Transplant-associated thrombotic microangiopathy is an endothelial complication associated with refractoriness of acute GvHD.

There is increasing evidence that endothelial dysfunction is involved in refractoriness of acute GvHD (aGvHD). Here we investigated the hypothesis that another endothelial complication, transplant-associated thrombotic microangiopathy (TMA), contributes to the pathogenesis of aGvHD refractoriness. TMA was retrospectively assessed in 771 patients after allogeneic stem cell transplantation (alloSCT). Incidences of TMA and refractory aGvHD were correlated with biomarkers of endothelial damage obtained before alloSCT for patients receiving or not receiving statin-based endothelial prophylaxis (SEP). Diagnostic criteria for TMA and refractory aGvHD were met by 41 (5.3%) and 76 (10%) patients, respectively. TMA was overrepresented in patients with refractory aGvHD (45.0 vs 2.3% in all other patients, P<0.001). TMA independently increased mortality. Elevated pretransplant suppressor of tumorigenicity-2 and nitrates along with high-risk variants of the thrombomodulin gene were associated with increased risk of TMA. In contrast, SEP abolished the unfavorable outcome predicted by pretransplant biomarkers on TMA risk. Patients on SEP had a significantly lower risk of TMA (P=0.001) and refractory aGvHD (P=0.055) in a multivariate multistate model. Our data provide evidence that TMA contributes to the pathogenesis of aGvHD refractoriness. Patients with an increased TMA risk can be identified pretransplant and may benefit from pharmacological endothelium protection.

Pre-transplant soluble CD30 in combination with total DSA but not pre-transplant C1q-DSA predicts antibody-mediated graft loss in presensitized high-risk kidney transplant recipients.

Presensitized kidney transplant recipients are at high-risk for early antibody-mediated rejection. We studied the impact of pre- and post-transplant donor-specific human leukocyte antigen (HLA) antibodies (DSA) and T-cell-activation on the occurrence of antibody-mediated rejection episodes (AMR) and graft loss (AMR-GL) in a unique cohort of 80 desensitized high-risk kidney transplant recipients. Patients with pre-transplant DSA demonstrated more AMR episodes than patients without DSA, but did not show a significantly increased rate of AMR-GL. The rates of AMR and AMR-GL were not significantly increased in patients with complement split product (C1q)-binding pre-transplant DSA. Pre-transplant C1q-DSA became undetectable post-transplant in 11 of 13 (85%) patients; 2 (18%) of these 11 patients showed AMR but no AMR-GL. In contrast, the post-transplant presence of C1q-DSA was associated with significantly higher rates of AMR (86 vs 33 vs 0%; P < 0.001) and AMR-GL (86 vs 0 vs 0%; log-rank P < 0.001) compared with post-transplant DSA without C1q-binding or the absence of DSA. Patients with both pre-transplant DSA and evidence of pre-transplant T-cell-activation as indicated by soluble CD30-positivity showed a significantly increased risk for AMR-GL [HR = 11.1, 95% confidence interval (CI) = 1.68-73.4; log-rank P = 0.013]. In these high-risk patients, AMR-GL was associated with total DSA in combination with T-cell-activation pre-transplant, and de novo or persistent C1q-binding DSA post-transplant.

Bortezomib improves outcome after SCT in multiple myeloma patients with end-stage renal failure.

Patients with multiple myeloma and dialysis-dependent renal failure have dismal outcomes. In this retrospective analysis of a case series, we evaluated 27 consecutive patients, all of whom required haemodialysis at the time of first-line induction therapy with either bortezomib or a standard regimen followed by high-dose chemotherapy and auto-SCT. The overall response rate was significantly better after bortezomib-based induction before auto-SCT (83% vs 36%, P=0.02) and at day +100 post auto-SCT (100% vs 58%, P=0.01). Bortezomib also prolonged EFS and furthermore, a trend towards a shorter time on haemodialysis was observed in the bortezomib group at a median of 6.1 months (0.2-68.2 months) vs 17.1 months (0.7-94.3 months, P=0.38) in patients who had received vincristine, adriamycin, dexamethasone or vincristine, adriamycin, dexamethasone-like induction regimens. These data demonstrate the superior efficacy of bortezomib-based induction therapy in transplant-eligible patients with end-stage renal failure.

[Modern immunosuppression after solid organ transplantation]. / Moderne Immunsuppression nach Organtransplantation.

The one common factor in solid organ transplantation is the need for lifelong maintenance immunosuppression. Drug regimens after organ transplantation typically comprise a combination of different immunosuppressive drugs. In most cases a triple drug regimen with different mechanisms of action is used. The aim is to improve both patient and graft survival while minimizing potential side effects of immunosuppressive medication. The basis of most immunosuppressive regimens is calcineurin inhibitors in combination with mycophenolic acid. There are various stages of immunosuppression after solid organ transplantation involving induction therapy, initial and long-term maintenance therapy. In each phase an individual combination of immunosuppressants is set up depending on the risk profile of the individual patient to prevent transplant rejection and organ loss. Based on these considerations, concepts of calcineurin inhibitor or steroid reduction have been established in transplant medicine in recent years. The key role in terms of development of new immunosuppressive strategies is taken by kidney transplantation, the most common solid organ transplantation performed.

Cytomegalovirus infection of the major duodenal papilla in a renal allograft recipient with severe biliary obstruction and acalculous cholecystitis.

Cytomegalovirus (CMV) can cause severe infections with serious consequences in renal transplant recipients. Disseminated CMV infections can affect almost every organ, but obstructive cholestasis and cholangitis, as a consequence of a CMV-induced papillitis, is extremely rare. We are reporting a rare case of obstructive cholestasis and cholecystitis due to CMV-related inflammation of the major duodenal papilla in a 60-year-old woman 3 months after renal transplantation. In addition, the patient suffered from a disseminated CMV infection with ulcerative esophagitis and gastritis. Because of the severe CMV infection, failure of the renal graft occurred. Obstructive cholestasis was resolved through internal stenting, and the progressive cholecystitis necessitated an emergency cholecystectomy. Following antiviral therapy with ganciclovir, the gastrointestinal ulcerations regressed and renal function was restored. Diagnosis of the CMV-related disease was established only in tissue samples, whereas standard serologic tests had failed.

Familial Mediterranean fever in Germany: clinical presentation and amyloidosis risk.

OBJECTIVE: To characterize patients with familial Mediterranean fever (FMF) with and without AA amyloidosis living in Germany. METHOD: Clinical and genetic data from 64 FMF patients were analysed for amyloidosis risk factors. RESULTS: Fifty-five patients (85%) were of Turkish or Armenian origin. Thirty-one patients (48%) developed FMF symptoms before the age of 16 years. Sixteen patients (26%) became symptomatic after age 20. Symptoms reported were peritonitis (95%), fever (78%), pleuritis (59%), arthralgia (60%), arthritis (32%), erysipelas-like erythema (23%), and vasculitis (8%). FMF diagnosis was delayed for a median of 8.0 years. Genetic analysis confirmed M694V as the most prevalent Mediterranean fever (MEFV) gene mutation in 46 out of 59 patients (78%). M694V homozygosity was associated with an earlier FMF onset (median age 5.5 years, p = 0.0001) and a higher prevalence of peritonitis (p = 0.007) and pleuritis (p = 0.0007) compared to patients without an M694V mutation. AA amyloidosis was detected in 16 patients (25%) at a median age of 36.5 years and tended to be associated with a higher age at disease onset (p = 0.062) and a higher FMF activity score (p = 0.093). AA amyloidosis was significantly associated with a higher age at FMF diagnosis (p = 0.0022). CONCLUSIONS: Clinical symptoms of FMF-affected migrants living in Germany resemble those observed in their home country. In particular, patients with an onset of FMF symptoms after age 20 and a later FMF diagnosis have a high risk of AA amyloidosis. Symptomatic patients who originate from countries with a higher FMF prevalence should be screened for FMF and proteinuria.

[Systemic amyloidoses]. / Systemische Amyloidosen.

Amyloidoses are rare protein folding disorders, in which proteins are deposited as insoluble fibrillar aggregates due to a conformational change. This can occur in a local or systemic form. Systemic amyloidoses are life-threatening complications of monoclonal gammopathy, chronic inflammatory diseases or within hereditary diseases. The causative treatment of amyloidosis is the reduction of the amyloid precursor protein by chemotherapy, anti-inflammatory treatment, or liver transplantation. Early diagnosis of the disease is essential in order to effectively treat patients and avoid further deterioration of organ functions.

Borderline rejection after renal transplantation--to treat or not to treat.

According to the Banff classification of renal allograft pathology, the category borderline changes defines changes insufficient for a diagnosis of acute rejection. The relationship between borderline changes and acute renal allograft rejection still remains unclear. The appropriate clinical management for patients showing such changes is controversial. One possible interpretation of the high incidence of subacute tubulitis is that these changes in the absence of graft dysfunction are of no consequence and that treatment with intensified immunosuppression is unnecessary and perhaps harmful. Another view, consistent with the high incidence of CAN in late protocol biopsy studies, is that immunosuppression has become so powerful, that rejection may not even be manifested by a rising serum creatinine. Borderline changes should be used as part of an algorithm, but not as the only criterion, for therapeutic decision making. Based on the weak evidence of existing studies, in our patients with clinical borderline rejection, we have to weigh the individual immunological risk against the potential side effects of increased immunosuppression. Even in the knowledge that a majority of patients with borderline infiltrates will not progress into rejection, in many transplant centers, borderline rejection is treated with additional steroids or augmentation of maintenance immunosuppression.

Cardiac biomarkers and survival in haemodialysis patients.

BACKGROUND: In dialysis patients, cardiac troponin T (cTNT) is often elevated despite the absence of acute myocardial ischaemia, and amino-terminal pro-B-natriuretic peptide (NT-proBNP) is markedly higher compared to non-haemodialysis patients. In a longitudinal observation, we evaluated the association of cTNT and NT-proBNP on cardiovascular morbidity and mortality in haemodialysis patients with and without fluid overload. MATERIALS AND METHODS: Plasma cTNT levels of 134 haemodialysis patients were measured before and after a dialysis session by 3rd generation electro-chemoluminiscence immunoassay. NT-proBNP was determined using a polyclonal antibody recognizing the N-terminal fragment of BNP (Elecsys autoanalyzer 2010, Roche Diagnostics, Mannheim, Germany). Volume status was determined by a clinical score system. Cardiovascular morbidity and mortality were assessed over a follow-up period of 36 months. RESULTS: Plasma cTNT > 0.03 ng mL(-1) was found in 39.6% of all patients. Patients with hypervolaemia had significantly higher cTNT levels compared to euvolaemic patients (median 0.054 ng mL(-1), interquartile range 0.019-0.153 vs. 0.005 ng mL(-1), < 0.001-0.034; P < 0.001). All haemodialysis patients had excessively high levels of NT-proBNP (median 4524; interquartile range 2000-10 250 pg mL(-1)), and NT-proBNP was significantly higher in hypervolaemic haemodialysis patients (11 988, 5307-19 242) compared to euvolaemic haemodialysis patients (3247, 1619-5574); P < 0.001. Receiver operator curves showed a threshold of cTNT > 0.026 ng mL(-1) and NT-proBNP > 5300 pg mL(-1) as predictors of hypervolaemia. Asymptomatic chronic haemodialysis patients with cTNT > 0.026 ng mL(-1) and NT-proBNP > 5300 pg mL(-1) were more likely to die due to cardiac events in the follow-up period. Multivariate analysis documented that elevated cTNT and NT-proBNP levels were highly predictive for cardiovascular events. CONCLUSIONS: Plasma levels of cTNT are elevated in approximately 40% and NT-proBNP levels in 100% of asymptomatic chronic haemodialysis patients. Both parameters depend on volume status. Increased NT-proBNP and cTNT are strongly associated with adverse outcome in end-stage renal disease patients undergoing haemodialysis, and are a useful tool for risk stratification in chronic haemodialysis patients.

Four cases of sirolimus-associated interstitial pneumonitis: identification of risk factors.

Sirolimus-associated interstitial pneumonitis is a severe side effect of sirolimus therapy; fatal outcomes have been described. We report 4 patients with sirolimus-associated interstitial pneumonitis and review the literature for risk factors for the development of disease. Until June 2005, 48 patients received either de novo sirolimus treatment (n = 7) or were switched from a calcineurin inhibitor-containing regimen to a sirolimus-based protocol for various indications (n = 41). Compared with the 44 patients on sirolimus therapy with no evidence of a disorder, the 4 patients (8.3%) who developed suspected sirolimus-associated interstitial pneumonitis showed no difference in gender, immunosuppressive therapy, days posttransplantation, comorbidity, or preexistent lung disease. Several points, however, are of interest. None of the de novo-treated patients except 4 patients (9.8%) with late administration of sirolimus developed interstitial pneumonitis. The 4 patients with interstitial pneumonitis tended to be older (58.7 +/- 5.5 vs 46.9 +/- 1.7 years) and received higher sirolimus doses (3.5 +/- 0.5 vs 1.4 +/- 0.2 mg/d) with greater trough levels (15.4 +/- 2.9 vs 8.0 +/- 1.2 micro g/L) at the onset of symptoms. Most notably, all patients with interstitial pneumonitis had a loading dose at the start of therapy, and an increase in sirolimus dose (or trough level) within 3 weeks prior to the onset of symptoms. Additional potential risk factors identified from the literature include allograft dysfunction, hypervolemia, and male gender. With careful monitoring (or even exclusion from therapy) of patients at risk for the development of disease, we have had no case of sirolimus-associated interstitial pneumonitis since September 2004.

Desensitization strategies enabling successful renal transplantation in highly sensitized patients.

Currently, the number of highly sensitized patients awaiting a renal transplant is increasing on the waiting lists of different organ exchange organizations. Due to the presence of antibodies against a broad variety of human leukocyte antigen (HLA) specificities, highly sensitized patients have a markedly reduced chance of receiving a crossmatch-negative organ. It has long been recognized that hyperacute rejection is associated with the presence of donor-specific anti-HLA antibodies at the time of transplantation. Meanwhile treatment protocols have been developed to achieve successful transplantation across antibody barriers. Therefore, the presence of donor-specific anti-HLA antibodies and a positive serological crossmatch are no longer considered as an absolute contraindication to renal transplantation. Mainly, two desensitization protocols have been established in order to overcome a positive crossmatch or to enhance the chance of highly sensitized patients to receive a crossmatch-negative organ: high-dose intravenous immunoglobulin (IVIg) or low-dose IVIg in combination with plasmapheresis. Herein, we summarize the characteristics of these two treatment regimes along with other alternative approaches that are currently used for the management of kidney graft recipients with broad alloantibody reactivity against potential kidney donors.

Cyclophosphamide treatment in systemic necrotizing vasculitis and lupus nephritis. How long? How much?

The gold standard for inducing remission in systemic necrotizing vasculitis (SNV) and severe lupus nephritis is (and remains) the combination of cyclophosphamide and glucocorticoids. Long-term treatment with cyclophosphamide is limited because of toxicity. Recent prospective studies in antineutrophil cytoplasmic antibody (ANCA)-associated SNV revealed that after achievement of clinical remission (usually within 3-4 months after starting cyclophosphamide) cyclophosphamide can be replaced by azathioprine with no increase in relapse rates if treatment is continued for at least 1 year. Methotrexate is inferior to cyclophosphamide because of increased relapse rates-particularly in those with renal involvement-during follow-up. An ongoing study comparing mycophenolate mofetil (MMF) with azathioprine will clarify whether MMF is as successful as azathioprine or even better. The concomitant use of tumor necrosis factor (TNF)-alpha blockers increases the efficacy of immunosuppression. TNF-alpha blockers may be added if SNV is refractory to standard immunosuppressive therapy. However, with this addition to therapy, systemic infections are more frequent. In patients with severe lupus nephritis (WHO IV) the efficacy of combined i.v. therapy with cyclophosphamide and glucocorticoids was shown by NIH trials. This NIH regimen competes with the EURO-Lupus nephritis schedule with a lower dose of i.v. cyclophosphamide followed by maintenance therapy with azathioprine. Long-term follow-up is, however, still lacking in the EURO-Lupus trial. Ongoing prospective studies will reveal whether cyclophosphamide may be substituted by MMF from the very beginning or whether MMF is superior to azathioprine during maintenance therapy of lupus nephritis.