Living Kidney Donation: How Safe Is It?

Living Kidney Donation: How Safe Is It?
R. Michael Hofmann, MD
September 13 2010

More than 85,000 individuals are on the kidney transplant waiting list, according to the United Network for Organ Sharing (UNOS). Living kidney transplantation confers a survival benefit as well as a cost savings to the Medicare system.1 Although strategies for increasing the deceased donor pool—such as the use of kidneys donated after cardiac death and kidneys from expanded criteria donors (ECDs)—have been modestly successful, they have still been unable to keep pace with the annual growth of eligible kidney transplant recipients. Therefore, the impetus for increasing sources of potential kidney donors has never been greater.

The first successful living kidney transplantation was performed between identical twins in Boston in 1954 by Joseph Murray. At that time, it was considered experimental and highly controversial to be doing a kidney transplant for end-stage renal disease (ESRD), let alone putting the life of another individual at risk by removing a kidney with no medical benefit to the donor. Fifty-six years later, living kidney donation happens at transplant centers across the nation on a daily basis for those at ESRD who are lucky enough to have a living donor willing to share the gift of life with them.

But what do we really know about the safety of living kidney donation? The short term risks of surgical complications, including mortality and morbidity, are well defined and so informing the potential donor about his risk of dying, developing a wound infection, bleeding, chronic pain, and so forth are fairly well established. However, when it comes to providing information about long-term risks to the living donor, this information is more nebulous. The dearth of safety data two, three, and four decades after kidney donation creates some uncertainty when obtaining informed consent from a young potential donor.

Perioperative Risk of Death

Perioperative risk is characterized as any death within a defined period of time after surgical donation of a kidney. Studies have defined this period anywhere from 30 days up to 90 days after donation. The risk of death due to donation has been reported from 0 per 1,000 2-3 donations up to 3.1 per 100,000 donations4. The study by Segev et al. was the largest study of donors to date and was therefore best powered to detect a difference in mortality as compared to most of the previous single-center studies. The study also noted an increased risk in males, blacks, and those with hypertension. It is interesting to note that the mortality rate did not increase despite the increasing age of the donors over the study period. In general, this is considered an acceptable rate of surgical death. This mortality rate is similar to that seen with laparoscopic cholecystectomy but with one tremendous difference: the living kidney donor receives no medical benefit.

Long Term Risk of Death

Many single-center studies have found no increased risk of death in long-term living kidney donors, and some researchers have even suggested improved overall survival of kidney donors 3,5,6. But these studies have been hampered by small size, frequent patient loss to follow up, and lack of an adequate control group to adequately study this question. Standard mortality rates for the general population are often used as a control but these rates can potentially fail to adequately control for co-morbid diseases found in the general population. In one of the largest single-center studies of living donors, there did not appear to be an increased risk of death compared with the general population even up to 40 years after donation7. However, the number of donors studied beyond 20 years after donation is limited, so it is difficult to draw long-term conclusions. This lack of long-term data has further bolstered the call for a unified national donor registry in the United States.

The Risk of Hypertension

The risk of developing hypertension (HTN) after living kidney donation is a complex issue. First, there are often subtle differences in what each center defines as HTN. Some centers have defined HTN as a systolic BP greater than 130 mm Hg 6,8, whereas others have used a systolic BP greater than 140 mm Hg as their cut off. Also, there is a high rate of donors who display white coat HTN at evaluation. Not surprisingly, the risk of developing HTN after living kidney donation has been evaluated in multiple studies with conflicting results. Saran and colleagues noted that up to 75% of their donors had developed HTN, which was significantly above the rate predicted by data from the National Health and Nutritional Examination Survey. However, the number of donors—47—was small 9. It is well known that as a person ages the elasticity of the arteries decreases. This, combined with cardiovascular calcification, is felt to be at the root of age-related HTN. Whether there is an increased risk of HTN due to the decrease in renal mass following living kidney donation as suggested by Kasiske and colleagues remains unclear.10 This makes interpreting the normal age-related risk of HTN difficult to assess versus an increased risk due to living kidney donation. Gossmann et al. found an increase in systolic pressures 11 years after living kidney donation. It is interesting to note that none of the donors were hypertensive prior to donation, but 30% were taking antihypertensive medications 11 years after donation11. However, when comparing age-matched controls they noted that there was no significant difference in BP after living kidney donation. And when Williams, et al. compared BP in living donors versus non-donor siblings—thus controlling for genetic susceptibility, they found no increased risk of hypertension after kidney donation.12

However, in a meta-analysis of 5,145 living donors, Boudville et al., found a 5 mm Hg increase in BP five to 10 years after living kidney donation.13 The researchers noted that a higher risk for developing hypertension occurred in donors older than 60 years, donors with higher pre-donation BP, African-American donors, and those with low pre-donation glomerular filtration rate (GFR). This seems like a relatively small increase in BP but it should be kept in mind that a 10 mm Hg increase in systolic pressure and a 5 mm Hg increase in diastolic pressure translate into a 1.5 fold increase risk of death from myocardial infarction and ischemic stroke.14.

With the continued shortage of living donors, some centers have begun the practice of accepting certain donors who are hypertensive prior to kidney donation.15 Although short-term results demonstrate no adverse outcomes, it remains a group where long-term data are sorely needed.

Proteinuria

Proteinuria, specifically albuminuria, is generally considered a marker of early renal disease. It often signals endothelial dysfunction within the glomerulus and is correlated with increased cardiovascular mortality risk.16 Whether this holds true for living kidney donors after donation is unclear. There is a suggestion that the proteinuria following living kidney donation may occur through a different mechanism than normally occurs in renal disease, suggesting the risk of developing progressive CKD is reduced.17 In either case, proteinuria has been noted as a long-term consequence of living kidney donation in 5%-56% of donors.3,6,9,11,12,18 In the study by Gossmann et al., there was a particularly high rate of proteinuria after living kidney donation (56%) but the number of patients with albuminuria was much lower. This suggests that their method for detecting proteinuria was extremely sensitive, leading to an unusually high rate of proteinuria after kidney donation. Similar to studies assessing the risk of hypertension, most studies looking the proteinuria following living kidney donation were small single-center studies with many donors lost to follow up and relatively homogenous donor ethnicity, which limited the applicability of the findings to all populations. In a recent large study, Ibrahim et al. found that the risk of developing proteinuria increased with time after donation and in male donors.7 Their results demonstrated microalbuminuria in 11.5% of living donors; 1.2% had macroalbuminuria. A recent meta-analysis designed to assess the risk of proteinuria after living kidney donation determined the rate of proteinuria to be 12% at an average of seven years post donation.17 Therefore, it appears the true incidence is close to the findings of the two aforementioned studies.

Changes in Renal Function

After surgical donation of a kidney, the remaining kidney hypertrophies and increases single-nephron GFR to compensate for the decrease in nephron mass. After kidney donation, there is a significant drop in GFR with the loss of one kidney. A meta-analysis showed that there is an average 26 mL/min/1.73 m2 decrease in GFR.17 In cases of renal disease, renal hyperfiltration contributes to the progression of CKD. Whether this process is deleterious to the remaining kidney following living kidney donation is unclear. This is often difficult to interpret given the variable ages of the donors at the time of donation. It is well known that GFR declines with advancing age and whether living kidney donation hastens that process remains unclear. A recent study has suggested that decline in renal function may accelerate with increasing age.19 Other studies, however, suggest that the decline in GFR reflects only the normal decline in renal function associated with the ageing process.5 In a similar study, Gossmann et al. noted a drop in estimated GFR from 92 to 71 mL/min/1.73 m2 over an average of 12 year after donation.11 The study found no correlation with the drop in GFR and time after donation, but showed that the largest declines in GFR were associated with the highest GFRs prior to donation. This suggests that the rate of decline mirrors the age-related decline in GFR. In the study by Ibrahim et al., the average GFR was 76% of the pre-donation GFR. In addition, 85.5% of donors had an iohexol-measured GFR greater than 60 mL/min/1.73 m2. 7 No donor had a GFR below 30 mL/min and the average rate of decline was calculated to be 0.49 mL/min annually. Although living kidney donation does not appear to cause an accelerated decline in GFR, it should be noted that these studies focused on primarily homogenous Caucasian populations, so their applicability to other races is unknown. There is a current concern that outcomes may be significantly worse after living kidney donation in African-American donors.20

Risk of ESRD

The risk of developing ESRD after living kidney donation does not appear to be worse than the general population, supporting the notion that living kidney donation is safe. This is controversial, however. According to the current literature, the risk of developing ESRD after living kidney donation ranges from 0.1% - 1.1%. 21,22 Most studies, however, were not sufficiently powered to provide an accurate assessment of risk. The study by Ibrahim et al. found that the ESRD rate among living kidney donors was 180 per 1 million people, which compares favorably to the national rate of 268 per 1 million. However, individuals have to undergo rigorous screening to become donors, raising the question of whether the general population is an adequate control group for comparison.

Changing Demographics

Although living kidney donation is considered relatively safe, long-term risks of living kidney donation remain unclear. Even more concerning is the slow shift in demographics of the average living donor. The average age of living donors has increased with time. In 1998, 13.9% of donors were aged 50 years or older compared with 22.8% in 2008.4 In addition, obesity within the donor population has also increased. In 2000, 17% of donors were obese; this percentage rose to 21% in 2007.23 In addition, some centers now accept select patients with hypertension for living kidney donation. In fact, in a recent review of kidney donors, up to 24% were found to be medically complex, which was defined as obese (BMI greater than 30 kg/m2), hypertensive, or having a GFR less than 60 mL/min /1.73 m2. 24 The increasing demand for living donors to fill the void between new potential kidney recipients and deceased kidney donors has caused more transplant centers to consider living donors with isolated medical abnormalities (IMA) as potential donors. These are people who would likely have been turned down as living donors one or two decades ago. However, long-term outcome data for donors with IMAs are lacking.25 Clearly, there is a critical need for better and larger studies reviewing long-term outcomes for living kidney donors. The creation of a national database to study outcomes of living kidney donors would be a large step forward in that direction. As physicians, we all take the Hippocratic oath and pledge to first and foremost cause no harm to our patients, but in this case, do we really know?

Dr. Hofmann is Associate Professor of Nephrology at the University of Wisconsin in Madison.

REFERENCES

1. Schweitzer EJ, Wiland A, Evans, D, et al. The shrinking renal replacement therapy "break-even" point. Transplantation. 1998;66:1702-1708.

2. Mjøen G, Øyen O, Holdaas H, et al. Morbidity and mortality in 1022 consecutive living donor nephrectomies: benefits of a living donor registry. Transplantation. 2009;881273-1279.

3. Najarian JS, Chavers BM, McHugh LE, Matas AJ. 20 years or more of follow-up of living kidney donors. Lancet. 1992;340:807-810.

4. Segev DL, Muzaale AD, Caffo BS, et al. Perioperative mortality and long-term survival following live kidney donation. JAMA. 2010;303:959-966.

5. Fehrman-Ekholm I, Elinder CG, Stenbeck M, et al. Kidney donors live longer. Transplantation. 1997;64:976-978.

6. Eberhard OK, Kliem V, Offner G, et al. Assessment of long-term risks for living related kidney donors by 24-h blood pressure monitoring and testing for microalbuminuria. ClinTransplant. 1997;11(5 Pt 1):415-419.

7. Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med. 2009;360:459-469.

8. Gracida C, Espinoza R, Cedillo U, Cancino J. Kidney transplantation with living donors: nine years of follow-up of 628 living donors. Transplant Proc. 2003; 35: 946-947.

9. Saran R, Marshall SM, Madsen R, et al. Long-term follow-up of kidney donors: a longitudinal study. Nephrol Dial Transplant. 1997;12:1615-1621.

10. Kasiske BL, Ma JZ, Louis TA, Swan SK. Long-term effects of reduced renal mass in humans. Kidney Int. 1995;48:814-819.

11. Gossmann J, Wilhelm A, Kachel HG, et al. Long-term consequences of live kidney donation follow-up in 93% of living kidney donors in a single transplant center. Am J Transplant. 2005;5:2417-2424.

12. Williams SL, Oler J, Jorkasky DK. Long-term renal function in kidney donors: a comparison of donors and their siblings. Ann Intern Med. 1986;105:1-8.

13. Boudville N, Prasad GV, Knoll G, et al. Meta-analysis: risk for hypertension in living kidney donors. Ann Intern Med. 2006;145:185-196.

14. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-1913.

15. Textor SC, Taler SJ, Driscoll N, et al. Blood pressure and renal function after kidney donation from hypertensive living donors. Transplantation. 2004;78:276-282.

16. Hemmelgarn BR, Manns BJ, Lloyd A, et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010;303:423-429.

17. Garg AX, Muirhead N, Knoll G, et al. Proteinuria and reduced kidney function in living kidney donors: A systematic review, meta-analysis, and meta-regression. Kidney Int. 2006;70:1801-1810.

18. Beekman GM, van Dorp WT, van Es LA, et al. Analysis of donor selection procedure in 139 living-related kidney donors and follow-up results for donors and recipients. Nephrol Dial Transplant. 1994;9:163-168.

19. Poggio ED, Rule AD, Tanchanco R, et al. Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors. Kidney Int. 2009;75:1079-1087.

20. Nogueira JM, Weir MR, Jacobs S, et al. A study of renal outcomes in African American living kidney donors. Transplantation. 2009;88:1371-1376.

21. Pereira RB, Scheeren J, Castro D, et al. Follow-up of kidney donors who developed uremia and went on the waiting list for a transplant: should they have allocation priority? Transplant Proc. 2008;40:1012-1013.

22. Gibney EM, Parikh CR, Garg AX. Age, gender, race, and associations with kidney failure following living kidney donation. Transplant Proc. 2008;40:1337-1340.

23. Davis CL. Living kidney donors: current state of affairs. Adv Chronic Kidney Dis. 2009;16:242-249.

24. Reese PP, Feldman HI, McBride MA, et al. Substantial variation in the acceptance of medically complex live kidney donors across US renal transplant centers. Am J Transplant. 2008;8:2062-2070.

25. Young A, Storsley L, Garg AX, et al. Health outcomes for living kidney donors with isolated medical abnormalities: a systematic review. Am J Transplant. 2008; 8:1878-1890.

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