Changes in Kidney Function Follow Living Donor Nephrectomy

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Ngan N. Lam1,2, Anita Lloyd3, Krista L. Lentine4, Robert R. Quinn1,2, Pietro Ravani1,2, OPEN Brenda R. Hemmelgarn1,2, Scott Klarenbach3 and Amit X. Garg5,6,7

1Department of Medicine, Division of Nephrology, University of Calgary, Calgary, Alberta, Canada; 2Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; 3Department of Medicine, Division of Nephrology, University of Alberta, Edmonton, Alberta, Canada; 4Department of Medicine, Center for Abdominal Transplantation, Saint Louis University, St. Louis, Missouri, USA; 5Department of Medicine, Division of Nephrology, Western University, London, Ontario, Canada; 6Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada; and 7Institute for Clinical Evaluative Sciences (ICES), Ontario, Canada

A better understanding of kidney function after living donor nephrectomy and how it differs by donor characteristics can inform patient selection, counseling, and follow-up care. To evaluate this, we conducted a retrospective matched cohort study of living kidney donors in Alberta, Canada between 2002-2016, using linked healthcare administrative databases. We matched 604 donors to 2,414 healthy non-donors from the general population based on age, sex, year of cohort entry, urban residence, and the estimated glomerular filtration rate (eGFR) before cohort entry (nephrectomy date for donors and randomly assigned date for non-donors). The primary outcome was the rate of eGFR change over time (median follow-up seven years; maximum 15 years). The median age of the cohort was 43 years, 64% women, and the baseline (pre-donation) eGFR was 100 mL/min/1.73 m2. Overall, from six weeks onwards, the eGFR increased by D0.35 mL/min/1.73 m2 per year (95% confidence interval D0.21 to D0.48) in donors and significantly decreased by -0.85 mL/min/1.73 m2 per year (-0.94 to -0.75) in the matched healthy non-donors. The change in eGFR between six weeks to two years, two to five years, and over five years among donors was D1.06, D0.64, and -0.06 mL/min/1.73 m2 per year, respectively. In contrast to the steady age-related decline in kidney function in non-donors, post-donation kidney function on average initially increased by 1 mL/min/1.73 m2 per year attributable to glomerular hyperfiltration, which began to plateau by five years post-donation. Thus, the average change in eGFR over time is significantly different between donors and non-donors.

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Following donor nephrectomy, there is a 25%–40% early reduction in glomerular filtration rate (GFR), rather than a 50% reduction, due to the compensatory hyperfiltration of the remaining kidney.1–3 A systematic review of 8 studies reported that 12% of donors developed a GFR between 30 and 59 ml/min per 1.73 m2, and 0.2% had a GFR <30 ml/min per 1.73 m2 over a mean follow-up that ranged between 3 and 20 years.1 However, many studies that assessed post-donation renal function are limited by small sample sizes, lack of appropriate nondonor control groups, and significant loss to follow-up.1,4,5 Studies with more donors lost to follow-up demonstrate a larger decrement in GFR after donation.1

A prospective study with excellent follow-up reported renal function at 6 months, and 1, 2, and 3 years after donation for 182 living kidney donors and 173 non-donor controls.2 At 3 years of follow-up, the average measured GFR by plasma iohexol clearance for donors was 78 versus 104 ml/ min for non-donor controls. From months 6 to 36, the measured GFR for all donors increased at an annual rate of þ1.5 ml/min, whereas it decreased at an annual rate of –0.4 ml/min for non-donor controls. In this study, age did not affect the rate of change in measured GFR; however, this study was limited by the relatively short observation period.

A better understanding of the trends in post-donation GFR, and how this varies by donor characteristics, can inform the evaluation, selection, and counseling of living kidney donor candidates. Recognizing the risk factors associated with a greater ongoing loss of post-donation GFR may also enable physicians to identify donors who could benefit from closer monitoring and surveillance. We performed a retrospective cohort study using healthcare administrative databases in Alberta, Canada to describe the trends in post-donation GFR in living kidney donors.

RESULTS

Baseline characteristics

We matched 604 living kidney donors to 2414 healthy non-donors from the general population. The baseline characteristics for the cohort are presented in Table 1. The median age was 43 years (interquartile range [IQR], 33–51) and 64% were

ACR, albumin-creatinine ratio; eGFR, estimated glomerular filtration rate; NA, not applicable; PCR, protein-creatinine ratio.

"Standardized difference provides a measure of the difference between groups divided by pooled SD. A value of >10% is interpreted as a meaningful difference between groups. Income was categorized according to the fifths of average neighborhood income.

Cuban indicates a population >10，000 or a population >1000 with population density >400/km². dFor distance from the transplant center, >500 km was imputed as 500 km.

*Includes all visits/measurements, even if multiple visits/measurements occurred on the same day.

'Laboratory values were based on the most recent measurement (inpatient, outpatient, or emergency room) in the 1 yr before the index date.eGFR was calculated using the Chronic Kidney Disease-Epidemiology Collaboration equation. Albuminuria was defined by ACR, PCR, or urine dipstick result and categorized based on the Kidney Disease: Improving Global Outcomes definition as none/mild (A1:dipstick negative or trace, PCR <15 ma/mmol or ACR <30 ma/g), moderate (A2; dipstick 1+, PCR 15-50 mg/mmol, or ACR 30-300 mg/a）， and severe （A3; dipstick 2+， PCR 三51 mg/mmol， or ACR 301 mg/g）.- comorbid conditions were based on algorithms of diagnostic or procedural codes in the 3 VR prior to donation for which the validations are presented in Supplementary Table S1, where available,

Data are presented as median [interquartile range] or count (percent). Time of cohort entry (index date) was the nephrectomy date for donors and was randomly assigned to nondonors.

women. As expected, living kidney donors had more physician visits in the year before the index date compared to nondonors, likely related to their evaluation process (11 vs. 2). The median pre-donation estimated GFR (eGFR) was 100 Kidney International (2020) 98, 176–186 ml/min per 1.73 m2 (IQR, 88– 112), and 12% of donors had pre-existing hypertension.

The median follow-up was 6.6 years (IQR, 3.4– 10.4) for donors and 6.8 years (IQR, 3.8– 10.7) for nondonors, with a maximum follow-up of 14.7 years. By the end of study follow-up (March 31, 2017), the observed follow-up time was censored for the following reasons: 6 (1.0%) donors and 31 (1.3%) nondonors at the time of death, 0 (0%) donors, and 3 (0.1%) nondonors at the time of developing the end-stage renal disease, and 21 (3.5%) donors and 20 (0.8%) nondonors at the time they emigrated from the province. Based on the last available serum creatinine measurement, the majority of donors (60%) had an eGFR between 60 and 89 ml/min per 1.73 m2, whereas 29%, 1.7%, and 0.2% had an eGFR of 45– 59, 30–44, and 15–29 ml/min per 1.73 m2, respectively (Table 2).

Rate of change in kidney function

The 604 living kidney donors had a total of 7106 serum creatinine measurements after the index date, compared to 15,970 serum creatinine measurements for the 2414 non- donors. For both groups, most serum creatinine measurements were done in the outpatient setting (62% for donors and 76% for non-donors). From 6 weeks onward, donors had a median of 7 (IQR, 3– 11) serum creatinine measurements compared to 4 (IQR, 3–7) for nondonors during follow-up. The median time between measurements was 214 days (IQR, 133–359) for donors versus 359 days (IQR, 183– 500). The median number of measurements per year was 1.1 (IQR, 0.7– 1.6) for donors and 0.8 (IQR, 0.5– 1.2) for nondonors.

The mean eGFRs at various timepoints, for donors and nondonors, are presented in Figure 1, whereas the median eGFR values are presented in Supplementary Table S2. Overall, the eGFR on average increased by þ0.35 ml/min per 1.73 m2 per year (95% confidence interval [CI], þ0.21 to þ0.48) in donors and decreased by –0.85 ml/min/1.73 m2 per year (95% CI, –0.94 to –0.75) in non-donors (P < 0.001; Table 3). Based on the linear spline model, the average change in eGFR between 6 weeks to <2 years, 2 to <5 years, and $5 years onward in donors was þ1.06 (95% CI, þ0.41 to þ1.72), þ0.64 (95% CI, þ0.30 to þ0.98), and –0.06 (95% CI, –0.31 to þ0.19) ml/min per 1.73 m2 per year, respectively. Among nondonors, the rate of change in eGFR during these periods did not differ substantially and remained consistently negative over time (Table 3).

Table 2| eGFR (ml/min per 1.73 m2) category for donors and matched non-donor controls based on the last available measurement