Education and debate

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.

	Risk factors for diabetes

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).

	Risk factors for development of 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

View larger version (103K): [in this window] [in a new window]   Benefit to the recipient must be balanced against possible long term harm to the living related donor

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.

	Assessment of the potential living related donor

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.

	Conclusion

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.

	References

Top References

1. In: Disney APS, ed. ANZDATA report 1994. Adelaide: Australia and New Zealand Dialysis and Transplant Registry , 1994.
2. Simmons D. Epidemiology of diabetes and its complications in New Zealand. Diabetic Med 1996; 13: 371-375[Medline].
3. Disney APS. ANZDATA report 1993. Adelaide: Australia and New Zealand Dialysis and Transplant Registry , 1993.
4. Simmons D, Gatland BA, Leakehe L, Fleming C. Frequency of diabetes in family members of diabetic probands. J Intern Med 1995; 237: 315-321[Medline].
5. Seaquist ER, Goek FC, Rich S. Barbosa J. Familial clustering of diabetic kidney disease: evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989; 320: 1161-1165[Abstract].
6. McCarty D, Zimmet P. Diabetes 1994 to 2010: global estimates and projections. Melbourne: International Diabetes Institute, 1994:46.
7. Morales PA, Mitchell BD, Valdez RA, Hazuda HP, Stern MP, Haffner SM. Incidence of NIDDM and impaired glucose tolerance in hypertensive subjects: the San Antonio heart study. Diabetes 1993; 42: 154-161[Abstract].
8. Nagi DK, Knowler WC, Charles MA, Liu QZ, Hanson RL, McCance DR, et al. Early and late insulin response as predictors of NIDDM in Pima Indians with impaired glucose tolerance. Diabetologia 1995; 38: 187-192[Medline].
9. Zimmet PZ, Collins VR, Dowse GK, Knight LT. Hyperinsulinaemia in youth is a predictor of type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992; 35: 534-541[Medline].
10. McCance DR, Hanson RL, Pettitt DJ, Jacobsson LTH, Bennett PH, Bishop DT, et al. Diabetic nephropathy: a risk factor for diabetes mellitus in the offspring. Diabetologia 1995; 38: 221-226[Medline].
11. Klein R, Klein B, Moss SE. Incidence of gross proteinuria in older onset diabetes: A population perspective. Diabetes 1993; 42: 381-389[Abstract].
12. Fabre J, Balant LP, Dayer PG, Fox HM, Vernet AT. The kidney in maturity-onset diabetes mellitus: a clinical study of 510 patients. Kidney Int 1982; 21: 730-738[Medline].
13. Kunzelman CL, Knowler WC, Pettitt DJ, Bennett PH. Incidence of proteinuria in type 2 diabetes mellitus in Pima Indians. Kidney Int 1989; 35: 681-687[Medline].
14. Krolewski AS, Canessa M, Warram JH, Laffel LMB, Christlieb AR, Knowler WC, et al. Predisposition to hypertension and susceptibility to renal disease in insulin dependent diabetes mellitus. N Engl J Med 1988; 318: 140-145[Abstract].
15. Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other nephropathies. Am J Med 1982; 72: 375-380[Medline].
16. Steffes MW, Brown SM, Mauer SM. Diabetic glomerulopathy following unilateral nephrectomy in the rat. Diabetes 1978; 27: 35-41[Abstract].
17. Grossman HB, Sommerfield D, Konnak JW, Bromberg J. Long term assessment of renal function following nephrectomy for stage I renal carcinoma. Br J Urol 1994; 74: 279-282[Medline].
18. Schmitz A, Christensen CK, Christensen T, Solling K. No microalbuminuria or other adverse effects of long standing hyperfiltration in humans with one kidney. Am J Kidney Dis 1989; 13: 131-136[Medline].
19. Nielson FS, Gall M, Parving HH. Acquired oligonephropathy and diabetic nephropathy. Am J Kidney Dis 1995; 26: 893-903.
20. Sampson MJ, Drury PL. Development of nephropathy in diabetic patients with a single kidney. Diabetic Med 1990; 7: 258-260[Medline].
21. Bernstein J. The morphogenesis of renal parenchymal maldevelopment (renal dysplasia). Pediatr Clin North Am 1971; 18: 395-400[Medline].
22. Meneilly GS, Tessier D. Diabetes in the elderly. Diabetic Med 1995; 12: 949-960[Medline].
23. Simmons D, Williams DRR. Diabetes in the elderly: an under-diagnosed condition. Diabetic Med 1993; 10: 264-266[Medline].
24. Ali Z, Alexis SD. Occurrence of diabetes mellitus after gestational diabetes mellitus in Trinidad. Diabetes Care 1990; 13: 527-529[Abstract].
25. O'Sullivan JB. Subsequent morbidity among gestational diabetic women. In: Sutherland HW, Stowers JM, eds. Carbohydrate metabolism in pregnancy and the newborn. Edinburgh: Churchill Livingstone, 1984:174-80.
26. Harris MI. Impaired glucose tolerance-prevalence and conversion to NIDDM. Diabetic Med 1996; 13(suppl 2): S9-11[Medline].
27. Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Erikkson J, et al. Concordance for type 1 (insulin dependent) and type 2 (non-insulin dependent) diabetes mellitus in a population based cohort of twins in Finland. Diabetologia 1992; 36: 1060-1067.
28. Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinaemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990; 113: 909-915.
29. Riley WJ, MacLaren NK, Krischer J, Spillar RP, Silverstein JH, Schak DA, et al. A prospective study of the development of diabetes in relatives of patients with insulin dependent diabetes. N Engl J Med 1990; 323: 1167-1172[Abstract].
30. Lorenzon T, Pociot F, Hougaard P, Nerup J. Long term risk of IDDM in first-degree relatives of patients with IDDM. Diabetologia 1994; 37: 321-327[Medline].

(Accepted 29 July 1997)