Jessica van der Weijden

Background and hypothesis: A more pronounced short-term increase in single-kidney GFR (ΔskGFR) has been associated with better long-term kidney function in living kidney donors. Whether this also applies to non-donors is unknown. We evaluated whether ΔskGFR is associated with long-term risk of eGFR decline in individuals undergoing unilateral nephrectomy. Methods: This study included 1777 participants from the SCREAM cohort who underwent radical unilateral nephrectomy in Stockholm between 2006 and 2021. The ΔskGFR was calculated as the early (1–6 months) post-nephrectomy eGFR minus 50% of the pre-nephrectomy eGFR. Multivariable Cox regression was used to study the association between Δsk-GFR and the subsequent risk of progressive eGFR decline, defined as composite of an eGFR decline >30% compared to the early (6 months) post-nephrectomy eGFR or kidney failure. Results: Mean age at nephrectomy was 68 ± 11 years, 40% were female, 92% had kidney cancer, and median (IQR) pre-nephrectomy eGFR was 76 (61–89) ml/min/1.73 m2. Median Δsk-GFR was 11 (7–20) ml/min/1.73 m2. Pre-nephrectomy determinants of Δsk-GFR were age (inverse association) and pre-nephrectomy eGFR (positive association). During a median follow-up of 5 years (range 0.6–15 years), 178 participants developed progressive eGFR decline. Individuals with a Δsk-GFR above the median had a lower rate of progressive eGFR decline (adjusted HR: 0.58, 95% CI: 0.42–0.80), compared to those with a Δsk-GFR below the median, independent of baseline eGFR and age. Conclusions: A stronger increase in single-kidney eGFR early after unilateral nephrectomy was associated with a lower long-term risk of progressive eGFR decline. Evaluation of Δsk-GFR could help identify patients at higher risk of progressive kidney function decline following unilateral nephrectomy.

Accurate estimation of glomerular filtration rate (GFR) is crucial in living kidney donation. While most eGFR equations are based on plasma creatinine, its levels are strongly influenced by muscle mass. Application of cystatin C (CysC)-based estimates before donation may improve both estimation of current GFR and prediction of post-donation GFR. We assessed the performance of CKD-EPI equations based on creatinine (eGFR_creat-2009, eGFR_creat-2021), cystatin C (eGFR_CysC-2012), or both (eGFR_{combined-2012}, eGFR_{combined-2021}) for estimating pre- and post-donation measured GFR in 486 living kidney donors. We subsequently focused on a subgroup of individuals with high/low muscle mass (25% highest/lowest 24-hour urinary creatinine excretion, sex-stratified and height-indexed). Pre-donation eGFR_{combined 2012} and eGFR_{combined 2021} showed the strongest associations with pre- and post-donation mGFR. Pre-donation eGFR_{combined 2021} was most accurate for estimating both pre-donation (bias 0.01±11.9 mL/min/1.73m²) and post-donation mGFR (bias 1.3±8.5 mL/min/1.73 m²). In donors with high/low muscle mass, CysC-based equations (with or without creatinine) performed better compared to equations based on only creatinine. In conclusion, combined eGFR equations yielded a better estimate of pre- and post-donation mGFR, compared to estimates based on creatinine or CysC only. The added value of CysC seems particularly pronounced in donors with high or low muscle mass.

Background: In most screening guidelines, high body mass index (BMI) is considered a contraindication for kidney donation. New insights suggest that central body fat distribution might provide greater power in assessing kidney risk. This study aimed to determine whether BMI and central body fat distribution measures are associated with long-term kidney function after donor nephrectomy. We hypothesized that higher BMI, waist circumference (WC), and waist-to-height ratio (WHtR) were associated with lower kidney function long term after donation. Methods: The study population consisted of living kidney donors. BMI, WC, and WHtR were measured during donor screening. The outcome postdonation kidney function was assessed using measured GFR (mGFR) (mGFR, ¹²⁵ I-iothalamate infusion) at 3 months ( n =1042), 5 years ( n =556), and 10 years ( n =210) of follow-up. Primary multivariable linear regression analyses were performed with BMI and WC and secondary analyses with WHtR. Linear mixed models were performed to investigate change in postdonation eGFR. Results: The donor age was 52±11 years, and 48% were male. The mean BMI was 26.1±3.6 kg/m ² , and WC was 91±11 cm. Higher predonation BMI was associated with lower mGFR throughout follow-up: −1.35 (95% confidence interval [CI], −1.95 to −0.80), −1.55 (95% CI, −2.50 to −0.65), and −2.35 (95% CI, −4.10 to −0.60) ml/min per m ² per 5 kg/m ² higher BMI at 3 months, 5, and 10 years after donation, respectively, adjusted for sex, age, and predonation GFR. For WC, differences in mGFR were −1.30 (95% CI, −1.70 to −0.90), −1.50 (95% CI, −2.20 to −0.80), and −1.70 (95% CI, −3.00 to −0.50) ml/min per m ² per 10 cm higher WC at 3 months, 5, and 10 years after donation, respectively. In male donors, BMI and WC were significantly associated with a negative postdonation change in eGFR. Conclusions: Higher BMI and WC were independently associated with lower GFR (long term) after living kidney donation.

Background: Peritubular capillary rarefaction plays an important role in the progression of chronic kidney disease. Little is known about the relation between peritubular capillary density, glomerular volume and filtration rate in the healthy kidney. Methods: In this single-center study, we included 69 living kidney donors who donated between 2005 and 2008 and had representative renal biopsies available. In all donors, glomerular filtration rate was measured using ¹²⁵ I-Iothalamate before donation and at five years after donation. Before donation, the increase in glomerular filtration rate after dopamine stimulation was measured. Glomerular volume and peritubular capillary density were determined in biopsies taken at the time of transplantation. Pearson’s correlation coefficient and linear regression were used to assess relations between parameters. Results: Mean donor age was 52 ± 11 years and mean measured glomerular filtration rate was 119 ± 22 mL/min before donation and 82 ± 15 mL/min at five years after donation. While peritubular capillary density (measured by either number of peritubular capillaries/50,000 μm ² or number of peritubular capillaries/tubule) was not associated with measured glomerular filtration rate before or after donation, number of peritubular capillaries/tubule was associated with the increase in measured glomerular filtration rate after dopamine stimulation (St. β = 0.33, p = 0.004), and correlated positively with glomerular volume ( R = 0.24, p = 0.047). Glomerular volume was associated with unstimulated measured glomerular filtration rate before donation (St. β = 0.31, p = 0.01) and at five years (St. β = 0.30, p = 0.01) after donation, independent of age. Conclusions: In summary, peritubular capillary density was not related to unstimulated kidney function before or after kidney donation, in contrast to glomerular volume. However, number of peritubular capillaries/tubule correlated with the increase in glomerular filtration rate after dopamine stimulation in healthy kidneys, and with glomerular volume. These findings suggest that peritubular capillary density and glomerular volume differentially affect kidney function in healthy living kidney donors. Graphical

Although guidelines recommend a kidney biopsy in prospective living kidney donors with unexplained microscopic hematuria, individuals with mild hematuria are commonly allowed to donate without a biopsy. However, the prognostic implications of pre-donation hematuria are unclear. We investigated whether pre-donation microscopic hematuria is associated with changes in post-donation eGFR, proteinuria, or blood pressure. We included 701 living kidney donors with two pre-donation urinalyses and post-donation annual evaluations of the estimated glomerular filtration rate (eGFR), protein/creatinine ratio (PCR), and systolic blood pressure (SBP). The association between pre-donation microscopic hematuria and outcomes was assessed using generalized linear mixed models. The median [interquartile range] follow-up was 5 (2–8) years. Eighty-eight donors had pre-donation microscopic hematuria. There were no significant associations between microscopic hematuria at screening and the course of eGFR (0.44 mL/min/1.73 m² increase/year for hematuria donors vs. 0.34 mL/min/1.73 m² increase/year for non-hematuria donors (p = 0.65)), PCR (0.02 vs. 0.04 mg/mmol increase/year, p = 0.38), or SBP (1.42 vs. 0.92 mmHg increase/year, p = 0.17) post-donation, even after adjusting for potential confounders. Additional analyses in high-risk subgroups yielded similar results. In this study, pre-donation microscopic hematuria was not associated with post-donation eGFR decline, proteinuria, or hypertension. Microscopic hematuria may reflect primary kidney disease in only a limited subset of donors. Future studies should identify high-risk donor profiles that require further investigation.

Background: Most transplant centers in the Netherlands use estimated glomerular filtration rate (eGFR) for evaluation of potential living kidney donors. Whereas eGFR often underestimates GFR, especially in healthy donors, measured GFR (mGFR) allows more precise kidney function assessment, and therefore holds potential to increase the living donor pool. We hypothesized that mGFR-based donor screening leads to acceptance of donors with lower pre-donation eGFR than eGFR-based screening. Methods: In this longitudinal cohort study, we compared eGFR (CKD-EPI) before donation in one center using mGFR-based screening (mGFR-cohort, n = 250) with two centers using eGFR-based screening (eGFR-cohort1, n = 466 and eGFR-cohort2, n = 160). We also compared differences in eGFR at five years after donation. Results: Donor age was similar among the cohorts (mean±standard deviation (SD) mGFR-cohort 53±10 years, eGFR-cohort1 52±13 years, P = 0.16 vs. mGFR-cohort, and eGFR-cohort2 53±9 years, P = 0.61 vs. mGFR-cohort). Estimated GFR underestimated mGFR by 10±12 mL/min/1.73m² (mean±SD), with more underestimation in younger donors. In the overall cohorts, mean±SD pre-donation eGFR was lower in the mGFR-cohort (91±13 mL/min/1.73m²) than in eGFR-cohort1 (93±15 mL/min/1.73m², P2, P2, eGFR-cohort1 61±14 mL/min/1.73m², eGFR-cohort2 62±11 mL/min/1.73m², P = 0.76 and 0.95 vs. mGFR-cohort respectively). In the mGFR-cohort, 38 (22%) donors were excluded from donation due to insufficient mGFR with mean±SD mGFR of 71±9 mL/min/1.73m². Conclusions: Despite the known underestimation of mGFR by eGFR, we did not show that the routine use of mGFR in donor screening leads to inclusion of donors with a lower pre-donation eGFR. Therefore eGFR-based screening will be sufficient for the majority of the donors. Future studies should investigate whether there is a group (e.g. young donors with insufficient eGFR) that might benefit from confirmatory mGFR testing.

One of the challenges in living kidney donor screening is to estimate remaining kidney function after donation. Here we developed a new model to predict post-donation measured glomerular filtration rate (mGFR) from pre-donation serum creatinine, age and sex. In the prospective development cohort (TransplantLines, n = 511), several prediction models were constructed and tested for accuracy, precision and predictive capacity for short- and long-term post-donation ¹²⁵I-iothalamate mGFR. The model with optimal performance was further tested in specific high-risk subgroups (pre-donation eGFR 65 years) and validated in internal (n = 509) and external (Mayo Clinic, n = 1087) cohorts. In the development cohort, pre-donation estimated GFR (eGFR) was 86 ± 14 mL/min/1.73 m² and post-donation mGFR was 64 ± 11 mL/min/1.73 m². Donors with a pre-donation eGFR ≥90 mL/min/1.73 m² (present in 43%) had a mean post-donation mGFR of 69 ± 10 mL/min/1.73 m² and 5% of these donors reached an mGFR 2. A model using pre-donation serum creatinine, age and sex performed optimally, predicting mGFR with good accuracy (mean bias 2.56 mL/min/1.73 m², R² = 0.29, root mean square error = 11.61) and precision [bias interquartile range (IQR) 14 mL/min/1.73 m²] in the external validation cohort. This model also performed well in donors with pre-donation eGFR 65 years of age [bias 0.003 mL/min/1.73 m² (IQR 9)]. We developed a novel post-donation mGFR prediction model based on pre-donation serum creatinine, age and sex.