Andreas Kahl

Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts.

Background. Although the incidence of early acute rejection could have been diminished in the past, the long-term renal allograft survival could not benefit from the introduction of more effective immunosuppressive regimens mainly aiming at cellular rejection mechanisms. The cause of chronic rejection is still discussed controversially. Here, we demonstrate to what extent human leukocyte antigen (HLA) antibodies (HLAab) posttransplant contribute to late graft outcome. Methods. A total of 1014 deceased kidney transplant recipients transplanted at the Charité hospital were monitored in a cross-sectional manner for the development of HLAab using Luminex Single Antigen beads. Patients with stable kidney function at a median of 5-years posttransplant were tested once for HLAab and monitored for 5.5 years after testing. Results. Thirty percent of recipients showed HLAab. Donor-specific antibodies (DSA) were found in 31% of antibody positive patients. The presence of DSA was associated with a significantly lower graft survival of 49% vs. 83% in the HLAab negative group (P≤0.0001). Non-DSAs also had an adverse effect on graft survival (70% vs. 83%; P=0.0001). In a prospective analysis of 195 patients with repeatedly no detectable HLAab, the survival probability was 94% as opposed to 79% survival among patients who developed HLAab de novo after the first testing (P=0.05). Conclusions. We confirmed that HLAab produced even late after transplantation are detrimental to graft outcome. DSA were proven to have a strong adverse impact on graft survival. The results indicate that a posttransplant HLAab monitoring routine could be appropriate to improve long-term results.

Nephrotoxicity following orthotopic liver transplantation : a comparison between cyclosporine and FK506

Nephrotoxicity represents a serious side effect of immunosuppression following liver transplantation. In order to compare the nephrotoxic action of CsA and FK506 in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 of whom were randomly assigned to CsA- and 61 to FK506-based immunosuppression. Early postoperative renal insufficiency (between PODs 0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (38.3%) and FK506 (42.6%). Early postoperative acute renal failure (ARF) (SCr > 3 mg/dl) was observed in 18.0% of patients in the FK506 treatment group and 18.3% of patients receiving CsA therapy. Approximately half the patients with ARF required hemodialysis (CsA: 11.7%; and FK506: 8.2%). All patients with early postoperative ARF requiring hemodialysis survived for more than one year. New onset of late ARF (between PODs 30 and 365) was observed in 6.6% of patients receiving FK506 therapy and in 1.7% in the CsA treatment group as a result of severe infection with multiple organ failure syndrome (MOFS). There was 100% mortality in patients with late ARF requiring hemodialysis. Etiology and prognosis of early and late ARF seem to be completely different. Early ARF was associated with severe coagulopathy and a rise in bilirubin and free hemoglobin, and was accompanied by impaired liver function. Mean onset of hemodialysis in CsA-treated patients was POD 1 and in FK506-treated patients POD 6, which disclosed a different time course of drug-specific nephrotoxicity of CsA and FK506 in early ARF. In contrast, late ARF occurred in both treatment groups only as a part of the MOFS in association with severe infections, an observation consistent with the assumption of overimmunosuppression rather than a primary nephrotoxic effect. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity of CsA and FK506. These preliminary results demonstrate a similar outcome in terms of both early and late nephrotoxicity, but longer follow-up will delineate the overall efficacy and toxicity in humans.

SIGNIFICANCE OF A T-LYMPHOCYTOTOXIC CROSSMATCH IN LIVER AND COMBINED LIVER-KIDNEY TRANSPLANTATION

Background. In contrast to kidney transplants a positive crossmatch is no contraindication for liver transplantation (OLT). In liver transplantation, antibody mediated rejections are rarely reported and a liver graft is suspected to have protective effects for kidney grafts when transplanted simultaneously. The aim of this study was to evaluate the effect of a positive crossmatch on outcome after OLT and combined liver and kidney transplantation (CLKTx). Methods. We analyzed retrospectively the impact of a positive crossmatch on graft survival and rejection episodes after OLT (793pats) and CLKTx (18pats, 2.2%). Immunosuppression consisted of either Cyclosporine- or Tacrolimus-based regimens. Results. A total of 50/811 (6%) of patients had a positive crossmatch, 45/793 (5.6%) with liver transplantation alone and 5/18 (28%) of patients with CLKTx. Follow-up ranged from 1 to 122.5 months (median 45.8 months). One- and 5-year graft survival rates of liver transplants alone with a positive crossmatch were 89.6% and 75.3%, respectively and were 88% and 77.5% in crossmatch negative recipients. Additionally, the incidence of acute and steroid-resistant rejection (44% and 15.5%) was not significantly increased in patients with a positive crossmatch when compared with patients with a negative crossmatch (38% and 19%). None of the patients with a positive crossmatch and CLKTx underwent a hyperacute-rejection episode after transplantation, and kidney graft survival 100%. Conclusions. In conclusion, a positive crossmatch is no contraindication for OLT and CLKTx. Furthermore, not having to wait for results of donor/recipient crossmatching can shorten cold ischemia time and may improve the clinical outcome.

Chronic renal dysfunction following liver transplantation

Abstract:  With most of the immunosuppressive protocols consisting of calcineurin inhibitors (CI), nephrotoxicity has become a major long‐term complication often compromising outcome. In a single‐center retrospective study, we reviewed 1173 liver transplantations to identify variables indicative for the occurrence of chronic renal dysfunction (CRD) (defined as ≥1 episode of serum creatinine increase ≥1.8 mg/dL ≥2 wk). Chronic renal dysfunction was found in 137 (11.7%) of all transplants [82 (7%) early (after 3–12 months), 55 (4.7%) late‐onset (>12 months)]. Compared to 5‐/10‐yr survival rates in non‐CRD transplants (84/74%) survival was significantly decreased in early (66/46%), but unchanged in late‐onset CRD (98/86%). Rates of alcoholic cirrhosis and prior renal dysfunction were significantly increased in patients with CRD. In a multivariate logistic regression analysis, only cyclosporine A (CyA) as immunosuppression remained an independent risk factor. No correlations to age, gender, rejection/retransplantation or diabetes were found. Surprisingly, renal function (creatinine) showed no difference between patients on CI monotherapy (FK/CyA) compared to those who had mycophenolate mofetil (MMF) added. In liver transplantation, early onset CRD significantly compromises survival. CyA‐based immunosuppression appears to have a stronger impact than FK. The fact that patients with long‐term severe chronic renal dysfunction failed to improve under MMF rescue therapy emphasizes the importance of new diagnostic strategies to earlier identify at‐risk patients.

Long-term Results of Subtotal vs Total Parathyroidectomy Without Autotransplantation in Kidney Transplant Recipients

HYPOTHESIS Total parathyroidectomy without autotransplantation in kidney transplant recipients leads to reduced recurrence rates and similar improvement of clinical symptoms compared with subtotal parathyroidectomy. DESIGN A retrospective cohort study. SETTING University clinic. PATIENTS Thirty-three patients with functioning renal grafts who underwent primary total (n = 17; group 1) or subtotal (n = 16; group 2) parathyroidectomy for renal hyperparathyroidism. MAIN OUTCOME MEASURES Long-term levels of intact parathyroid hormone, serum calcium, phosphate, alkaline phosphatase, creatinine, and vitamin D; bone pain; use of medication; and incidence of persistent or recurrent hyperparathyroidism. RESULTS The mean length of follow-up was 31 months in group 1 and 41 months in group 2. In all patients, postoperative serum calcium and phosphate levels normalized and bone pain markedly decreased. Persistent hypocalcemia was not observed. Serum creatinine levels intermittently increased in both groups but returned to preoperative levels in most of the patients. In group 1, all patients had undetectable intact parathyroid hormone levels throughout the study period. In group 2, 2 patients had persistent and 3 patients developed recurrent hyperparathyroidism (31%) that required therapy with cinacalcet hydrochloride in 3 cases. In 4 of these 5 patients, intact parathyroid hormone levels were greater than 54 ng/L directly after operation. In all, 27 of 33 patients (82%) received cholecalciferol therapy. Additional calcium supplementation was used by 12 group 1 patients (71%) and 3 group 2 patients (19%). CONCLUSIONS Total parathyroidectomy in kidney transplant recipients appears to be safe and protective against persistent and recurrent disease. If subtotal parathyroidectomy is performed, the remnant should be small.

Treatment of Epstein-Barr virus-induced posttransplantation lymphoproliferative disorder with foscarnet alone in an adult after simultaneous heart and renal transplantation.

BACKGROUND The kind and intensity of immunosuppression as well as Epstein-Barr virus, a transforming herpes virus that selectively infects B lymphocytes and causes infectious mononucleosis, have been implicated in the development of posttransplantation lymph-proliferative disorders (PT-LPD), a life-threatening complication of solid organ transplantation. The morphologic spectrum of PT-LPD ranges from polymorphous hyperplasia to monomorphous B-non-Hodgkin lymphomas. Among different modalities of treatment, reduction of immunosuppression with or without co-administration of antiviral agents may result in PT-LPD regression especially in mononucleosis-like disease. METHODS Nonmononucleosis-like PT-LPD in a simultaneous heart and renal recipient was treated with Foscarnet, a potent inhibitor of different herpes viruses with a low profile of toxicity, although intensive immunosuppression therapy was maintained. RESULTS AND CONCLUSIONS A 4-week course of Foscarnet resulted in relapse-free complete remission (follow-up 10+ months). Thus, antiviral treatment with Foscarnet, may induce prolonged remission in nonmononucleosis-like PT-LPD without reduction of immunosuppression.

Contribution of color and power Doppler sonography to the differential diagnosis of acute and chronic rejection, and tacrolimus nephrotoxicity in renal allografts

The aim of the present study was to differentiate acute rejection, chronic rejection, and tacrolimus nephrotoxicity with color and power Doppler imaging of renal transplants. One hundred examinations were obtained from 45 patients. Pulsatility and resistive indices were calculated from color Doppler images. The grade of renal vascularization was quantified using computer‐assisted pixel analysis in a rectangular region‐of‐interest. The percentage of vessel‐covered renal parenchyma (POV) was calculated using a histogram that discriminated renal vessels from renal parenchyma via power Doppler images. Furthermore, the distance from the most peripherally located vessels to the renal capsule (PVD) was measured. A reduced POV ± 55 % proved to be the best discriminator when chronic rejection was suspected (sensitivity 79 %, specificity 87 %). Tacrolimus nephrotoxicity showed not only a moderate elevation of the Doppler signal but also an increased PVD±3.9 mm and a normal POV. We conclude that the evaluation of renal vessels by power Doppler images improves diagnostic accuracy for patients with renal allografts.

Sexual Dysfunction After Simultaneous Pancreas–Kidney Transplantation

Simultaneous pancreas-kidney transplantation (SPK) is the treatment of choice for patients with type 1 diabetes mellitus and end-stage renal disease (ESRD) because it improves survival, is cost-effective, and can mitigate secondary complications of diabetes. Patient-reported outcomes such as quality of life (QoL) have recently received increased attention among transplant recipients. However, the impact of erectile dysfunction on patient QoL has not been investigated in this high-risk group with a history of diabetes and uremia. We applied the International Index of Erectile Function (IIEF) to describe the prevalence and severity of self-reported changes in erectile function after transplantation, comparing the quality of well-being (QWB) index of subgroups of 101 consecutive male SPK recipients with varying degrees of erectile function. Only 21% of patients did not suffer from erectile dysfunction; 18% were classified as mild erectile dysfunction, 31% as mild to moderate, 21% as moderate, and 9% as severe according to the IIEF scores. Forty-one percent of patients reported subjective overall improvement in erectile dysfunction compared with their pretransplant status; 7% considered their sexual function to be worse than before, and 51% did not note any change. The QWB index was highest among the group of patients without erectile dysfunction, decreasing gradually but significantly with increasing severity. A direct impact of erectile dysfunction on QoL, as well as a confounding effect of underlying vascular comorbidities, could explain this finding.

Long‐term outcome of cytomegalovirus infection in simultaneous pancreas–kidney transplant recipients without ganciclovir prophylaxis

As cytomegalovirus (CMV) infection frequently occurs in simultaneous pancreas kidney transplantation (SPKT), most centers use general ganciclovir prophylaxis. The aim of the study was to analyze the impact of CMV in a patient cohort with preemptive therapy only. Incidence, course and risk factors of CMV infection were retrospectively analyzed in 94 adult SPK recipients without prophylaxis. Patients with asymptomatic pp65‐antigenemia were treated preemptively with intravenous ganciclovir for 14 days. Survival rates after 1, 3, and 5 years were 98%, 97%, and 94% for patients, 96%, 94%, and 88% for renal grafts and 88%, 85%, and 82% for pancreas grafts. CMV infections occurred in 51% of patients and CMV syndrome in 16%. No tissue‐invasive disease was observed. Thirty‐eight per cent of patients with CMV infection developed a recurrence. Risk factors for CMV in multivariate analysis were the D+/R− constellation, acute rejections, anti‐rejection therapy and coronary heart disease. CMV had no impact on patient or graft survival, occurrence of acute or chronic rejection and bacterial infections. Preemptive therapy seems to be safe and effective in SPK recipients, but as the present study was retrospective, prospective randomized studies are needed to confirm our results.

Combination of bortezomib-based chemotherapy and extracorporeal free light chain removal for treating cast nephropathy in multiple myeloma

Besides amyloidosis and light chain deposition disease, the most common histological type of renal lesion is cast nephropathy in 30% of patients with multiple myeloma [2]. In contrast to amyloidosis, cast nephropathy is believed to be potentially reversible when circulating light chains are rapidly reduced. We report on three patients with multiple myeloma and cast nephropathy treated with a bortezomib-based chemotherapy in addition to a newly developed high-cutoff polyflux® haemofilter. Reduction in serum free light chain levels was achieved within 10–12 days, with all three patients improving their renal function.