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BMJ 1998;316:846-848 ( 14 March )

 

Education and debate

Personal paper

Risk of diabetic nephropathy in potential living related kidney donors

D Simmons, senior lecturer in medicine,  M Searle, renal physician. 

University of Auckland, Middlemore Hospital, Private Bag 93 311, Auckland 6, New Zealand

Correspondence to: Dr Simmons

Diabetic nephropathy is the leading cause of end stage renal failure in New Zealand.¹ Cadaveric organs are in short supply here, as elsewhere, and we need to consider living related donation. Kidneys from living related donors also provide a better graft and improved survival of transplant patients. However, donors from ethnic groups who have a high incidence of end stage renal failure because of diabetes and glomerulonephritis are also at increased risk of developing diabetes.² This risk is compounded by environmental factors such as obesity. In New Zealand the ethics of living related donation within the diabetic family are being questioned.

Renal transplantation is preferred to dialysis in diabetic patients who are fit enough for surgery. It is associated with an improved quality of life, lower morbidity and mortality, reduced long term costs, and greater incremental benefit in diabetic patients compared with patients without diabetes.³ The main reason for not transplanting kidneys into suitable candidates is the low availability of compatible organs for transplantation. Some ethnic groups object to donating body parts after death for cultural and spiritual reasons. The resulting underrepresentation of these ethnic groups in the donor pool further reduces the likelihood that patients with end stage renal failure from these ethnic groups will receive an organ. Organ donation from living relatives is therefore particularly encouraged in these groups.

Diabetes and the development of nephropathy once diabetes has occurred are familial and cluster in families. ^{4 5} It is therefore important to be able to advise a potential donor of his or her personal risk of developing end stage renal failure.

Apart from a few rare cases in patients with impaired glucose tolerance, development of clinical diabetes precedes the onset of diabetic nephropathy. Undiagnosed diabetes may already be present, but if it is not there are four major predictors of future diabetesethnic group, previous gestational diabetes, a high titre of islet cell antibody (for insulin dependent diabetes mellitus), and impaired glucose tolerance (table). The underlying prevalence of diabetes is a major determinant of risk for both impaired glucose tolerance and gestational diabetes. In those aged 30-64 years, the prevalence of non-insulin dependent diabetes varies from 1% to 50% between ethnic groups.⁶ The prevalence also varies within the same ethnic group in different geographical locations.⁶ The risk of diabetes in terms of familial relationship and type of diabetes in different ethnic groups is shown in the table.

Prospective studies have shown that other components of the metabolic syndrome are risk factors for developing diabetes. In the eight year follow up of the middle aged cohort of the San Antonio heart study, 34% of hypertensive people and 30% of overweight subjects went on to develop non-insulin dependent diabetes mellitus or impaired glucose tolerance (compared with 15% of people without hypertension and 10% of those with a normal weight).⁷ Other risk factors for the development of non-insulin dependent diabetes include the degree of fasting hyperglycaemia and hyperinsulinaemia after an oral glucose load. ^{8 9}

Among Pima Indians, a family history of diabetic nephropathy is itself a risk factor for the development of diabetes.¹⁰ The risk of developing non-insulin dependent diabetes mellitus is three times greater where both parents have diabetes and one has renal disease than where both parents are diabetic but neither has kidney disease. If this applies to other ethnic groups, the people who are most likely to be asked to give kidneys may be those with the highest chance of developing diabetes (and possibly nephropathy).

Only a proportion of people with diabetes progress to nephropathy and then to end stage renal failure. Many of the modifiable risk factors for diabetic nephropathy depend upon the quality of health care and self care (for example, blood pressure, glycaemia, smoking, and obesity).¹¹ Ethnic and familial factors are also important for determining those with diabetes who will probably develop nephropathy. While few (around 0.4%) Europeans with non-insulin dependent diabetes mellitus develop end stage renal failure,¹² overt nephropathy occurs in up to 50% of Pima Indians who have had non-insulin dependent diabetes mellitus for more than 20 years.¹³ Ethnic groups at high risk of diabetes related to end stage renal failure often have a relatively high prevalence of microalbuminuria but are not overtly diabetic, and this should be considered by any potential donor. A parental history of hypertension is associated with an increased the risk of microalbuminuria.¹⁴

The findings of the study by Seaquist et al are of particular concern.⁵ The development of nephropathy and end stage renal failure was compared in the diabetic siblings of insulin dependent diabetics with and without end stage renal failure.⁵ Although 17% of siblings of subjects without nephropathy developed albuminuria, most of the siblings of patients with diabetic nephropathy developed either albuminuria (41%) or end stage renal failure (41%).

Does having only one kidney increase the risk of nephropathy?
The final and most relevant question is whether having only one kidney increases the risk of nephropathy should diabetes develop. The few animal studies undertaken suggest that the resulting hyperfiltration is associated with increased renal morbidity. ^{15 16} Clinical studies are few. Two follow up studies of patients with either unilateral agenesis or uninephrectomy included eight patients with diabetes, two of whom experienced progression of renal disease. ^{17 18} In two studies, one of 363 patients with non-insulin dependent diabetes mellitus¹⁹ and the other of over 5000 patients with both non-insulin dependent and insulin dependent diabetes mellitus,²⁰ the proportions of albuminuric patients with reduced renal mass were 8% and 3% respectively. None of the patients without albuminuria was known to have a reduced renal mass (although these subjects were not as extensively investigated as the patients with albuminuria). Unilateral renal agenesis occurs in approximately 1/1000 births.²¹ Studies are urgently needed to investigate this issue further.

The clinical information that needs to be collected for assessment of the potential living related donor is shown in the box. Clearly, the risk of developing diabetic nephropathy in relatives of those with insulin dependent diabetes mellitus complicated by end stage renal failure incorporates a low risk of developing diabetes with a high risk of developing nephropathy should diabetes occur. The risk of diabetic nephropathy in relatives of people with end stage renal failure caused by non-insulin dependent diabetes mellitus is especially high in those with impaired glucose tolerance and previous gestational diabetes. Some ethnic groups have a very high risk of developing non-insulin dependent diabetes mellitus, but a variable risk of developing end stage renal failure, depending on ethnic group. Other risk factors, such as obesity and hypertension, may be cumulative. The final calculation will be an assessment of clinical risk rather than of a true actuarial risk.

There may be an increased risk of developing nephropathy after nephrectomy, but this has not been quantified. The issues need to be carefully discussed with potential living donors, and clinicians need to balance the immediate benefit to the intended recipient with the possible harm, some time in the future, to the potential donor.

Clin Nephrol. 1993 May;39(5):260-4.

The influence of donor age on function of renal allografts from live related donors.

Sumrani N, Daskalakis P, Miles AM, Hong JH, Sommer BG.

Department of Surgery, State University of New York Health Science Center, Brooklyn 11203.

To assess the influence of donor age on renal allograft outcome, we retrospectively analyzed all 169 consecutive cyclosporine-treated live related donor kidney transplants, of whom 40 were HLA identical siblings. All recipients were similar with respect to demographic and immunologic characteristics. Incidence of rejection episodes and graft survival rates at 1 and 5-year posttransplant were independent of donor age. Best renal function, as assessed by the mean of the lowest 3 serum creatinine concentration levels in the first 2 months posttransplant correlated positively with donor age, particularly among HLA mismatched male recipients (r = 0.4, P < 0.002). Short and intermediate term renal function was inferior, but stable in the older donor recipient group when compared to the younger cohort. Mean serum creatinine levels at 5 years in recipients of kidneys from older donors (age > 55 years) was 2.6 mg/dl compared to 1.7 and 1.9 mg/dl in recipients of kidneys from donors between the ages of 18-39 and 40-54 years, respectively (P < 0.001). In view of the universal shortage of organs and the negligible morbidity to the donors, our results should not discourage the use of kidneys from elderly (age > 55 years) donors.

Cancer Detect Prev Suppl. 1987;1:149-57.

Neoplastic consequences of transplantation and chemotherapy.

Penn I.

Department of Surgery, University of Cincinnati Medical Center, OH 45267-0558.

An increased incidence of certain neoplasms occurs in immunodeficiency states. The incidence of cancer in organ transplant patients is approximately 4%. The predominant tumors are lymphomas, carcinomas of the skin and lips, carcinomas of the vulva/perineum, in situ carcinomas of the uterine cervix, and Kaposi sarcoma (KS). Tumors appear a relatively short time after transplantation. Unusual features of the lymphomas are the high incidence of non-Hodgkin lymphomas, frequent involvement of extranodal sites, and marked predilection for the brain. Skin cancers present unusual features: predominance of squamous cell carcinomas, young age of the patients, and a high incidence of multiple tumors. Cancers of the vulva/perineum occur at a younger age than in the general population and may be preceded by condyloma acuminatum or herpes genitalis. Lymphomas, leukemias, and skin cancers are increased in nontransplant patients who receive immunosuppressive therapy for nonmalignant diseases. Second tumors that develop in cancer patients, after treatment with cytotoxic therapy, are mainly leukemias, lymphomas, and bladder carcinomas.

Int J Urol. 1998 Nov;5(6):521-5.

Malignant neoplasm in kidney transplantation.

Kishikawa H, Ichikawa Y, Yazawa K, Hanafusa T, Fukunishi T, Ebisui C, Okuyama A, Nagano S.

Department of Urology, Hyogo Prefectural Nishinomiya Hospital, Japan.

BACKGROUND: The kidney recipient is at a higher risk for cancer than is the general population, although the incidence of neoplasms in general is considered lower in Japan than in Western countries. The cause of this increased risk associated with either transplantation or geography has not yet been established. METHOD: The incidences and sites of malignant neoplasms were analyzed in 285 kidney recipients, who had been followed up for 3007 patient-years. The relationship between immunosuppressive states, the numbers of CD4-positive T lymphocytes, and the presence of malignant neoplasms was studied retrospectively. RESULTS: Eighteen malignant neoplasms were found in 17 of the 285 patients (6%). The malignancies developed in these patients an average of++ 1 26.5 months after transplantation. The incidence was only 3.9% at 10 years, increasing to 13.9% at 20 years. No difference in the time-course incidence was found between azathioprine-based and cyclosporin-based immunosuppressive regimens. The malignancies developed in the digestive organs in more than half of the patients, and were mainly in the liver, colon and rectum, and stomach, with a relatively low incidence of skin cancer and lymphoma. There was only one case of Epstein-Barr virus genome found in 5 specimens that were tested. Concerning the immunosuppressive state, CD4-positive T lymphocyte counts were not related directly with malignancies in our series. CONCLUSION: The cumulative incidence of malignancy increased markedly in the second posttransplant decade. The site of cancers in kidney recipients mirrors that of general Japanese malignancies. Our results revealed neither the cause nor predictor for malignancies in kidney transplant patients.

Adv Ren Replace Ther. 1996 Apr;3(2):147-53.

Home hemodialysis: survival, quality of life, and rehabilitation.

Oberley ET, Schatell DR.

Medical Education Institute, Madison, WI 53711, USA.

Choice of treatment modality for patients with end-stage renal disease ideally should not only increase the chances of survival but also improve quality of life and facilitate rehabilitation goals. These goals include employment, enhanced physical functioning, improved understanding of dialysis, increased control, and resumption of activities enjoyed before dialysis. Home hemodialysis has been consistently associated with improved long-term patient survival and quality of life compared with patients treated with in-center hemodialysis or peritoneal dialysis. Home hemodialysis is also well suited to rehabilitation. Home hemodialysis training programs educate patients and partners to become responsible for dialysis treatments, thus encouraging independence and permitting flexible scheduling, which promotes greater participation in exercise and employment. Further information about modality choice and rehabilitation outcomes could be obtained by systematic data collection to enable comparisons between modalities. Patients should have the opportunity to choose from among all modalities, including home hemodialysis.

Adv Ren Replace Ther. 1998 Oct;5(4):267-74.

Daily hemodialysis: dialysis for the next century.

Kjellstrand C, Ting G.

Aksys, Ltd, Lincolnshire, IL 60069, USA. ckjellstrand@aksys.com

There are currently over 150 patients receiving daily hemodialysis in over 12 centers worldwide. The experiences of over 200 daily hemodialysis patients spanning 30 years have been reviewed. The reports uniformly describe subjective and objective improvements. There are decreased symptoms during and after dialysis, improved functional status, and better quality-of-life ratings. There are improved nutritional indices, improved blood pressure with fewer blood pressure medications, and improved hematocrit with reduced transfusion or eythropoietin requirements. There also appear to be economic advantages, related to the significant reductions in the need for recombinant human erythropoietin and blood pressure medications. Early data suggest that there may be a significant decrease in days of hospitalization for very ill patients as well. This is important clinically and financially when the global costs of caring for dialysis patients are considered. Substantial issues remain before daily hemodialysis will be widely accepted. These include logistical problems (additional time for transportation, set up and disinfection), economic problems (increased supply costs or labor associated with more frequent treatments), and medical problems (deficiency syndromes and blood access). Technological improvements are close to overcoming many of the recognized problems, although additional payor education, research into deficiency syndromes, and an even greater focus on creating natural arterio-venous fistulae all need to occur before daily hemodialysis is more widely accepted. We are convinced, however, that daily dialysis will be increasingly used in the next century because it is more physiologic, makes many patients feel much better, produces better outcomes, and decreases overall cost for end-stage renal disease patients compared with current dialysis regimes.

Am J Kidney Dis. 1998 Dec;32(6 Suppl 4):S76-82.

Comment in:

Am J Kidney Dis. 1998 Dec;32(6 Suppl 4):S86-7.

Daily hemodialysis: why the renewed interest?

Pierratos A.

Humber River Regional Hospital, University of Toronto, Ontario, Canada. a.pierratos@utoronto.ca

There has been an increasing interest in new hemodialysis regimens aiming to address issues of inadequate dialysis, poor quality of life, and poor outcomes. This article reviews the current state of short daily and nocturnal hemodialysis and outlines the advantages of daily over conventional hemodialysis reviews. Furthermore, it attempts to compare these two dialysis regimens