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Managing diabetes in hemodialysis

January 31st, 2016 | by h4uclinic
Managing diabetes in hemodialysis
Long Term Complications
516

Managing diabetes in hemodialysis patients: Observations and recommendations

Both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue activity of insulin.

ABSTRACT
Diabetes is challenging to manage in patients who have end-stage renal disease (ESRD), as both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin. The authors summarize the available evidence and make practical recommendations.

CCJM 2009 Nov;76(11):649-655.

10.3949/ccjm.76a.09054

KUMARPAL SHRISHRIMAL, MD, MS at ALL
Department of Hospital Medicine, Cleveland Clinic

 

KEY POINTS

  • Blood glucose levels can fluctuate widely due to various and opposing effects of ESRD and dialysis.
  • The hemoglobin A1clevel can be falsely high in ESRD, but it is still a reasonable measure of glycemic control in this population.
  • Most diabetes drugs are excreted at least in part by the kidney, so that patients in ESRD are at greater risk of hypoglycemia.
  • Insulin is the cornerstone of treatment, since most oral diabetes drugs are contraindicated or not recommended in this population. Insulin doses should be lowered in those with low glomerular filtration rates.

 

ALTHOUGH DIABETES is the most common cause of end-stage renal disease (ESRD) worldwide, accounting for 44.2% of ESRD patients in the US Renal Data System in 2005,1data are scarce on how diabetes should best be treated in patients in ESRD.

We do know that blood glucose levels need to be well controlled in these patients. Several observational studies and one nonrandomized interventional study2–10 showed that higher levels of hemoglobin A1c were associated with higher death rates in patients with diabetes and chronic kidney disease after adjusting for markers of inflammation and malnutrition.

However, ESRD significantly alters glycemic control, the results of hemoglobin A1c testing, and the excretion of antidiabetic medications. The various and opposing effects of ESRD and dialysis can make blood glucose levels fluctuate widely, placing patients at risk of hypoglycemia—and presenting a challenge for nephrologists and internists.

In this review, we summarize the available evidence and make practical recommendations for managing diabetes in patients on hemodialysis.

GLUCOSE LEVELS MAY FLUCTUATE WIDELY

In ESRD, both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.

Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In type 2 diabetes without kidney disease, insulin resistance leads to increased insulin secretion. This does not occur in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxyvitamin D, and secondary hyperparathyroidism.11,12 Hemodialysis further alters insulin secretion, clearance, and resistance as the result of periodic improvement in uremia, acidosis, and phosphate handling.

The dextrose concentration in the dialysate can also affect glucose control. In general, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in peritoneal dialysis to increase ultrafiltration, but this can lead to hyperglycemia.10,13

Thus, ESRD and hemodialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. For example, one would think that a patient who has insulin resistance would need more supplemental insulin; however, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in variable net effects in different patients. In addition, ESRD and hemodialysis alter the pharmacokinetics of diabetic medications. Together, all of these factors contribute to wide fluctuations in glucose levels and increase the risk of hypoglycemic events.

HEMOGLOBIN A1c MAY BE FALSELY HIGH

Self-monitoring of blood glucose plus serial hemoglobin A1c measurements are the standard of care in diabetic patients without renal failure.

However, in diabetic patients with ESRD, elevated blood urea nitrogen causes formation of carbamylated hemoglobin, which is indistinguishable from glycosylated hemoglobin by electrical-charge-based assays and can cause the hemoglobin A1cmeasurement to be falsely elevated. Other factors such as the shorter red life span of red blood cells, iron deficiency, recent transfusion, and use of erythropoietin-stimulating agents may also cause underestimation of glucose control.14

Despite these limitations, the hemoglobin A1c level is considered a reasonable measure of glycemic control in ESRD. Glycated fructosamine and albumin are other measures of glycemic control with some advantages over hemoglobin A1c in dialysis patients. However, they are not readily available and can be affected by conditions that alter protein metabolism, including ESRD.15–18

Self-monitoring of blood glucose and continuous glucose monitoring systems provide real-time assessments of glycemic control, but both have limitations. Self-monitoring is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. Continuous monitoring is expensive and is less reliable at lower glucose concentrations, and thus it needs to be used in conjunction with other measures of glucose control. For these reasons, continuous glucose monitoring is not yet widely used.

The guidelines of the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative did not clearly establish a target hemoglobin A1c level for patients with diabetes and ESRD, but levels of 6% to 7% appear to be safe. The target fasting plasma glucose level should be lower than 140 mg/dL, and the target postprandial glucose level should be lower than 200 mg/dL.19

MOST ORAL DIABETES DRUGS ARE CONTRAINDICATED IN ESRD
RTEmagicC_Shrishrimal_DiabetesAndHemodialysis_T1.gifOral antihyperglycemic drugs include the insulin secretagogues (sulfonylureas and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors (TABLE 1). Most of these drugs are contraindicated in ESRD.

Sulfonylureas

Sulfonylureas reduce blood glucose by stimulating the pancreatic beta cells to increase insulin secretion.

Sulfonylureas have a wide volume of distribution and are highly protein-bound,20 but only the unbound drug exerts a clinical effect. Because of protein binding, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. Furthermore, many ESRD patients take drugs such as salicylates, sulfonamides, vitamin K antagonists, beta-blockers, and fibric acid derivatives, which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.

The first-generation sulfonylureas—chlorpropamide (Diabinese), acetohexamide (Dymelor), tolbutamide (Orinase), and tolazamide (Tolinase)—are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD.21 Second-generation agents include glipizide (Glucotrol), glimepiride (Amaryl), glyburide (Micronase), and gliclazide (not available in the United States). Although these drugs are metabolized in the liver, their active metabolites are excreted in the urine, and so they should be avoided in ESRD.22

The only sulfonylurea recommended in ESRD is glipizide, which is also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD, sustained-release forms should be avoided because of concerns of hypoglycemia.23

Meglitinides

The meglitinides repaglinide (Prandin) and nateglinide (Starlix) are insulin secretagogues that stimulate pancreatic beta cells. Like the sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. Repaglinide, in contrast, is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys.24,25 The meglitinides still pose a risk of hypoglycemia, especially in ESRD, and hence are not recommended for patients on hemodialysis.24,25

Biguanides

Metformin (Glucophage) is a biguanide that reduces hepatic gluconeogenesis and glucose output. It is excreted essentially unchanged in the urine and is therefore contraindicated in patients with renal disease due to the risks of bioaccumulation and lactic acidosis.22

Thiazolidinediones

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma). These drugs do not bioaccumulate in renal failure and so do not need dosing adjustments.26

The main adverse effect of these agents is edema, especially when they are combined with insulin therapy. Because of this effect, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association (NYHA) class III or IV heart failure.27 Furthermore, caution is required in patients in compensated heart failure (NYHA class I or II) or in those at risk of heart failure, such as patients with previous myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age greater than 70 years, or diabetes for more than 10 years.27

In summary, although ESRD and dialysis do not affect the metabolism of thiazolidinediones, these agents are not recommended in ESRD because of the associated risk of fluid accumulation and precipitation of heart failure.

Alpha-glucosidase inhibitors

The alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in renal failure,22 and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD.

GLP-1 ANALOGUES AND ‘GLIPTINS,’ NEW CLASSES OF DRUGS

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic beta cells and inhibits inappropriate postprandial glucagon release. It also slows gastric emptying and reduces food intake. Dipeptidyl peptidase IV (DPP-IV) is an active ubiquitous enzyme that deactivates a variety of bioactive peptides, including GLP-1.

Exenatide (Byetta) is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-IV and has a longer half-life. Given subcutaneously, exenatide undergoes minimal systemic metabolism and is excreted in the urine.

No dose adjustment is required if the glomerular filtration rate (GFR) is greater than 30 mL/min, but exenatide is contraindicated in patients undergoing hemodialysis or in patients who have a GFR less than 30 mL/min (TABLE 1).

Sitagliptin (Januvia) is a DPP-IV inhibitor, or “gliptin,” that can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea,28 metformin,29–31 or a thiazolidinedione,32 and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control.28Sitagliptin is not extensively metabolized and is mainly excreted in the urine.

The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a GFR of 30 to 50 mL/min, and 25 mg for patients with a GFR less than 30 mL/min.33 Sitagliptin may be used at doses of 25 mg daily in ESRD, irrespective of dialysis timing (TABLE 1).

Other drugs of this class are being developed. Saxagliptin (Onglyza) was recently approved by the US Food and Drug Administration and can be used at a dosage of 2.5 mg daily after dialysis.

Sitagliptin has been associated with gastrointestinal adverse effects. Anaphylaxis, angioedema, and Steven-Johnson syndrome have been reported. The risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.

ESRD REDUCES INSULIN CLEARANCE

In healthy nondiabetic people, the pancreatic beta cells secrete half of the daily insulin requirement (about 0.5 units/kg/day) at a steady basal rate independent of glucose levels. The other half is secreted in response to prandial glucose stimulation.

Secreted into the portal system, insulin passes through the liver, where about 75% is metabolized, with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus, and 40% is actively secreted into the nephric tubules.34 Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.

For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake.35 But once the GFR drops below 20 mL/min, the kidneys clear markedly less insulin, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia.36 Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD.37

A variety of insulin preparations are available, including rapid-acting, intermediate-acting, and long-acting forms and premixed combinations, each with its specific onset, peak, and duration of action (TABLE 2). To our knowledge, no study of neutral protamine Hagedorn (NPH) insulin or other long-acting insulins has been done in patients with ESRD, and very few studies have described the use of insulin analogues in ESRD.

Aisenpreis et al38 showed that the pharmacokinetic profile of insulin lispro (Humalog), which has a short onset of action and a short duration of action, may not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients.

On the basis of the available evidence,39,40 we recommend a long-acting insulin such as insulin glargine (Lantus) or NPH insulin for basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart (NovoLog) before meals two or three times daily.

When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the filtration rate is below 10 mL/min, as in ESRD, the insulin dose should be decreased by 50% from the previous amount.41,42

The newer insulins such as glargine and lispro are more favorable than NPH and regular insulin, but they cost more, which can be an obstacle for some patients.

RTEmagicC_Shrishrimal_DiabetesAndHemodialysis_T2.gif

OBSERVATIONS AND RECOMMENDATIONS

After reviewing the available evidence for the use of diabetic therapy in ESRD, we offer the following observations and recommendations:

  • Glycemic control and monitoring in ESRD are complex.
  • Patients with ESRD are especially susceptible to hypoglycemia, so diabetic drug therapy requires special caution.
  • ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycemia.
  • Diabetic pharmacotherapy in ESRD should be individualized. The targets of therapy are a hemoglobin A1cvalue between 6% and 7%, a fasting blood glucose level less than 140 mg/dL, and a postprandial glucose level less than 200 mg/dL.
  • Of the oral antidiabetic drugs available, glipizide, sitagliptin, and saxagliptin may be used in ESRD. Glipizide, starting with 2.5 mg daily, should be reserved for ESRD patients with a hemoglobin A1cvalue less than 8.5%.
  • Thiazolidinediones may cause fluid overload and thus should be avoided in ESRD.
  • We recommend a long-acting insulin (glargine or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily.
  • The newer basal insulin (glargine) and rapid-acting insulin analogues (lispro or aspart insulin) are more favorable than NPH and regular insulin, but their higher cost could be an issue.
  • Some patients may prefer a premixed insulin combination for convenience of dosing. In that case, NPH plus lispro insulin may be better than NPH plus regular insulin.
  • For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5 IU/kg, which is half the calculated dose in patients without renal failure.
  • For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25 IU/kg.
  • Further adjustments to the regimen should be individualized based on self-monitored blood glucose patterns.
  • We recommend consulting an endocrinologist with expertise in managing diabetes in ESRD.

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REFERENCES

  1. National Institute of Diabetes and Digestive and Kidney Diseases: United States Renal Data System: USRDS 2005 Annual Data Report. Bethesda, MD:National Institutes of Health, 2005.
  2. Wu MS, Yu CC, Yang CW, et al. Poor pre-dialysis glycaemic control is a predictor of mortality in type II diabetic patients on maintenance haemodialysis.Nephrol Dial Transplant1997; 12:2105–2110.
  3. Morioka T, Emoto M, Tabata T, et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care2001; 24:909–913.
  4. McMurray SD, Johnson G, Davis S, McDougall K. Diabetes education and care management significantly improve patient outcomes in the dialysis unit. Am J Kidney Dis2002; 40:566–575.
  5. Oomichi T, Emoto M, Tabata T, et al. Impact of glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year observational study.Diabetes Care2006; 29:1496–1500.
  6. Williams ME, Lacson E, Teng M, Ofsthun N, Lazarus JM. Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival. Kidney Int2006; 70:1503–1509.
  7. Tzamaloukas AH, Yuan ZY, Murata GH, Avasthi PS, Oreopoulos DG. Clinical associations of glycemic control in diabetics on CAPD. Adv Perit Dial1993;9:291–294.
  8. Tzamaloukas AH, Murata GH, Zager PG, Eisenberg B, Avasthi PS. The relationship between glycemic control and morbidity and mortality for diabetics on dialysis. ASAIO J1993; 39:880–885.
  9. Kalantar-Zadeh K, Kopple JD, Regidor DL, et al. A1C and survival in maintenance hemodialysis patients. Diabetes Care2007; 30:1049–1055.
  10. Kovesdy C, Sharma K, Kalantar-Zadeh. Glycemic control in diabetic CKD patients: where do we stand?Am J Kidney Dis 2008; 52:766–777.
  11. Mak RH. Intravenous 1,25-dihydroxycholecalciferol corrects glucose intolerance in hemodialysis patients. Kidney Int1992; 41:1049–1054.
  12. Hajjar SM, Fadda GZ, Thanakitcharu P, Smogorzewski M, Massry SG. Reduced activity of Na(+)-K+ ATPase of pancreatic islet cells in chronic renal failure: role of secondary hyperparathyroidism. J Am Soc Nephrol1992; 2:1355–1359.
  13. Grodstein GP, Blumenkrantz MJ, Kopple JD, Moran JK, Coburn JW. Glucose absorption during continuous ambulatory peritoneal dialysis. Kidney Int1981;19:564–567.
  14. Joy MS, Cefali WT, Hogan SL, Nachman PH. Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis2002;39:297–307.
  15. Lamb E, Venton TR, Cattell WR, Dawnay A. Serum glycated albumin and fructosamine in renal dialysis patients. Nephron1993; 64:82–88.
  16. Inaba M, Okuno S, Kumeda Y, et al; Osaka CKD Expert Research Group. 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 Nephrol2007; 18:896–903.
  17. Constanti C, Simo JM, Joven J, Camps J. Serum fructosamine concentration in patients with nephrotic syndrome and with cirrhosis of the liver: the influence of hypoalbuminaemia and hypergammaglobulinaemia. Ann Clin Biochem1992; 29:437–442.
  18. Ford HC, Lim WC, Crooke MJ. Hemoglobin A1 and serum fructosamine levels in hyperthyroidism. Clin Chim Acta1987; 166:317–321.
  19. Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial2000; 13:4–8.
  20. Skillman TG, Feldman JM. The pharmacology of sulfonylureas. Am J Med1981; 70:361–372.
  21. Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea-induced hypoglycemia in diabetic patients with end-stage renal disease. Am J Kidney Dis2000;35:500–505.
  22. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial2004;17:365–370.
  23. United Kingdom Prospective Diabetes Study (UKPDS) 13. Relative efficacy of randomly allocated diet, sulphonylureas, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ1995; 310:83–88.
  24. Inoue T, Shibahara N, Miyagawa K, et al. Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure. Clin Nephrol2003; 60:90–95.
  25. Nagai T, Imamura M, Iizuka K, Mori M. Hypoglycemia due to nateglinide administration in diabetic patient with chronic renal failure. Diabetes Res Clin Pract2003; 59:191–194.
  26. Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res2002;30:391–399.
  27. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care2004; 27:256–263.
  28. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab2007;9:733–745.
  29. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, et al; Sitagliptin Study 020 GroupEfficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006; 29:2638–2643.
  30. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care2007; 30:1979–1987.
  31. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab2007; 9:194–205.
  32. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther2006; 28:1556–1568.
  33. Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care2007;30:1862–1864.
  34. Carone FA, Peterson DR. Hydrolysis and transport of small peptides by the proximal tubule. Am J Physiol1980; 238:F151–F158.
  35. Rabkin R, Simon NM, Steiner S, Colwell JA. Effects of renal disease on renal uptake and excretion of insulin in man. N Engl J Med1970; 282:182–187.
  36. Mak RH, DeFronzo RA. Glucose and insulin metabolism in uremia. Nephron1992; 61:377–382.
  37. Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic type 1 and insulin-treated type 2 diabetic patients. Diabet Med2003; 20:642–645.
  38. Aisenpreis U, Pfützner A, Giehl M, Keller F, Jehle PM. Pharmacokinetics and pharmacodynamics of insulin Lispro compared with regular insulin in hemodialysis patients with diabetes mellitus. Nephrol Dial Transplant1999; 14( suppl 4):5–6.
  39. Tunbridge FK, Newens A, Home PD, et al. A comparison of human ultralente- and lente-based twice-daily injection regimens. Diabet Med1989; 6:496–501.
  40. Freeman SL, O’Brien PC, Rizza RA. Use of human ultralente as the basal insulin component in treatment of patients with IDDM. Diabetes Res Clin Pract1991;12:187–192.
  41. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab2000; 26(suppl 4):73–85.
  42. Aronoff GR, Berns JS, Brier ME, et al, eds. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults, 4th ed. Philadelphia, PA: American College of Physicians, 1999.

 

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