Risk of graft loss: single-factor and multifactor analysis in kidney transplantation from expanded criteria donors

How to best estimate glomerular filtration rate (GFR) in kidney transplant recipients on steroid-free immunosuppression has not been established. Within 3 months of transplantation, iothalamate GFR (iGFR) was measured in 107 recipients on steroid-free and 27 on steroid-maintenance immunosuppression. A year later, a second GFR was performed. Serum creatinine was calibrated against a reference laboratory, and GFR was estimated (eGFR) using the re-expressed Cockcroft-Gault equation, eGFRCG; the Mayo Clinic equation, eGFRMC; the Modification of Diet in Renal Disease (MDRD) study equation, eGFRMDRD; and the newly introduced Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. All models overestimated GFR regardless of steroid use or timing of GFR. In those not receiving steroids, eGFRCG was least biased: 1.85 +/- 15.2 ml/min at the first GFR and 0.23 +/- 15.2 ml/min at the second. eGFRMC and eGFRCKD-EPI were most biased and were within 30% of iGFR less than 60% of the time in contrast to eGFRCG which was within 30% of iGFR 80.2% of the time. eGFRMDRD was intermediate in its performance at the first GFR but was comparable to eGFRCG at the second measurement. Importantly, the four models had comparable but poor precision. Exposure to steroids for a whole year did not appreciably alter the models' bias or relative accuracy but resulted in a dramatic fall in their precision, R2 = 0.05-0.12. GFR prediction equations overestimate measured GFR in recipients on and off steroid regimens. Long-term exposure to steroids results in a marked reduction in the precision of all models. In all, eGFRCG and eGFRMDRD are the two best available models.

Living kidney donors (LKDs) are at increased risk of chronic kidney disease, whereas transplant recipients experience progressive reduction of graft function. We examined the predictive value of quantitative stereology on renal function in LKDs and recipients of living donor kidneys, based on perioperative biopsies from the donated kidney. Cortex volume of both donor kidneys was determined by contrast-enhanced computed tomography and single-kidney glomerular filtration rate (GFR) by 51 chrome-EDTA clearance together with renography. Glomerular density was used to estimate total glomeruli number in addition to glomerular volume, glomerular sclerosis, kidney fibrosis, and arteriole dimensions. GFR measurements were repeated 1 y after transplantation in both LKDs and recipients. Associations between GFR at follow-up and cortex volume and histomorphometric parameters after adjustment of age, gender, body mass index, smoking status, 24-h blood pressure, and single-kidney GFR were examined. We included 49 LKDs (age, 51 ± 12 y) and 51 recipients (age, 44 ± 13 y). At follow-up, GFR was 71 ± 16 mL/min in LKDs and 61 ± 18 mL/min in recipients with hyperfiltration being more prominent in LKDs (30.4%) as compared to recipients (16.4%; P < 0.05). One-year GFR in donors correlated to cortex volume ( P < 0.001) but not to any histological parameters, whereas GFR in recipients correlated to the amount of interstitial fibrosis ( P < 0.01) but not to other histological parameters or cortex volume. Kidney cortex volume, but not renal histology parameters, predicts 1-y renal outcome in LKDs. In contrast, the amount of interstitial fibrosis, but not cortex volume, predicts 1-y graft function in recipients.

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.

Expanded criteria donors for kidney transplantation

Delayed graft function is a major determinant of long-term renal allograft survival. Despite considerable efforts to improve donor selection and matching, incidence of delayed graft function remains close to 25%. As neutrophil gelatinase-associated lipocalin (NGAL) has been shown to predict acute renal failure, the authors tested the hypothesis that NGAL measurement in brain-dead donors predicts delayed graft function in kidney recipients. In a prospective, multicenter, observational study, serum NGAL was measured in donors at the time of transfer to operating room. The primary endpoint was the delayed graft function, defined as the need for renal replacement therapy during the first week posttransplantation. Among 159 included brain-dead donors, 146 were analyzable leading to 243 renal transplantations. Of these, 56 (23%) needed renal replacement therapy. Donors' NGAL values were similar in case of both delayed and normal graft function in recipients. The area under the receiver-operating curve for NGAL to predict the need for renal replacement therapy before day 8 was 0.50 (95% CI, 0.42 to 0.59). The area under curve for NGAL to predict failure to return to a normal graft function at day 8 was 0.51 (95% CI, 0.44 to 0.59). Using multivariate analysis, NGAL was not associated to the need for renal replacement therapy (odds ratio, 0.99; 95% CI, 0.98 to1.00) or failure to return to a normal graft function at day 8 (odds ratio, 1.00; 95% CI, 0.99 to 1.00). NGAL measurement in brain-dead donors at the time of recovery failed to predict delayed or normal graft function in kidney recipients.

Predictive Model for the Optimal Glomerular Filtration Rate in Living Kidney Transplant Recipients

BackgroundThe transplantation of organs from expanded criteria donors (ECDs) increases the risk of delayed graft function. In our hospital, when such kidneys are transplanted quadruple treatment is used: basiliximab, mycophenolate,...

Anti-Human Leukocyte Antigen Antibodies After Islet Transplantation: What do They Really Mean?

Increased Serum Sodium Values in Brain-dead Donor's Influences Its Long-term Kidney Function

Background/Objectives: Donor kidney function measured by glomerular filtration rate (GFR) is widely used as a selection criterion in kidney transplantation (KT). This study addresses the knowledge gap regarding the relationship between donor GFR at organ procurement and graft function in deceased donor KT. Methods: We retrospectively analyzed 918 deceased donor KTs and compared donor GFRs at procurement and recipient GFRs after KT at hospital discharge and in the one-year follow-up. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was used to estimate and compare GFRs. Donor baseline GRF was defined as the last available estimated GRF prior to organ procurement. The Kaplan-Meier analysis was used to estimate recipient and graft survival. Results: The median donor GFR was 92.8 mL/min/1.73 m2, while the median recipient GFR at hospital discharge was 37.5 mL/min/1.73 m2 (-60% to donor baseline, p < 0.001), increasing to 51.4 mL/min/1.73 m2 (+37%, p < 0.001) at one-year follow-up. One-year graft and patient survival rates were 95.3% and 98.1%, respectively. Except for grafts from donors with a GFR < 15 mL/min/1.73 m2 due to acute renal failure that resulted in a significantly higher delayed graft function (DGF) rate and inferior graft survival (71.4%), no correlation was observed between baseline GFRs and DGF occurrence nor graft survival. Conclusions: Excellent results can be achieved in KT with subnormal donor GFR. The decision to refuse a kidney offer for KT should not solely be based on donor GFR. Kidneys from donors with very low GFR (<15 mL/min/1.73 m2) may be transplanted, but our observation is based on a very small sample (n = 7) and should therefore be interpreted with caution, particularly given the associated higher risk of DGF and lower graft survival.

We hypothesized that predictors of outcome in live donor transplants were likely to differ significantly from deceased donor transplants, in which cold ischaemia time, cause of donor death and other donor factors are the most important predictors. The primary aim was to explore the independent predictors of graft function in recipients of live donor kidneys (LDK). Our secondary aim was to determine which donor characteristics are the most useful predictors. A retrospective analysis was undertaken of all patients receiving live donor (n = 206) renal transplants at our institution between 31 May 1994 and 15 October 2002. Twelve patients were excluded from the analysis. Follow-up was completed on all patients until graft loss, death or 22 November 2003. We explored predictors of Nankivell glomerular filtration rate (GFR) at 6 months by multivariate linear regression. In the 194 patients studied, the mean recipient 6-month Nankivell GFR was 59 +/- 15 ml/min/1.73 m(2). Independent predictors of recipient GFR in at 6 months were donor Cockcroft-Gault GFR (CrCl; beta 0.16; CI 0.13 to 0.29; P < 0.0001), steroid resistant rejection (beta-6.07; CI -12.05 to -0.09; P = 0.006) and delayed graft function (DGF) (beta-10.0; CI -19.52 to -0.49; P = 0.039). Renal function in an LDK transplant recipients is predicted by donor GFR, episodes of steroid resistant rejection and DGF. Importantly, donor Cockcroft-Gault GFR is the most important characteristic for predicting the recipient renal function.

Relationship Between Individual Components of the Extended-Criteria Donor Definition and the First Post-transplant Kidney Graft Resistance Index, Measured by Doppler Sonography

We evaluated survival and renal function of cadaveric donor grafts according to donor age. The median age of the pediatric donors was 7.0 (0.7-16) years in 46 patients [median age 11.8 years (range) 3-16.8 years]. The median age of the adult donors was 34.4 (19-54) years in 59 patients [median age 12.1 years (range) 7-17.3 years]. Thirty patients were treated with azathioprine and prednisolone and 75 with cyclosporine A and prednisolone. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were determined by the clearances of 51chromium-EDTA and 125iodine-hippurate 1-48 months after kidney transplantation. There was no difference in graft survival between pediatric and adult grafts. There were also no differences in GFR in patients receiving grafts from pediatric or adult donors; 2-3 months after transplantation the GFR in recipients of pediatric grafts was 62 +/- 20 ml/min per 1.73 m2 compared with 61 +/- 21 in those receiving adult grafts. The ERPF in recipients of adult grafts was significantly higher in the 1st month after transplantation: 486 +/- 239 versus 362 +/- 158 ml/min per 1.73 m2. From the 4th to the 6th month after transplantation this difference disappeared: the ERPF of grafts from pediatric donors was 279 +/- 131 ml/min per 1.73 m2 compared with 273 +/- 123 ml/min per 1.73 m2 in grafts from adult donors. Using the single-kidney GFR and ERPF on an age-matched group of probands with minor diseases as references, 2-3 months after transplant the mean GFR of grafts from pediatric donors increased to 118% +/- 51%, whereas the GFR of adult donor grafts fell to 60% +/- 22% over the same period. After 4-6 months the ERPF in pediatric grafts was 96% +/- 55% compared with 50% +/- 22% in adult grafts. We conclude that graft survival and function in children with either a pediatric or an adult graft may not differ because graft function adapts to the requirement of the recipient.

One of the most important advances in transplantation medicine has been the recognition that anti-human leucocyte antigen (HLA) antibodies are destructive. Various studies over the past decade have indicated that the alloimmune response, mediated by anti-HLA antibodies, plays a key role in the failure of kidney allografts 1,2; this concept has been extended to heart, lung and composite tissue transplants 3. Although anti-HLA antibodies are considered to be harmful, there is a wide spectrum of graft injury related to these antibodies, ranging from no recognizable damage to florid rejection. The presence or absence and characteristics of donor-specific anti-HLA antibodies (DSA) are therefore crucial to determine patient outcomes following transplantation. Activation of the complement cascade is known to be a key component of antibody-mediated rejection (ABMR), and deposition of C4d is often used as a marker for complement activation 4–6. It is the ability of anti-HLA antibodies to bind complement that determines the cytotoxic potential of these antibodies 5. Therefore, we hypothesized that the presence of DSA and their ability to bind and activate complement would play a key role in solid organ transplant. A total of 1016 consecutive kidney transplant recipients were enrolled into this population-based study 7. All patients were screened for the presence of circulating DSA at the time of transplantation and at 1 year after transplantation, in patients with no immunological event or at the time of rejection using the Luminex assay. The complement-binding capacity of any detected DSA was also analysed. Of the 1016 patients, 1 year post-transplantation, 700 patients (69%) were devoid of circulating DSA and 316 patients (31%) had circulating DSA, 77 of whom (24%) were C1q-positive, i.e. had complement-binding DSA. The patients with complement-binding DSA (representing 7% of the overall population) had the poorest outcome, with a risk of graft loss 11-fold higher than patients with non-complement-binding DSA (C1q-negative) 7. Assessment of allograft biopsies (n = 1016) demonstrated that DSA, both complement (C1q-positive)- and non-complement (C1q-negative)-binding, were capable of inducing injury to the graft. Histologically, the incidence of microvascular inflammation, C4d deposition, early transplant glomerulopathy and interstitial inflammation tubulitis were significantly higher in allografts from patients with DSA (P < 0·05), particularly in those patients with C1q-positive, complement-binding DSA (P < 0·05) 7. These results were confirmed further by molecular microscopy with higher ABMR score, higher endothelial cell injury response and higher numbers of natural killer cells and interferon (IFN)-γ-inducible transcripts observed in patients with C1q-positive, complement-binding DSA. In order to translate our findings into clinical practice, we developed a risk prediction model at 1 year post-transplantation based on all histological and immunological parameters, defined by the current classical diagnosis tools. When C1q-positive, complement-binding DSA were added to the model we observed an increase in the performance and discrimination capacity, and reclassification of patients at lower or higher risk of graft loss 8. Compared with a traditional approach to predicting graft loss, we demonstrate that a new approach, which integrates the capacity of DSA to bind complement, identifies patients at high risk of graft loss and increases our risk stratification performance in kidney transplant recipients. An improved understanding of DSA mechanism of action, better patient identification and construction of risk models will pave the way to specific and personalized treatment for patients undergoing solid organ transplantation. As promising therapeutic agents targeting complement [e.g. a C5 inhibitor (eculizumab) or a C1 inhibitor] are used increasingly in patients undergoing transplantation, this study may serve as a basis for future clinical trials.

The left kidney is often preferred for living donor kidney transplantation because of its anatomical advantages. However, the right kidney may be procured due to donor conditions. Few studies have assessed the safety and graft outcome of right retroperitoneal laparoscopic donor nephrectomy (RDN). This study aimed to compare the outcomes between right and left RDN with respect to donor outcome and the graft function of recipients. This retrospective study included 230 consecutive living donor kidney transplants performed at our institution between May 2019 and March 2023. We reviewed the outcomes of kidney transplant in the right and left kidneys after RDN. A total of 230 living donor kidney transplants were performed, with 32 donors receiving right RDN (right RDN group) and 198 donors receiving left RDN (left RDN group). The renal veins and ureters were significantly shorter in the right RDN group than in the left RDN group (both p < .001). Donor operation and warm ischemia time were significantly longer in the right RDN group than in the left RDN group (p = .012 and p < .001, respectively). None of the groups exhibited any cases of delayed graft function owing to donor-related reasons. Perioperative changes in the estimated glomerular filtration rate of recipients and death-censored graft survival were not significantly different between the two groups. In RDN, the outcomes of right donor nephrectomy were comparable to those of left donor nephrectomy in terms of donor safety and recipient renal function.