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Dialysis: Continuous ambulatory peritoneal dialysis and haemodialysis
7
Dialysis: Continuous Ambulatory Peritoneal Dialysis and Haemodialysis RAMESH KHANNA DIMITRIOS G. OREOPOULOS
SELECTION FOR DIALYSIS A decade ago diabetics with uraemia were excluded from dialysis because of the uniformly poor outcome of dialysis and transplantation, and the progressive deterioration of vision. By 1978, however, owing to technical advances in haemodialysis and reduction of complications, survival among chronically haemodialysed diabetics improved considerably. During the past five years, continuous ambulatory peritoneal dialysis (CAPO) has established itself as a viable alternative to haemodialysis in the diabetic patient with end-stage renal disease (ESRD). Thus, the uraemic diabetic patient today has several options once the decision is made to start dialysis. The therapy of each diabetic renal failure patient accepted for renal replacement needs to be tailored to the severity of the illness and adapted to the personal and family situation. Unless there is some contraindication every potentially rehabilitable uraemic diabetic, younger than 55 years, should first be offered a kidney transplantation. For others the choice of transplantation, peritoneal dialysis or haemodialysis depends on the individual medical condition and socioeconomic situation. Both peritoneal dialysis and haemodialysis have specific advantages and disadvantages (Table 1). Because of the widespread use of haemodialysis in the past two decades, this treatment is readily available in the majority of centres in most countries. However, about 25% of the patients so treated fail to thrive and the mortality rate on haemodialysis is equivalent to that of cadaver kidney transplant. Also, retinopathy continues to progress and only a small percentage of patients are fully rehabilitated. CAPO is indicated especially for those capable of self-care at home and those with an unstable cardiovascular system because CAPO gives excellent haemodynamic control. Furthermore intraperitoneal insulin administration allows good control of blood sugar and the control of blood pressure is excellent on CAPO. Its principle disadvantages are recurrent peritonitis, progression of 823 Clinics in Endocrinology and Metabolism-Vol. 15, No.4, November 1986
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R. KHANNA AND D. G. OREOPOULOS
target-organ damage and our lack of long-term experience. Centres with a large experience with either hacmodialysis or CAPO show similar results but we know of no prospective studies which have compared the efficacy of these modes of dialysis in diabetics with ESRD. In the two years before ESRD develops, the diabetic often experiences an accelerated progression of nephropathy, neuropathy and retinopathy. Often renal function deteriorates rapidly when serum creatinine reaches 500-800 ~lIllOUI. During this period, management is complicated by impaired vision and autonomic insufficiency, and autonomic symptoms in the gastrointestinal tract overlap those of the uraemia. In comparison to non-diabetic patients with advanced renal failure, a patient with diabetic nephropathy exhibits symptoms of uraemia at higher levels of renal function. Therefore, patients with diabetic renal failure require dialysis when serum creatinine reaches 600-800 umol/l. Table I.
Advantages and shortcomings of haemodialysis and peritoneal dialysis.
Advantages Haemodialysis Short treatment duration Easily available Lower rate of amputation
CAPD Excellent blood glucose control No anglo-access required Stable hacrnodynamic status during therapy Liberal fluid and diet Ease of mobility due to life without machine
Disadvantages Repeated surgery for vascular access Need for heparinization Cardiovascular instability during dialysis therapy Failure to thrive Peritonitis Protein loss Catheter related infection Failure to thrive
HAEMODIALYSIS For several reasons, one should begin planning for haemodialysis at an early stage in the patient with diabetic nephropathy. Because of the coexistence of extensive vascular disease, few of these patients achieve successful vascular access. Therefore, one should create an arteriovenous fistula when the serum creatinine reaches 500-800 umol/l. To avoid the steal syndrome we recommend end-to-end artery-to-vein anastomosis. In patients with a poor cephalic vein or radial artery, the primary vascular access should be bovine artery or Gortex graft. Patients in advanced renal failure who require urgent dialysis may need subclavian access; however, in diabetics, complications of such a device are common and it should be used only for a brief period until one can establish a firm internal access. Alternatively one may employ peritoneal dialysis as a temporary measure. During haemodialysis the diabetic should be dialysed against a solution
DIALYSIS
825
contammg glucose to avoid stimulating glycogenolysis and gluconeogenesis, which may induce a negative nitrogen balance. We recommend a dialysis solution with a glucose concentration of 150-200 mg/dl (8.3-11.1 mmol/I). From extensive experience, Whitley and Shapiro (1985) recommend standard heparinization for diabetics on dialysis. In the recent past they have observed a much lower incidence of vitreous haemorrhages and blindness in their diabetics with little or no change in heparinization regimens. However, they avoid long-term anticoagulation with coumarin because it may involve a considerable increase in the risk of intraocular haemorrhage. They believe early and better management of ocular complications has brought an impressive decrease in development of blindness during haemodialysis.
Gastrointestinal complications During the early months of haemodialysis, diabetics may have numerous gastrointestinal complications because of associated autonomic disease. With improved control of uraemia during haemodialysis, these symptom~ progressively decrease. The therapeutic challenges in the newly dialysed diabetic are: management of blood glucose with insulin, changes in diet, control of hypertension and hypotension during dialysis, and control of fluid balance between periods of dialysis.
Diet
011
hacmodialysis
The diabetic with renal failure needs a special diet because he must contend with the restrictions of the diabetic diet and those of the renal diet. A typical daily diabetic diet comprises 2600 calories with 90 g protein, 330 g carbohydrates, 90 g fat, 2 g sodium, 1000 mg phosphorus, and 60 mg potassium. This diet is spread evenly among four meals-breakfast, lunch, dinner and snack. Good blood glucose control in the diabetic is important for several reasons. Hyperglycaemia increases thirst and may lead to fluid overload, hypertension or congestive heart failure. A diet which controls blood glucose may also reduce the risk of protein malnutrition because excess insulin causes gluconeogenesis, which inhibits protein synthesis. As in all diabetics, good control also reduces secondary diabetic complications such as neuropathy, retinopathy, gastrointestinal disturbances and skin lesions. The diabetic renal diet differs from the usual diabetic diet in several important respects: sodium restriction eliminates many foods. For example, the diabetic no longer would be able to use dill pickles, soy sauce, steak sauce or bouillon cubes. Several vegetables, considered 'free' in the diabetic diet, must be counted in the diabetic renal diet because of the potassium content. Vegetables such as potatoes are considered a starch serving in the diabetic diet but are now counted as vegetables due to the potassium content. Finally, the diet becomes monotonous with the elimination of high phosphorus foods such as milk, cheese and peanut butter snacks.
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R. KHANNA AND D. G . OREOPOULOS
Hypoglycaemia The diabetic with renal failure must also treat hypoglycaemia differently. Patients with normal renal function can use orange juice which must be avoided in the presence of renal failure because of its high potassium content. The diabetic with renal failure should use sugar water, honey or hard sweets to treat hypoglycaernia .
Insulin requirements The haernodialysis patient's requirements reflect a balance between increased insulin sensitivity, secondary to reduced renal excretion, and increased insulin resistance in both peripheral tissues and liver. The patient usually achieves a satisfactory gluco se regulation by twice daily injections containing mixtures of the regular and long-acting forms of insulin . We strongly recommend self-monitoring of blood glucose by reagent strips and/or a glucose for diabetics on dialysis. In advanced renal failure urine tests for glucose are inaccurate and may even be impossible in the presence of low urine output.
Blood pressure control on haemodialysis During haernodialysis episodes of hypotension are common and in some 5-10% of diabetics may pose a challenging therapeutic problem. Because of the orthostatic hypotension associated with advanced autonomic neuropathy it is difficult to achieve a dry body weight in these patients. Often the diabetic on dialysis may display supine hypertension with severe orthostatic hypotension-a complication that can be reduced by allowing the patient to retain some excess fluid and wear elastic support stockings during the day. In the diabetic as in the non-diabetic hypertension is due chiefly to intravascular volume expansion and hence responds to ultrafiltration during dialysis, and fluid restriction between dialyses. Because of the associated autonomic insufficiency, it may be impossible to achieve effective ultrafiltration and hence to establish ideal dry body weight. Careful fluid and salt restriction between dialyses and gradual weight reduction during haemodialysis may bring the blood pressure back to normal levels in most patients without hypotensive medications. However, a certain degree of orthostatic hypotension is unavoidable in most patients. In addition maintenance of normal blood pressure minimizes the cardiac, cerebral and vascular complications.
Blindness
Oil
liaemodialysis
During the early years, there was an extremely high incidence of blindness in diabetic patients after starting haemodialysis. However, in insulin dependent diabetics there has been a striking decrease of blindness from 44% to 3% during periods from 1966 to 1971 and after 1976 respectively (Whitley and Shapiro, 1985). Non-insulin dependent diabetics did not
DIALYSIS
827
show dramatic improvement during the same period. They attributed this improvement to more intensive ophthalmic care, more stringent blood pressure control and better blood glucose control. They do not believe that systemic heparinization during haemodialysis made any significant contribution to the development of blindness. Other studies (Ramsay et al, 1985) have also shown a marked improvement in maintenance of vision during therapy.
Amputations Most diabetic patients starting dialysis have some peripheral vascular disease. As the disease progresses many of them require amputation of the whole or part of a leg. However, amputations in diabetics on chronic haemodialysis may be needed less frequently than in transplanted diabetics, Kjellstrand (1985) reported that 15% of transplanted diabetic patients had amputations compared with 5% of those on dialysis. At 10 years, 31 % of transplanted diabetic patients had had lower extremity amputations (Bentley et al, 1984). There seems to be no similar increase in amputations for dialysed diabetic patients. Whitley and Shapiro (1985). reported amputations in 4.2% and 8.3% of their 188 insulin dependent and 180 non-insulin dependent diabetic patients respectively on haemodialysis since 1976. In a smaller population of diabetic patients on peritoneal dialysis, they observed a strikingly higher amputation rate (21 % of 33 insulin dependent and 18% of 33 non-insulin dependent diabetics). The authors explain the difference between the hacrnodialysis and peritoneal dialysis amputation rates by selection bias, since patients in whom haernoaccess could not be established because of severe peripheral vascular disease were offered peritoneal dialysis as an alternative. Centres offering peritoneal dialysis especially CAPO as the preferred treatment report a much smaller amputation incidence comparable to the haemodialysis population (Khanna et al, 1985). Because of their experience Whitley and Shapiro (1985) suggest that diabetics with severe peripheral vascular disease may represent a unique group in whom dialysis may be superior to transplantation as judged by both survival and rehabilitation.
Infections These patients frequently have infections involving the vascular access. Pulmonary and skin infections cause smaller morbidity.
Survival on haemodialysis Diabetics with end-stage renal disease die earlier than non-diabetic renal failure patients. In most haernodialysis centres the average survival at one year is about 75% and nearly 40% at three years. This contrasts with non-diabetics on haemodialysis who show a one-year survival of about 80% and a three-year survival of about 55%. During the first year, survival of diabetics on haemodialysis is comparable to that after cadaver renal
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R. KHANNA AND D. G. OREOPOULOS
transplantation. However, long-term survival in these two groups is strikingly different. Three-year survival in transplant patients is about 65% in contrast to 40% in those on haemodialysis. The difference between survival in diabetics on haemodialysis and those with living, related renal transplants is even more striking. However, cumulative survival on haemodialysis for diabetics less than 61 years of age has improved steadily and the cumulative survival of non-insulin dependent diabetics on haemodi alysis has also improved in comparison with similar patients in early 1970s. Table 2 summarizes recent cumulative survival results of diabetic patients on haemodialysis in experienced centres . The causes of death amongst diabetics on haemodialysis during the first two or three years are not related to the dialysis . During the early years after initiation of haemodialysis, Whitley and Shapiro (1985) reported that 58% of the 105 deaths were due to cardiovascular and cerebrovascular events. Uraemic deaths (which result from discontinuation of dialysis) contributed 17% of deaths in diabetic patients. After two years of dialysis infections (45%) become increasingly important as a cause of death, although cardiovascular cause s (30%) remain high.
Table 2.
Cumulative survival results for diabetic patients on hacmodialysis,
Author
Kjcllstrand (1985) Whitley et al (1985) Legrain et al (1985)
Year
1985 1985 1984
No. of patients treated
I year
3 year s
5 years
617
SO
3/lS
80 85
50 55 65
40 40
67
Cumulative survival (%)
CONTINUOUS AMBULATORY PERITONEAL DIALYSIS Technique of CAPD Patients are dialysed through an indwelling Tenckhoff or Toronto Western Hospital catheter using the same technique as for non-diabetics. The patients exchange four 2-litre bags per day. Dialysis solutions are available in four dextrose concentrations: 0.5, 1.5,2.5 and 4.25 g/dl. The patients are taught to add insulin to the dialysis solution according to the protocol described below (Amair et ai, 1982). After a daily shower, the patient paints the catheter exit site with povidone. Nurses change the connection tubing (between catheter and bag) every month at the time of clinic visits or, with the recent long-life tubings, every five to six months. Technique for intraperitoneal insulin administration Insulin administration during CAPO has been compared to treatment with an artificial pancreas (Flynn and Nanson, 1979a); indeed, there are certain
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829
similarities between physiological insulin secretion and th e response to intraperitoneal insulin administration (Porte and Bagdadc, 1970; Flynn et al, 1979; Editorial , 1979; Greenwood et al, 1979; Flynn and Nanson, 1979b; Graber, 1981). In the normal state, insulin is secreted into the portal vein in response to various sccretagogues (Porte and Bagdade , 1970) and the peak blood insulin level is attained approximately 40 minutes after a carbohydrate load. Fifty per cent of the insulin secreted into the portal vein is removed as the blood flows through the liver (Flynn and Nanson, 197%)'. Intraperitoneally administered insulin closely mimics physiological events and a large percentage of intraperitoneal insulin is absorbed into the portal vein (Flynn et al, 1979). Peak insulin levels lag about 20-30 min behind the physiological peak, and the duration of peak is longer (Porte and Bagdade , 1970; Flynn et al, 1979; Editorial, 1979; Greenwood et al, 1979; Flynn and Nanson, 1979b; Schade et al, 1980). From the peritoneal cavity , insulin can be absorbed into the portal circulation and the lymph (Schade et al, 1981). Part of the intraperitoneal insulin is absorbed from the peritoneal cavity through the capsule and parenchyma of the liver (Zingg et aI, 1982), although the exact route is unknown. Even though we. lack a clear understanding of the kinetics of insulin absorption across the peritoneum, the similarities between the physiological state and intraperitoneal insulin administration during CAPO suggest that this method would give excellent blood glucose control and achieve more desirable long-term results in diabetics with ESRD. In patients on CAPO and receiving intraperitoneal (IP) insulin, blood glucose control is superior to that achieved with subcutaneous injections, but the IP route usually requires higher daily insulin doses. These high insulin requirements may be due to such factors (Twardowski et al, 1983a,b; Johnson et aI, 1983) as: substantial binding and retention of insulin in the dialysis bag and tubing; slow absorption from the peritoneal cavity with losses in the drained dialysate; degradation of insulin by insulinase in the peritoneum or during transit to the systemic circulation; altered effectiveness of insulin absorbed via the portal system; or a combination of these. Studies of the kinetics of insulin transport across the peritoneum in dogs show that peritoneal permeance of insulin (mol.wt 6000) is 3-6 ml/min (Shapiro et aI, 1979). Rubin et al (1986) found that in six CAPO diabetic patients the mass transfer coefficients for intraperitoneally administered insulin using 1.5% and 4.25% dextrose were 2.9 and 2.0 ml/min respectively. By the end of 6 h in the peritoneal cavity nearly 40-50% of the 15-20 units of insulin which had been administered had disappeared. Such absorption is independent of either blood or dialysate glucose concentration (Blumenkrantz et al, 1983).
Protocol for insulin administration During the day, the bags are exchanged 20 min before the three major meals and for a fourth time at 11 p.m. At this time the patient has a snack consisting of a sandwich and a small drink. He is encouraged to follow a
830
R. KHANNA AND D. G. OREOPOULOS
diet providing 20-75 kcal per kg body weight per day and containing 1.2-1.5 g of protein per kg body weight. During the initial control period, blood glucose is measured four times a day, i.e. in the morning fasting , and 1 h after breakfast, lunch and supper. Regular (soluble) insulin is added to each bag just before the fluid is infused, and the bag is inverted two or three times to aid mixing . The insulin dose is proportional to the concentration of glucose in the dialysate. On the first day, one-quarter of the predialysis insulin is added to each bag of dialysate, with a supplemental dose that is determined according to the blood glucose concentration. On the second day , the insulin added to each bag is increased or decreased according to the previous day's blood glucose levels . The insulin dose in the 11 p.m . exchange is based on the level of fasting blood sugar next morning. The adjustment of the insulin dose in the dialysate exchange immediately before meals is based on the blood glucose level after the corresponding meal. Patients are trained to check the blood glucose level by the 'finger prick' technique. The test is performed 5-10 min before each bag exchange, and whenever necessary the insulin added to the next bag is adjusted according to a sliding scale. During the training period, the patient becomes familiar with such a scale and practises them under observation. Three or four days are needed to establish blood glucose control. The intraperitoneal insulin requirements may vary from 10 to 200 units daily. Nocturnal insulin requirements arc 30-50% of the daytime dose required for each bag. Hyperglycaemia is seen frequently in association with peritonitis, systemic infection, and in the period immediately following discontinuation of CAPO. During these periods, the patient needs a higher dose of insulin to control hyperglycaemia than is usual during CAPO, and some patients may require intravenous infusions of insulin for 24-48 h. Amair et al (1982) reported that hyperglycaemic ketoacidosis is extremely uncommon during CAPO. However, hypoglycaemia may occur during intraperitoneal administration of insulin, and patients and/or family should be trained to respond by draining the dialysis fluid from the peritoneal cavity and , if necessary, providing additional oral glucose. If necessary, a solution containing no insulin should be infused into the peritoneal cavity without delay. In comatose patients, glucagon injections may be life-saving. Complications of CAPD Peritonitis As in non-diabetics, peritonitis in diabetics is caused predominantly by skin flora such as Staphylococcus epidermidis, Staph. aureus and Streptococcus viridans, gram-negative enteric organisms, and, rarely, anaerobic organisms. A few peritonitis episodes are caused by fungi. The pathogenesis and clinical presentation, and the spectrum of peritonitis in diabetics on CAPO does not differ from that seen in the non-diabetic (Slingeneyer et ai, 1981;
DIALYSIS
831
Thomson et aI, 1981; Madden et aI, 1982; Rottembourg et aI, 1983; Williams and the University of Toronto Collaboratory Dialysis Group, 1983; Flynn, 1983; Grcfbcrg, 1983; Khanna et aI, 1985). Treatment for peritonitis is the same in both groups. Owing to the enhanced and rapid absorption of glucose during peritonitis, hyperglycaemia is frequent in diabetics, and insulin requirements increase. Some may need intravenous infusion of insulin for the control of blood glucose. Rapid glucose absorption may provoke fluid retention, and these patients may require additional dialysis. Because of increased protein losses during peritonitis, the patient's nutrition must be watched closely during the acute phase and some may require parenteral nutrition. Generally the outcome of treatment is good. Most patients continue on CAPO after the peritonitis is cured. A small percentage (2-5%) will drop out of the CAPO programme for a variety of reasons. Some fail only after one or two episodes of peritonitis, while others fail because of the severity of peritonitis. Complications other than peritonitis during CAPD
Hernias and dialysate leakage Complications that are a direct result of increased intra-abdominal pressure 'such as dialysate leaks, hernia, haemorrhoids and compromised cardiopulmonary function occur with the same frequency in diabetics and non-diabetics. Because of delayed wound healing, dialysate leakage is more frequent in diabetics during the first dialysis after catheter insertion. To minimize this risk the catheter should be implanted through a lateral approach and dialysis should be postponed for 24-48 h.
Protein losses and malnutrition Losses of protein, amino acids, polypeptides and vitamins in the dialysate contribute to malnutrition and slow rehabilitation. Such losses pose a special problem in diabetics who may be malnourished already because of poor food intake, vomiting, catabolic stresses and intercurrent illness. Twenty-four-hour amino acid losses in the dialysate average 2.25 g/day with about 8 glday of protein. These are small in comparison to the recommended intake of 1.1-1.3 g protein per kg body weight per day. During peritonitis, protein losses are excessive and, when accompanied by inadequate food intake due to poor appetite or weakness, may induce severe hypoproteinaemia, hypoalbuminaernia and hypoimmunoglobulinaemia. Thus, the physician should consider parenteral nutrition early in an episode of peritonitis which appears to be responding poorly.
Visual impairment There have been many reports of stabilization in vision in diabetic patients maintained on CAPO (Thomson et aI, 1981; Rottembourg et aI, 1983). Our experience (Khanna et aI, 1985) in 46 eyes of insulin dependent
832
R . KHANNA AND D . G . OREOPOULOS
diabetic CAPO patients followed for 12 months to over 25 months indicated that of the 19 eyes with good vision at initiation, three deteriorated, of the 18 eyes with impaired vision , four deteriorated , of the 12 eyes in patients on treatment for over 25 months, two eyes deteriorated. Overall, of the 46 eyes, 85% remained unchanged and 15% deteriorated. The reasons for deterioration of vision were: glaucoma, retinal detachment, epiretinal membrane, vitreous haemorrhage, choroidal vascular insufficiency, optic atrophy and cataract. Patients in whom vision docs deteriorate either have advanced proliferative retinopathy or other ophthalmological diseases. More experience in a larger number of patients is required before the effect of CAPO on visual function is accurately known.
Peripheral vascular disease and amputations Initial short-term experience with CAPO diabetics does not suggest that the rate of amputation is any different from that of haernodialysed diabetics. The combined experience of two North American centres recently reported amputations in 7.4% of 81 diabetic patients on CAPO (Khanna et ai, 1985). In a smaller population of 34 CAPO diabeticpatients amputations were reported by Mejia and Zimmerman (1985) in 3%, whereas in 37 comparable haernodialysed diabetic patients treated during the same period, amputations were needed in 10.8%. Since CAPO does not prevent vascular disease, long-term CAPO patients might be expected to develop this complication more frequently. Furthermore, exacerbation of underlying peripheral vascular disease during CAPO has been noted in a small series of patients with persistent hypotension (Brown et ai, 1981). Thus in patients on CAPO with known peripheral vascular disease , it seems wise to accept a less stringent control of blood pressure .
Gastrointestinal complications As in those on haernodialysis, patients on CAPO frequently suffer nausea and vomiting from gastroparesis, resulting in a high morbidity and malnutrition. Metoclopramide (Reglan , Maxeran) may control this cornplication . Similarly, in advanced ESRD, one may encounter episodes of diarrhoea and poor sphincter control.
Causes of death among diabetics on CAPD In most centres, the most common causes are cardio- or cerebrovascular events and infection. Contrary to expectation and unlike the experience in non-diabetics, infection does not seem to be a major cause of death in diabetics on CAPO.
Drop-out of diabetics on CAPD Despite the impressive improvement in survival, diabetics drop out of CAPO programmes at a high rate for various reasons including deaths and
DIALYSIS
833
transfers to other forms of treatment. The cumulative technique survival rate, i.e. the percentage of those remaining on CAPO is approximately 55% by the second year-which is not different from non-diabetics. In both groups, episodes of peritonitis are the main reason for transfer to other forms of treatment. Ultrafiltration failure, a relatively new entity, has not been observed among diabetics. Outcome of diabetics on CAPD The two-year cumulative survival rate is significantly better than that achieved by intermittent PO perhaps because diabetics, who tend to have significant cardiovascular disease, seem to tolerate CAPO better. Furthermore, during the past four or five years, significant improvements in peritoneal dialysis have helped to increase survival. Also we are able to manage complications more efficiently; CAPO gives better control of blood pressure than intermittent PO and has clearly reduced morbidity. The average CAPO patient with diabetes is 10 years younger, but tends to have significantly more cardiovascular disease than the non-diabetics; this may explain his shorter survival. Previously (1985) we reported that the one- and two-year cumulative survivals for insulin dependent diabetics on CAPO were 92% and 75% respectively. Non-insulin dependent diabetics had similar cumulative survival rates-90% and 75% at one and two years respectively. Several centres in North America and Europe have reported similarly encouraging one-year cumulative survivals for diabetics on CAPO. Non-insulin dependent diabetics have a comparatively poor prognosis because, as a group, they are older, usually have severe atherosclerotic heart disease, and generally have other medical problems as well. One-year cumulative survival of diabetics reported in the literature is summarized in Table 3. Mejia and Zimmerman (1985) reviewed experiences in their programme in all patients with ESRD due to diabetic nephropathy who started haemodialysis (HD) or CAPO. Patients who had any previous form of renal replacement therapy including a transplant or had a follow-up of less than one month were excluded. There were 37 HD patients and 34 CAPO patients. HD was primarily in-centre. In the CAPO group, actuarial survival was 81% at both one and three years and in the HD groups 76% and 40% at one and three years respectively. These values were significantly different between the two therapies. CAPO patients initially spent more days in the hospital for catheter placement and training but thereafter had fewer hospital days. Infections, other than peritonitis or in relation to the catheter, were more frequent in HD patients. The groups were considered comparable in respect of sex distribution, age, prevalence and duration of hypertension, and the presence of neuropathy, vascular disease, retinopathy and blindness. At the end of follow-up (24 months HD, 27 months CAPO) technique survivals (death and a transfer to another modality were considered technique failures while transplant was a loss to follow-up) were at one, two and three years for CAPO, 71, 71 and 71%, for HD patients 76,54 and 18% respectively. HD patients spent more than twice as
834
R. KHANNA AND D. G. OREOPOULOS Table 3.
One-year cumulative survival of diabetics on CAPO.
Madden et al (1982) Rottembourg et al (1983) Kurtz et al (1983) Flynn (1983) Blind diabetics Sighted diabetics Grefberg et al (1983) Khanna et a] (1983) (Type I) (Type 11) Williams and University of Toronto Collaborative Group (1983) (Type I) (Type 11) Combined report of EDTA and ERA (Wing et ai, 1983) Age 15-34 years Age 35-44 years Age 45-54 years Age 55-64 years National CAPO Registry (1986)
Year
No. of patients treated
Cumulative one-year survival (%)
1982 1983 1983
14 24 29
70 84 78
1983 1983 1983
26 12 24
92 80
1983 1983
29 8
87 82
1983 1983
60 29
92 90
1983 1983 1983 1983 1985
33 39 49
77
64
1345
64
92 80 71 78
many days in hospital per patient month when compared with CAPO patients (4.1 vs 1.8, P <: 0.01). Although this comparison is of interest the results must be interpreted with caution since it is not a prospective randomized study and an inapparent bias in selection may have been present. Although there is no great difference in short-term survival (one to three years) between diabetics and non-diabetics with ESRD on CAPO, it remains to be established whether there is any difference in long-term survival. Not many diabetic patients have been on CAPO for long periods because CAPO has only existed for five to six years. However, non-diabetics on haemodialysis and after kidney transplantation show a significantly longer survival mainly because the diabetic shows a steady progression of the underlying cardiovascular disease. In the future, when larger numbers of diabetic patients have been treated for a longer period, there may be a similar trend with CAPO. REFERENCES Arnair P, Khanna R, Leibel B et al (1982) Continuous ambulatory peritoneal dialysis in diabetics with end stage renal disease. New England Journal of Medicine 106: 652.
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Bentley F, Menth L, Nylander W et al (198ot) Status of diabetic renal allograft recipients who survive for 10 or more years after transplant. Tenth International Congress of the Transplantation Society (abstract), p 219. Blumcnkrantz MJ, Salehmghaddan S & Salusky I (1983) Treatment of patients with end stage diabetic nephropathy. In LaGreca (ed.) Peritoneal Dialysis, pp 289-306. Milan, Italy: Wichtig Editor. Brown PM, Johnson KCO, Fenton SS ct al (1981) Symptomatic exacerbation of peripheral vascular disease with CAPO. Clinical Nephrology 16: 258-261. Editorial (1979) New insulin delivery system for diabetics. Lancet i: 1275-1277. Flynn CT (1983) The diabetic patient on continuous ambulatory peritoneal dialysis. Peritoneal Dialysis Bulletin 351: 16-20. Flynn CT &. Nanson JA (1979a) Intraperitoneal insulin with CAPO-an artificial pancreas. Transactio lIS of the American Society for Artificial Internal Organs 25: 114-117. Flynn CT & Nanson JA (1979b) Intraperitoneal insulin in diabetics. Lancet ii: 591. Flynn CT, Hibbard J & Dohrman B (1979) Advantages of continuous ambulatory peritoneal dialysis to the diabetic with renal failure. Proceedings of the European Dialysis and Transplant Association 16: 184-193. Graber AL (1981) Chronic peritoneal dialysis in insulin dependent diabetes mellitusdiabetic clinical care conference. Journal of the Tennessee Medical Association 2: 7ot. Greenwood RH, Davies CJ, Senator GB et al (1979) Intraperitoneal insulin in diabetics. Lancet ii: 312. Grefberg N (1983) Clinical aspects of continuous ambulatory peritoneal dialysis. Scandinavian Journal of Urology and Nephrology 72: S7-38. . Johnson CA et al (1983) Adsorption of insulin to the surface of peritoneal dialysis solution containers. American Journal of Kidney Disease 3: ~24-228. Khanna R, Wu G, Chisholm L & Oreopoulos DG (1983) Further experience with CAPO in diabetics with end-stage renal disease. In Keen H & Legrain M (cds) Prevention and Treatment of Diabetic Nephropathy, pp 279-288. Boston: MTP Press. Khanna R, Wu G, Prowant B et al (1985) Continuous ambulatory peritoneal dialysis in diabetics with ESRD: a combined experience of two North American Centers. In Friedman EA & L'Esperance FA (eds) Diabetic Renal-Retinal Syndrome, pp 363-381. Orlando, FL: Grune & Stratton. Kjellstrand CM (1985) A comparison of dialysis and transplantation in patients with end-stage renal failure of diabetes. In Friedman EA & L'Esperance FA (eds) Diabetic Renal-Retinal Syndrome, pp 333-340. Orlando, FL: Grune & Stratton. Kurtz SB, Wong VH, Anderson CF et al (1983) Continuous ambulatory peritoneal dialysis. Three years' experience at the Mayo Clinic. Mayo Clinic Proceedings 58: 633-639. Legrain M, Rottembourg J, deGroc F & Boudjcrnaa A (1985) Selecting the best uremia therapy. In Friedman EA & L'Esperance FA (eds) Diabetic Renal-Retinal Syndrome, pp 453-468. Orlando FL: Grune & Stratton. Madden MA, Zimmerman SW & Simpson DP (1982) CAPO in diabetes mellitus. American Journal of Nephrology 2: 133-139. Mejia G & Zimmerman SW (1985) Comparison of CAPO and hemodialysis for diabetics. Peritoneal Dialysis Bulletin 5: 7-11. National CAPO Registry (1986) Report of the National CAPD Registry of the National Institutes of Health, January 1986, p. 2ot. Bethesda: National Institutes of Health. Porte 0 Jr & Bagdade JD (1970) Human insulin secretion: an integrated approach. Annual Re~'ielV of Medicine 21: 219-240. Ramsey RC, Cantrill HL, Knobloch WH et al (1985) Visual status in diabetic patients following therapy for end stage nephropathy. In Friedman EA & L'Esperance FA (eds) Diabetic Renal-Retinal Syndrome, pp 443-452. Orlando FL: Grune & Stratton. Rottembourg J, Shahat EL, Agrafiotis A et al (1983) CAPO in insulin dependent diabetic patients, and a 40 month experience. Kidney International 23: 40. Rubin J, Reed V, Adair RN, Dower J & Klein E (1986) American Journal of the Medical Sciences 291: 81-87. Schade OS, Eaton RP, Friedman NM & Spencer W (1980) Five day programmed intraperitoneal insulin infusion in diabetic man. Abstracts of the American Diabetic Association, p 71.
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Schade DS, Eaton RP & Spencer W (1981) The advantages of the peritoneal route of insulin delivery. In Irsiglcr K, Kunz D, Owens D & RegalH (cds) Nell' Approaches to Insulin Therapy, pp 31-39. Lancaster: MTP Press. Shapiro DJ, B1umenkrantz MJ, Levin SR & Coburn JW (1979) Absorption and action of insulin added to peritoneal dialysate in dogs. Nephron 23: 174-180. Slingeneyer A, Mion C & Selam JL (1981) Home intermittent and CAPD as a long term treatment of end-stage renal failure in diabetics. In Gahl GM et al (eds) Adl'Gnces in Peritoneal Dialysis, pp 378-388. Amsterdam: Excerpta Medica. Thomson NM, Simpson RW, Hooke D & Atkin RC (1981) Peritoneal dialysis in the treatment of diabetic end stage renal failure. In Atkins RC, Thomson NM & Farrel PC (eds) Peritoneal Dialysis, pp 345-355. New York: Churchill Livingstone. Twardowski ZJ, Nolph KD, McGary TJ et al (1983a) Insulin binding to plastic bags: a methodologic study. American Journal of Hospital Pharmacy 40: 575-579. Twardowski ZJ, Nolph KD, McGary TJ, Moore HL et al (1983b) Nature of insulin binding to plastic bags. American Journal of Hospital Pharmacy 40: 579-582. Whitley KY & Shapiro FL (1985) Hemodialysis for the uremic diabetic. In Friedman EA & Peterson CM (eds) Diabetic Nephropathy, pp 85-103. Boston: Martinus Nijhoff Publishing. Williams C, and the University of Toronto Collaborative Dialysis Group (1983) CAPD in Toronto-an overview. Peritoneal Dialysis Bulletin 35: 2-6. Wing AF, Breyer M, Brunner FP et al (1983) Combined report on regular dialysis and transplantation in Europe 1982. Proceedings of the European Dialysis and Transplant AssociationiIiuropcun Rellal Association 20: 1-78. Zingg W, Shirriff JM & Liebel B (1982) Experimental routes of insulin administration. Peritoneal Dialysis Bulletin 2: S24-27.
Dialysis: Continuous Ambulatory Peritoneal Dialysis and Haemodialysis RAMESH KHANNA DIMITRIOS G. OREOPOULOS
SELECTION FOR DIALYSIS A decade ago diabetics with uraemia were excluded from dialysis because of the uniformly poor outcome of dialysis and transplantation, and the progressive deterioration of vision. By 1978, however, owing to technical advances in haemodialysis and reduction of complications, survival among chronically haemodialysed diabetics improved considerably. During the past five years, continuous ambulatory peritoneal dialysis (CAPO) has established itself as a viable alternative to haemodialysis in the diabetic patient with end-stage renal disease (ESRD). Thus, the uraemic diabetic patient today has several options once the decision is made to start dialysis. The therapy of each diabetic renal failure patient accepted for renal replacement needs to be tailored to the severity of the illness and adapted to the personal and family situation. Unless there is some contraindication every potentially rehabilitable uraemic diabetic, younger than 55 years, should first be offered a kidney transplantation. For others the choice of transplantation, peritoneal dialysis or haemodialysis depends on the individual medical condition and socioeconomic situation. Both peritoneal dialysis and haemodialysis have specific advantages and disadvantages (Table 1). Because of the widespread use of haemodialysis in the past two decades, this treatment is readily available in the majority of centres in most countries. However, about 25% of the patients so treated fail to thrive and the mortality rate on haemodialysis is equivalent to that of cadaver kidney transplant. Also, retinopathy continues to progress and only a small percentage of patients are fully rehabilitated. CAPO is indicated especially for those capable of self-care at home and those with an unstable cardiovascular system because CAPO gives excellent haemodynamic control. Furthermore intraperitoneal insulin administration allows good control of blood sugar and the control of blood pressure is excellent on CAPO. Its principle disadvantages are recurrent peritonitis, progression of 823 Clinics in Endocrinology and Metabolism-Vol. 15, No.4, November 1986
824
R. KHANNA AND D. G. OREOPOULOS
target-organ damage and our lack of long-term experience. Centres with a large experience with either hacmodialysis or CAPO show similar results but we know of no prospective studies which have compared the efficacy of these modes of dialysis in diabetics with ESRD. In the two years before ESRD develops, the diabetic often experiences an accelerated progression of nephropathy, neuropathy and retinopathy. Often renal function deteriorates rapidly when serum creatinine reaches 500-800 ~lIllOUI. During this period, management is complicated by impaired vision and autonomic insufficiency, and autonomic symptoms in the gastrointestinal tract overlap those of the uraemia. In comparison to non-diabetic patients with advanced renal failure, a patient with diabetic nephropathy exhibits symptoms of uraemia at higher levels of renal function. Therefore, patients with diabetic renal failure require dialysis when serum creatinine reaches 600-800 umol/l. Table I.
Advantages and shortcomings of haemodialysis and peritoneal dialysis.
Advantages Haemodialysis Short treatment duration Easily available Lower rate of amputation
CAPD Excellent blood glucose control No anglo-access required Stable hacrnodynamic status during therapy Liberal fluid and diet Ease of mobility due to life without machine
Disadvantages Repeated surgery for vascular access Need for heparinization Cardiovascular instability during dialysis therapy Failure to thrive Peritonitis Protein loss Catheter related infection Failure to thrive
HAEMODIALYSIS For several reasons, one should begin planning for haemodialysis at an early stage in the patient with diabetic nephropathy. Because of the coexistence of extensive vascular disease, few of these patients achieve successful vascular access. Therefore, one should create an arteriovenous fistula when the serum creatinine reaches 500-800 umol/l. To avoid the steal syndrome we recommend end-to-end artery-to-vein anastomosis. In patients with a poor cephalic vein or radial artery, the primary vascular access should be bovine artery or Gortex graft. Patients in advanced renal failure who require urgent dialysis may need subclavian access; however, in diabetics, complications of such a device are common and it should be used only for a brief period until one can establish a firm internal access. Alternatively one may employ peritoneal dialysis as a temporary measure. During haemodialysis the diabetic should be dialysed against a solution
DIALYSIS
825
contammg glucose to avoid stimulating glycogenolysis and gluconeogenesis, which may induce a negative nitrogen balance. We recommend a dialysis solution with a glucose concentration of 150-200 mg/dl (8.3-11.1 mmol/I). From extensive experience, Whitley and Shapiro (1985) recommend standard heparinization for diabetics on dialysis. In the recent past they have observed a much lower incidence of vitreous haemorrhages and blindness in their diabetics with little or no change in heparinization regimens. However, they avoid long-term anticoagulation with coumarin because it may involve a considerable increase in the risk of intraocular haemorrhage. They believe early and better management of ocular complications has brought an impressive decrease in development of blindness during haemodialysis.
Gastrointestinal complications During the early months of haemodialysis, diabetics may have numerous gastrointestinal complications because of associated autonomic disease. With improved control of uraemia during haemodialysis, these symptom~ progressively decrease. The therapeutic challenges in the newly dialysed diabetic are: management of blood glucose with insulin, changes in diet, control of hypertension and hypotension during dialysis, and control of fluid balance between periods of dialysis.
Diet
011
hacmodialysis
The diabetic with renal failure needs a special diet because he must contend with the restrictions of the diabetic diet and those of the renal diet. A typical daily diabetic diet comprises 2600 calories with 90 g protein, 330 g carbohydrates, 90 g fat, 2 g sodium, 1000 mg phosphorus, and 60 mg potassium. This diet is spread evenly among four meals-breakfast, lunch, dinner and snack. Good blood glucose control in the diabetic is important for several reasons. Hyperglycaemia increases thirst and may lead to fluid overload, hypertension or congestive heart failure. A diet which controls blood glucose may also reduce the risk of protein malnutrition because excess insulin causes gluconeogenesis, which inhibits protein synthesis. As in all diabetics, good control also reduces secondary diabetic complications such as neuropathy, retinopathy, gastrointestinal disturbances and skin lesions. The diabetic renal diet differs from the usual diabetic diet in several important respects: sodium restriction eliminates many foods. For example, the diabetic no longer would be able to use dill pickles, soy sauce, steak sauce or bouillon cubes. Several vegetables, considered 'free' in the diabetic diet, must be counted in the diabetic renal diet because of the potassium content. Vegetables such as potatoes are considered a starch serving in the diabetic diet but are now counted as vegetables due to the potassium content. Finally, the diet becomes monotonous with the elimination of high phosphorus foods such as milk, cheese and peanut butter snacks.
826
R. KHANNA AND D. G . OREOPOULOS
Hypoglycaemia The diabetic with renal failure must also treat hypoglycaemia differently. Patients with normal renal function can use orange juice which must be avoided in the presence of renal failure because of its high potassium content. The diabetic with renal failure should use sugar water, honey or hard sweets to treat hypoglycaernia .
Insulin requirements The haernodialysis patient's requirements reflect a balance between increased insulin sensitivity, secondary to reduced renal excretion, and increased insulin resistance in both peripheral tissues and liver. The patient usually achieves a satisfactory gluco se regulation by twice daily injections containing mixtures of the regular and long-acting forms of insulin . We strongly recommend self-monitoring of blood glucose by reagent strips and/or a glucose for diabetics on dialysis. In advanced renal failure urine tests for glucose are inaccurate and may even be impossible in the presence of low urine output.
Blood pressure control on haemodialysis During haernodialysis episodes of hypotension are common and in some 5-10% of diabetics may pose a challenging therapeutic problem. Because of the orthostatic hypotension associated with advanced autonomic neuropathy it is difficult to achieve a dry body weight in these patients. Often the diabetic on dialysis may display supine hypertension with severe orthostatic hypotension-a complication that can be reduced by allowing the patient to retain some excess fluid and wear elastic support stockings during the day. In the diabetic as in the non-diabetic hypertension is due chiefly to intravascular volume expansion and hence responds to ultrafiltration during dialysis, and fluid restriction between dialyses. Because of the associated autonomic insufficiency, it may be impossible to achieve effective ultrafiltration and hence to establish ideal dry body weight. Careful fluid and salt restriction between dialyses and gradual weight reduction during haemodialysis may bring the blood pressure back to normal levels in most patients without hypotensive medications. However, a certain degree of orthostatic hypotension is unavoidable in most patients. In addition maintenance of normal blood pressure minimizes the cardiac, cerebral and vascular complications.
Blindness
Oil
liaemodialysis
During the early years, there was an extremely high incidence of blindness in diabetic patients after starting haemodialysis. However, in insulin dependent diabetics there has been a striking decrease of blindness from 44% to 3% during periods from 1966 to 1971 and after 1976 respectively (Whitley and Shapiro, 1985). Non-insulin dependent diabetics did not
DIALYSIS
827
show dramatic improvement during the same period. They attributed this improvement to more intensive ophthalmic care, more stringent blood pressure control and better blood glucose control. They do not believe that systemic heparinization during haemodialysis made any significant contribution to the development of blindness. Other studies (Ramsay et al, 1985) have also shown a marked improvement in maintenance of vision during therapy.
Amputations Most diabetic patients starting dialysis have some peripheral vascular disease. As the disease progresses many of them require amputation of the whole or part of a leg. However, amputations in diabetics on chronic haemodialysis may be needed less frequently than in transplanted diabetics, Kjellstrand (1985) reported that 15% of transplanted diabetic patients had amputations compared with 5% of those on dialysis. At 10 years, 31 % of transplanted diabetic patients had had lower extremity amputations (Bentley et al, 1984). There seems to be no similar increase in amputations for dialysed diabetic patients. Whitley and Shapiro (1985). reported amputations in 4.2% and 8.3% of their 188 insulin dependent and 180 non-insulin dependent diabetic patients respectively on haemodialysis since 1976. In a smaller population of diabetic patients on peritoneal dialysis, they observed a strikingly higher amputation rate (21 % of 33 insulin dependent and 18% of 33 non-insulin dependent diabetics). The authors explain the difference between the hacrnodialysis and peritoneal dialysis amputation rates by selection bias, since patients in whom haernoaccess could not be established because of severe peripheral vascular disease were offered peritoneal dialysis as an alternative. Centres offering peritoneal dialysis especially CAPO as the preferred treatment report a much smaller amputation incidence comparable to the haemodialysis population (Khanna et al, 1985). Because of their experience Whitley and Shapiro (1985) suggest that diabetics with severe peripheral vascular disease may represent a unique group in whom dialysis may be superior to transplantation as judged by both survival and rehabilitation.
Infections These patients frequently have infections involving the vascular access. Pulmonary and skin infections cause smaller morbidity.
Survival on haemodialysis Diabetics with end-stage renal disease die earlier than non-diabetic renal failure patients. In most haernodialysis centres the average survival at one year is about 75% and nearly 40% at three years. This contrasts with non-diabetics on haemodialysis who show a one-year survival of about 80% and a three-year survival of about 55%. During the first year, survival of diabetics on haemodialysis is comparable to that after cadaver renal
828
R. KHANNA AND D. G. OREOPOULOS
transplantation. However, long-term survival in these two groups is strikingly different. Three-year survival in transplant patients is about 65% in contrast to 40% in those on haemodialysis. The difference between survival in diabetics on haemodialysis and those with living, related renal transplants is even more striking. However, cumulative survival on haemodialysis for diabetics less than 61 years of age has improved steadily and the cumulative survival of non-insulin dependent diabetics on haemodi alysis has also improved in comparison with similar patients in early 1970s. Table 2 summarizes recent cumulative survival results of diabetic patients on haemodialysis in experienced centres . The causes of death amongst diabetics on haemodialysis during the first two or three years are not related to the dialysis . During the early years after initiation of haemodialysis, Whitley and Shapiro (1985) reported that 58% of the 105 deaths were due to cardiovascular and cerebrovascular events. Uraemic deaths (which result from discontinuation of dialysis) contributed 17% of deaths in diabetic patients. After two years of dialysis infections (45%) become increasingly important as a cause of death, although cardiovascular cause s (30%) remain high.
Table 2.
Cumulative survival results for diabetic patients on hacmodialysis,
Author
Kjcllstrand (1985) Whitley et al (1985) Legrain et al (1985)
Year
1985 1985 1984
No. of patients treated
I year
3 year s
5 years
617
SO
3/lS
80 85
50 55 65
40 40
67
Cumulative survival (%)
CONTINUOUS AMBULATORY PERITONEAL DIALYSIS Technique of CAPD Patients are dialysed through an indwelling Tenckhoff or Toronto Western Hospital catheter using the same technique as for non-diabetics. The patients exchange four 2-litre bags per day. Dialysis solutions are available in four dextrose concentrations: 0.5, 1.5,2.5 and 4.25 g/dl. The patients are taught to add insulin to the dialysis solution according to the protocol described below (Amair et ai, 1982). After a daily shower, the patient paints the catheter exit site with povidone. Nurses change the connection tubing (between catheter and bag) every month at the time of clinic visits or, with the recent long-life tubings, every five to six months. Technique for intraperitoneal insulin administration Insulin administration during CAPO has been compared to treatment with an artificial pancreas (Flynn and Nanson, 1979a); indeed, there are certain
DIALYSIS
829
similarities between physiological insulin secretion and th e response to intraperitoneal insulin administration (Porte and Bagdadc, 1970; Flynn et al, 1979; Editorial , 1979; Greenwood et al, 1979; Flynn and Nanson, 1979b; Graber, 1981). In the normal state, insulin is secreted into the portal vein in response to various sccretagogues (Porte and Bagdade , 1970) and the peak blood insulin level is attained approximately 40 minutes after a carbohydrate load. Fifty per cent of the insulin secreted into the portal vein is removed as the blood flows through the liver (Flynn and Nanson, 197%)'. Intraperitoneally administered insulin closely mimics physiological events and a large percentage of intraperitoneal insulin is absorbed into the portal vein (Flynn et al, 1979). Peak insulin levels lag about 20-30 min behind the physiological peak, and the duration of peak is longer (Porte and Bagdade , 1970; Flynn et al, 1979; Editorial, 1979; Greenwood et al, 1979; Flynn and Nanson, 1979b; Schade et al, 1980). From the peritoneal cavity , insulin can be absorbed into the portal circulation and the lymph (Schade et al, 1981). Part of the intraperitoneal insulin is absorbed from the peritoneal cavity through the capsule and parenchyma of the liver (Zingg et aI, 1982), although the exact route is unknown. Even though we. lack a clear understanding of the kinetics of insulin absorption across the peritoneum, the similarities between the physiological state and intraperitoneal insulin administration during CAPO suggest that this method would give excellent blood glucose control and achieve more desirable long-term results in diabetics with ESRD. In patients on CAPO and receiving intraperitoneal (IP) insulin, blood glucose control is superior to that achieved with subcutaneous injections, but the IP route usually requires higher daily insulin doses. These high insulin requirements may be due to such factors (Twardowski et al, 1983a,b; Johnson et aI, 1983) as: substantial binding and retention of insulin in the dialysis bag and tubing; slow absorption from the peritoneal cavity with losses in the drained dialysate; degradation of insulin by insulinase in the peritoneum or during transit to the systemic circulation; altered effectiveness of insulin absorbed via the portal system; or a combination of these. Studies of the kinetics of insulin transport across the peritoneum in dogs show that peritoneal permeance of insulin (mol.wt 6000) is 3-6 ml/min (Shapiro et aI, 1979). Rubin et al (1986) found that in six CAPO diabetic patients the mass transfer coefficients for intraperitoneally administered insulin using 1.5% and 4.25% dextrose were 2.9 and 2.0 ml/min respectively. By the end of 6 h in the peritoneal cavity nearly 40-50% of the 15-20 units of insulin which had been administered had disappeared. Such absorption is independent of either blood or dialysate glucose concentration (Blumenkrantz et al, 1983).
Protocol for insulin administration During the day, the bags are exchanged 20 min before the three major meals and for a fourth time at 11 p.m. At this time the patient has a snack consisting of a sandwich and a small drink. He is encouraged to follow a
830
R. KHANNA AND D. G. OREOPOULOS
diet providing 20-75 kcal per kg body weight per day and containing 1.2-1.5 g of protein per kg body weight. During the initial control period, blood glucose is measured four times a day, i.e. in the morning fasting , and 1 h after breakfast, lunch and supper. Regular (soluble) insulin is added to each bag just before the fluid is infused, and the bag is inverted two or three times to aid mixing . The insulin dose is proportional to the concentration of glucose in the dialysate. On the first day, one-quarter of the predialysis insulin is added to each bag of dialysate, with a supplemental dose that is determined according to the blood glucose concentration. On the second day , the insulin added to each bag is increased or decreased according to the previous day's blood glucose levels . The insulin dose in the 11 p.m . exchange is based on the level of fasting blood sugar next morning. The adjustment of the insulin dose in the dialysate exchange immediately before meals is based on the blood glucose level after the corresponding meal. Patients are trained to check the blood glucose level by the 'finger prick' technique. The test is performed 5-10 min before each bag exchange, and whenever necessary the insulin added to the next bag is adjusted according to a sliding scale. During the training period, the patient becomes familiar with such a scale and practises them under observation. Three or four days are needed to establish blood glucose control. The intraperitoneal insulin requirements may vary from 10 to 200 units daily. Nocturnal insulin requirements arc 30-50% of the daytime dose required for each bag. Hyperglycaemia is seen frequently in association with peritonitis, systemic infection, and in the period immediately following discontinuation of CAPO. During these periods, the patient needs a higher dose of insulin to control hyperglycaemia than is usual during CAPO, and some patients may require intravenous infusions of insulin for 24-48 h. Amair et al (1982) reported that hyperglycaemic ketoacidosis is extremely uncommon during CAPO. However, hypoglycaemia may occur during intraperitoneal administration of insulin, and patients and/or family should be trained to respond by draining the dialysis fluid from the peritoneal cavity and , if necessary, providing additional oral glucose. If necessary, a solution containing no insulin should be infused into the peritoneal cavity without delay. In comatose patients, glucagon injections may be life-saving. Complications of CAPD Peritonitis As in non-diabetics, peritonitis in diabetics is caused predominantly by skin flora such as Staphylococcus epidermidis, Staph. aureus and Streptococcus viridans, gram-negative enteric organisms, and, rarely, anaerobic organisms. A few peritonitis episodes are caused by fungi. The pathogenesis and clinical presentation, and the spectrum of peritonitis in diabetics on CAPO does not differ from that seen in the non-diabetic (Slingeneyer et ai, 1981;
DIALYSIS
831
Thomson et aI, 1981; Madden et aI, 1982; Rottembourg et aI, 1983; Williams and the University of Toronto Collaboratory Dialysis Group, 1983; Flynn, 1983; Grcfbcrg, 1983; Khanna et aI, 1985). Treatment for peritonitis is the same in both groups. Owing to the enhanced and rapid absorption of glucose during peritonitis, hyperglycaemia is frequent in diabetics, and insulin requirements increase. Some may need intravenous infusion of insulin for the control of blood glucose. Rapid glucose absorption may provoke fluid retention, and these patients may require additional dialysis. Because of increased protein losses during peritonitis, the patient's nutrition must be watched closely during the acute phase and some may require parenteral nutrition. Generally the outcome of treatment is good. Most patients continue on CAPO after the peritonitis is cured. A small percentage (2-5%) will drop out of the CAPO programme for a variety of reasons. Some fail only after one or two episodes of peritonitis, while others fail because of the severity of peritonitis. Complications other than peritonitis during CAPD
Hernias and dialysate leakage Complications that are a direct result of increased intra-abdominal pressure 'such as dialysate leaks, hernia, haemorrhoids and compromised cardiopulmonary function occur with the same frequency in diabetics and non-diabetics. Because of delayed wound healing, dialysate leakage is more frequent in diabetics during the first dialysis after catheter insertion. To minimize this risk the catheter should be implanted through a lateral approach and dialysis should be postponed for 24-48 h.
Protein losses and malnutrition Losses of protein, amino acids, polypeptides and vitamins in the dialysate contribute to malnutrition and slow rehabilitation. Such losses pose a special problem in diabetics who may be malnourished already because of poor food intake, vomiting, catabolic stresses and intercurrent illness. Twenty-four-hour amino acid losses in the dialysate average 2.25 g/day with about 8 glday of protein. These are small in comparison to the recommended intake of 1.1-1.3 g protein per kg body weight per day. During peritonitis, protein losses are excessive and, when accompanied by inadequate food intake due to poor appetite or weakness, may induce severe hypoproteinaemia, hypoalbuminaernia and hypoimmunoglobulinaemia. Thus, the physician should consider parenteral nutrition early in an episode of peritonitis which appears to be responding poorly.
Visual impairment There have been many reports of stabilization in vision in diabetic patients maintained on CAPO (Thomson et aI, 1981; Rottembourg et aI, 1983). Our experience (Khanna et aI, 1985) in 46 eyes of insulin dependent
832
R . KHANNA AND D . G . OREOPOULOS
diabetic CAPO patients followed for 12 months to over 25 months indicated that of the 19 eyes with good vision at initiation, three deteriorated, of the 18 eyes with impaired vision , four deteriorated , of the 12 eyes in patients on treatment for over 25 months, two eyes deteriorated. Overall, of the 46 eyes, 85% remained unchanged and 15% deteriorated. The reasons for deterioration of vision were: glaucoma, retinal detachment, epiretinal membrane, vitreous haemorrhage, choroidal vascular insufficiency, optic atrophy and cataract. Patients in whom vision docs deteriorate either have advanced proliferative retinopathy or other ophthalmological diseases. More experience in a larger number of patients is required before the effect of CAPO on visual function is accurately known.
Peripheral vascular disease and amputations Initial short-term experience with CAPO diabetics does not suggest that the rate of amputation is any different from that of haernodialysed diabetics. The combined experience of two North American centres recently reported amputations in 7.4% of 81 diabetic patients on CAPO (Khanna et ai, 1985). In a smaller population of 34 CAPO diabeticpatients amputations were reported by Mejia and Zimmerman (1985) in 3%, whereas in 37 comparable haernodialysed diabetic patients treated during the same period, amputations were needed in 10.8%. Since CAPO does not prevent vascular disease, long-term CAPO patients might be expected to develop this complication more frequently. Furthermore, exacerbation of underlying peripheral vascular disease during CAPO has been noted in a small series of patients with persistent hypotension (Brown et ai, 1981). Thus in patients on CAPO with known peripheral vascular disease , it seems wise to accept a less stringent control of blood pressure .
Gastrointestinal complications As in those on haernodialysis, patients on CAPO frequently suffer nausea and vomiting from gastroparesis, resulting in a high morbidity and malnutrition. Metoclopramide (Reglan , Maxeran) may control this cornplication . Similarly, in advanced ESRD, one may encounter episodes of diarrhoea and poor sphincter control.
Causes of death among diabetics on CAPD In most centres, the most common causes are cardio- or cerebrovascular events and infection. Contrary to expectation and unlike the experience in non-diabetics, infection does not seem to be a major cause of death in diabetics on CAPO.
Drop-out of diabetics on CAPD Despite the impressive improvement in survival, diabetics drop out of CAPO programmes at a high rate for various reasons including deaths and
DIALYSIS
833
transfers to other forms of treatment. The cumulative technique survival rate, i.e. the percentage of those remaining on CAPO is approximately 55% by the second year-which is not different from non-diabetics. In both groups, episodes of peritonitis are the main reason for transfer to other forms of treatment. Ultrafiltration failure, a relatively new entity, has not been observed among diabetics. Outcome of diabetics on CAPD The two-year cumulative survival rate is significantly better than that achieved by intermittent PO perhaps because diabetics, who tend to have significant cardiovascular disease, seem to tolerate CAPO better. Furthermore, during the past four or five years, significant improvements in peritoneal dialysis have helped to increase survival. Also we are able to manage complications more efficiently; CAPO gives better control of blood pressure than intermittent PO and has clearly reduced morbidity. The average CAPO patient with diabetes is 10 years younger, but tends to have significantly more cardiovascular disease than the non-diabetics; this may explain his shorter survival. Previously (1985) we reported that the one- and two-year cumulative survivals for insulin dependent diabetics on CAPO were 92% and 75% respectively. Non-insulin dependent diabetics had similar cumulative survival rates-90% and 75% at one and two years respectively. Several centres in North America and Europe have reported similarly encouraging one-year cumulative survivals for diabetics on CAPO. Non-insulin dependent diabetics have a comparatively poor prognosis because, as a group, they are older, usually have severe atherosclerotic heart disease, and generally have other medical problems as well. One-year cumulative survival of diabetics reported in the literature is summarized in Table 3. Mejia and Zimmerman (1985) reviewed experiences in their programme in all patients with ESRD due to diabetic nephropathy who started haemodialysis (HD) or CAPO. Patients who had any previous form of renal replacement therapy including a transplant or had a follow-up of less than one month were excluded. There were 37 HD patients and 34 CAPO patients. HD was primarily in-centre. In the CAPO group, actuarial survival was 81% at both one and three years and in the HD groups 76% and 40% at one and three years respectively. These values were significantly different between the two therapies. CAPO patients initially spent more days in the hospital for catheter placement and training but thereafter had fewer hospital days. Infections, other than peritonitis or in relation to the catheter, were more frequent in HD patients. The groups were considered comparable in respect of sex distribution, age, prevalence and duration of hypertension, and the presence of neuropathy, vascular disease, retinopathy and blindness. At the end of follow-up (24 months HD, 27 months CAPO) technique survivals (death and a transfer to another modality were considered technique failures while transplant was a loss to follow-up) were at one, two and three years for CAPO, 71, 71 and 71%, for HD patients 76,54 and 18% respectively. HD patients spent more than twice as
834
R. KHANNA AND D. G. OREOPOULOS Table 3.
One-year cumulative survival of diabetics on CAPO.
Madden et al (1982) Rottembourg et al (1983) Kurtz et al (1983) Flynn (1983) Blind diabetics Sighted diabetics Grefberg et al (1983) Khanna et a] (1983) (Type I) (Type 11) Williams and University of Toronto Collaborative Group (1983) (Type I) (Type 11) Combined report of EDTA and ERA (Wing et ai, 1983) Age 15-34 years Age 35-44 years Age 45-54 years Age 55-64 years National CAPO Registry (1986)
Year
No. of patients treated
Cumulative one-year survival (%)
1982 1983 1983
14 24 29
70 84 78
1983 1983 1983
26 12 24
92 80
1983 1983
29 8
87 82
1983 1983
60 29
92 90
1983 1983 1983 1983 1985
33 39 49
77
64
1345
64
92 80 71 78
many days in hospital per patient month when compared with CAPO patients (4.1 vs 1.8, P <: 0.01). Although this comparison is of interest the results must be interpreted with caution since it is not a prospective randomized study and an inapparent bias in selection may have been present. Although there is no great difference in short-term survival (one to three years) between diabetics and non-diabetics with ESRD on CAPO, it remains to be established whether there is any difference in long-term survival. Not many diabetic patients have been on CAPO for long periods because CAPO has only existed for five to six years. However, non-diabetics on haemodialysis and after kidney transplantation show a significantly longer survival mainly because the diabetic shows a steady progression of the underlying cardiovascular disease. In the future, when larger numbers of diabetic patients have been treated for a longer period, there may be a similar trend with CAPO. REFERENCES Arnair P, Khanna R, Leibel B et al (1982) Continuous ambulatory peritoneal dialysis in diabetics with end stage renal disease. New England Journal of Medicine 106: 652.
DIALYSIS
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