COMPLICATIONS OF DIALYSIS - PART 9 doc

700 Miles and Friedman predisposition of diabetic patients to access thrombosis in earlier reports. F. Vascular Steal Syndromes An arteriovenous access (particularly a brachiocephalic access or a side-to-side radiocephalic fistula) creates a low-pressure run-off system, which may short-circuit blood from the palmar arch and ulnar arteries to such a degree that a steal syndrome results. With the pre- existing, severe medial arterial calcinosis of the ulnar and digital arteries, which is common in diabetic di- alysis patients (19), progressive ischemic pain leading to dry gangrene of one or more fingers may develop days to weeks after placement of the access. Nonheal- ing wounds of the fingers may also be a manifestation of vascular steal (20), and in cases of clinical uncer- tainty, digital pressures of <50 mmHg on noninvasive vascular studies and arteriography help to confirm the diagnosis. In severe cases of arterial steal syndromes, the onset may be more acute, within hours of creation of the access, and signs of acute arterial insufficiency such as pallor and pulselessness may be seen. Ligation of the distal limb of the radial artery in a side-to-side radiocephalic fistula or ligation or removal of a bra- chiocephalic access is necessary to correct the syn- drome. Amputation of one or more digits and even be- low elbow amputation may sometimes be necessary. G. Ischemic Monomelic Neuropathy The term ischemic monomelic neuropathy was coined in 1983 by Wilbourn (21). It is a complication of vas- cular access seen almost exclusively in diabetic patients (22) and refers to the development of acute pain, weak- ness, and paralysis of the muscles of the forearm and hand, often with sensory loss, developing immediately after placement of an arteriovenous access, usually in the brachiocephalic or antecubital location. The con- dition results from diversion of the blood supply to the nerves of the forearm and hand, the ischemic insult being severe enough to damage nerve fibers but insuf- ficient to produce necrosis of other tissues. Hence, un- like in vascular steal syndromes, the radial pulse is usu- ally present, digital pressures normal or only mildly decreased, and necrosis, ulcers, and gangrene of the digits are absent. The propensity to development of the complication with brachiocephalic accesses relates to the fact that the brachial artery constitutes the sole ar- terial inflow to the forearm and hand and, in the ab- sence of collateral vessels about the elbow, diversion of all or most brachial arterial blood through a fistula or graft results in distal ischemia. Nerve conduction studies are helpful in diagnosing the syndrome, and early access removal or ligation is necessary to prevent permanent paralysis of the hand. Unfortunately, even with prompt access closure, paralysis of the hand may be permanent. H. Venous Hypertension Chronic swelling of the hand, and especially of the thumb (‘‘sore thumb’’ syndrome), related to the pres- ence of the distal segment of the vein used for creation of the access, may occur in both diabetic and nondi- abetic patients. Venous hypertension occurs in associ- ation with venous stenosis of the access or a more proximal stenosis at the level of the subclavian vein, which may have been previously catheterized for tem- porary vascular access. Ligature of the distal venous limb of the fistula or graft will usually correct the problem. III. BONE DISEASE Adynamic bone disease is a form of renal osteodystro- phy commonly seen in diabetics, particularly those on peritoneal dialysis (23). It is characterized by low rates of bone turnover without excess unmineralized osteoid and is associated with parathyroid hormone levels be- low 100 pg/mL. Decreased osteoblast proliferation and defective mineralization contribute to a low rate of bone formation in diabetic rats (24), and a similar mechanism may underlie adynamic bone disease in hu- mans. Diabetic dialysis patients also tend to experience higher rates of low-turnover bone disease associated with aluminum deposition: reduced bone formation may allow time for enhanced deposition of aluminum on the ossification front, and within 1 year of hemo- dialysis, aluminum deposition (usually related to use of aluminum-containing phosphate binders) is observed on bone surfaces in diabetics, and symptoms of bone pain and fractures related to aluminum bone disease may start as early as 2 years after initiation of hemo- dialysis (25). Aluminum bone disease may also be un- masked or accelerated after parathyroidectomy. Alu- minum-containing phosphate binders should therefore be avoided in diabetics, and all diabetics with bone pain and/or fractures should have plasma aluminum levels measured before and after a single infusion of desferrioxamine. Aluminum-associated bone disease in Complications of Dialysis in Diabetic Patients 701 hemodialyzed diabetics responds to a regimen of vita- min D, calcium, and desferrioxamine. IV. DIABETIC RETINOPATHY Visual loss in diabetic ESRD patients is most com- monly related to proliferative retinopathy with associ- ated vitreous hemorrhage and retinal detachment but may also result from macular edema, glaucoma, cata- racts, and corneal disease. The presence of proliferative retinopathy is correlated with age of onset and duration of diabetes, glycemic control, and degree of blood pres- sure control. Heparin use during hemodialysis is no longer considered a significant contributor to progres- sion of diabetic retinopathy or to intraocular hemor- rhage. No reports definitively link heparin use on di- alysis with progression of diabetic retinopathy or visual loss. Indeed, in a study of 112 diabetics followed for 20 months, progression of retinopathy was shown to be independent of dialysis modality (hemo- or peritoneal dialysis), while the significant correlation between blood pressure control and vision preservation was re- inforced (26). In addition, because of the rarity (0.05%) of intraocular hemorrhage in diabetics treated with thrombolytic agents, diabetic retinopathy is not consid- ered a contraindication to thrombolytic therapy for acute myocardial infarction (27). Focal or panretinal laser photocoagulation can reduce the incidence of se- rious visual loss in patients with proliferative retinop- athy, and vitrectomy may restore vision in patients with vitreous hemorrhage. V. UNDERNUTRITION Malnutrition is frequently seen in diabetic hemodialysis patients, particularly in the presence of intercurrent ill- nesses. Causes of malnutrition in diabetics on hemo- dialysis include (a) poor glycemic control leading to gluconeogenesis and catabolism of muscle, (b) gastro- paresis leading to nausea and vomiting, (c) diabetic di- arrhea, and (d) underdialysis related to difficulties with vascular access or to repeated early termination of di- alysis sessions caused by recurrent hypotension (28). A diet of 25–30 kcal/kg/day, with 50% of the calories coming from complex carbohydrates, and protein con- tent of 1.3–1.5 g/kg/day is recommended for hemodi- alyzed diabetics. In diabetic hemodialysis patients who develop intercurrent illnesses (e.g., sepsis), early and intensive nutritional support with enteral or peripheral parenteral nutrition is necessary. Dialysate fluid should contain at least 200 mg/dL glucose because use of glu- cose-free dialysate results in rapid glucose loss, hypo- glycemia, and production of acute starvation with aci- dosis and hyperkalemia (29). VI. HYPERGLYCEMIA Insulin requirements after beginning maintenance he- modialysis vary (30), and it is important to teach pa- tients home glucose monitoring so as to determine changing insulin requirements. Most diabetic patients with ESRD experience reduction in insulin needs due to decreased renal excretion and catabolism of injected and endogenous insulin. Many diabetics who start di- alysis will no longer need insulin, and some type 2 diabetics previously on insulin may achieve glycemic control with a small dose of a short-acting sulfonylurea drug such as glyburide or glipizide, or indeed with no hypoglycemic medications at all. The new oral hypo- glycemic agent troglitazone has been approved for use in type 2 diabetics to decrease insulin requirements or for use alone or in combination with a sulfonylurea to prevent need for insulin therapy. The drug works by increasing the sensitivity of peripheral tissues to insulin and decreasing hepatic glucose production. It under- goes hepatic metabolism and hence does not require dose reduction in renal failure. It is effective in only 50% of treated patients, however, and produces mild liver injury in 1.9% of patients and sporadic cases of fulminant hepatic failure requiring liver transplantation. Liver function tests should be monitored at the start of therapy with troglitazone and at monthly intervals for the first 6 months of therapy, and then every 2 months for the remainder of the first year. Rosiglitazone ap- pears to be a safer option with equivalent efficacy. With control of uremia by dialysis, improved appe- tite and weight gain in some diabetics may result in increased insulin needs. In addition, noncompliance with hypoglycemic medications related to depression in the often stormy period surrounding dialysis initia- tion may contribute to hyperglycemia. Hyperosmolar coma is uncommon in diabetics on dialysis unless there is significant residual renal function. Ketoacidosis is also not frequently seen but may occur in association with sepsis or other severe intercurrent illness. Both conditions are managed by low-dose hourly regular in- sulin infusions for blood sugar levels above 450–500 mg/dL. It is usually possible to achieve rapid control of blood sugar, and indeed in some patients an initial single dose of 10 units of regular insulin may suffice 702 Miles and Friedman if the patient is not seriously ill. The usual fluid re- plenishment regimens for nonuremic diabetics are of course not required unless the patient is in shock. Usu- ally, fluid replacement during hemodialysis suffices. VII. COMPLICATIONS OF PERITONEAL DIALYSIS IN DIABETIC PATIENTS Eleven percent of diabetics entering renal replacement programs in the United States are treated with some form of peritoneal dialysis (2). In other countries such as Canada, the percentage of diabetic ESRD patients treated by peritoneal dialysis (PD) is much higher, in- deed, PD is the treatment of choice for diabetics with ESRD in these countries. Physician bias, national re- sources, patient preference, and the presence of severe cardiovascular disease are the major factors that deter- mine the selection of PD over hemodialysis in diabet- ics. The more gentle ultrafiltration afforded by CAPD will prevent or ameliorate hypotension in diabetics so prone because of left ventricular dysfunction or auto- nomic neuropathy. Diabetic hemodialysis patients younger than 60 years have a similar or lower relative risk of death than diabetics of the same age on CAPD (31,32). In diabetic CAPD patients older than 60 years, there is a 19% higher relative risk of death compared with diabetic hemodialysis patients (26). The higher death rate in el- derly diabetics treated with CAPD is related to ad- vanced atherosclerotic cardiovascular and cerebrovas- cular disease. Diabetics are subject to a similar spectrum and rate of technique-related complications as in nondiabetics on CAPD, and a discussion of some of the most common problems of diabetics on PD follows. A. Peritonitis Within the first year of starting PD, 49% of patients will switch to another modality of renal replacement therapy (33), while only 37% of hemodialysis patients change treatment modality during the first year. It is more likely that a CAPD or continuous cyclic PD (CCPD) patient will switch to hemodialysis (15.6%) than that a hemodialysis patient will switch to CAPD (4.4%) (34). The high technique failure rate on CAPD is due mainly to peritonitis (35). Recurrent peritonitis, usually caused by Staphylococcus epidermidis or Staphylococcus aureus, often in association with exit site infections, is the major disadvantage of CAPD. Peritonitis in diabetic CAPD patients occurs at a rate of one episode per 11–21 patients per month (26,29,36). Diabetics on CAPD need twice the number of hospitalization days as nondiabetic CAPD patients (37), and peritonitis accounts for 30–50% of the hos- pitalization days (38). Fungal peritonitis is seen more commonly in diabetic than in nondiabetic CAPD pa- tients and usually requires removal of the peritoneal catheter. There is, however, no overall increased risk of peritonitis in diabetics over nondiabetics (39), and the rates of catheter replacement are the same in both groups. Because of delayed wound healing, dialysate leak- age and exit site infections may occur in diabetics if a newly implanted Tenchoff catheter is used too early; and we recommend that, if possible, at least 2–3 weeks elapse before starting regular CAPD exchanges through a newly implanted Tenchoff catheter in a diabetic. Al- ternatively, starting nighttime cycling exchanges 1–2 weeks after catheter insertion and leaving the abdomen dry during the daytime to reduce intra-abdominal pres- sure during ambulation may reduce the risk of dialysate leakage. The Moncrief-Popovich peritoneal catheter is a recently introduced double-cuffed catheter with an external cuff, which is longer than that of the standard Tenchoff catheter, and whose external segment (exter- nal cuff and tubing) is buried subcutaneously for 4–6 weeks before being externalized and used (40). Be- cause tissue ingrowth into the external cuff has oc- curred during the period of subcutaneous implantation, it is anticipated that the rates of leaks and peritonitis will be less with this catheter, and indeed we have had excellent results, with no dialysate leaks so far with this catheter. B. Underdialysis Patients on CAPD tend to have higher levels of blood urea nitrogen and creatinine than hemodialysis patients, and there is concern about the adequacy of CAPD as long-term uremia therapy (41). Based on peritoneal equilibration testing, a minimum clearance of 6–7 L/ day is recommended for patients on peritoneal dialysis. The amount of dialysis delivered on CAPD may have to be increased with time as residual renal function is lost, and peritoneal clearance decreases owing to ad- vanced vascular disease or recurrent episodes of peri- tonitis. Microangiopathy and increased vascular per- meability to small and large molecules and resultant increased diffusive transport of glucose (42) may pro- duce type I ultrafiltration failure in some diabetic patients. Complications of Dialysis in Diabetic Patients 703 C. Undernutrition Malnutrition may occur in up to 40% of long-term CAPD patients (43,44). Malnutrition in CAPD-treated diabetics may occur because of (a) reduced appetite caused by the large glucose load in dialysate or by early satiety from increased intra-abdominal pressure or (b) large protein losses (8–10 g/day) in the dialysate effluent that may lower serum albumin and total protein levels (45). Loss of protein through the peritoneal membrane is increased during episodes of peritonitis and may worsen with time because of a generalized increase in permeability related to diabetic microangio- pathy involving the peritoneal vessels or nausea and vomiting related to diabetic gastroparesis. To maintain adequate nutrition, CAPD patients should ingest at least 1.5 g protein/kg/day and between 130 and 150 g carbohydrates/day. D. Hyperglycemia Blood glucose control may sometimes be difficult in diabetics on CAPD because of the absorption of a mean of 182 Ϯ 61 g glucose/day from the peritoneal cavity (46). A combination of subcutaneous and intraperito- neal insulin administration usually results in adequate glucose control, however. The total dose of intraperi- toneal regular insulin required is usually two to three times the usual subcutaneous total dose. Oral antidi- abetic agents (sulfonylureas with short half-lives and hepatic metabolism, e.g., glipizide, glyburide) to reduce the risk of prolonged hypoglycemia may be used in patients requiring less than 20–25 units of insulin per day. VIII. SUMMARY Diabetic dialysis patients require extra effort on the part of nephrologists to prevent and treat macro- and mi- crovascular disease, to manage intradialytic complica- tions, and to achieve the usually difficult goal of main- taining good vascular access. A multidisciplinary team approach is required, and the services of an experi- enced vascular access surgeon are invaluable. As the epidemic of type 2 diabetes mellitus afflicting devel- oped countries continues and diabetics comprise an in- creasing percentage of incident and prevalent ESRD patients, nephrologists must target the problems pecu- liar to, or prevalent in the diabetic dialysis population in order to reduce morbidity and mortality in this high- risk group. REFERENCES 1. U.S. Renal Data System, USRDS 1997 Annual Data Report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1991. 2. Miles AMV, Friedman EA. Managing co-morbid dis- orders in the uremic diabetic patient. Sem Dial 1997; 10:225–230. 3. Shideman JR, Buselmeier TJ, Kjellstrand CM. Hemo- dialysis in diabetics. Arch Intern Med 1976; 136:1126– 1130. 4. Collins AL, Liao A, Umen A, Hanson G, Keshaviah P. Diabetic hemodialysis patients treated with a high Kt/ V have a lower risk of death than standard Kt/V. J Am Soc Nephrol 1991; 2:318. 5. Nakamoto M. The mechanism of intradialytic hypoten- sion in diabetic patients. Nippon Jinzo Gakkai Shi. Jap J Nephrol 1994; 36:374–381. 6. Ritz E, Strumpf C, Katz F, et al. Hypertension and car- diovascular risk factors in hemodialyzed diabetic pa- tients. Hypertension 1985; 7(suppl II):118–124. 7. Daugirdas JT. Dialysis hypotension: A hemodynamic analysis. Kidney Int 1991; 39:223–246. 8. Gotch FA, Keen ML, Yarian SR. An analysis of thermal regulation in hemodialysis with one and three com- partment models. Trans Am Soc Artif Intern Organs 1989; 35:622–624. 9. Dorhout Mees EJ. Rise in blood pressure during he- modialysis ultrafiltration: a paradoxical situation? Int J Artificial Organs 1996; 19:569–570. 10. Ifudu O, Dulin A, Lundin AP, et al. Diabetics manifest excess weight gain on maintenance hemodialysis. Am Soc Artif Intern Org 1992; 21:85. 11. Jones R, Poston R, Hinestrota A, et al. Weight gain between dialysis in diabetics. Possible significance of raised intracellular sodium content. Br Med J 1980; 1: 153–154. 12. U.S. Renal Data System. USRDS 1997 Annual Data Report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1997. 13. Miles AMV, Hong JH, Sumrani N, et al. Outcome and complications of vascular access placement in elderly diabetic patients with end stage renal disease. J Korean Am Med Assoc 1996; 2:25–28. 14. Taber TE, Maikranz PS, Haag BW, et al. Maintenance of adequate hemodialysis access. Prevention of neoin- timal hyperplasia. ASAIO J 1995; 41:842–846. 15. Gensini GF, Abbate R, Favilla S, Neri Serneri GC. Changes of platelet function and blood clotting in dia- betes mellitus. Thromb Hemost 1979; 42:983–993. 16. Halushka PV. Increased platelet thromboxane. J Lab Clin Med 1981; 97:87–92. 17. U.S. Renal Data System. USRDS 1993 Annual Data Report. Bethesda, MD: National Institutes of Health. 704 Miles and Friedman National Institute of Diabetes and Digestive and Kidney Diseases, 1993. 18. Woods JD, Turenne MN, Strawderman RL, et al. Vas- cular access survival among incident hemodialysis pa- tients in the United States. Am J Kidney Dis 1997; 30: 50–57. 19. Tzamaloukas AH, Murata GH, Harford AM, et al. Hand gangrene in diabetic patients on chronic dialysis. Trans Am Soc Artif Intern Organs 1991; 37:638–643. 20. Redfern AB, Zimmerman NB. Neurologic and ischemic complications of upper extremity vascular access for dialysis. J Hand Surg 1995; 20:199–204. 21. Wilbourn AJ, Furlan AJ, Hulley W, Ruschhaupt W. Is- chemic monomelic neuropathy. Neurology 1983; 33: 447–451. 22. Riggs JE, Moss AH, Labosky DA, Liput JH, et al. Up- per extremity ischemic monomelic neuropathy: a com- plication of vascular access procedures in uremic dia- betic patients. Neurology 1989; 39:997–998. 23. Vincenti F, Arnaud SB, Recker R, et al. Parathyroid and bone response of the diabetic patient to uremia. Kidney Int 1984; 25:677–682. 24. Weiss RE, Reddi AH. Influence of experimental dia- betes and insulin on matrix-induced cartilage and bone differentiation. Am J Physiol 1980, 238:E200–E207. 25. Andress DL, Kopp JB, Maloney NA, et al. Early dep- osition of aluminum in bone in diabetic patients on he- modialysis. N Engl J Med 1987; 316:292–296. 26. Diaz-Buxo JA, Burgess WP, Greenman M, et al. Visual function in diabetic patients undergoing dialysis: com- parison of peritoneal had hemodialysis. Int J Artificial Organs 1984; 7:257–262. 27. Mahaffey KW, Granger CB, Toth CA, et al. Diabetic retinopathy should not be a contraindication to throm- bolytic therapy for acute myocardial infarction: review of ocular hemorrhage incidence and location in the GUSTO-I trial. J Am Coll Cardiol 1997; 30:1606– 1610. 28. Cheigh J, Raghavan J, Sullivan J, et al. Is insufficient dialysis a cause for high morbidity in diabetic patients. J Am Soc Nephrol 1991; 2:317. 29. Davis M, Comty C, Shapiro F. Dietary management of patients with diabetes treated by hemodialysis. J Am Diet Assoc 1979; 75:265–269. 30. Davis M, Comty C, Shapiro F. Dietary management of patients with diabetes treated by hemodialysis. J Am Diet Assoc 1979; 75:265–269. 31. Maiorca R, Vonesh EF, Cavalli PL, et al. A multicenter, selection-adjusted comparison of patient and technique survivals on CAPD and hemodialysis. Perit Dial Int 1991; 11:118–127. 32. Gokal R, Jakubowski C, Hunt L. Multicenter study of outcome of CAPD and hemodialysis patients. Nephrol Dial Transplant 1986; 1:111–114. 33. Held PJ, Port FK, Blagg CR, et al. The United States renal data systems annual data report. Am J Kidney Dis 1990; 16(suppl 2):34–43. 34. Yuan ZY, Balaskas E, Gupta A, et al. Is CAPD or he- modialysis better for diabetic patients? CAPD is more advantageous. Semin Dialysis 1992; 5:181–188. 35. Nolph KD. Continuous ambulatory peritoneal dialysis as long term treatment for end stage renal disease. Am J Kidney Dis 1991; 17:154–157. 36. Scarpioni LL, Balocchi S, Castelli A, et al. Continuous ambulatory peritoneal dialysis in diabetic patients. Con- trib Nephrol 1990; 84:50–74. 37. Khanna R, Oreopoulos DG. Continuous ambulatory peritoneal dialysis in diabetics with end stage renal dis- ease. A combined experience of 2 North American cen- ters. In: Friedman EA, L’Esperance FA, eds. Diabetic Renal Retinal Syndrome. New York: Grune and Strat- ton, 1986; 363–381. 38. Rottemburg J. Peritoneal dialysis in diabetics. In: Nolph KD, ed. Peritoneal Dialysis. Boston: Martinus Nijhoff, 1985:365–379. 39. Rubin J, Oreopoulos DG, Blair RDG, et al. Chronic peritoneal dialysis in the management of diabetics with terminal renal failure. Nephron 1977; 19:265–270. 40. Moncrief JW et al. The Moncrief-Popovich catheter. A new peritoneal access technique for patients on peri- toneal dialysis. ASAIO J 1993; 39:62. 41. Diaz-Buxo JA. Is continuous ambulatory peritoneal di- alysis adequate long-term therapy for end-stage renal disease? A critical assessment. J Am Soc Nephrol 1992; 3:1039–1048. 42. Lin JJ, Wadhwa NK, Suh H, et al. Increased peritoneal solute transport in diabetic peritoneal dialysis patients. Adv Peritoneal Dial 1995; 11:63–66. 43. Young GA, Kopple JD, Lindholm B, et al. Nutritional assessment of chronic ambulatory peritoneal dialysis patients: an international study. Am J Kidney Dis 1991; 17:462–471. 44. Rotellar C, Black J, Winchester JF, et al. Ten years experience with continuous ambulatory peritoneal di- alysis. Am J Kidney Dis 1991; 17:158–164. 45. Blumenkrantz MJ, Gahl GM, Kopple JD, et al. Protein losses during peritoneal dialysis. Kidney Int 1981; 19: 593–602. 46. Grodstein GP, Blumenkrantz MJ, Kopple JD, et al. Glu- cose absorption during continuous ambulatory perito- neal dialysis. Kidney Int 1981; 19:564–567. 705 40 Problems of Women on Dialysis Susan S. Hou Loyola University School of Medicine, Maywood, Illinois Susan Grossman St. Vincent’s Medical Center of Richmond, Staten Island, New York The care of dialysis patients has been focused first on survival and then on decreased morbidity. Rehabilita- tion has generally emphasized return to employment or family and community activities. Pregnancy and child- bearing have been regarded as unfortunate accidents rather than as goals of treatment. Our attention to gy- necological problems affecting dialysis patients has been overshadowed by attention to cardiovascular dis- ease, infection, and other life-threatening complications of dialysis. Pregnancy in dialysis patients is still un- common and carries a high risk for both mother and fetus. However, with the increasing length of survival of young dialysis patients and the increasing wait for transplantation, the problems associated with child- bearing and contraception have become more impor- tant. The possibility and implications of conception need to be addressed with each patient. While rarely life-threatening, the problems of sexual dysfunction, dysfunctional uterine bleeding, and gynecological in- fections contribute to a diminished quality of life. Gy- necological neoplasms are life-threatening when they occur, although they are not the most common cause of death in dialysis patients. I. CONTRACEPTION Early literature reported that only 10% of female di- alysis patients of childbearing age menstruated (1), but a more recent report (2) indicates that the frequency of menses has increased to 42%. It is not certain how many of these women could conceive, but the risks and possibility of pregnancy and the need for contraception should be discussed with all dialysis patients of child- bearing age. Oral contraceptives offer many advantages for di- alysis patients. Many dialysis patients are estrogen de- ficient, and women with irregular periods may be ex- posed to the effects of unopposed estrogen for prolonged periods of time. Estrogen deficiency is added to the many other factors that contribute to bone dis- ease, and unopposed estrogen may increase the risk of endometrial cancer. The use of oral contraceptives would not only prevent pregnancy but would treat es- trogen deficiency and allow for regular hormonal cy- cling. Oral contraceptives should be used with caution in hypertensive women and women at risk for throm- boembolic disease. These drugs may increase the risk for lupus flares in women whose end-stage renal dis- ease is secondary to lupus. Mechanical methods of contraception can be used in women for whom estrogen is contraindicated. Intra- uterine devices may be associated with increased uter- ine bleeding when patients are heparinized, and an in- crease in the risk of peritonitis would be expected in peritoneal dialysis patients. Other mechanical methods of birth control are acceptable in dialysis patients. II. PREGNANCY A. Frequency of Conception Fertility is markedly reduced in dialysis patients. Esti- mates of the frequency of conception in dialysis pa- 706 Hou and Grossman tients range from 1.4% per year in Saudi Arabia (3) to 0.5% in the United States (4) and 0.3% in Belgium (5). The estimates from the United States and Saudi Arabia are based on surveys that covered only half the women of childbearing age treated with dialysis, while the sur- vey from Belgium included a response from all of the dialysis units in the country. Only the report from the American National Registry for Pregnancy in Dialysis Patients (NRPDP) included a substantial number of peritoneal dialysis patients (4). Of note is that the fre- quency of conception in hemodialysis patients was two to three times higher than in peritoneal dialysis patients. The reasons for the rarity of pregnancy in dialysis patients are not well understood. The hormonal changes in dialysis patients are reviewed elsewhere in this book. Nonhormonal causes of infertility have not been investigated. It is not clear whether the difference in the frequency of conception between hemodialysis patients and CAPD patients is the result of endocrine differences or is in some way related to peritoneal dialysis itself. Re- current peritonitis might be expected to cause tubal ob- struction in peritoneal dialysis patients, but if tubal damage were a major contributor to infertility, an in- crease in tubal pregnancies would be expected. Few tubal pregnancies have been described in dialysis pa- tients and none in peritoneal dialysis patients. It is pos- sible that hypertonic dextrose damages the ovum or that the volume of fluid in the intraperitoneal space interferes with transport of the ovum from the ovary to the fallopian tubes. Most pregnancies occur during the first few years on dialysis, but conception rates as a function of time on dialysis have not been determined. Pregnancy has oc- curred in women who have been on dialysis as long as 20 years. Repeat pregnancies in women who become pregnant on dialysis are not uncommon. In the 318 women whose pregnancies are recorded by the NRPDP, 8 became pregnant twice, 8 became pregnant three times, and one conceived four times (4). Although it would be expected that pregnancy would be more likely in women with regular menses, pregnancy has been reported in a woman after 9 years of amenorrhea. In contrast to dialysis patients, approximately 12% of women transplant recipients of childbearing age be- come pregnant. B. Outcome of Pregnancy in Dialysis Patients In 1980, the European Dialysis and Transplant Asso- ciation reported 115 pregnancies in dialysis patients (6). Of those that were not electively terminated, only 23% resulted in surviving infants. Success rate for pregnancy in dialysis patients has improved since the EDTA report. In Saudi Arabia 30% of pregnancies re- sulted in surviving infants. The NRPDP recorded 222 pregnancies in women who were receiving dialysis at the time of conception. Of the 141 pregnancies that reached the second trimester, 55% resulted in surviving infants. Eighteen percent of live-born infants died in the neonatal period; 8.5% of pregnancies reaching the second trimester resulted in stillbirth, and 22% resulted in spontaneous abortion. The four induced abortions done in the second trimester were done for life-threat- ening maternal problems (three hypertension and one critical aortic stenosis) rather than for social reasons or anticipated problems. C. Maternal Complications 1. Maternal Death There have been three maternal deaths reported to the NRPDP. One death resulted from lupus cerebritis in a woman who started dialysis after conception. There were two deaths in women who conceived after starting dialysis, one as a result of hypertension and one from unknown causes. All three infants survived. 2. Hypertension Hypertension is the most common life-threatening complication of pregnancy in dialysis patients. Of 57 case reports published in the medical literature in which blood pressure was noted in a pregnant dialysis patient, only 30% of women were normotensive throughout pregnancy (7). Sixty percent of women had blood pressures over 140/90 at some time during preg- nancy, and in 25% the blood pressure exceeded 170/ 110. Ten percent were treated with antihypertensive medications, but blood pressure was not specified. In cases reported to the NRPDP, approximately 80% of the 68 women for whom blood pressure measure- ments were available either had a blood pressure greater than 140/90 or required antihypertensive med- ication at some time during pregnancy (4). In over half of hypertensive pregnant dialysis patients, the blood pressure exceeds 170/110. Five of these women re- quired intensive care unit admissions in addition to the maternal one death. Thirty-eight percent of patients who developed severe hypertension did so in the first trimester. In such cases, it was usually possible to con- trol the blood pressure without terminating the preg- nancy. Fifty percent of women with severe hyperten- Problems of Women on Dialysis 707 sion reached blood pressures of >170/110 in the second trimester. These cases were problematic in that pre- eclampsia could not be excluded and the fetus was still not viable. Three of 16 women required therapeutic abortion for hypertension. Of note, severe hypertension could be seen as late as 6 weeks postpartum. 3. Anemia A drop in hematocrit is almost invariable in dialysis patients who become pregnant. In pregnancies reported to the NRPDP, 33% of women treated with erythro- poietin and 77% of women not treated with erythro- poietin required transfusion (4). Iron stores usually dropped, but there were several instances in which the hematocrit dropped despite iron saturation, which re- mained at acceptable levels. D. Prematurity and Growth Restriction Eighty-five percent of infants born to women who con- ceived after starting dialysis reported to the NRPDP were born before 37 weeks gestation (mean gestational age 32.4 weeks). Thirty-six percent weighed less than 1500 g at birth, and 28% were small for gestational age. Their neonatal course was complicated by respi- ratory distress and other complications of prematurity. Eleven of 116 live-born infants and 1 stillborn infant reported to the NRPDP had congenital anomalies (4). Eleven of 49 infants for whom follow-up data were available had long-term medical or developmental problems, most of which appeared to be the result of prematurity rather than an azotemic intrauterine envi- ronment. The mean gestational age was lower for in- fants who had long-term problems compared to those with normal growth and development (30.6 vs. 34.3 weeks). III. MANAGEMENT ISSUES IN PREGNANT DIALYSIS PATIENTS A. Preconception Counseling Counseling of dialysis patients who are attempting pregnancy is all but impossible. The infrequency of conception makes it impossible to plan except in women who have already conceived once on dialysis. Even if a woman is actively trying to become pregnant, the likelihood of conception is low enough that changes in dialysis regimen cannot be justified. However, folic acid supplementation should be increased and good blood sugar control should be achieved in diabetic women who are attempting conception. B. Diagnosis of Pregnancy Pregnancy is usually diagnosed late in dialysis patients. Irregular menses are common and abdominal com- plaints are often attributed to other causes. A high index of suspicion is required to make the diagnosis early. Urine tests for human chorionic gonadotropin (hcg) are inaccurate even in women who have residual renal function. Small amounts of hcg are made by somatic cells, and because the hormone is partially excreted by the kidney, serum tests for ␤ hcg are sometimes bor- derline or falsely positive in women who are not preg- nant (8). The titers of ␤ hcg may be higher than ex- pected for the stage of gestation. The diagnosis and stage of gestation must be confirmed by ultrasound. C. Management of Hypertension Dialysis patients, particularly those on home treatment modalities, should measure their own blood pressure twice daily since severe increases in blood pressure can be abrupt. As with dialysis patients who are not preg- nant, the first line of treatment is correction of volume overload. Assessment of volume status is difficult be- cause of the expected 9 L increase in total body water during pregnancy, but cautious fluid removal should be attempted when hypertension develops. If fluid removal does not correct blood pressure, pharmacological treat- ment can be started. There is experience with a wide variety of antihypertensive medications in pregnancy (Table 1). Of the widely used antihypertensive drugs, only angiotensin-converting enzyme (ACE) inhibitors and, by inference, angiotensin receptor blockers are strongly contraindicated in pregnancy. 1. Angiotensin-Converting Enzyme Inhibitors This group of drugs has been associated with oligo- hydramnios, which results in a number of complica- tions. Amniotic fluid is necessary for fetal lung devel- opment, and the most serious consequence of oligohydramnios is pulmonary hypoplasia leading to neonatal death as a result of respiratory failure (9). Oli- gohydramnios also accounts for limb contractures in infants exposed to the drug. Direct pressure of the uter- ine muscle on the fetal skull is thought to result in abnormal calcification of the skull. Several instances of patent ductus have been described. This effect is 708 Hou and Grossman Table 1 Antihypertensive Drugs Used in Pregnancy Drug (category) Comments Chronic Hypertension ACE inhibitors (D) Contraindicated; 2nd and 3rd trimester use associated with pulmonary hypoplasia, hypocalvaria, renal dysplasia, neonatal anuria, contractures; no known harm in 1st trimester ␣ Methyl dopa (C) Safe; 40 year use; careful developmental testing of children at ages 4 and 7; rare Coombs ϩ hemolytic anemia, rare hepatitis ␤ Blockers (C) Probably safe; fetal bradycardia, hypoglycemia, respiratory depression at birth, intrauterine growth restriction? ↓ fetal tolerance of anoxic stress Labetolol (C) Limited first trimester experience; less bradycardia and growth restriction than ␤ blockers Clonidine (C) Probably safe; limited 1st trimester experience Calcium channel blockers (C) Profound ↓ BP with when used with magnesium; limited experience; reserve for severe hypertension Hydralazine (C) Safe; long experience with use in pregnancy; no ↑ birth defects; ineffective as a single agent Minoxidil (C) Very limited experience; hypertricosis and congenital anomalies in one the infant Prazocin (C) Limited experience; no problems noted Thiazide diuretics (D) ↑ congenital anomalies with chlorthaldone; subnormal intravascular volume expansion, neonatal thrombocytopenia, hemolytic anemia, electrolyte abnormalities Hypertensive Crisis Hydralazine (C) Used for 40 years without serious side effects Labetolol (C) Shorter length of use; appears safe Nitroprusside (C) Fetal cyanide toxicity Diazoxide (C) Fatal maternal hypotension reported; limit dose to 30 mg boluses; ↓ uterine contraction; neonatal hyperglycemia thought to be the result of the effects of ACE inhibitors on prostaglandin metabolism. While exposure to ACE inhibitors in the second and third trimesters may have serious consequences, no ill effects have been identified as a result of first trimester exposure. Two studies, one involving 46 infants and one involving 86 infants, showed no adverse effect of exposure to ACE inhibitors in the first trimester (10). In the latter report there were four congenital anoma- lies, a number that was not significantly different from the expected three. Women with inadvertent first tri- mester exposure need not be advised to terminate the pregnancy. There is less experience with angiotensin II receptor blockers, but it is expected that problems caused by decreased angiotensin effect will be similar to those seen in women treated with ACE inhibitors. 2. Other Antihypertensive Drugs a. ␣ Methyl Dopa ␣ Methyl dopa has been used in pregnant women for over 40 years and is still the drug of first choice for essential hypertension. Careful developmental studies have been done at 4 and 7 years of age in children exposed to the drug in utero, and no problems have been found (11). b. ␤ Blockers There are several case reports of neonatal bradycardia, hypoglycemia, and respiratory depression associated with ␤ blockers, but these problems are generally easily managed by the neonatologist (12). There are mixed data concerning whether blockers are associated with intrauterine growth restriction. There are reports of small-for-gestational-age infants of mothers treated with ␤ blockers for diseases not usually associated with growth restriction (13). There are also data from animal models suggesting a decreased ability of the fetus to withstand anoxic stress (14). None of these problems has turned out to be a major contraindication to the use of this category of drugs in pregnant humans. Fetal bradycardia may make it difficult to interpret antenatal monitoring, which depends on changes in fetal heart rate. Problems of Women on Dialysis 709 c. Labetolol Labetolol is not associated with fetal bradycardia and growth restriction and, it is widely used in preference to ␤ blockers. Nonetheless, data on first trimester ef- fects of the drug are still limited (10). Moreover, con- trolled studies have not shown it to be superior to other antihypertensive agents (15). d. Clonidine Clonidine is a centrally acting ␣ 2 -agonist, which has been reported in one study to have efficacy and safety similar to methyl dopa (16). In view of the limited experience with it, there is no reason to use it in pref- erence to ␣ methyl dopa. e. Prazocin No adverse effects on the fetus have been demonstrated with prazocin, but the experience with it is more lim- ited than with labetolol, ␣ methyl dopa, and ␤ blockers, and it does not appear to offer any advantage. The drug can be continued in women whose blood pressure is well controlled on it at the time of conception. f. Calcium Channel Blockers Nifedipine, nicardipine, and verapamil have been used in severe hypertension. They do not appear to be as- sociated with any increase in congenital anomalies when used in the first trimester. These drugs have been used for treatment of premature labor in the third tri- mester. Experience with diltiazem is more limited. Cal- cium channel blockers may potentiate the hypotensive effects and neuromuscular blockade of magnesium and the interaction should be kept in mind when the drugs are used in women with a possibility of developing preeclampsia (17,18). Because of the limited experi- ence with all members of this group of drugs, their use is best limited to severe hypertension unresponsive to other drugs. g. Vasodilators Hydralazine has been used safely during pregnancy for 40 years. It is ineffective as a single oral agent but can be added to a first-line drug if the latter does not ade- quately control blood pressure. The more potent vaso- dilator, minoxidil has been associated with hypertri- chosis and congenital anomalies in one case report (19). It is ineffective unless combined with a diuretic and a sympatholytic agent. 3. Drugs for Hypertensive Emergencies a. Hydralazine Intravenous hydralazine in doses of 5–10 mg every 20–30 minutes is the drug of first choice for hyperten- sive crisis in pregnancy. A single study has shown a high frequency of malignant ventricular arrhythmias in eclamptic women treated with hydralazine than in women treated with labetolol (20). Nine studies com- paring hydralazine with other drugs, most often intra- venous labetolol, have found no advantage of one drug regimen over another (21). b. Labetolol Intravenous labetolol given either as a 20 mg loading dose followed by 20 mg every 30 minutes or a 1–2 mg/min drip is the second most commonly used regi- men for treating hypertensive emergencies in pregnant women. There are occasional reports of fetal bradycar- dia, and the newborn should be monitored for hypo- tension. c. Diazoxide There is extensive experience with the use of diazoxide in pregnancy, but the drug is now primarily of historic interest. In doses of 150–300 mg it has been associated with at least one maternal fatality from hypotension. It is also associated with decreased uterine contractions and neonatal hyperglycemia. Its only advantage is a long duration of action, which may make it useful in a woman who must be transported with minimal moni- toring capability or when other drugs have failed. It should be used only in 30 mg boluses every 1–2 minutes until the desired blood pressure is reached. D. Infections Pregnant hemodialysis patients are probably at no more risk of infection than those who are not pregnant, but the use of antibiotics will be influenced by pregnancy. Most penicillins are safe during pregnancy. First-gen- eration cephalosporins such as cephazolin and cephal- exin are safe in pregnancy (10). Cephalosporins with a methyltetrathiazole moiety (cefoperozone, cefotetan, moxalactam, and cefamandole) are usually avoided in pregnancy because studies have shown infertility in an- imals (22). Sulfa drugs, such as sulfamethoxiazole, can be used in the early part of pregnancy but should be avoided in the latter part of pregnancy because there is a risk of kernicterus. Trimethoprim and trimethoprim- sulfamethoxiazole combinations are generally avoided [...]... Rosenthal MH Metabolic alkalosis due to plasmapheresis Am J Med 198 5; 79: 391 – 393 Mousson C, Charhon SA, Ammar M, Accominotti M, Rifle G Aluminum bone deposits in normal renal function patients after long-term treatment by plasma exchange Int J Artif Organs 198 9; 23:664–667 Complications During Plasma Exchange 90 91 92 93 94 95 96 97 98 99 100 101 102 Milliner DS, Shinaberger JH, Shurman P, Coburn JW... N Engl J Med 199 4; 331: 792 – 799 Schaumann D, Olbricht CJ, Welp M, et al Extracorporeal removal of LDL-cholesterol: prospective evaluation of effectivity, selectivity and biocompatibility (abstr) J Am Soc Nephrol 199 2; 3: 392 Olbricht CJ, Schauman D, Fisher D Anaphylactoid reactions, LDL apheresis with dextran sulphate and ACE inhibitors Lancet 199 2; 3 :90 8 90 9 Kroon AA, Mol MJTM, Stalenhoff APH ACE inhibitors... the Kingdom of Saudi Arabia Am J Kidney Disease 199 2; 19: 235–238 Okundaye IB, Abrinko P, Hou SH A registry for pregnancy in dialysis patients Am J Kidney Dis 199 8; 31: 766–773 718 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Hou and Grossman Bagon JA, Martens J, Van Roost G, Vernaeve H, De Muylder X Pregnancy and dialysis Am J Kidney Dis 199 8; 31:756–765 Registration Committee of the European Dialysis and... exchange: complications and management Am J Kidney Dis 199 4; 23:817–827 Sutton DMC, Nair RC, Rock G, and the Canadian Apheresis Study Group Complications of plasma exchange Transfusion 198 9; 29: 124–127 Flaum MA, Cuneo RA, Appelbaum FR, Disseroth AB, Engel WK, Gralnick HR The hemostatic imbalance of plasma exchange transfusion Blood 197 9; 54: 694 – 702 Complications During Plasma Exchange 26 27 28 29 30 31... plasma infusion in the treatment of TTP N Engl J Med 199 1; 325: 393 – 397 Ring J, Messmer K Incidence and severity of anaphylactoid reactions to colloid volume substitutes Lancet 197 7; 1:466–4 69 Bambauer R, Jutzler GA, Albrecht D, Keller HE, Kohler M Indications of plasmapheresis and selection of different substitution solutions Biomater Artif Cells Artif Organs 198 9; 17 :9 27 Huestis DW Mortality in therapeutic... haemapheresis (letter) Lancet 198 3; 1:1043 Sutton DMC, Nair R, Rock G, and the Canadian Apheresis Study Group Complications of plasma exchange Transfusion 198 9; 29: 124–127 Stafford CT, Lobel SA, Fruge BC, Moffitt JE, Hoff RG, Fadel HE Anaphylaxis to human serum albumin Ann Allergy 198 8; 61:85–88 Brecher ME, Owen HG, Collins ML Apheresis and ACE inhibitors (letter) Transfusion 199 3; 33 :96 3– 96 4 Owen HG, Brecher... associated with use of angiotensin-converting enzyme inhibitors and apheresis Transfusion 199 4; 34: 891 – 894 Apter AJ, Kaplan AA An approach to immunologic reactions with plasma exchange J Allergy Clin Immunol 199 2; 90 :1 19 124 Snyder Jr HW, Henry DH, Messerschmidt GL, et al Minimal toxicity during protein A immunoadsorption treatment of malignant disease: an outpatient therapy J Clin Apheresis 199 1; 6:1–10 Case... myasthenia gravis Lancet 197 9; 2:438–440 734 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 Kaplan Newsom-Davis J, Wilson SG, Vincent A, Ward CD Long-term effects of repeated plasma exchange in myasthenia gravis Lancet 197 9; 1:464–468 Winklestein A, Volkin RL, Starz TW, Maxwell NG, Spero JA The effects of plasma exchange on immunologic factors (abstr) Clin Res 197 9; 27: 691 Pohl MA, Lan SP, Berl T,... Epidemiology Donor Study N Engl J Med 199 6; 334:1685–1 690 AuBuchon JP, Birkmeyer JD, Busch MP Safety of the blood supply in the United States: Opportunities and Controversies Ann Intern Med 199 7; 127 :90 4 90 9 Biesert L, Suhartono H Solvent/detergent treatment of human plasma—a very robust method for virus inactivation Validated virus safety of OCTAPLAS Vox Sang 199 8; 74(suppl 1):207–212 Klein HG, Dodd... Schattauer Verlag, 198 0:3 69 371 Ashkar FS, Katims RB, Smoak WM, Gilson AJ Thyroid storm treatment with blood exchange and plasmapheresis J Am Med Assoc 197 9; 214:1275– 12 79 Talbert RL, Wong YY, Duncan DB Propranolol plasma concentrations and plasmapheresis Drug Intell Clin Phram 198 1; 15 :99 3 99 6 McClellan SD, Whitaker CH, Friedberg RC Removal of vancomycin during plasmapheresis Ann Pharmacother 199 7; 31:1132–1136 . neuropathy: a com- plication of vascular access procedures in uremic dia- betic patients. Neurology 198 9; 39: 997 99 8. 23. Vincenti F, Arnaud SB, Recker R, et al. Parathyroid and bone response of the diabetic. GC. Changes of platelet function and blood clotting in dia- betes mellitus. Thromb Hemost 197 9; 42 :98 3 99 3. 16. Halushka PV. Increased platelet thromboxane. J Lab Clin Med 198 1; 97 :87 92 . 17. U.S Kidney Disease 199 7; 29: 685– 690 . 3. Souqiyyeh MZ, Huraib SO, Saleh AGM, Aswad S. Pregnancy in chronic hemodialysis patients in the King- dom of Saudi Arabia. Am J Kidney Disease 199 2; 19: 235–238. 4.