Pancreas transplant rejection episodes are not revealed by biopsies of the donor duodenum in a prospective study with paired biopsies.

The surgical technique with duodeno-duodenal enteroanastomosis of pancreas transplants allows for representative endoscopic ultrasound-guided needle biopsies of the donor duodenum and the pancreas graft. We assessed whether histological findings in transplanted donor duodenal biopsies can indicate rejection in the transplanted pancreas. Since September 2012, a duodeno-duodenal enteroanastomosis has been the default technique for pancreas transplantations at our center. In 67 recipients we prospectively examined 113 endoscopic ultrasound-guided procedures with representative biopsies from the duodenum grafts and the pancreas grafts (97 per protocol and 16 on indication). All graft biopsies were evaluated according to established rejection criteria. A total of 22 biopsy-proven pancreas rejections were detected, with 2 matching duodenal biopsies showing rejection. This gives a sensitivity of 9% for detection of a pancreas rejection by duodenal biopsies. The other matching duodenal biopsies were either normal (n = 13) or indeterminate (n = 7). Rejection of the donor duodenum was found in only 6/113 biopsies, with 2 concurrent pancreas rejections. In conclusion, the donor duodenum is not a useful reporter organ for rejection in the pancreas graft.

European perspective on human polyomavirus infection, replication and disease in solid organ transplantation.

Human polyomaviruses (HPyVs) are a growing challenge in immunocompromised patients in view of the increasing number of now 12 HPyV species and their diverse disease potential. Currently, histological evidence of disease is available for BKPyV causing nephropathy and haemorrhagic cystitis, JCPyV causing progressive multifocal leukoencephalopathy and occasionally nephropathy, MCPyV causing Merkel cell carcinoma and TSPyV causing trichodysplasia spinulosa, the last two being proliferative skin diseases. Here, the current role of HPyV in solid organ transplantation (SOT) was reviewed and recommendations regarding screening, monitoring and intervention were made. Pre-transplant screening of SOT donor or recipient for serostatus or active replication is currently not recommended for any HPyV. Post-transplant, however, regular clinical search for skin lesions, including those associated with MCPyV or TSPyV, is recommended in all SOT recipients. Also, regular screening for BKPyV replication (e.g. by plasma viral load) is recommended in kidney transplant recipients. For SOT patients with probable or proven HPyV disease, reducing immunosuppression should be considered to permit regaining of immune control. Antivirals would be desirable for treating proven HPyV disease, but are solely considered as adjunct local treatment of trichodysplasia spinulosa, whereas surgical resection and chemotherapy are key in Merkel cell carcinoma. Overall, the quality of the clinical evidence and the strength of most recommendations are presently limited, but are expected to improve in the coming years.

Single transplanted kidneys from a 90-year-old deceased donor perform acceptably at 1 year.

Most centers are reluctant to accept expanded criteria donors above 70 to 75 years of age. We accepted kidneys from a 90-year-old male and report the 1-year outcome. The kidneys were used as single transplants and both had immediate graft function. Recipient A was a 71-year-old male, with cold ischemia time of 4 hours 49 minutes. One rejection was successfully treated with intravenous methylprednisolone. At 1 year, serum creatinine was 146 µmol/L with estimated glomerular filtration rate (eGFR) 41 mL/min. Recipient B was a 79-year-old male with known panel-reactive antibody positivity prior to transplantation. Cold ischemia time was 10 hours 4 minutes. He experienced no rejections. At 1 year serum-creatinine was 99 µmol/L with eGFR 63 mL/min. Both recipients performed a surveillance biopsy at 1 year with identical findings: interstitial fibrosis and tubular atrophy grade 1 with moderate to severe arteriolosclerosis. We conclude that both kidneys performed acceptably 1 year after engraftment. The use of old kidneys in old recipients gives them a properly functioning kidney and improves quality of life. Longer observation is needed.

Early, abrupt conversion of de novo renal transplant patients from cyclosporine to everolimus: results of a pilot study.

In a single-center study, 20 kidney transplant patients without prior rejection were abruptly converted from cyclosporine to everolimus at seven wk post-transplant. All patients received basiliximab induction with maintenance enteric-coated mycophenolate sodium and corticosteroids. Biopsy-proven acute rejection had occurred in three of 20 patients (15.0%) by the end of week seven post-conversion. All episodes were mild and reversible, with subsequent recovery of renal function. Calculated glomerular filtration rate (GFR) improved significantly (51 +/- 11 mL/min at time of conversion, 58 +/- 12 mL/min at week seven post-conversion, 57 +/- 17 mL/min at month six post-conversion; p = 0.001). No patient developed proteinuria in the nephrotic range. Twenty-two adverse events were reported in 10 patients, three of which had a suspected relationship to everolimus. Mean leukocyte and platelet count decreased significantly, and triglyceride level increased. This study suggests that kidney transplant patients without prior rejection can be converted abruptly from cyclosporine to everolimus at seven wk post-transplant, resulting in significantly improved renal function with no apparent increase, in risk of rejection and good tolerability.

Can a diagnosis of renal allograft rejection be based on histology alone?

Acute renal allograft rejection is suspected by the clinician when the serum creatinine value increases in a patient for no other particular cause. A renal allograft biopsy may confirm the diagnosis. This report describes 2 patients with stable serum creatinine; however, protocol biopsy showed acute rejection changes according to the Banff criteria. No anti-rejection treatment was started and their graft function remained stable for 6 months. These two cases focus on the fact that renal allograft rejection should first of all be regarded as a clinical diagnosis which could be substantiated by histological findings.

Increased potency and decreased elimination of lamifiban, a GPIIb-IIIa antagonist, in patients with severe renal dysfunction.

Activation of the platelet membrane receptor glycoprotein (GP) IIb-IIIa is essential for thrombus formation. The novel nonpeptide GPIIb-IIIa antagonist, lamifiban, represents a promising approach for antiplatelet therapy in patients with cardiovascular disease. Since renal impairment frequently occurs in these patients, we designed a phase I study to assess the tolerability, pharmacodynamics and pharmacokinetics of lamifiban in patients with renal impairment. Four healthy volunteers (Group 1) with creatinine clearance (CLCR) >75 ml/min, eight patients (Group 2) with mild to moderately impaired renal function (CLCR 30-74 ml/min) and eight patients (Group 3) with severe renal impairment (CLCR 10-29 ml/min) were studied. They received stepwise increased doses of lamifiban intravenously (i.v.). There was a linear relationship between the systemic clearance of the drug and renal function (R2 = 0.86). The mean plasma concentration required for half-maximal inhibition of thrombin-receptor agonist peptide (TRAP) induced platelet aggregation (EC50) ex vivo was 21, 28 and 11 ng/ml in Groups 1, 2 and 3. The patients in Group 3 were sensitized to the antiplatelet effect allowing an 18-fold dosage reduction without compromising the pharmacodynamics. In conclusion, the decreased clearance of lamifiban may act in concert with increased potency of the drug in patients with severe renal impairment, and the drug dosage should be reduced accordingly.

Insulin resistance is a common denominator of post-transplant diabetes mellitus and impaired glucose tolerance in renal transplant recipients.

BACKGROUND: Post-transplant diabetes mellitus is a known complication of steroid therapy in renal transplant recipients. Both insulin resistance and insulin deficiency have been shown to be necessary for development of post-transplant diabetes mellitus. It is not known whether recipients with impaired glucose tolerance have similar degree of insulin resistance or deficient insulin response as recipients with post-transplant diabetes mellitus. METHOD: To address this question, we used an oral glucose tolerance test to categorize 46 renal transplant recipients on triple immunosuppressive medication to groups with normal glucose tolerance, impaired glucose tolerance or post-transplant diabetes mellitus. Insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp. Insulin response was calculated from the increase in serum insulin concentration during the oral glucose tolerance test. RESULTS: Twenty-five were categorized to normal glucose tolerance, 15 to impaired glucose tolerance and six to post-transplant diabetes mellitus. There were no statistically significant differences between the groups regarding prednisolone dose, azathioprine dose, use of beta-blocker, age, gender, weight, waist-hip ratio, body mass index, donor source, smoking habits, or first-degree relatives with histories of diabetes mellitus. The impaired glucose tolerance and post-transplant diabetes mellitus groups showed a significant reduction in insulin-stimulated glucose disposal rate (mg/kg.min) compared to the normal glucose tolerance group (4.6 +/- 1.6 and 3.4 +/- 1.3 respectively vs 7.1 +/- 2.4, P < 0.05). The insulin response (picomol/l) was not different between the normal glucose tolerance and impaired glucose tolerance groups but was significantly reduced in the post-transplant diabetes mellitus group (448 +/- 310 and 450 +/- 291 respectively vs 170 +/- 128, P < 0.05). CONCLUSION: Insulin resistance is a common denominator of post-transplant diabetes mellitus and impaired glucose tolerance in renal transplant recipients.