Risk of kidney disease after living kidney donation

Abstract

Living donor kidney transplantation benefits the recipient. However, kidney failure can occur in a small fraction of donors — the risk is not uniform but varies according to donor characteristics. Studies to date have failed to match on important factors, such as era, environment or family history. Long-term studies with well-matched healthy controls are therefore needed.

The best available treatment for kidney failure is transplantation from a living donor, but long-term kidney health in the donor remains a concern. The current chronic kidney disease (CKD) classification was developed to define stages of kidney dysfunction owing to kidney-specific or systemic disease, and this limitation is crucial to the discussion of kidney disease after donation. In the general population, even modest reductions in glomerular filtration rate (GFR) associate with an increased risk of cardiovascular disease, mortality and kidney failure. However, this CKD classification might not be applicable to kidney donors who lose 50% of GFR owing to nephrectomy in the absence of a kidney or systemic disease. Within 6 weeks of donation, the remaining kidney compensates for the loss in filtration capacity and the measured GFR (mGFR) returns to ~70% of baseline. For a donor with a baseline GFR of 80 ml/min/1.73 m², the post-donation GFR would be ~56 ml/min/1.73 m², which would meet the definition criteria for CKD stage 3a. Unfortunately, since laboratories automatically provide an estimated GFR (eGFR) when reporting a serum creatinine level, many donors are subsequently told that they have CKD, leading to considerable stress and panicked calls to the transplant centre.

Studies that compared donors with individuals from the general population matched for age, gender and ethnicity found no differences in long-term kidney outcomes. By contrast, studies that compared donors with health-matched controls have raised concerns. In a prospective study, Kasiske et al. compared 205 donors with 203 controls without medical conditions that would preclude donation; of these, 136 donors and 114 controls were followed-up for 9 years¹. Between 6 months and 9 years, mGFR increased slightly in the donors but decreased in the controls. Blood pressure, urinary protein or albumin, glucose, haemoglobin A1c, lipoproteins or carotid-femoral pulse wave velocity did not differ between the groups. However, donors had higher levels of parathyroid hormone, homocysteine and uric acid than controls. Their small arteries were also less elastic by radial artery applanation tonometry, suggesting endothelial dysfunction and increased cardiovascular risk. Two retrospective studies that compared donors with controls, also selected on good health, reported a small increased risk of kidney failure in the donors^2,3. Of note, in both studies, the incidence of kidney failure among donors was small — 9 of 1,901 donors in one study and 99 of 96,217 in the other — and the donors were from different eras and environments than the controls. The groups were also not matched on key risk factors for kidney disease allowed in donors, including a family history of kidney failure. In the first study, all 9 donors who developed kidney failure were first degree relatives of the recipients; in the second study, 83 of 99 donors with kidney failure were related to the recipient. Importantly, a family history of kidney failure is an established risk factor for developing kidney failure⁴.

One possible mechanism for an increased risk of kidney failure after donation is that the post-donation decrease in renal reserve experienced by kidney donors might accelerate the development of kidney failure as their GFR progressively decreases owing to ageing and age-related comorbidities, such as type 2 diabetes mellitus and hypertension. Of note, in the USA, similarly to the general population, the two most common causes of kidney failure after donation are the presence of diabetes mellitus and hypertension⁵. A second possibility might be that the functional compensation in the remaining kidney, although initially beneficial, might subsequently lead to kidney dysfunction owing to sustained glomerular hyperfiltration. Accordingly, Kasiske et al. found that, over 9 years, donor mGFR increased¹; others have reported increases in eGFR after more than 15 years post-donation⁶. However, an excessive rate of any kidney diseases thought to be associated with glomerular hyperfiltration, such as focal segmental glomerulosclerosis, has not been reported among kidney donors. A third, and most likely, explanation for donor kidney failure was suggested by a study that reported that eGFR remained stable until the development of new-onset disease in patients who developed post-donation kidney failure⁷. Therefore, rather than harm from glomerular hyperfiltration, donors might simply progress sooner to kidney failure than non-donors with any new-onset disease owing to their lower baseline kidney function with one kidney.

Research suggests that not all donors have the same kidney failure risk and numerous initial donor evaluation risk factors have been identified, including age, gender, ethnicity, relationship to the recipient, obesity, low GFR, smoking history, and the presence of hypertension, albuminuria or diabetes⁸,⁹. Notably, these risk factors are similar to those identified for kidney failure in the general population. Three web-based risk calculators have been developed to help counsel donor candidates on future kidney-related health risks (models and references in Supplementary Table 1) and are based on information available at the time of donor evaluation. The first calculator, which is based on a meta-analysis of healthy population studies, provides the 15-year and lifetime risk of developing kidney failure in the absence of donation. The second, which is based on US donor registry data, provides a 20-year risk of post-donation kidney failure. The third, based on single-centre data, provides the 40-year risk of post-donation low GFR, proteinuria, diabetes or hypertension. Each calculator has limitations related to the population studied, the length of follow-up and the clinical data used to develop the calculator. These calculators can be used as part of the discussion with donor candidates regarding long-term risks and can facilitate informed decision-making, although none of them provide a much-needed individualized estimate of kidney failure risk with, versus without, donation.

Donor outcome studies have provided crucial data on the long-term effects of kidney donation but they have important limitations. In addition to the small number of events in the donor and control groups, all but a few donor outcome studies are based on historical data that might not reflect current donor outcomes. For example, the definitions of hypertension and diabetes have changed over time and some donors who were approved decades ago would meet the current criteria for diagnosis of these diseases, and might thus not be eligible for donation in the current era. Moreover, until the 1990s, almost all living donors were related to the transplant recipient; follow-up of unrelated donors is therefore shorter and fewer donors have reached the age range with a high incidence of kidney failure. In the USA, only 10% of lifetime kidney failure risk is accrued by 44 years of age, whereas half is accrued after 64 years of age¹⁰. Studies with short follow-up will therefore only identify risk factors for developing kidney failure shortly after donation. Several long-term donor follow-up studies are currently ongoing and, as these populations mature, long-term donor risks will become clearer.

Importantly, although they describe donor risk, most studies do not determine the risk attributable to donation, in part because appropriate controls are lacking. A study in which donors are matched to controls that have undergone the same extensive evaluation required for kidney donation is unlikely. Rather, future studies should approximate this ideal design and include a control group from the same era and similar environment, as well as information on whether a family history of CKD or kidney failure exists, and a health assessment at the time of donation that ideally includes the measurement of blood pressure, proteinuria and GFR.

Importantly, data from observations to date support a proactive approach to donor care. Donors should be informed that donation undoubtedly causes a reduction in GFR. Moreover, for any donor, some form of subsequent kidney disease (for example, immunity-driven kidney disease) might be inevitable but unpredictable at the time of evaluation and likely to affect both kidneys. However, diseases such as diabetes and hypertension are related to lifestyle and donors should therefore be aware that being a kidney donor requires a commitment to living a healthy lifestyle, which, in combination with regular health-maintenance check-ups that screen for early kidney disease and kidney disease risk factors, can help minimize the risk of kidney failure.