BK Polyomavirus-Specific 9mer CD8 T Cell Responses Correlate With Clearance of BK Viremia in Kidney Transplant Recipients: First Report From the Swiss Transplant Cohort Study.

BK polyomavirus (BKPyV) causes premature kidney transplant (KT) failure in 1-15% of patients. Because antivirals are lacking, most programs screen for BKPyV-viremia and, if positive, reduce immunosuppression. To evaluate the relationship of viremia and BKPyV-specific immunity, we examined prospectively cryopreserved plasma and peripheral blood mononuclear cells at the time of transplantation (T0) and at 6 mo (T6) and 12 mo (T12) after transplant from 28 viremic KT patients and 68 nonviremic controls matched for the transplantation period. BKPyV IgG seroprevalence was comparable between cases (89.3%) and controls (91.2%; p = 0.8635), but cases had lower antibody levels (p = 0.022) at T0. Antibody levels increased at T6 and T12 but were not correlated with viremia clearance. BKPyV-specific T cell responses to pools of overlapping 15mers (15mer peptide pool [15mP]) or immunodominant CD8 9mers (9mer peptide pool [9mP]) from the early viral gene region were not different between cases and controls at T0; however, clearance of viremia was associated with stronger 9mP responses at T6 (p = 0.042) and T12 (p = 0.048), whereas 15mP responses were not informative (T6 p = 0.359; T12 p = 0.856). BKPyV-specific T cells could be expanded in vitro from all patients after transplant, permitting identification of 78 immunodominant 9mer epitopes including 50 new ones across different HLA class I. Thus, 9mP-responses may be a novel marker of reconstituting CD8 T cell function that warrants further study as a complement of plasma BKPyV loads for guiding immunosuppression reduction.

CRTC2 polymorphism as a risk factor for the incidence of metabolic syndrome in patients with solid organ transplantation.

Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (Pcorrected<0.05). CRTC2 rs8450-AA genotype was associated with NODAT in the second STCS replication sample (odd ratio (OR)=2.01, P=0.04). In the combined STCS replication samples, the effect of rs8450-AA genotype on NODAT was observed in patients having received SOT from a deceased donor and treated with tacrolimus (n=395, OR=2.08, P=0.02) and in non-kidney transplant recipients (OR=2.09, P=0.02). Moreover, rs8450-AA genotype was associated with overweight or obesity (n=1215, OR=1.56, P=0.02), new-onset hyperlipidemia (n=1007, OR=1.76, P=0.007), and lower high-density lipoprotein-cholesterol (n=1214, ß=-0.08, P=0.001). In the population-based samples, a proxy of rs8450G>A was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.

[Purulent lymphadenitis after peritonsillar abscess under immunosuppression. An often forgotten differential diagnosis]. / Eitrige Lymphadenitis nach Abszesstonsillektomie bei Immunsuppression. Eine oft vergessene Differenzialdiagnose.

In the present case study, a 75-year-old, immunosuppressed man presented with recurrent cervical abscesses after a peritonsillar abscess. In the cervical region, an ulcer developed with persistent wound healing deficit. Subsequently, the patient's general condition deteriorated, showing symptoms of a Landouzy sepsis. In the course of the examination, Mycobacteria tuberculosis was detected in the cervical ulcer. He suffered from latent tuberculosis, which was reactivated by a combination of his disease, immunosuppressive therapy and the preceding peritonsillar abscess. Upon treatment with tuberculostatics, the patient fully recovered.

[Swiss clinical practice guidelines for skin cancer in organ transplant recipients]. / Recommandations suisses pour la prise en charge des cancers cutanés chez les patients transplantés d'organe.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients Transplant patients have increased over the last decades. As a consequence of long-term immunosuppression, skin cancer, in particular squamous cell carcinoma (SCC), has become an important problem. Screening and education of potential organ transplant recipients (OTRs) regarding prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, OTRs should be seen yearly by a dermatologist to ensure compliance with sun avoidance as well as for treatment of precancerosis and SCC. Early removal is the best treatment for SCC. Reduction of immunosuppression, switch to mTOR inhibitors and chemoprevention with acitretin may reduce the incidence of SCC. The dermatological follow-up of OTRs should be integrated into a comprehensive post-transplant management strategy.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients.

Patients with a solid organ transplant have increased in numbers and in individual survival in Switzerland over the last decades. As a consequence of long-term immunosuppression, skin cancer in solid organ recipients (SOTRs) has been recognized as an important problem. Screening and education of potential SOTRs about prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, SOTRs should be seen by a dermatologist yearly for repeat education as well as early diagnosis, prevention and treatment of skin cancer. Squamous cell carcinoma of the skin (SCC) is the most frequent cancer in the setting of long-term immunosuppression. Sun protection by behaviour, clothing and daily sun screen application is the most effective prevention. Cumulative sun damage results in field cancerisation with numerous in-situ SCC such as actinic keratosis and Bowen's disease which should be treated proactively. Invasive SCC is cured by complete surgical excision. Early removal is the best precaution against potential metastases of SCC. Reduction of immunosuppression and switch to mTOR inhibitors and potentially, mycophenolate, may reduce the incidence of further SCC. Chemoprevention with the retinoid acitretin reduces the recurrence rate of SCC. The dermatological follow-up of SOTRs should be integrated into the comprehensive post-transplant care.

A Comparison of Two Types of Rabbit Antithymocyte Globulin Induction Therapy in Immunological High-Risk Kidney Recipients: A Prospective Randomized Control Study.

BACKGROUND: Induction treatment with rabbit polyclonal antithymocyte globulins (ATGs) is frequent used in kidney transplant recipients with donorspecific HLA antibodies and shows acceptable outcomes. The two commonly used ATGs, Thymoglobulin and ATG-F have slightly different antigen profile and antibody concentrations. The two compounds have never been directly compared in a prospective trial in immunological high-risk recipients. Therefore we performed a prospective randomized controlled study comparing the two compounds in immunological high-risk kidney recipients in terms of safety and efficacy. METHODS: Immunological high-risk kidney recipients, defined as the presence of HLA DSA but negative CDC-B and T-cell crossmatches were randomized 1:1 to receive ATG-F or Thymoglobulin. Maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and steroids. RESULTS: The per-protocol analysis included 35 patients. There was no immediate infusion reaction observed with both compounds. No PTLD or malignancy occurred during the follow-up in both groups. The incidence of viral and bacterial infections was similar in both groups (p = 0.62). The cumulative incidence of clinical and subclinical antibody mediated allograft rejection as well as T-cell mediated allograft rejection during the first year between ATG-F and Thymoglobulin was similar (35% versus 19%; p = 0.30 and 11% versus 18%; 0.54 respectively). The two-year graft function was similar with a median eGFR of 56 ml/min/1.73m2 (range 21-128) (ATG-F-group) and 51 ml/min/1.73m2 (range 22-132) (Thymo-group) (p = 0.69). CONCLUSION: We found no significant differences between the compared study drugs for induction treatment in immunological high-risk patients regarding safety and efficacy during follow-up with good allograft function at 2 years after transplantation.

Blood eosinophilia in tacrolimus-treated patients: an indicator of Pneumocystis carinii pneumonia.

BACKGROUND: Pneumocystis carinii pneumonia (PcP) in immunocompromised patients is suggested if the following symptoms develop: dyspnea, fever, and interstitial infiltrates on chest x-ray. We observed a significant blood eosinophilia in kidney recipients with PcP under immunosuppressive treatment with tacrolimus. METHODS: Blood eosinophil counts of kidney recipients under immunosuppression with tacrolimus suffering from PcP were compared to eosinophil counts of patients without evidence of PcP and to patients showing PcP under immunosuppression with cyclosporine. RESULTS: PcP-positive patients treated with tacrolimus showed a significantly higher blood eosinophil count compared to PcP-positive patients treated with cyclosporine (P=0.01), and to patients under immunosuppression with tacrolimus without PcP, respectively (P=0.006). Eosinophilia preceded the time of a definitive PcP diagnosis by bronchoalveolar lavage and decreased after successful treatment. CONCLUSIONS: An increasing blood eosinophil count can be an indicator of P. carinii pneumonia in patients under immunosuppressive therapy with tacrolimus.

Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss.

BACKGROUND: Manifest polyomavirus (PV) renal graft infection is a rare complication. We diagnosed 5 cases among 70 kidney recipients undergoing transplants since December 1995; however, there were no cases at our institution before December 1995. METHOD: To identify risk factors promoting manifest PV graft infection, we compared those 5 patients with kidney recipients who had signs of PV replication but no manifest graft infection (n=23, control group). PV replication was judged by the presence of intranuclear inclusion cells in the urine. RESULTS: Before the infection, five of five patients had recurrent rejection episodes. All were switched from cyclosporine A to high dose tacrolimus as rescue therapy. Infection was diagnosed histologically 9+/-2 months posttransplantation; it persisted and led to graft loss in four of five patients. In control patients, graft function was stable, 1 of 23 patients were switched to tacrolimus as rescue therapy, and graft loss occurred in 4 of 23 patients. CONCLUSION: Recurrent rejection episodes and high dose immunosuppressive therapy, including tacrolimus, are risk factors for manifest PV kidney graft infection, which has an ominous prognosis.

Heparin-induced thrombocytopenia associated with thrombotic microangiopathy.

Some cases of thrombotic microangiopathy (TMA) are refractory to plasma exchange therapy (PE) with persistence or recurrence of thrombocytopenia. We report two patients suffering from TMA of different aetiologies (associated with disseminated malignancy, typical haemolytic uraemic syndrome) with recurrent or persistent thrombocytopenia despite adequate therapy including PE. Since both patients were exposed to unfractionated heparin, heparin-induced thrombocytopenia (HIT) was suspected as a cause. Pretest probabilities for HIT were intermediate. ELISA for PF4/heparin antibodies was strongly positive in both cases, and HIT was confirmed by heparin-induced platelet activation assay. Anticoagulation with lepirudin was initiated, with subsequent rapid increase of the platelet count. TMA might represent a predisposition for HIT. This could be due to TMA-related platelet activation with increased PF4 release. In TMA patients exposed to heparin and with refractory or rapidly recurrent thrombocytopenia HIT should always be considered as a possible cause.

Assessment of an Interferon-gamma release assay for the diagnosis of latent tuberculosis infection in haemodialysis patient.

BACKGROUND: The accurate diagnosis of latent tuberculosis infection (LTBI) in haemodialysis patients remains elusive. Impaired immune function associated with chronic kidney failure causes a high number of anergic tuberculin skin tests (TST). Interferon-gamma (INF-gamma) release assays (IGRAs) measuring the INF-gamma secretion of tuberculosis specific T-cells have several advantages over the TST but their significance in dialysis patients is currently uncertain. METHODS: This study examines the test-performances of the QuantiFERON Gold InTube (QFT-GIT) in a cohort of 39 haemodialysis (HD) patients and 52 healthy individuals. RESULTS: INF-gamma secretion in HD patients was significantly lower than in healthy controls, however, mitogen-anergic QFT-GIT results were only found in 2.5% of HD-patients. INF-gamma secretion was independent of duration of HD treatment, dialysis quality and nutritional status. The QFT-GIT showed a closer association with TB risk factors as a proxy for past exposure to TB than the TST. CONCLUSIONS: We conclude that the QFT-GIT is a valid alternative to the TST. Together with the survey of TB risk factors, it may help to diagnose LTBI more accurately in HD-patients.

Polyomavirus BK-specific cellular immune response to VP1 and large T-antigen in kidney transplant recipients.

Polyomavirus BK (BKV) is the primary cause of polyomavirus-associated nephropathy (PVAN) in kidney transplant (KT) recipients. Using ELISpot assays, we compared the frequency of interferon-gamma (IFN-gamma) secreting peripheral blood mononuclear cells (PBMC) after stimulation with overlapping peptide pools covering BKV large T-antigen (LT) and VP1 capsid proteins (VP1). In 10 healthy donors, LT and VP1 responses were low with median 24 (range 15-95) and 25 (7-113) spot-forming units/10(6) PBMC (SFU), respectively. In 42 KT patients with current or recent plasma BKV loads, median LT and VP1 responses of 29 (0-524) and 114 (0-1432) SFU were detected, respectively. In KT patients with decreasing or past plasma BKV loads, significantly higher median BKV-specific IFN-gamma responses were detected compared to KT patients with increasing or persisting BKV loads [LT: 78 (8-524) vs. 22 (0-120) SFU, p=0.003; VP1: 285 (45-1432) vs. 53 (0-423) SFU, p=0.001, respectively]. VP1-specific IFN-gamma responses were higher and more likely to involve CD4(+) T cells, while CD8(+) T cells were more frequently directed against LT. Stimulation with JCV-specific VP1 and LT peptides indicated only low-level cross-recognition. The data suggest that control of BKV replication is correlated with differentiated expansion of BKV-specific cellular immune responses.

Occupational risk assessment of aspergillosis after renal transplantation.

Returning to work after transplantation is a much-discussed topic today, especially as a measure to avoid permanent work disability. Many transplant patients regain their ability to work 2-6 months after transplantation. However, returning to work should not endanger their health. This means that occupational risks such as occupational exposure to Aspergillus spores must be evaluated. We evaluated the community-acquired aspergillosis risk and in particularly the occupational aspergillosis risk, using the example of a 39-year-old construction worker immunosuppressed after renal transplantation. On one hand the risk is linked to the exposure to microorganisms that the individual is likely to be subjected to, and on the other hand to the factors that modify his state of susceptibility or resistance to these infectious agents. The necessity of immunosuppressive therapy after transplantation elevates the aspergillosis risk, especially 1-6 months after transplantation. There are many professions in which exposure to Aspergillus spores can occur. The risk of acquiring aspergillosis at work exists, but is not quantifiable today. Nevertheless, the risk should be minimized during the period of vulnerability by preventive measures such as restriction of certain activities, changing work methods and reorganizing the work day to adapt to the risk, and wearing personal protective equipment, as well as attention to information about aspergillosis risk and about the likelihood of exposure in the patient's professional and leisure activities.

[Infectious risk factors with special attention to elderly patients]. / Facteurs de risque infectieux avec une attention plus particulière pour les patients âgés.

This short review focuses on non-specific defences against infectious agents and the immune response in the elderly patient. The problem of hypogammaglobulinemia in patients with myeloma or leukemia, and its treatment with intravenous immunoglobulins, is also discussed.

Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A.

UNLABELLED: Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. BACKGROUND: Endothelins may play an important role in cyclosporine A (CsA)-induced renal vasoconstriction. Therefore, the effects of a mixed endothelin A and B receptor antagonist, bosentan (BO), on CsA were studied. METHODS: BO was given either alone or combined with CsA to healthy subjects in a double-blind, placebo-controlled, cross-over study. Standardized renal hemodynamics took place after a single dose of BO or placebo and after seven days of regular intake of CsA + BO or CsA + placebo. CsA was administered as a dose-adjusted regimen to achieve predetermined target trough levels. A pharmacokinetic study of CsA and BO was performed. RESULTS: A single dose of BO did not affect renal hemodynamics. After seven days of coadministration with CsA, BO significantly attenuated both the overall CsA-induced fall of renal plasma flow (RPF; placebo, 594 +/- 85; CsA + placebo, 490 +/- 93; CsA + BO, 570 +/- 106* mL/min, *P < 0.01) and the maximal RPF fall (P < 0.01) observed five hours after CsA intake. The CsA-induced rise of blood pressure and the decrease of glomerular filtration rate (GFR) were not influenced by comedication with BO. After seven days of CsA + BO, the area under the curve (AUC) of BO was nearly doubled compared with the AUC after a single dose of BO (P < 0.05). To reach the CsA target trough levels after seven days, the average CsA dose was increased by 35% when given with BO, as compared with placebo (P = 0.01). CsA exposure (trough levels, AUC) was not statistically different after CsA + placebo and after CsA + BO. CONCLUSIONS: Assuming CsA nephrotoxicity is mainly due to vasoconstriction, BO has the potential to attenuate the CsA renal toxicity by markedly blunting the renal hypoperfusion effect of CsA. A complex drug interaction between BO and CsA was observed.

Granulomatous Pneumocystis carinii pneumonia in Wegener's granulomatosis.

This study reports on a first case of granulomatous Pneumocystis carinii pneumonia (PCP) in a human immunodeficiency virus-negative patient with antineutrophil cytoplasmic antibody-positive Wegener's granulomatosis whilst receiving immunosuppressive treatment. The patient presented with diffuse alveolar haemorrhage, pauci-immune rapid progressive glomerulonephritis and leukocytoclastic vasculitis of the skin. Granulomatous Pneumocystis carinii pneumonia developed under immunosuppressive treatment with cyclophosphamide and prednisone. At the time Pneumocystis carinii pneumonia developed, there was a marked lymphopenia with a very low CD8+ cell count in the blood. Grocott staining in bronchoalveolar lavage fluid revealed no Pneumocystis carinii. The diagnosis was made via a video-assisted thoracoscopic lung biopsy which showed granulomas containing high numbers of Pneumocystis carinii cysts.

Outcome in emotionally related living kidney donor transplantation.

BACKGROUND: The growing shortage of cadaver kidneys, the limited possibilities to expand the living related donor pool and the good results obtained in our centre with poorly matched cadaver kidneys, led us in 1991 to begin accepting highly motivated, unrelated, living kidney donors who had a strong emotional bond with the recipients. METHODS: Between 1 January 1991 and 1 January 1996, 46 potential living kidney donors and their emotionally related recipients were evaluated. Twenty-three cases were accepted for renal transplantation after thorough somatic and psychological evaluation. The mean post-transplant follow-up until 1 April 1996 was of 28 +/- 3 months. Compatible blood groups and a negative cross-match were mandatory, but no minimal HLA matching was required. RESULTS: There was a 50% drop-out rate following the initial screening. The main reasons for not performing transplantation were immunological contraindications in 39% of the cases, somatic in 30.5%, psychological in 26% and socioeconomic in 4.5%. In the accepted group of recipients, 48% (11/23) received transplants without chronic dialysis. Donor survival was 91%; two deaths unrelated to nephrectomy occurred 1 year after donation. The 2-year actuarial recipient and graft survivals were 100% and 91% respectively, compared to 99% (recipients) and 93% (grafts) in the non-HLA-identical living related kidney transplant group, and to 93% (recipients) and 83% (grafts) in the cadaver kidney transplant group. Recipient rehabilitation was completed after 4 +/- 1 months. Emotionally related donors returned to work 5 +/- 2 weeks after nephrectomy, and no donor regretted his decision, even in the case of failure. CONCLUSIONS: Kidney transplantation from emotionally related living donors represents a valuable option, allowing more patients with end-stage renal disease to avoid chronic dialysis. Recipient and graft outcomes were superior to cadaver kidney transplantation. Motivated and emotionally related donors should be allowed to donate one of their kidneys provided that they are carefully selected and thoroughly informed.

[Kidney transplantation from living donors]. / Die Nierentransplantation von Lebendspendern.

Because of the severe shortage of cadaver organs, the transplantation of living donated organs from related and also from unrelated donors has been suggested; graft survival is similar or better than with cadaver kidneys. Therefore, kidneys from living donors are a large and valuable source for transplantation which help increase the pool of organs and thus decrease the time spent waiting for organ transplantation.