Kidney Donation, How Safe Is It? The ERA-EDTA Descartes Working Group Position

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Long-term risks of kidney living donation: review and position paper by the ERA-EDTA DESCARTES working group

Nephrology, Dialysis and Transplantation 2017, 32 (2): 216-223.

PMID: 28186535

Umberto Maggiore, Klemens Budde, Uwe Heemann, Luuk Hilbrands, Rainer Oberbauer, Gabriel C. Oniscu, Julio Pascual, Soren Schwartz Sorensen, Ondrej Viklicky and Daniel Abramowicz for the ERA-EDTA DESCARTES working group

The NephJC will be on April 11 and 12, 2017.

Previous #NephJC coverage of topic: Summary from Tom Oates 

Also see Paul Phelan's RFN post on this topic. 

Background

Patients on dialysis have a very high mortality and renal transplantation is the treatment of choice in suitable patients with end stage renal disease (ESRD). Living kidney transplantation is preferred over deceased donor transplant due to longer graft and patient survival. According to the United States Renal System (USRDS)

  • One-year post-transplant survival is
    • 96% in deceased-donor kidney transplants
    • 99% in living-donor kidney transplants
  • One-year graft survival is
    • 92% in deceased-donor kidney transplants
    • 97% in living-donor kidney transplants
  • The US Kidney transplant waiting list has over 100,000 patients
  • The average waiting time is 3.6 years for a first kidney transplant
  • Living donation comprises a third of kidney transplants

Because of the shortage of transplant organs, lengthening waitlists, and better transplant outcomes, living donation is strongly encouraged. Encouraging living donation means talking to recipients and potential donors about the risks from donating a kidney.

Unfortunately, since the literature on the risks of kidney transplant is not robust, in response the ERA and the DESCARTES working group summarized the current evidence on the long-term risks of living kidney donation in this position paper.

Does Harmful Hyperfiltration occur in Living Kidney Donors?

Half of total kidney mass is lost with a donor nephrectomy. The remaining kidney adapts to this loss, but some think that this adaptation may be maladaptive in the long run. Albuminuria, progressive renal failure, and focal segmental glomerulosclerosis are all consequences of the glomerular hypertension that follows a ⅚ nephrectomy in a rat model. However, this does not occur in humans where the 40% increase in single-kidney filtration is due to hyperperfusion and hypertrophy rather than glomerular hypertension. This was backed up by a study of living donors 3 years after nephrectomy. Renal function returns to 70-80% of the baseline due to compensatory hypertrophy and renal hyperfiltration of the remaining kidney post nephrectomy. This data is limited to retrospective studies and short term prospective studies.

Does Living Donation Increase the Risk of End Stage Kidney Disease?

Early studies that looked into the risk of ESKD following kidney donation compared donors with their non-donating siblings, did not find an increased risk of ESRD after 10-20 years of follow up. Table 1 shows two recent matched cohort studies that questioned this orthodoxy. In spite of the increase in the relative risk of ESRD by 11-fold in the Norwegian study (see #NephJC coverage of this topic here) and by 8-fold in the US study, the absolute lifetime risk of ESKD was very small, 0.5% in the Norwegian study (vs. 0.06% in controls) and 0.1% in the US study (vs. 0.04% in controls). In fact, the difference in the absolute risk between donors and controls was < 0.3% after 15 years. Some have questioned the study since the controls were not matched for some baseline risk factors like family history of kidney disease (important with 67-80% of donors being first degrees relatives of a person with ESKD).

Identifying Prospective Donors who are at Increased Long-term ESKD Risk

Predicting long-term consequences, think 30 years after nephrectomy, in young donors is difficult. During evaluation, it is essential to identify potential donors that are at increased increased risk of ESKD following nephrectomy. Risk factors include:

  • hypertension
  • obesity
  • old age
  • borderline normal or decreased GFR

Young donors with a normal pre-evaluation workup can have masked risk, since the initial manifestation of some clinical disorders (e.g. diabetes, hypertension, IgA nephropathy) may only be revealed decades after donatin. Subjects with a first degree relative with ESKD due to non-hereditary disease have a 4 fold higher risk of developing ESKD compared with individuals with no family history. Grams, et al, Found that the risk of ESKD was highest among persons in the youngest age group, particularly among young African Americans. Assessing the candidacy of young African Americans for living donation therefore is of particular importance, as a normal medical evaluation will not reduce the 7% lifetime risk for a “normal” 25-year old African American donor or the 2-3% risk for an otherwise similar Caucasian donor.

Predicting the Risk of developing ESKD in the General Healthy Population

The pre-donation, lifetime risk, for ESKD can be calculated for all donors using an online calculator, which is based on 10 demographic and clinical characteristics. This should be used to help donors to make an informed decision. The Risk of ESKD varies according to sex and race, and in a 40-year old person, the 15-year projected risk of ESKD is:

  • 0.24% among black men

  • 0.15% among black women

  • 0.06% among white men

  • 0.04% among white women

As expected, ESRD risk was shown to be higher in the presence of:

  • Lower estimated glomerular filtration rate

  • Albuminuria

  • Hypertension

  • Smoking

  • Diabetes

  • Obesity

However, the calculator has its own limitations, especially in young donors (since it is based on studies with only 4-16 years of follow-up). Additionally it's does not take into account family history of kidney disease.

The Effect of Nephrectomy on Long-term Risk of Death

Nephrectomy increases the risk of cardiovascular mortality and all cause mortality by 30-40% in a Norwegian study with fifteen years of follow up. Table 2 shows some plausible mechanisms to explain this finding. Post nephrectomy there is no increase in the risk of acute kidney injury or cardiovascular events, but minor abnormalities like elevated PTH, increased homocysteine, and increased risk of gout develop. Presently, based on current evidence, the mechanisms of the increased risk of long-term death following nephrectomy remain unclear.

Table 2. Theoretical Mechanisms by which Nephrectomy might affect Long-term Mortality

Risk of Bias of the Estimated Effect of Donor Nephrectomy on Mortality

Nephrectomy had no adverse effect on survival in US Army personnel compared to controls during World War II with 45 years of follow-up. Segev et al. was unable to find an association with nephrectomy and mortality when donors were compared with healthy controls instead of the general population with 6 years of follow-up. It is likely that Mjoen et al’s finding of increased mortality risk, 20-25 years after nephrectomy is an overestimation due to the confounding effect of family history on kidney disease (80% of donors were first degree relatives of recipients). In addition to the increase in risk of ESKD in first degree relatives, the baseline risk of death also increases. Skrunes et al showed a 10% increase in the risk of death following donation in donors with family history of kidney disease. When this risk was applied to the matched controls of Mjoen study, there was an upward shift in the mortality function (depicted by the dotted line in Figure 1).

Figure 1. Observed mortality in the study by Mjoen at al in donors (red line) and controls (blue line).  Dotted blue line represents the mortality in consanguinity-matched controls.

The Effect of Nephrectomy on Adverse Pregnancy Outcomes

Women are concerned if donating a kidney will have adverse maternal or fetal outcomes. According to the European Best Practice Guidelines (EBPG), women of childbearing age willing to donate should be informed, that their risk will increase from below that of the general population to that of the general population, since they are selected from the healthiest lot. There is an absolute increase in the risk of gestational hypertension or preeclampsia from 4.8% to 11.5% in living donors post nephrectomy vs. non donors, and the risk is higher in women over 32 years compared to younger women. Thankfully, this was not associated with increased maternal mortality or adverse fetal outcomes.  

Summary

I have summarized  the salient features of the paper:

  • Even though 50% of kidney mass is lost, renal function returns to 70-80% of baseline due to renal hyperfiltration post-nephrectomy

  • Patients should be educated that the risk of nephrectomy can be counterbalanced by regular monitoring of renal function, healthy lifestyle and adequate control of  hypertension and proteinuria.

  • The 15 year risk of ESRD post-donation is 3-5 fold higher with only 0.3% increase in the absolute risk as compared to the projected risks in the absence of donation.

  • Careful evaluation should be done to predict risk of ESRD post nephrectomy in young healthy donors especially those of African American ethnicity.

  • Living donation from older donors is safe and older donors should be encouraged to donate

  • Donor nephrectomy is associated with slightly increased risk of hypertension (by 5 mm Hg of blood pressure) and proteinuria, which can be successfully managed by renin angiotensin aldosterone system blockade.

  • In women of childbearing age, nephrectomy is associated with increased risk of preeclampsia and gestational hypertension.

In summary, living donation is a relatively a safe procedure, with measurable but small risks to the donor. The long-term risks can be predicted and every effort should be made to enable the donor to make an informed decision. Future directions include designing studies to predict accurately the risk of ESRD and mortality in young donors, and determining if the lifetime risk of ESRD is reduced by current donor exclusion protocols.

The authors also provide an information sheet for live kidney donors as supplementary material

Summary by Silvi Shah