose levels during peritoneal equilibrium tests.Am. J. Kidney Dis.43, 927–9 (2004). www.ncbi.nlm.gov/pubmed/15112185
- Diaz-Buxo, J. A., Crawford, T. L. inDial. Ther.(eds. Nissenson, A. R. & Fine, R. N.) 429–434 (Hanley & Belfus, 2002).
- Wolf, F., Markell, M. S. inClin. Dial.(eds. Nissenson, A. R. & Fine, R. N.) 877–890 (McGraw-Hill Medical Publication, 2005).
- Feriani, M., Dell’Aquila, R., La Greca, G. The treatment of diabetic end-stage renal disease with peritoneal dialysis.Nephrol. Dial. Transplant13 Suppl 8, 53–6 (1998). www.ncbi.nlm.gov/pubmed/9870427
- Almalki, M. H., Altuwaijri, M. A., Almehthel, M. S., Sirrs, S. M., Singh, R. S. Subcutaneous versus intraperitoneal insulin for patients with diabetes mellitus on continuous ambulatory peritoneal dialysis: meta-analysis of non-randomized clinical trials.Clin. Invest. Med.35, E132-43 (2012). www.ncbi.nlm.gov/pubmed/22673316
- K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.Am. J. Kidney Dis.49, S12-154 (2007). www.ncbi.nlm.gov/pubmed/17276798
- American Diabetes Association. Standards of medical care in diabetes–2006.Diabetes Care29 Suppl 1, S4-42 (2006). www.ncbi.nlm.gov/pubmed/16373931
- Koppe, L., Pelletier, C. C., Alix, P. M., Kalbacher, E., Fouque, D., Soulage, C. O., Guebre-Egziabher, F. Insulin resistance in chronic kidney disease: new lessons from experimental models.Nephrol. Dial. Transplant29, 1666–74 (2014). www.ncbi.nlm.gov/pubmed/24286973
- Teta, D. Insulin Resistance as a Therapeutic Target for Chronic Kidney Disease.J. Ren. Nutr.(2014). doi:10.1053/j.jrn.2014.10.019 www.ncbi.nlm.gov/pubmed/25511524
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