Management of hyperglycemia in diabetics with end-stage renal disease 신장내과 R4 최선영 /Prof. 이태원

CRF – insulin resistance (↓insulin degradation)  marked decrease in insulin requirement, cessation of insulin therapy (esp. DM) dialysis  reverse Insulin requirement Improving tissue sensitivity Restoring normal hepatic insulin metabolism

Monitoring glycemic control HbA1c (glycated hemoglobin) Column-, ion-exchange chromatography, agar gel EP ￪ urea  carbamylated Hb  false elevation Recent transfusion, iron deficiency, accelerated erythropoiesis d/t administration of EPO, metabolic acidosis Boronate-agarose affinity chromatography, thiobarbituric acid method -- more reliable in ESRD

DM + chronic dialysis Fasting blood glucose < 140mg/dL pp1h < 200mg/dL HbA1c : 6~7% (type 1 DM), 7~8% (type 2 DM) Excellent glycemic control – less popular in dialysis severe hypoglycemia with aggressive control Lack of symptoms with hyperglycemia Perceived inability to significantly alter progressive hyperglycemia-induced organ damage Lack of accuracy of HbA1c in dialysis patients Good glycemic control – goal of diabetic ESRD

Oral hypoglycemic agents Sulfonylurea Protein (albumin) - bound Plasma drug level – cannot efficiently reversed by HD  -blocker, salicylate, warfarin  displace OHA from albumin  free drug  Hypoglycemia

Basic principles of sulfonylurea metabolism Chlorpropamide : exclusively by the kidney Acetohexamide, tolazamide : active metabolite  kidney Glyburide : weak active metabolite  urine Glimepiride : primarily liver, active metabolite  urine Glipizide, tolbutamide : primarily liver, inactive metabolites  urine ∴ DOC in CRF Glipizide : 2.5~10mg/day Glyburide : GFR > 50ml/min – reduced dose

Thiazolidinediones Tissue sensitivity to insulin Rosiglitazone, pioglitazone Metabolized by the liver Renal insufficiency – no accumulation of parent drug or metabolite Edema, heart failure  should be avoided in patients with advanced kidney failure

Alpha-glucosidase inhibitor Adarbose, miglitol ↓ carbohydrate absorption from GI tract, lower postprandial sugar peak Increased levels of parent drug or metabolite in renal insufficiency Contraindication in renal dysfunction

Meglitinide Nateglinide, repaglinide Stimulate insulin secretion Nateglinide : hepatically metabolized, renal excretion of active metabolites Renal failure  accumulation  hypoglycemia Repaglinide : metabolized by liver, renal excretion < 10% Not need dose adjustment

Metformin Primarily excreted unchanged in the urine Drug accumulation and lactic acidosis Should be avoided in renal insufficiency ESRD K/DOQI guideline Insulin regimen Glipizide

Use of insulin GFR > 50 ml/min : no dose adjustment 10 < GFR < 50 ml/min : 75% reduction of baseline GFR < 10 ml/min : reduce by 50%

Subcutaneous insulin in dialysis patients Correction of uremia with dialysis  ↓ insulin resistance, ￪ insulin degradation Variable net effect on glycemic control General therapeutic goal FBS < 140 mg/dL pp1h < 200 mg/dL

NPH/RI 2/3 of the daily insulin (55~60% NPH) : in the morning 1/3 of the daily insuin : 30 min before supper Ultralente/RI 50~60% of total dose : ultralente  before breakfast, supper Remain : premeal RI (40%-breakfast, 20%-lunch, 40%- supper) Sliding scale of RI 1u sliding scale = 1u add to premeal dose / ￪ 50mg/dL above 150 mg/dL

Intraperitoneal insulin in peritoneal dialysis Advantages Continuous insulin infusion Eliminate the need for injection More physiologic route of absorption Disadvantages Source of bacterial contamination of dialysate Higher total insulin doses (losses of spent dialysate) Risk of peritoneal fibroblastic proliferation, hepatic subcapsular steatosis

Toronto Western protocol 2-L exchanger, 4 times/day First 3 exchanges : 20 min before each major meal 4 th exchange : 11pm BST : fasting, pp1h after each meal 1 st day 1/4 of total daily SC insulin dose  RI in each exchanges 1.5% dextrose dialysis soln : add 2 unit 2.5% dextrose dialysis soln : add 4 unit 4.25% dextrose dialysis soln : add 6 unit

Fasting serum glucose level (mg/dL) 1-h postprandial serum glucose level Amount of insulin change (unit/2-L bag) <40-6 < No change >400>300variable 2 nd day insulin adjustment

Uncontrolled diabetic pts on CAPD : PET High transporter : rapid glucose absorption  blood glucose increase, lower osmotic gradient between dialysate and blood  reduced UF  fluid retention  2.5% or 4.25% dextrose dialysis soln.  further hyperglycemia

Approach to problem patients Persistent hyperglycemia HbA1c > 9% Inadequate insulin dose, Noncompliance Microvascular disease  erratic absorption of insulin from subcutaneous tissue

Severe hyperglycemia and ketoacidosis Severe hyperglycemia (s-glc > 1000mg/dL) Hypovolemia and marked hyperosmolality : not occur  Minimal Sx Ketoacidosis in Type 1 DM Management Low dose IV insulin (2 units/hour) S-glucose and potassium concentration : close monitoring

Hypoglycemia Poor calorie intake, Occult disease (infection, malignancy) Frequent adjustment of insulin dose, evaluation of blood glucose diaries Beta blocker, ling-acting insulin and OHA - discontinue

Alternating hypoglycemia and hyperglycemia Often gastroparesis Dx : gastric emptying study Tx : metoclopramide, bethanechol, cisapride Other cause Misunderstanding of the timing of insulin injections Poor timing CAPD exchanges Noncompliance Impaired vision Depressive illness