Timing of parathyroidectomy in kidney transplant candidates with secondary hyperparathryroidism: effect of pretransplant versus early or late post-transplant parathyroidectomy.

BACKGROUND: The timing of parathyroidectomy in kidney transplant candidates suffering from secondary hyperparathyroidism before versus early or late after transplantation remains controversial. METHODS: The short-term follow-up cohort comprised 66 patients with 1-year post-transplant follow-up, while the long-term follow-up cohort contained 123 patients. Risk-adjusted identification of independent risk factors for compromised renal graft function (KDIGO stage ≥ IV) was performed using multivariable regression analysis adjusted for propensity score logits for parathyroidectomy before versus after renal transplantation. Intra-individual matched-pairs analyses were used to identify significant effects of post-transplant parathyroidectomy on graft function as assessed by estimated glomerular filtration rate (eGFR) and paired t tests. RESULTS: Donor kidney function KDIGO stage III (P = .030; OR = 5.191, 95% CI: 1.100-24.508), donor blood group 0 (P = .005; OR = 0.176, 95% CI: 0.048-0.642), and post-transplant parathyroidectomy (P = .032; OR = 17.849, 95% CI: 1.086-293.268) were revealed as independent significant risk factors for compromised renal graft function in the short-term follow-up cohort using propensity score risk adjustment while post-transplant parathyroidectomy had no independent influence in the long-term follow-up cohort (P = .651). Parathyroidectomy after renal transplantation compromised graft function early after parathyroidectomy and at last follow-up in all post-transplant parathyroidectomy cases (P ≤ .004). Parathyroidectomy within the first post-transplant year was associated with compromised renal graft function until last follow-up (P = .004), while parathyroidectomy late post-transplant was not. CONCLUSION: Parathyroidectomy should be conducted before transplantation or, if this is not possible, preferably after the first post-transplant year.

External validation of a proposed prognostic model for the prediction of 1-year postoperative eGFR after living donor nephrectomy.

PURPOSE: The goal of this study was to externally validate the recently proposed prognostic model for the prediction of estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 1 year after living donor nephrectomy. METHODS: 130 living kidney donors (median age at donation 52.3 years, range 24.7-75.6 years) were investigated before and after donation between March 2000 and April 2016. Preoperative eGFR values varied between 61.7 and 148.4 ml/min (mean: 89, median: 88). Observed eGFR 1 year after transplantation (±45 days) ranged between 36.3 and 97.1 ml/min (mean: 55, median: 53). 70.8% of donors displayed eGFR values < 60 ml/min 1 year after donation. Predicted eGFR 1 year after donation was determined using the prognostic model proposed by Benoit et al. (Int Urol Nephrol 49(5):793-801. doi: 10.1007/s11255-017-1559-1 , 2017): postoperative eGFR ml/min/1.73 m2 = 31.71 + (0.521 × eGFR in ml/min prior to donation -0.314 × Age in years at donation). Pearson correlation and receiver operating characteristics curve (ROC-curve) were used to assess external validity of the proposed prognostic model to predict postoperative eGFR in ml/min and eGFR < 60 ml/min. RESULTS: The correlation between predicted and observed eGFR 1 year after donation was significant (p < 0.001; R 2 = 0.594). The area under the ROC-curve (AUROC) demonstrated a high sensitivity and specificity for predicted eGFR values < 60 ml/min (AUROC = 0.866). CONCLUSIONS: The proposed prognostic model for the prediction of postoperative eGFR was successfully validated in our cohort. We therefore consider the model as generally applicable.

Matched-pair analysis: identification of factors with independent influence on the development of PTLD after kidney or liver transplantation.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) adversely affects patients' long-term outcome. METHODS: The paired t test and McNemar's test were applied in a retrospective 1:1 matched-pair analysis including 36 patients with PTLD and 36 patients without PTLD after kidney or liver transplantation. Matching criteria were age, gender, indication, type of transplantation, and duration of follow-up. All investigated PTLD specimen were histologically positive for EBV. Risk-adjusted multivariable regression analysis was used to identify independence of risk factors for PTLD detected in matched-pair analysis. The resultant prognostic model was assessed with ROC-curve analysis. RESULTS: Patients suffering with PTLD had shorter mean survival (p = 0.004), more episodes of CMV infections or reactivations (p = 0.042), and fewer recipient HLA A2 haplotypes (p = 0.007), a tacrolimus-based immunosuppressive regimen (p = 0.052) and higher dosages of tacrolimus at hospital discharge (Tac dosage) (p = 0.052). Significant independent risk factors for PTLD were recipient HLA A2 (OR = 0.07, 95 % CI = 0.01-0.55, p = 0.011), higher Tac dosages (OR = 1.29, 95 % CI = 1.01-1.64, p = 0.040), and higher numbers of graft rejection episodes (OR = 0.38, 95 % CI = 0.17-0.87, p = 0.023). The following prognostic model for the prediction of PTLD demonstrated good model fit and a large area under the ROC curve (0.823): PTLD probability in % = Exp(y)/(1 + Exp(y)) with y = 0.671 - 1.096 × HLA A2-positive recipient + 0.151 × Tac dosage - 0.805 × number of graft rejection episodes. CONCLUSIONS: This study suggests prognostic relevance for recipient HLA A2, CMV, and EBV infections or reactivations and strong initial tacrolimus-based immunosuppression. Patients with risk factors may benefit from intensified screening for PTLD.

Identification of patients at risk for renal impairment after living donor kidney transplantation.

PURPOSE: Outcome after living donor kidney transplantation is highly relevant, since recipient and donor were exposed to notable harm. Reliable identification of risk factors is necessary. METHODS: Three hundred sixty-six living donor kidney transplants were included in this observational retrospective study. Relevant risk factors for renal impairment 1 year after transplantation and delayed graft function were identified with univariable and multivariable binary logistic regression and ordinal regression analysis. RESULTS: Eighty-four patients (26.6 %) suffered from renal impairment KDIGO stage ≥4 1 year post-transplant; median estimated glomerular filtration rate was 35.3 ml/min. In multivariable ordinal regression, male recipient sex (p < 0.001), recipient body mass index (p = 0.006), donor age (p = 0.002) and high percentages of panel reactive antibodies (p = 0.021) were revealed as independent risk factors for higher KDIGO stages. After adjustment for post-transplant data, recipient male sex (p < 0.001), donor age (p = 0.026) and decreased early renal function at the first post-transplant outpatient visit (p < 0.001) were identified as independent risk factors. Delayed graft function was independently associated with long stay on the waiting list (p = 0.011), high donor body mass index (p = 0.043), prolonged warm ischemic time (p = 0.016) and the presence of preformed donor-specific antibodies (p = 0.043). CONCLUSIONS: Broadening the donor pool with non-blood related donors seems to be legitimate, although with respect to careful medical selection, since donor age in combination with male recipient sex were shown to be risk factors for decreased graft function. Warm ischemic time and waiting time need to be kept as short as possible to avoid delayed graft function. Transplantation across HLA and ABO borders did not affect outcome significantly.

Removal of methadone by extended dialysis using a high cut-off dialyzer: implications for the treatment of overdose and for pain management in patients undergoing light chain removal.

The synthetic opioid methadone hydrochloride has a low molecular weight of 346 D, a high volume of distribution (4 - 7 L/kg), and is lipophilic. It is used as an analgesic and for the maintenance treatment of opiate dependence. In drug addicts, methadone is frequently involved in mixed intoxications that can lead to death. Here we present the case of a drug addict in whom a high cut-off dialysis membrane together with extended dialysis was used in the setting of suspected overdose and acute kidney injury. Although the observed dialyzer plasma clearance (31.5 mL/min) and reduction ratio (38%) were higher than previously reported for standard hemodialysis, the total amount of methadone in the spent dialysate after 1 extended dialysis session was quite low. Hence, even extended dialysis with a high cut-off membrane does not seem to offer a clinically relevant benefit in the setting of overdose for enhanced methadone removal. On the other hand, in patients undergoing high cut-off dialysis for the removal of light chains, methadone could still be used as an analgesic without an additional dose after high cut-off hemodialysis.

Azacytidine impairs NK cell reactivity while decitabine augments NK cell responsiveness toward stimulation.

Azacytidine and decitabine are approved for treatment of acute myeloid leukemias and myelodysplastic syndromes. While clinical responses are attributed to epigenetic effects and induction of apoptosis in malignant cells, these azanucleosides also affect antitumor immune responses. NK cells as components of innate immunity may confine development and progression of cancer. Numerous therapeutic strategies presently aim to reinforce NK reactivity against hematopoietic malignancies. We here comparatively analyzed the effect of the two clinically available azanucleosides and report that NK cytotoxicity and IFN-γ production are significantly impaired by pharmacological concentrations of azacytidine but enhanced by decitabine. This was not due to alterations in the target cells but caused by direct effects on NK cells depending on the chemical modifications by which azanucleosides differ from their physiological analogues. Although azacytidine impaired mRNA synthesis and induced apoptosis in NK cells, decitabine did not per se alter NK cell viability or reactivity but enhanced responsiveness to activating stimuli by inducing transcription of genes involved in NK reactivity. Tantalizingly, these effects were independent of incorporation of the azanucleosides into DNA during cell division. While azacytidine impairs NK antitumor immunity, decitabine augments NK reactivity by yet unidentified mechanisms and may thus serve well in therapeutic strategies combining its effects on malignant cells with its ability to enhance NK functions.