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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2001  |  Volume : 12  |  Issue : 4  |  Page : 487-493
Long-term Complications in Hemodialysis

Division of Nephrology, Department of Medicine, Northwest Kidney Centers, University of Washington, Seattle, Washington, USA

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How to cite this article:
Blagg CR. Long-term Complications in Hemodialysis. Saudi J Kidney Dis Transpl 2001;12:487-93

How to cite this URL:
Blagg CR. Long-term Complications in Hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2001 [cited 2021 Nov 30];12:487-93. Available from: https://www.sjkdt.org/text.asp?2001/12/4/487/33541
Long-term hemodialysis (HD) for chronic renal failure began in 1960 with development of the Teflon arteriovenous shunt by Scribner and co-workers at the University of Washington in Seattle. For the next twelve years, the number of patients treated by HD increased only slowly, and dialysis programs were situated mainly in university centers in the United States and elsewhere. Since then, the number of patients has steadily increased in relation to the availability of funding in various countries, and there are now more than a quarter of a million dialysis patients in the United States and more than half a million patients worldwide. At the same time, the population of patients treated has changed, so that in the United States some 40% of patients have end-stage renal disease (ESRD) due to diabetes and the average age of patients starting dialysis has risen to 64 years. As a result, patients generally suffer from more co-existent diseases, including those associated with diabetes and aging. Similar changes are occurring in many countries. [1]

The other change occurring across the world is that more HD patients are living longer. For example, the three longest surviving Seattle patients who started HD in 1963, 1965 and 1966 have all had one or more transplants, but all have been on dialysis for more than half the time since they started treatment, and all have various complications. Even in the United States, where survival of dialysis patients is relatively poor compared with that of patients in Japan, Europe and Australasia, more than twenty percent of patients are still alive after ten years on dialysis, and there are now many who have lived for twenty or more years.

Apart from the usual complications associated with diabetes and aging, the most frequent long-term complications occurring in HD patients relate to cardio­vascular disease, β2-microglobulin (β2M) amyloidosis, renal osteodystrophy and the effects of malnutrition. The role of less than adequate dialysis as one factor in the genesis of these problems is something that has become obvious in recent years.

Cardiovascular disease is the major cause of death in ESRD patients and athero­sclerosis is present in all long-term dialysis patients. Premature cardiac death has reached epidemic levels in the world's dialysis populations, occurring five to ten times as commonly as in the age-matched general population and accounting for at least half of all patient deaths. [2] Increasing numbers of dialysis patients are requiring coronary artery bypass surgery, but the post-operative mortality with this is more than three times that of patients who do not have ESRD. [3] Hypertension is a major risk factor for cardiovascular disease[4] and is often poorly controlled. Some of the other risk factors include hyper-phosphatemia and elevated calcium-phosphorus product with calcium deposition in the coronary arteries, the cardiac conduction system [5],[6],[7] heart valves [5] and vessels elsewhere, anemia, [8] hyper­triglyceridemia, [9] low HDL-cholesterol, [10] increased lipoprotein[a], [11] insulin deficiency or resistance, [12] hyper-homocysteinemia, [13] endothelial dysfunction, [14] inflammation and elevated C-reactive protein, [15] and smoking. [16] Many or all of these risk factors may have been present during the years of chronic renal insufficiency before starting dialysis.

There are a number of means to minimize the complications of cardiovascular disease by modifying the obvious risk factors such as stopping smoking, and the control of diabetes and hypertension, and perhaps of hypercholesterolemia. Management of hyper­tension is of paramount importance, [17],[18] but is often difficult to achieve unless adequate and slower dialysis is used. [19] Lowering cholesterol levels with medications, parti­cularly the LDL-cholesterol concentration, may also be helpful as this has been shown to reduce the risk of myocardial infarction in non-renal patients with coronary heart disease. [20] Lipid lowering in ESRD patients has been discussed recently in this journal. [21] Vitamin E has been suggested as a means of reducing oxidative stress and cardiovascular mortality. It can be given as an oral supplement [22] or dialyzers are available with membranes that have been modified with vitamin E. [23] An interesting ongoing study is a multicenter controlled trial of a new statin, Cerivastatin, that lowers LDL-cholesterol and may have anti­inflammatory and other effects. [24]

The importance of abnormalities of calcium and phosphorus metabolism, hyperphosphatemia and an elevated calcium phosphorus product, and the use of calcium­based phosphate binders in contributing to vascular calcification has become of interest recently. [6],[25] The new technique of electron beam computer tomography [5] should be helpful in studying the possible benefits of using low calcium dialysate, selective vitamin D analogues, calcium-free phosphate binders and other improvements in the management of bone disease and vascular disease.

The use of erythropoietin to correct anemia in dialysis patients and thus improve cardio­vascular dynamics and exercise tolerance is well recognized. [8] The question remains unresolved as to whether it is even more beneficial to normalize the hematocrit rather than to maintain it at current target levels.

The importance of hyper-homocys­teinemia is uncertain. Possible measures to reduce this include dialysis using synthetic membranes, [26] and supplementation with cofactors and substrates important in homocysteine metabolism such as folic acid, vitamins B 6 and B 12 , betaine and serine. So far, lowering homocysteine blood levels has not been shown to affect endothelial dysfunction, but because folic acid is cheap and harmless, its use might be considered. [13] If so, large doses are required because high-flux and high-efficiency dialyzers remove folic acid.

Dialysis patients with cardiac disease may need the usual measures to treat cardiac ischemia. In addition to the usual drug therapies, interventions with percutaneous transluminal coronary angioplasty, stenting or bypass surgery is indicated for many patients. These treatments have a mortality and a frequency of re-stenosis and other complications that are higher than in the general population, [3] but it is unclear how much this reflects selection of higher-risk patients and how much it may relate to the continued presence of other risk factors such as vascular calcification. [25]

β2M amyloidosis is a major cause of the physical handicaps affecting the quality of life of patients who have been on dialysis for ten or more years, and is occasionally life threatening if it results in severe cervical spinal cord compression. [27] Deposits begin to appear within a few months of starting HD, although clinical and radiological findings do not begin to appear for five years or more. Any or all joints may be affected, but especially the sternoclavicular joint and hips. Clinical features characteristically include periarthritis of the shoulders, carpal tunnel syndrome, flexor tenosynovitis of the hands, stiffness, pain and swelling of other joints, deposits beneath the skin and spondyloarthropathy. [28] Systemic deposits affecting visceral organs may occur, but rarely result in symptoms and almost always are found in patients who have been on dialysis for more than fifteen years. The pathogenesis of βM amyloidosis is complex and poorly understood. [27]

There is no specific treatment for β2M-­amyloidosis. Transplantation will lower β2M levels and may halt progression of amyloidosis and ease symptoms [29] but is not readily available to most dialysis patients. Unfortunately, no modality of dialysis can remove more β2M than is generated, although removal is greater with biocompatible membranes and with hemofiltration and hemodiafiltration. [30] The effect on EM production of using ultrapure water to prepare dialysate, thereby reducing endotoxin contamination, is also uncertain, [31] as is the role of the chronic mild metabolic acidosis in stimulating βM production. [32] As a result, the general approach to treatment in those patients expected to survive for more than five years should be renal transplantation whenever possible, and high-flux dialysis using ultrapure water for production of the dialysate.

Secondary hyperparathyroidism and the associated osteodystrophy is the other major cause of serious morbidity in long­term dialysis patients. A key factor is the increase in parathyroid hormone with time on dialysis, an increase that is significant even after adjusting for calcium and phosphorus concentrations and other factors. [33] There is now an increasing prevalence of adynamic bone disease in dialysis patients, together with the impaired handling and buffering of calcium loads that accompany this. [34] The latter is a contributory factor for extra-osseous calcification in the coronary vessels and elsewhere. [6],[7],[35],[36] Another serious cause of morbidity associated with osteo­dystrophy is the frequency of hip fractures in dialysis patients, which is many times higher than in the general population matched for age, race and sex. [37] Now, with better understanding of the management of calcium and phosphorus metabolism and availability of new phosphate binders and other drugs, it seems likely that osteo-dystrophy and complications related to calcification may be better controlled in the future.

Malnutrition is common in dialysis patients, and time on dialysis is a strong predictor of malnutrition. [38] Even in patients who are well dialyzed and have an adequate protein intake, body weight often begins to decline during the second decade of treatment. [39] While anthropometric measurements show evidence of malnutrition, serum albumin, prealbumin and apoliprotein levels remain in the normal range. The cause of this malnutrition is unclear, although it might relate to chronic mild metabolic acidosis or to reduced physical activity as a result of β2M-amyloidosis. It does not appear to relate to changes in energy expenditure. A recent large study examined the relationship between survival and nutrition and adequacy of dialysis. Survival correlated with serum albumin and prealbumin levels, but adequacy of dialysis had no effect on survival in patients who were already well dialyzed. [40] The occurrence of adynamic bone disease also appears to relate to malnutrition, but it is unclear whether this is a causal relationship or whether both conditions are characteristic of long-term HD survivors. [41] Another nutritional concern is the role that trace elements may play in dialysis patients. While reverse osmosis water treatment may prevent accumulation of most trace elements, there is evidence that zinc and selenium deficiency may occur in some patients. [42]

What else may help HD patients live a longer and better life? First, in order to improve the lot of all ESRD patients it is essential to optimize the pre-ESRD care of patients with chronic renal insufficiency. It is already recognized that strict blood pressure control [43] including treatment with ACE-inhibitors, [44],[45] protein restriction, [46] strict metabolic control in diabetic patients, [47],[48] correction of anemia [49] as well as patient compliance in following treatment recom­mendations and consulting with their physicians are all important. There are also a number of other interventions that may slow progression of renal disease, including the use of cholesterol lowering drugs, aspirin, antioxidants, various vitamins and other measures. [50] The problem is to decide which, if any, of these may be effective and prudent to use before their worth is proved by clinical trial. There is also the need to establish vascular access early, with a native arteriovenous fistula whenever possible. [51] Finally, dialysis should be started early, as this reduces the frequency of complications [52] but may or may not improve patient survival during the first few months of treatment. [52],[53]

In patients who are already on HD, adequacy of dialysis is important. However, this should not be limited only to measuring Kt/V and three times weekly dialysis. Survival is related also to both time spent on each dialysis [19] and to frequency of dialysis. The benefits of dialyzing more frequently than three times weekly include hypertension control using few if any drugs, improved hematocrit, much better freedom from dialysis-related symptoms, better appetite and nutrition, improved sexual function, fewer complications requiring hospitalization, and better quality of life. [54] This is the case whether patients are dialyzed five, six or seven times weekly for short "daily" dialysis 55 or five, six or seven nights weekly for long "nocturnal' dialysis. [55],[56] The results of this approach are sufficiently striking that it has been described as "dialysis for the next century". [57] Whether, in addition to its remarkable other benefits it will have an impact on the long­term complications that develop in HD patients awaits further studies.

Given the many and varied factors that may affect the morbidity and mortality of HD patients and the steady increase worldwide in patients with ESRD, it is clear there is a crying need for more research, and particularly for outcomes research. [58] This is the only way to establish which of the many treatment modifications that have been suggested to be of value in HD patients truly have positive effects.

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Correspondence Address:
Christopher R Blagg
Northwest Kidney Centers, 700 Broadway, Seattle WA 98122
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