Donor organ intervention before kidney transplantation: Head-to-head comparison of therapeutic hypothermia, machine perfusion, and donor dopamine pretreatment. What is the evidence?

Therapeutic hypothermia, hypothermic pulsatile machine perfusion (MP), and renal-dose dopamine administered to stable brain-dead donors have shown efficacy to reduce the dialysis requirement after kidney transplantation. In a head-to-head comparison of the three major randomized controlled trials in this field, we estimated the number-needed-to-treat for each method, evaluated costs and inquired into special features regarding long-term outcomes. The MP and hypothermia trials used any dialysis requirement during the first postoperative week, whereas the dopamine trial assessed >1 dialysis session as primary endpoint. Compared to controls, the respective rates declined by 5.7% with MP, 10.9% with hypothermia, and 10.7% with dopamine. Costs to prevent one endpoint in one recipient amount to approximately $17 000 with MP but are negligible with the donor interventions. MP resulted in a borderline significant difference of 4% in 3-year graft survival, but a point of interest is that the preservation method was switched in 25 donors (4.6%) for technical reasons. Graft survival was not improved with dopamine on intention-to-treat but suggested an exposure-response relationship with infusion time. MP was less efficacious and cost-effective to prevent posttransplant dialysis. Whether the benefit on early graft dysfunction achieved with any method will improve long-term graft survival remains to be established.

Effects of Dopamine Donor Pretreatment on Graft Survival after Kidney Transplantation: A Randomized Trial.

BACKGROUND AND OBJECTIVES: Donor dopamine improves initial graft function after kidney transplantation due to antioxidant properties. We investigated if a 4 µg/kg per minute continuous dopamine infusion administered after brain-death confirmation affects long-term graft survival and examined the exposure-response relationship with treatment duration. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Five-year follow-up of 487 renal transplant patients from 60 European centers who had participated in the randomized, multicenter trial of dopamine donor pretreatment between 2004 and 2007 (ClinicalTrials.gov identifier: NCT00115115). RESULTS: Follow-up was complete in 99.2%. Graft survival was 72.6% versus 68.7% (P=0.34), and 83.3% versus 80.4% (P=0.42) after death-censoring in treatment and control arms according to trial assignment. Although infusion times varied substantially in the treatment arm (range 0-32.2 hours), duration of the dopamine infusion and all-cause graft failure exhibited an exposure-response relationship (hazard ratio, 0.96; 95% confidence interval [95% CI], 0.92 to 1.00, per hour). Cumulative frequency curves of graft survival and exposure time of the dopamine infusion indicated a maximum response rate at 7.10 hours (95% CI, 6.99 to 7.21), which almost coincided with the optimum infusion time for improvement of early graft function (7.05 hours; 95% CI, 6.92 to 7.18). Taking infusion time of 7.1 hours as threshold in subsequent graft survival analyses indicated a relevant benefit: Overall, 81.5% versus 68.5%; P=0.03; and 90.3% versus 80.2%; P=0.04 after death-censoring. CONCLUSIONS: We failed to show a significant graft survival advantage on intention-to-treat. Dopamine infusion time was very short in a considerable number of donors assigned to treatment. Our finding of a significant, nonlinear exposure-response relationship disclosed a threshold value of the dopamine infusion time that may improve long-term kidney graft survival.

Chorea in a patient with cryopyrin-associated periodic syndrome.

OBJECTIVE: To describe a patient with cryopyrin-associated periodic syndrome (CAPS) with an uncommon neurologic phenotype and a rare underlying genetic mutation. RESULTS: Our patient had CAPS with a rare NLPR3 missense mutation (p.Tyr859Cys) in exon 6 with chorea as the major symptom. Clinical symptoms were associated with persistent inflammatory changes of the CSF and serum and included elevated anticardiolipin immunoglobulin G; MRI showed prolonged gadolinium enhancement of 2 chronic inflammatory lesions. Conventional immunosuppressive treatment with prednisolone and hydroxychloroquine was insufficient. Neurologic symptoms, laboratory/chemical measures, and MRI abnormalities almost completely normalized following interleukin (IL)-1ß blockade with anakinra. CONCLUSIONS: This case is unique for its uncommon neurologic phenotype, the rare underlying genetic mutation, and the long course of the disease as well as almost complete recovery following appropriate therapy. In addition, the chronic inflammatory white matter lesions observed on brain MRI and the responsiveness to IL-1ß blockade with anakinra are unusual.

Excellent graft and patient survival after renal transplantation from donors after brain death with acute kidney injury: a case-control study.

BACKGROUND: Whether organs from donors after brain death (DBD) with acute kidney injury (AKI) should be accepted for transplantation is still a matter of debate. METHODS: This was a retrospective, center-based, matched cohort study of 33 renal transplant patients who received a renal allograft from a DBD with AKI. Sixty-five kidney transplants without donor AKI transplanted directly before and after the index transplantation served as controls. RESULTS: All AKI donors were classified according to RIFLE criteria: 9.1 % Risk, 54.6 % Injury, and 36.4 % Failure. Mean serum creatinine was 2.41 ± 0.88 mg/dL at procurement and 1.06 ± 0.32 mg/dL on admission. AKI donors had lower 24-h urine production (3.22 ± 1.95 vs. 4.59 ± 2.53 L, p = 0.009) and received more frequently noradrenaline (93.9 vs. 72.3 %, p = 0.02) and/or adrenaline (15.2 vs. 1.5 %, p = 0.02). Recipient and transplant characteristics were similar except a more favorable HLA match in control patients (p = 0.01). Hemodialysis posttransplant was more frequently used in AKI recipients (14/33 [42.4 %] vs. 18/65 [27.7 %], p = 0.17). While significant elevations in serum creatinine were noted in these patients until 10 days after transplantation, this difference lost statistical significance by day 14. One-year graft survival was very similar when comparing the groups (93.6 % [95 % CI 76.8-98.4 %] vs. 90.3 % [95 % CI 79.6-95.5 %], log rank p = 0.58). CONCLUSIONS: Kidneys from AKI donors can be transplanted with excellent intermediate prognosis and should not be discarded.

High interpatient variability in response to mycophenolic acid maintenance therapy in patients with ANCA-associated vasculitis.

BACKGROUND: Mycophenolic acid (MPA) is used in the maintenance therapy of antineutrophil cytoplasm antibody-associated systemic vasculitis (AASV). MPA exerts its immunosuppression by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), depleting activated lymphocytes of guanine nucleotides and retarding their proliferation. The purpose of our study was to examine the correlation between clinical outcome and pharmacokinetic-pharmacodynamic (PD) relationships of MPA in patients with AASV. METHODS: We studied 358 Caucasian control patients without any MPA therapy to examine basal IMPDH activity. Thirty Caucasian patients with AASV under maintenance therapy with mycophenolate mofetil (MMF) underwent therapeutic drug monitoring. RESULTS: We observed a high interindividual variability with regard to basal IMPDH activity in patients without any MPA treatment (0.8-35 nmol/mg protein/h). Patients were followed for a mean (±SD) period of 22 ± 8 months. During the observation period, seven patients had a relapse with an elevated Birmingham Vasculitis Activity Score of 9.2 ± 6. The basal IMPDH activity (Abasal) in patients who subsequently relapsed was raised at baseline, before receiving their first dose of MMF, and further increased at the time of relapse, when compared with stable patients. Patients with a relapse during the maintenance therapy had significantly higher levels of IMPDH activity [IMPDH enzyme activity curve (AEC) (0-12)] than stable patients (P = 0.001), indicating inadequate IMPDH suppression. MPA-AUC (0-12) was significantly decreased in relapse patients, in contrast to stable patients (P < 0.05). CONCLUSIONS: Due to the highly variable response to maintenance therapy with MPA, PD drug monitoring is a new tool for detecting inadequate immunosuppression in AASV patients.

Treatment of active lupus nephritis with the novel immunosuppressant 15-deoxyspergualin: an open-label dose escalation study.

INTRODUCTION: As the immunosuppressive potency of 15-deoxyspergualin (DSG) has been shown in the therapy of renal transplant rejection and Wegener's granulomatosis, the intention of this study was to evaluate the safety of DSG in the therapy of lupus nephritis (LN). METHODS: Patients with histologically proven active LN after prior treatment with at least one immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of one week. These cycles were repeated to a maximum of nine times. Doses of oral corticosteroids were gradually reduced to 7.5 mg/day or lower by cycle 4. Response was measured according to a predefined decision pattern. The dose of DSG was adjusted depending on the efficacy and side effects. RESULTS: A total of 21 patients were included in this phase-I/II study. After the first DSG injection, one patient was excluded from the study due to renal failure. Five patients dropped out due to adverse events or serious adverse events including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia. Eleven out of 20 patients achieved partial (4) or complete responses (7), 8 were judged as treatment failures and 1 patient was not assessable. Twelve patients completed all nine cycles; in those patients, proteinuria decreased from 5.88 g/day to 3.37 g/day (P = 0.028), Selena-SLEDAI (Safety of Estrogens in Lupus Erythematosus-National Assessment-systemic lupus erythematosus disease activity index) decreased from 17.6 to 11.7. In 13 out of 20 patients, proteinuria decreased by at least 50%; in 7 patients to less than 1 g/day. CONCLUSIONS: Although the number of patients was small, we could demonstrate that DSG provides a tolerably safe treatment for LN. The improvement in proteinuria encourages larger controlled trials. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00709722.

Differentiation between Wegener's granulomatosis and microscopic polyangiitis by an artificial neural network and by traditional methods.

OBJECTIVE: To investigate the operating characteristics of the American College of Rheumatology (ACR) traditional format criteria for Wegener's granulomatosis (WG), the Sørensen criteria for WG and microscopic polyangiitis (MPA), and the Chapel Hill nomenclature for WG and MPA. Further, to develop and validate improved criteria for distinguishing WG from MPA by an artificial neural network (ANN) and by traditional approaches [classification tree (CT), logistic regression (LR)]. METHODS: All criteria were applied to 240 patients with WG and 78 patients with MPA recruited by a multicenter study. To generate new classification criteria (ANN, CT, LR), 23 clinical measurements were assessed. Validation was performed by applying the same approaches to an independent monocenter cohort of 46 patients with WG and 21 patients with MPA. RESULTS: A total of 70.8% of the patients with WG and 7.7% of the patients with MPA from the multicenter cohort fulfilled the ACR criteria for WG (accuracy 76.1%). The accuracy of the Chapel Hill criteria for WG and MPA was only 35.0% and 55.3% (Sørensen criteria: 67.2% and 92.4%). In contrast, the ANN and CT achieved an accuracy of 94.3%, based on 4 measurements (involvement of nose, sinus, ear, and pulmonary nodules), all associated with WG. LR led to an accuracy of 92.8%. Inclusion of antineutrophil cytoplasmic antibodies did not improve the allocation. Validation of methods resulted in accuracy of 91.0% (ANN and CT) and 88.1% (LR). CONCLUSION: The ACR, Sørensen, and Chapel Hill criteria did not reliably separate WG from MPA. In contrast, an appropriately trained ANN and a CT differentiated between these disorders and performed better than LR.

Use of highly sensitive C-reactive protein for followup of Wegener's granulomatosis.

OBJECTIVE: Since Wegener's granulomatosis (WG) represents a relapsing disease, efforts have been made to reliably predict relapses using blood tests. Followup measures such as conventionally determined C-reactive protein (CRP), antineutrophil cytoplasmic antibody (C-ANCA) titer, and proteinase-3 (PR3) ELISA are applied. We evaluated whether during remission elevated highly sensitive CRP (hsCRP) precedes relapse as a marker of subclinical inflammation and thus might improve clinical assessment. METHODS: We investigated 227 sera of 57 patients with WG: 74 sera collected from patients in remission who subsequently relapsed (before relapse), 30 sera collected during relapse, and 123 sera from patients in remission without relapse. We also distinguished between major and minor relapse. hsCRP, conventionally determined CRP (CRP), C-ANCA, PR3-ELISA, and erythrocyte sedimentation rate (ESR) were measured using commercial kits, and levels were correlated to clinical status. RESULTS: Only hsCRP and ANCA titer, but not CRP levels, were higher in sera from patients who subsequently relapsed versus those who did not, indicating patients at risk. Levels of hsCRP, CRP, and ESR were higher in sera collected during relapse than in the sera before relapse. hsCRP, conventional CRP, and ESR were also higher in samples collected during major relapse than before major relapse. Looking at the levels just before relapse compared to previous levels during remission, none of these measures rose directly before the clinical manifestation of the relapse. CONCLUSION: Our study provides evidence for an additional value of hsCRP in the clinical assessment of patients with WG.

Proton pump inhibitors interfere with the immunosuppressive potency of mycophenolate mofetil.

OBJECTIVES: MMF is cleaved in the acidic milieu of the gastric compartment. However, its absorption might be impeded by proton pump inhibitors (PPIs), which suppress acid production and thus increase stomach pH. Since PPIs are widely used, it is useful to clarify whether the total drug amount of MMF is available in patients undergoing PPI treatment. METHODS: We analysed 36 patients with autoimmune diseases under stable MMF maintenance therapy. Twenty-three patients received co-medication with pantoprazole; 13 patients received no treatment with PPIs or antacids. To assess the immunosuppressive potency, we measured mycophenolic acid levels and inosin monophosphate dehydrogenase (IMPDH) activity with a validated HPLC method in plasma samples collected pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h after oral administration. RESULTS: The mean MMF dosage of the non-PPI patients was 770 (249) mg/12 h and 771 (291) mg/12 h in pantoprazole-treated patients (NS). The total area under the curve of MMF showed a 37% reduction in PPI patients vs those treated with no PPIs (P < 0.01), and the maximum peak concentration of MMF was 60% lower in the pantoprazole patients (P < 0.001). The MMF exposure correlated with the inhibition of IMPDH activity. The area of enzyme activity curve was 42% higher in the PPI patients (P < 0.01). CONCLUSIONS: The co-medication of pantoprazole with MMF significantly influences the drug exposure and immunosuppressive potency of MMF in patients with autoimmune diseases. This finding might at least partly explain the different outcomes in studies using MMF for maintenance therapy.

Retinoid X receptor beta polymorphisms do not explain functional differences in vitamins D and A response in Antineutrophil cytoplasmic antibody associated vasculitis patients.

It has been suggested that the retinoid X receptor beta (RXRB) gene is a risk factor for Wegener's granulomatosis. We addressed if there is a functional difference in the response to retinoic acid (RA) and vitamin D in Antineutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis (AASV) patients and if this was associated with RXRB genotypes. TNFalpha and IL-10 production were measured in whole blood assay from AASV patients (n = 51) and healthy controls (HC, n = 67). One micromolar of 1,25-(OH)(2) D3, 9-cis RA (9c-RA) or all-trans RA (ATRA) was added to the assay. Genotyping was performed for exons 7 and 2 of the RXRB gene and for a microsatellite in vicinity of the RXRB gene. Lipopolysaccharide (LPS) mediated TNFalpha production and IL-10 were significantly lower in patients. Addition of 1,25-(OH)(2) D3, ATRA or 9c-RA, blunted TNFalpha production, more pronounced in patients. Although all three compounds inhibited IL-10 production significantly in HC, only 1,25-(OH)(2) D3 was found to be effective in patients. Allele distribution of the RXRB microsatellite differed significantly between patients and HC. This was not found for the SNP in exons 2 and 7. Genotype of the latter correlated with the ability of 1,25-(OH)(2) D3 and ATRA to inhibit IL-10 production. We provide immunological evidence for a functional difference in vitamins D and A responsiveness in AASV patients. Since the inhibition of TNFalpha was more effective in patients, vitamin D supplementation might be an additional therapeutical approach.

Persistent T-cell activation and clinical correlations in patients with ANCA-associated systemic vasculitis.

BACKGROUND: Although in antineutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitis (AASV) patients, activation of T-cells has been described, persistence of these alterations has not been well characterized. This study was conducted to define persistent T-cell activation (PTA) in AASV patients and to assess whether this correlates with disease activity, disease severity, age or therapy. METHODS: The expression of CD4, CD45RO, CD25, CD26, CD28, CCR7 and HLA-DR was examined longitudinally in 38 consecutive AASV patients. Clinical parameters were compared by univariate and multiple analysis and Kaplan-Meier curves for relapse-free survival were calculated. RESULTS: PTA could be defined as either of two activation phenotypes, i.e. a low percentage of CD4+ CD45RO- T-cells or a high percentage of CD25 in the naïve CD4+ population (n = 26), since only these phenotypes were stable over time and were not associated with active disease. In patients with PTA, major organ involvement was significantly more often found than in patients without PTA. Moreover, the cumulative cyclophosphamide dose (26.86 vs 8.53 P < 0.01) was significantly increased in these patients, suggesting that PTA was associated with disease severity. In general, patients with PTA were older than those without (62.92 +/- 9.4 years vs 48.42 +/- 16.9 years respectively, P < 0.01). PTA was independent of disease duration. Interestingly, patients with a low percentage of CD4+CD45RO- T-cells were significantly more often diagnosed as microscopic polyangiitis (P < 0.01). CONCLUSION: We identified two independent phenotypes of T-cell activation in AASV patients. These phenotypes are persistent and do not reflect disease activity. PTA predominantly occurs in patients with severe disease. This might explain the higher cumulative cyclophosphamide dose found in these patients.

Severe TNF receptor-associated periodic syndrome due to 2 TNFRSF1A mutations including a new F60V substitution.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is typically characterized by episodic fever, myalgia, skin rash, conjunctivitis, and abdominal cramps. Recently, mutations in the TNFRSF1A gene on chromosome 12p13 encoding tumor necrosis factor receptor type 1 have been linked to this autoinflammatory syndrome. We report the case of a 29-year-old white woman who experienced periodic inflammatory manifestations with fever up to 40 degrees C, leukocytosis, and elevation of C-reactive protein level (>100 mg/L) in conjunction with acute peritonitis of unknown origin since the age of 19 years. The patient had undergone 2 laparotomies with appendectomy and left hemicolectomy. Familial Mediterranean fever was excluded by sequencing of the MEFV gene. In view of the possibility of TRAPS, sequence analysis of the TNFRSF1A gene was also performed. The patient carried a novel T-->G substitution in exon 3, leading to the replacement of phenylalanine by valine at amino acid position 60 (F60V), as well as the common R92Q low-penetrance mutation, encoded by exon 4. Upon the next flare, the patient started corticosteroid therapy, resulting in complete relief and normalization of elevated C-reactive protein levels. To the best of our knowledge, we report the first case of compound heterozygosity for 2 TNFRSF1A gene mutations, including a novel one that causes a severe form of TRAPS that responds to anti-inflammatory treatment. A history of recurrent sterile peritonitis should prompt genotyping for periodic fever syndromes.

Serial ANCA determinations for monitoring disease activity in patients with ANCA-associated vasculitis: systematic review.

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCAs) are considered by some investigators to be sensitive markers of disease activity and have been suggested to predict relapse and guide therapeutic decisions. Studies using serial ANCA monitoring in patients with ANCA-associated vasculitis (AASV) have yielded controversial results during the last 15 years. To assess the diagnostic value of serial ANCA testing in the follow-up of patients with AASV, we conducted a systematic review of the available literature. METHODS: Studies were identified by a comprehensive search of the PubMed and BIOSIS+/RRM databases, as well as hand searching. Method quality of all eligible studies was assessed with respect to external and internal validity according to established criteria for diagnostic studies. RESULTS: Twenty-two studies met our inclusion criteria, including a total of 950 patients. Whereas generalizability was not a major problem, assessment of internal validity showed that only a minority of studies reported the combination of consecutive patient recruitment, prospective data collection, and independent determination of both index and reference tests, considered as the ideal for diagnostic test studies. Quantitative meta-analytic calculations were not conducted because of the presence of considerable method heterogeneity. CONCLUSION: The presence of considerable methodological heterogeneity combined with methodological shortcomings with respect to internal validity in the majority of included studies preclude firm conclusions from the available literature concerning the clinical value of serial ANCA determinations for monitoring the follow-up of patients with AASV.

Prolonged treatment of refractory Wegener's granulomatosis with 15-deoxyspergualin: an open study in seven patients.

BACKGROUND: A subset of patients with Wegener's granulomatosis does not respond to daily oral cyclophosphamide (CYC) plus corticosteroids or suffers from intolerable side effects. A 6 month course of the immunosuppressant 15-deoxyspergualin (DSG) has previously been employed successfully in these refractory cases. However, there are no reports on long-term treatment with DSG. METHODS: To document the effects of prolonged DSG treatment, this study reports on seven patients suffering refractory Wegener's granulomatosis, who were successfully treated with DSG over an average of 26.5 months (range: 11-55.5 months). RESULTS: Before administration of DSG, patients had experienced an average of 6.6 relapses (range: 3-12) under an average of 5.4 (range: 2-11) different therapeutic approaches, which included CYC in all cases. All suffered active disease when DSG was initiated. Four were unresponsive to CYC and three did not tolerate it. DSG (0.5 mg/kg/day subcutaneous) was given for 2-3 weeks until the leukocyte count dropped to 3000/microl, followed by a rest until a leukocyte count of 4000/microl was reached again. No other immunosuppressants besides corticosteroids were given. All patients showed a long-lasting, favourable response to DSG with complete (n = 5) or partial (n = 2) remission. Only one case relapsed while being treated with DSG. Termination/interruption of DSG was followed by relapse in four of five occasions. Resumption of DSG led to complete remission. Currently, five of the seven patients are still treated with DSG and are in remission. Infections, mainly of the respiratory tract, were observed in five cases and resolved after treatment. One case developed a third-degree heart block that required pacing. CONCLUSIONS: In patients with refractory Wegener's granulomatosis, prolonged treatment with DSG seems safe and successful.

Newer insights into the aetiology and pathogenesis of myeloperoxidase associated autoimmunity.

In recent years there have been substantial developments in the understanding of the aetiology and pathogenesis of ANCA-associated vasculitides, including myeloperoxidase (MPO) associated autoimmunity. This review will describe genetic and environmental factors that may increase the risk for the disease and will summarise findings demonstrating that T-cells, B-cells and ANCA themselves are of pathogenetic significance. Leukocyte gene expression profiles indicate that the reactivation of granule protein genes contributes to the pathogenesis of AASV. Finally, data derived from closely related autoantibodies against proteinase 3 (PR3) suggest anti-idiotypic antibodies induced by antisense transcripts as potential pathological agents.