Pre-donation Assessment of Cystatin C to Improve Prediction of Pre- and Post-Donation GFR in Potential Living Kidney Donors.

BACKGROUND AND HYPOTHESIS: 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. METHODS: We assessed the performance of CKD-EPI equations based on creatinine (eGFRcreat-2009, eGFRcreat-2021), cystatin C (eGFRCysC-2012), or both (eGFRcombined-2012, eGFRcombined-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). RESULTS: Pre-donation eGFRcombined 2012 and eGFRcombined 2021 showed the strongest associations with pre- and post-donation mGFR. Pre-donation eGFRcombined 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. CONCLUSIONS: 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.

Sleep quality, fatigue, societal participation and health-related quality of life in kidney transplant recipients: a cross-sectional and longitudinal cohort study.

BACKGROUND: Fatigue and impaired health-related quality of life (HRQoL) are common among kidney transplant recipients (KTR). We hypothesized that both may partially be attributable to poor sleep. METHODS: Cross-sectional and longitudinal data of KTR enrolled in the TransplantLines Biobank and Cohort Study were used. Sleep quality was assessed using the Pittsburgh Sleep Quality Index questionnaire. Individual strength (i.e. a composite of fatigue, concentration, motivation and physical activity), societal participation and HRQoL were assessed using validated questionnaires. RESULTS: We included 872 KTR (39% female, age 56 ± 13 years) and 335 healthy controls. In total, 33% of male KTR and 49% of female KTR reported poor sleep quality, which was higher compared with male and female healthy controls (19% and 28%, respectively, P < .001 for both). In logistic regression analyses, female sex, anxiety, active smoking, low protein intake, physically inactive lifestyle, low plasma magnesium concentration, using calcineurin inhibitors, not using mTOR inhibitors and using benzodiazepine agonists were associated with poor sleep quality. In adjusted linear regression analyses, poor sleep was strongly and independently associated with lower individual strength [standardized ß (st.ß) = 0.59, 95% confidence interval (CI) 0.45 to 0.74, P < .001], poorer societal participation (frequency: st.ß = -0.17, 95% CI -0.32 to -0.01, P = .04; restrictions: st.ß = -0.36, 95% CI -0.51 to -0.21, P < .001; satisfaction: st.ß = -0.44, 95% CI -0.59 to -0.28, P < .001) and lower HRQoL (physical: st.ß = -0.53, 95% CI -0.68 to -0.38, P < .001; mental: st.ß = -0.64, 95% CI -0.78 to -0.50, P < .001). The associations with poorer societal participation and lower HRQoL were strongly mediated by individual strength (P < .001 for all), yet the suggested direct effects of poor sleep quality on HRQoL remained significant (Pphysical = .03, Pmental = .002). Longitudinal data of 292 KTR showed that sleep quality improves after kidney transplantation in males (P < .001), but not in females (P = .9). CONCLUSIONS: Poor sleep quality is common among KTR, and may be a potential target to improve fatigue, societal participation and HRQoL among KTR.

Prediction of measured GFR after living kidney donation from pre-donation parameters.

BACKGROUND: 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. METHODS: 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 <90 mL/min/1.73 m2, a declining 5-year post-donation mGFR slope or age >65 years) and validated in internal (n = 509) and external (Mayo Clinic, n = 1087) cohorts. RESULTS: 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 <55 mL/min/1.73 m2. 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 <90 mL/min/1.73 m2 [bias 0.35 mL/min/1.73 m2 (IQR 10)], in donors with a negative post-donation mGFR slope [bias 4.75 mL/min/1.73 m2 (IQR 13)] and in donors >65 years of age [bias 0.003 mL/min/1.73 m2 (IQR 9)]. CONCLUSIONS: We developed a novel post-donation mGFR prediction model based on pre-donation serum creatinine, age and sex.

Early increase in single-kidney glomerular filtration rate after living kidney donation predicts long-term kidney function.

Single-kidney glomerular filtration rate (GFR) increases after living kidney donation due to compensatory hyperfiltration and structural changes. The implications of inter-individual variability in this increase in single-kidney GFR are unknown. Here, we aimed to identify determinants of the increase in single-kidney GFR at three-month postdonation, and to investigate its relationship with long-term kidney function. In a cohort study in 1024 donors, we found considerable inter-individual variability of the early increase in remaining single-kidney estimated GFR (eGFR) (median [25th-75th percentile]) 12 [8-18] mL/min/1.73m2. Predonation eGFR, age, and cortical kidney volume measured by CT were the main determinants of the early postdonation increase in single-kidney eGFR. Individuals with a stronger early increase in single-kidney eGFR had a significantly higher five-year postdonation eGFR, independent of predonation eGFR and age. Addition of the postdonation increase in single-kidney eGFR to a model including predonation eGFR and age significantly improved prediction of a five-year postdonation eGFR under 50 mL/min/1.73m2. Results at ten-year follow-up were comparable, while accounting for left-right differences in kidney volume did not materially change the results. Internal validation using 125I-iothalamate-based measured GFR in 529 donors and external validation using eGFR data in 647 donors yielded highly similar results. Thus, individuals with a more pronounced increase in single-kidney GFR had better long-term kidney function, independent of predonation GFR and age. Hence, the early postdonation increase in single-kidney GFR, considered indicative for kidney reserve capacity, may have additional value to eGFR and age to personalize follow-up intensity after living kidney donation.

Age-adapted percentiles of measured glomerular filtration in healthy individuals: extrapolation to living kidney donors over 65 years.

OBJECTIVES: Most data on glomerular filtration rate (GFR) originate from subjects <65 years old, complicating decision-making in elderly living kidney donors. In this retrospective multi-center study, we calculated percentiles of measured GFR (mGFR) in donors <65 years old and extrapolated these to donors ≥65 years old. METHODS: mGFR percentiles were calculated from a development cohort of French/Belgian living kidney donors <65 years (n=1,983), using quantiles modeled as cubic splines (two linear parts joining at 40 years). Percentiles were extrapolated and validated in an internal cohort of donors ≥65 years (n=147, France) and external cohort of donors and healthy subjects ≥65 years (n=329, Germany, Sweden, Norway, France, The Netherlands) by calculating percentages within the extrapolated 5th-95th percentile (P5-P95). RESULTS: Individuals in the development cohort had a higher mGFR (99.9 ± 16.4 vs. 86.4 ± 14 and 82.7 ± 15.5 mL/min/1.73 m2) compared to the individuals in the validation cohorts. In the internal validation cohort, none (0%) had mGFR below the extrapolated P5, 12 (8.2%) above P95 and 135 (91.8%) between P5-P95. In the external validation cohort, five subjects had mGFR below the extrapolated P5 (1.5%), 25 above P95 (7.6%) and 299 (90.9%) between P5-P95. CONCLUSIONS: We demonstrate that extrapolation of mGFR from younger donors is possible and might aid with decision-making in elderly donors.

Urinary sulfate excretion and risk of late graft failure in renal transplant recipients - a prospective cohort study.

Hydrogen sulfide (H2 S), produced from metabolism of dietary sulfur-containing amino acids, is allegedly a renoprotective compound. Twenty-four-hour urinary sulfate excretion (USE) may reflect H2 S bioavailability. We aimed to investigate the association of USE with graft failure in a large prospective cohort of renal transplant recipients (RTR). We included 704 stable RTR, recruited at least 1 year after transplantation. We applied log-rank testing and Cox regression analyses to study association of USE, measured from baseline 24 h urine samples, with graft failure. Median age was 55 [45-63] years (57% male, eGFR was 45 ± 19 ml/min/1.73 m2 ). Median USE was 17.1 [13.1-21.1] mmol/24 h. Over median follow-up of 5.3 [4.5-6.0] years, 84 RTR experienced graft failure. RTR in the lowest sex-specific tertile of USE experienced a higher rate of graft failure during follow-up than RTR in the middle and highest sex-specific tertiles (18%, 13%, and 5%, respectively, log-rank P < 0.001). In Cox regression analyses, USE was inversely associated with graft failure [HR per 10 mmol/24 h: 0.37 (0.24-0.55), P < 0.001]. The association remained independent of adjustment for potential confounders, including age, sex, eGFR, proteinuria, time between transplantation and baseline, BMI, smoking, and high sensitivity C-reactive protein [HR per 10 mmol/24 h: 0.51 (0.31-0.82), P = 0.01]. In conclusion, this study demonstrates a significant inverse association of USE with graft failure in RTR, suggesting high H2 S bioavailability as a novel, potentially modifiable factor for prevention of graft failure in RTR.

CKD: A Call for an Age-Adapted Definition.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m2, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.

Clinical and neurohumoral associates of variations in plasma Na+ in the PREVEND cohort.

Plasma Na+ concentration is regulated within narrow limits. Yet, substantial interindividual differences exist even in the normal range. The determinants of these differences are not well understood. We therefore investigated the clinical and neurohumoral associates of plasma Na+. We studied 2,364 men (age: 48 ± 12 yr) and 2,710 women (age: 47 ± 12 yr) from the prospective Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort study. In the present study, we investigated the neurohumoral factors NH2-terminal prohormone of brain natriuretic peptide (NT-proBNP) and aldosterone as volume markers and copeptin as a marker for osmoregulation. Clinical associating variables of plasma Na+ were age, sex, and plasma glucose. Furthermore, plasma Na+ levels were associated with log2 copeptin (men: standardized ß = 0.18, P < 0.001; women: standardized ß = 0.17, P < 0.001), log2 NT-proBNP (men: standardized ß = 0.07, P = 0.008; women: standardized ß = 0.12, P < 0.001), and log2 aldosterone (men: standardized ß = -0.06, P = 0.005; women: standardized ß = -0.09, P < 0.001). Copeptin and NT-proBNP showed an interaction in their association with plasma Na+. Thus, our data 1) support that osmoregulation, as estimated from copeptin levels, is a main associate of plasma Na+; 2) show a consistent association with volume markers, with higher NT-proBNP and lower aldosterone in individuals with higher plasma Na+; and 3) show that the interaction between copeptin and NT-proBNP illustrates that osmoregulation and volume regulation act in concert in the regulation of plasma Na+.

Dermal tissue remodeling and non-osmotic sodium storage in kidney patients.

BACKGROUND: Excess dietary sodium is not only excreted by the kidneys, but can also be stored by non-osmotic binding with glycosaminoglycans in dermal connective tissue. Such storage has been associated with dermal inflammation and lymphangiogenesis. We aim to investigate if skin storage of sodium is increased in kidney patients and if this storage is associated with clinical parameters of sodium homeostasis and dermal tissue remodeling. METHODS: Abdominal skin tissue of 12 kidney patients (5 on hemodialysis) and 12 healthy kidney donors was obtained during surgery. Skin biopsies were processed for dermal sodium measurement by atomic absorption spectroscopy, and evaluated for CD68+ macrophages, CD3+ T-cells, collagen I, podoplanin + lymph vessels, and glycosaminoglycans by qRT-PCR and immunohistochemistry. RESULTS: Dermal sodium content of kidney patients did not differ from healthy individuals, but was inversely associated with plasma sodium values (p < 0.05). Compared to controls, kidney patients showed dermal tissue remodeling by increased CD68+ macrophages, CD3+ T-cells and Collagen I expression (all p < 0.05). Also, both N- and O-sulfation of heparan sulfate glycosaminoglycans were increased (all p < 0.05), most outspoken in hemodialysis patients. Plasma and urinary sodium associates with dermal lymph vessel number (both p < 0.05), whereas loss of eGFR, proteinuria and high systolic blood pressure associated with dermal macrophage density (all p < 0.05). CONCLUSION: Kidney patients did not show increased skin sodium storage compared to healthy individuals. Results do indicate that kidney failure associates with dermal inflammation, whereas increased sodium excretion and plasma sodium associate with dermal lymph vessel formation and loss of dermal sodium storage capacity. Trial registration The cohort is registered at clinicaltrials.gov as NCT (September 6, 2017). NCT, NCT03272841. Registered 6 September 2017-Retrospectively registered, https://clinicaltrials.gov.

Plasma ADMA, urinary ADMA excretion, and late mortality in renal transplant recipients.

Cardiovascular disease (CVD) is the leading cause of death in renal transplant recipients (RTR). Elevated plasma asymmetric dimethylarginine (pADMA), an endogenous nitric oxide synthase inhibitor produced from the turnover of methylated arginine moieties in proteins, is a risk factor for CVD and mortality. It is unknown how urinary ADMA excretion (uADMA), one of the main ADMA elimination routes, is associated with long-term survival. Furthermore, the association of pADMA and uADMA with markers for turnover of arginine-methylated proteins is unknown. We analyzed ADMA using a validated GC-MS/MS method in plasma and 24-h urine samples of 685 RTR, included ≥ 1 year after transplantation. We also analyzed urine symmetric dimethylarginine (uSDMA) using the same method. Urinary creatinine and urea excretions were used as markers for turnover of muscle protein and amino acids, respectively. We applied Cox regression analyses to study associations of pADMA, uADMA, and uSDMA with all-cause and CVD mortality. Mean pADMA was 0.61 ± 0.12 µM, uADMA was 31 ± 13 µmol/24 h, and uSDMA was 52 ± 19 µmol/24 h. Over median follow-up of 5.4 [4.9-6.1] years, 147 RTR died, of which 58 (39%) from CVD. High pADMA was associated with high all-cause mortality (HR per SD [95% CI]: 1.45 [1.26-1.67], P < 0.001), while high uADMA was associated with low all-cause and CVD mortality (HR per SD [95% CI]: 0.57 [0.47-0.69], P < 0.001, and 0.55 [0.40-0.74], P < 0.001, respectively). The associations were independent of adjustment for potential confounders. Creatinine excretion was associated with both pADMA (st. ß:- 0.21, P = 0.003) and uADMA (st. ß: 0.49, P < 0.001), and urea excretion was associated with uADMA (st. ß: 0.56, P < 0.001). Associations of uSDMA with outcomes and with creatinine excretion and urea excretion were comparable to those of uADMA. The associations of pADMA, uADMA and uSDMA with mortality were strongly affected by adjustment for creatinine excretion and urea excretion. We found for the first time that high uADMA and high uSDMA are associated with less risk of all-cause and CVD mortality. The links of uADMA and uSDMA with markers of muscle protein and amino acid turnover may serve to further understand ADMA and SDMA homeostasis and their clinical implications.

Effect of renal function on homeostasis of asymmetric dimethylarginine (ADMA): studies in donors and recipients of renal transplants.

Asymmetric dimethylarginine (ADMA) is a methylated form of arginine and an endogenous nitric oxide synthase inhibitor. Renal function decline is associated with increase of plasma ADMA in chronic kidney disease populations. It is yet unknown how isolated renal function impairment affects ADMA homeostasis in healthy humans. Here, we measured plasma concentrations and urinary excretion of ADMA using GC-MS/MS in 130 living kidney donors before and at 1.6 (1.6-1.9) months after donation. We additionally analyzed 201 stable renal transplant recipients (RTR) that were included > 1 year after transplantation, as a model for kidney disease in the context of single kidney state. We measured true glomerular filtration rate (mGFR) using 125I-iothalamate. To study enzymatic metabolism of ADMA, we also measured L-citrulline as primary metabolite. Mean age was 52 ± 10 years in donors and 54 ± 12 years in RTR. Renal function was significantly reduced from pre- to post-donation (mGFR: 104 ± 17 vs. 66 ± 10 ml/min per 1.73 m2 BSA, - 36 ± 7%, P < 0.001). Urinary ADMA excretion strongly and significantly decreased from pre- to post-donation (60.6 ± 16.0 vs. 40.5 ± 11.5 µmol/24 h, - 31.5 ± 21.5%, P < 0.001), while plasma ADMA increased only slightly (0.53 ± 0.08 vs. 0.58 ± 0.09 µM, 11.1 ± 20.1%, P < 0.001). Compared to donors post-donation, RTR had significantly worse renal function (mGFR: 49 ± 18 ml/min/1.73 m2, - 25 ± 2%, P < 0.001) and lower urinary ADMA excretion (30.9 ± 12.4 µmol/24 h, - 23.9 ± 3.4%, P < 0.001). Plasma ADMA in RTR (0.60 ± 0.11 µM) did not significantly differ from donors post-donation (2.9 ± 1.9%, P = 0.13). Plasma citrulline was inversely associated with mGFR (st. ß: - 0.23, P < 0.001), consistent with increased ADMA metabolism to citrulline with lower GFR. In both groups, the response of urinary ADMA excretion to renal function loss was much larger than that of plasma ADMA. As citrulline was associated with GFR, our data indicate that with renal function impairment, a decrease in urinary ADMA excretion does not lead to a corresponding increase in plasma ADMA, likely due to enhanced metabolism, thus allowing for lower renal excretion of ADMA.

Overweight young female kidney donors have low renal functional reserve postdonation.

Maintenance of adequate renal function after living kidney donation is important for donor outcome. Overweight donors, in particular, may have an increased risk for end-stage kidney disease (ESKD), and young female donors have an increased preeclampsia risk. Both of these risks may be associated with low postdonation renal functional reserve (RFR). Because we previously found that higher body mass index (BMI) was associated with lower postdonation RFR, we now studied the relationship between BMI and RFR in young female donors. RFR, the rise in glomerular filtration rate (GFR) (125I-iothalamate clearance) during dopamine, was measured in female donors (<45 yr) before and after kidney donation. Donors who are overweight (BMI >25) and nonoverweight donors were compared by Student's t-test; the association was subsequently explored with regression analysis. We included 105 female donors [age 41 (36-44) median(IQR)] with a BMI of 25 (22-27) kg/m2. Predonation GFR was 118 (17) ml/min [mean(SD)] rising to 128 (19) ml/min during dopamine; mean RFR was 10 (10) ml/min. Postdonation GFR was 76 (13) ml/min, rising to 80 (12); RFR was 4 (6) ml/min ( P < 0.001 vs. predonation). In overweight donors, RFR was fully lost after donation (1 ml/min vs. 10 ml/min predonation, P < 0.001), and BMI was inversely associated with RFR after donation, independent of confounders (standardized ß 0.37, P = 0.02). Reduced RFR might associate with the risk of preeclampsia and ESKD in kidney donors. Prospective studies should explore whether RFR is related to preeclampsia and whether BMI reduction before conception is of benefit to overweight female kidney donors during and after pregnancy.

Renal functional reserve capacity before and after living kidney donation.

Compensatory gomerular filtration rate (GFR) increase after kidney donation results in a GFR above 50% of the predonation value. The renal functional reserve (RFR) assessed by the renal response to dopamine infusion (RFRdopa) is considered to reflect functional reserve capacity and is thought to be a tool for living donor screening. However, it is unknown if the RFRdopa predicts long-term kidney function. Between 1984 and 2017, we prospectively measured GFR (125I-iothalamate) and RFR by dopamine infusion in 937 living kidney donors. We performed linear regression analysis of predonation RFRdopa and postdonation GFR. In donors with 5-yr follow-up after donation we assessed the association with long-term GFR. Mean donor age was 52 yr (SD 11); 52% were female. Mean predonation GFR was 114 ml/min (SD 22), GFRdopa was 124 ml/min (SD 24), resulting in an RFR of 9 ml/min (SD 10). Three months postdonation, GFR was 72 ml/min (SD 15) and GFRdopa was 75 ml/min (SD 15), indicating that donors still had RFRdopa [3 ml/min (SD 6), P < 0.001]. Predonation RFRdopa was not associated with predonation GFR [standardized (st.) ß -0.009, P = 0.77] but was positively associated with GFR 3 mo after donation (st. ß 0.12, P < 0.001). In the subgroup of donors with 5-yr follow-up data ( n = 383), RFRdopa was not associated with GFR at 5 yr postdonation (st. ß 0.05, P = 0.35). In conclusion, RFRdopa is a predictor of short-term GFR after living kidney donation but not of long-term kidney function. Therefore, measurement of the RFRdopa is not a useful tool for donor screening. Studies investigating long-term renal adaptation are warranted to study the effects of living kidney donation and improve donor screening.

Tubular maximum phosphate reabsorption capacity in living kidney donors is independently associated with one-year recipient GFR.

The donor glomerular filtration rate (GFR) measured before kidney donation is a strong determinant of recipient graft outcome. No tubular function markers have been identified that can similarly be used in donors to predict recipient outcomes. In the present study we investigated whether the pre-donation tubular maximum reabsorption capacity of phosphate (TmP-GFR), which may be considered a functional tubular marker in healthy kidney donors, is associated with recipient GFR at 1 yr after transplantation, a key determinant of long-term outcome. We calculated the pre-donation TmP-GFR from serum and 24-h urine phosphate and creatinine levels in 165 kidney donors, and recipient 125I-iothalamate GFR and eGFR (CKD-EPI) at 12 mo after transplantation. Kidney donors were 51 ± 10 yr old, 47% were men, and mean GFR was 118 ± 26 ml/min. The donor TmP-GFR was associated with recipient GFR 12 mo after transplantation (GFR 6.0 ml/min lower per 1 mg/dl decrement of TmP-GFR), which persisted after multivariable adjustment for donor age, sex, pre-donation GFR, and blood pressure and other potential confounders. Results were highly similar when eGFR at 12 mo was taken as the outcome. Tubular damage markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were low and not associated with recipient GFR. A lower donor TmP-GFR before donation, which may be considered to represent a functional measure of tubular phosphate reabsorption capacity, is independently associated with a lower recipient GFR 1 yr after transplantation. These data are the first to link donor tubular phosphate reabsorption with recipient GFR post-transplantation.

Estimated glomerular filtration rate for longitudinal follow-up of living kidney donors.

Background: Living kidney donor safety requires reliable long-term follow-up of renal function after donation. The current study aimed to define the precision and accuracy of post-donation estimated glomerular filtration rate (eGFR) slopes compared with measured GFR (mGFR) slopes. Methods: In 349 donors (age 51 ± 10, 54% female), we analysed eGFR according to the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault/body surface area (CG/BSA), creatinine clearance (CrCl) and mGFR (125I-iothalamate) changes from 3 months until 5 years post-donation. Results: Donors had a pre-donation mGFR of 116 ± 23 mL/min, at 3 months post-donation mGFR was 73 ± 14 mL/min and at 5 years it was 79 ± 16 mL/min. Between 3 months and 5 years post-donation, 28% of donors had a declining mGFR (-0.82 ± 0.79 mL/min/year), 47% were stable and 25% had an increasing mGFR. Overall, eGFR equations showed good slope estimates (bias eGFRCKD-EPI 0.13 ± 2.16 mL/min/year, eGFRMDRD 0.19 ± 2.10 mL/min/year, eGFRCG/BSA -0.08 ± 2.06 mL/min/year, CrCl -0.12 ± 4.75 mL/min/year), but in donors with a decreasing mGFR the slope was underestimated (bias eGFRCKD-EPI 1.41 ± 2.03 mL/min/year, eGFRMDRD 1.51 ± 1.96 mL/min/year, eGFRCG/BSA 1.20 ± 1.87 mL/min/year). The CrCl had a high imprecision [bias interquartile range -1.51-3.41 mL/min/year]. Conclusions: All eGFR equations underestimated GFR slopes in donors with a declining GFR between 3 months and 5 years post-donation. This study underlines the value of mGFR in the follow-up of donors with risk of progressive GFR loss.

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients.

Iron deficiency (ID) is independently associated with an increased risk of death in renal transplant recipients (RTRs). ID promotes production and cleavage of intact fibroblast growth factor 23 (iFGF23) into C-terminal fibroblast growth factor 23 (cFGF23), elevated levels of which are also prospectively associated with adverse outcomes. We hypothesized that in RTRs, the relationship between ID and mortality is mediated by FGF23. We measured plasma iFGF23 and cFGF23 levels in 700 stable RTRs at a median of 5.4 years after transplant. RTRs with ID had median (interquartile range) cFGF23 concentrations higher than those of RTRs without ID (223 [131-361] versus 124 [88-180] RU/ml; P<0.001), whereas iFGF23 concentrations were similar between groups. In multivariable-adjusted Cox regression analyses, ID associated with increased mortality (81 events; hazard ratio, 1.95; 95% confidence interval, 1.22 to 3.10; P<0.01). However, this association lost significance after additional adjustment for cFGF23 levels (hazard ratio, 1.45; 95% confidence interval, 0.87 to 2.51; P=0.15). In further mediation analysis, cFGF23 explained 46% of the association between ID and mortality, whereas iFGF23 did not mediate this association. In conclusion, we found that cFGF23 levels are increased in iron-deficient RTRs and that the underlying biologic process driving production and cleavage of iFGF23, or alternatively the increased level of cFGF23 fragments, probably is an important mediator of the association between ID and mortality. Our results underline the strong relationship between iron and FGF23 physiology, and provide a potential mechanism explaining the relationship between ID and adverse outcome in RTRs.

Central Body Fat Distribution and Kidney Function after Living Kidney Donation.

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.