Michael Kammer

Real-Time PCR Assays for the Quantification of HCV RNA: Concordance, Discrepancies and Implications for Response Guided Therapy

Background and Aims Monitoring of chronic Hepatitis C (CHC) treatment relies on HCV RNA quantification by means of real-time PCR methods. Assay specific analytical sensitivities may impact therapy management. Methods Comparative analysis between three commercial assays (Roche COBAS AmpliPrep/COBAS TaqMan Version 1 (CAP/CTM Ver. 1), Version 2 (CAP/CTM Ver. 2) and the Abbott RealTime HCV (ART) assay) was performed on 247 available samples taken at key decision time points during antiviral therapy of 105 genotype 1 patients (triple therapy: n = 70; dual therapy: n = 35). Results Overall concordance of HCV RNA measurements was high between the two Roche systems (89%; n = 220/247) but lower between the Roche assays and the ART (CAP/CTM Ver. 1 vs ART: 77.3%; n = 191/247 and CAP/CTM v.2 vs ART: 80.1%; n = 198/247). Most discrepancies were noted in week 4/8 samples with residual viremia (<LLOQ) detected by ART (<LLOQ: n = 45, 44.1%) but undetectable HCV RNA by CAP/CTM Ver. 1 (<LLOQ: n = 18, 17.6%) or CAP/CTM Ver. 2 (<LLOQ: n = 26, 25.5%). Based on results by CAP/CTM Ver. 1, 13 eligible patients underwent an abbreviated course of therapy (24 weeks). Only 1 patient experienced virologic breakthrough. If tested by ART, only 6/13 patients (46.2%) would have been eligible for shortened treatment. Consequently, RGT guidelines were adapted and shortening of therapy was allowed if residual viremia was detected by ART at week 4/8. Conclusion An abbreviated course of treatment can safely be applied in patients with residual viremia (<LLOQ) detected by ART in samples collected at week 4/8 of treatment.

The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study

Essentials Long‐term recurrence risk of venous thromboembolism (VTE) is uncertain. We performed a prospective cohort study of 839 patients with first unprovoked VTE. VTE recurrence risk is high, particularly in men with proximal thrombosis or pulmonary embolism. Sex and VTE site determine the recurrence risk and should be considered for patient counseling.

Survival analysis of conservative vs. dialysis treatment of elderly patients with CKD stage 5

Elderly patients represent a growing population among people suffering from ESRD. So far only limited data on actual survival benefits of elderly adults initiating dialysis have been published. Besides the high burden of preexisting comorbidities, dialysis treatment itself may be associated with a further deterioration in functional status in this population. We retrospectively analyzed the Austrian Dialysis and Transplant Registry and identified 8,622 patients who started maintenance hemodialysis after the age of 65 years between 2002 and 2009. We compared this data set to a cohort of 174 patients aged over 65 years with CKD stage 5 who progressed to an eGFR < 10ml/min/ and were managed conservatively in the same era. All patients who died of malignant disease were excluded from this analysis. The risk of mortality was analyzed using multivariable Cox proportional hazards models. Furthermore, a parametric model of time to event analysis was used for visualization of changing risk over time and precise calculation of time to equal risk assuming a Weibull distribution. Hemodialysis treatment was associated with a decreased risk for death with a HR of 0.23 (95% CI 0.18 to 0.29; p<0.001) compared to conservative treatment. The time to event analysis however showed, that although survival was initially superior in the hemodialysis group, hazards crossed thereafter. Time to equal risk was 2.9 months and 1.9 months for female and male patient aged 65, respectively, and decreased to one month in the very elderly aged 95. Elderly patients with ERSD did benefit from initiation of hemodialysis, as the conservative group showed a very high initial mortality rate. This survival benefit of dialysis treatment however did not persist beyond the first two months compared to survivors of the conservative group.

The influence of thiazide intake on calcium and parathyroid hormone levels in patients with primary hyperparathyroidism.

The effects of thiazide medication in patients with primary hyperparathyroidism (PHPT) have so far not been elucidated. The aim of this study was to analyse the extent to which the administration of thiazides may influence biochemical parameters and therefore the diagnosis of PHPT in a large cohort of patients.

Regression of left atrial diameter after kidney transplantation is associated with prolonged survival: an observational study

Renal transplantation reduces the dramatically elevated risk of cardiovascular death in dialysis patients. We previously showed that left atrial diameter before transplantation predicts cardiovascular and overall mortality. Now, we investigated the association of changes in cardiac morphology after transplantation and mortality. We retrospectively analyzed data from the Austrian transplant repository using multivariable Cox and competing risk models and multivariable logistic regression for the prediction of changes in cardiac morphology. We identified 414 patients with a median follow‐up of 8 years and observed a significant progression of mean diameter of left atrium (LA), right atrium and right ventricle and a significant regression of left ventricle. Complete case analysis of 243 patients with a regression of initially enlarged LA diameter had a significantly lower risk of adjusted overall and cardiovascular mortality; hazard ratio (HR 0.45, 95% CI 0.30–0.69, P < 0.001, 124 deaths), and HR of 0.43 [95% CI 0.21–0.92, P = 0.029, 48 cardiovascular (CV) deaths], respectively. Only age at transplantation was significantly associated with regression of LA (OR 0.75, 95% CI 0.60–0.93, P = 0.007). Patients with regression of LA after kidney transplantation exhibited a lower overall and CV mortality risk. Besides age, peritoneal dialysis and antihypertensive therapy were mediators of LA regression.

Natural antibodies to oxidation-specific epitopes: Innate immune response and venous thromboembolic disease

Essentials Natural antibodies to oxidation‐specific epitopes have antithrombotic properties. We evaluated the relation between natural IgM and IgG antibodies and the venous thrombosis risk. Risk of recurrent thrombosis was higher in patients with low natural IgM antibody levels. The protective effect of high IgM levels suggests a role of innate immune response in thrombosis.

Risk of venous thromboembolism during rehabilitation of patients with spinal cord injury

Background Patients with spinal cord injury (SCI) are at risk of thrombosis and bleeding. Data on the risks during rehabilitation are inconsistent, and thromboprophylactic strategies are heterogeneous. We aimed to evaluate the thrombotic risk and bleeding events of SCI patients during rehabilitation. Methods We retrospectively collected hospital record data of 263 consecutive SCI patients admitted at a rehabilitation clinic. 78 patients with acute venous thromboembolism (VTE) at the primary center, without acute trauma or lower extremity paresis, less than one month rehabilitation, or reasons for long-term therapeutic anticoagulation, were excluded. All patients received pharmacologic thromboprophylaxis throughout rehabilitation. Primary endpoint was objectively diagnosed VTE; secondary endpoint was bleeding. Results Of 185 patients, 162 (88%) were men; mean age was 47.8 years. 94 patients were tetraplegic, 91 paraplegic. During a mean (±SD) time of 5.1±2.1 months, VTE was diagnosed in 8 patients. After excluding five patients with VTE detected within 2 days after admission, the probability of developing VTE after 6 months of rehabilitation was 2% (95% CI 0–4.4%). Only high D-Dimer upon admission was associated with risk of VTE (adjusted HR 2.3, 95% CI 1.4–4.1). Of 24 bleedings, 14 (64%) occurred at the heparin injection site. Two patients had major bleeding and five had clinically relevant non major bleeding. Conclusion SCI patients are at risk of VTE and bleeding during rehabilitation. Strategies need to be developed to identify these patients in order to initiate adequate anticoagulation. Direct oral anticoagulants, which have a favourable risk-benefit profile and are convenient, should be explored.

Dialysis vintage and outcomes in renal transplantation

Pre-emptive kidney transplantation is the recommended strategy for patients with end-stage renal failure in all guidelines [Kidney Disease: Improving Global Outcomes (KDIGO), The Australian and New Zealand Dialysis and Transplantation Registry (ANZDATA), European Renal Best Practice Guideline (ERBP), British Transplant Society (BTS)]. This recommendation is intuitive and based on few older studies with considerable limitations. In addition, there is conflicting evidence as to whether the duration of dialysis vintage impacts on graft and patient survival after transplantation. The objective of this structured review was to critically review the published evidence on dialysis vintage and outcomes by including the most recent papers on that topic. We searched Medline using keywords for kidney transplantation, pre-emptive, dialysis vintage and relevant outcomes, and found 14 eligible cohort studies. The best evidence was found for pre-emptive transplantation, which was found to be associated with a lower risk of actual graft loss (including death as event) compared with non-pre-emptive transplantation. When only patients were considered that have been registered pre-emptively but then received or did not receive a pre-emptive transplant, the association with functional graft survival (excluding death as event) was only marginal. Dialysis vintage had a graded association with patient survival in most of the studies, but an unclear estimate with functional graft survival. Older studies also found an association of dialysis vintage with death-censored graft survival, but this association is likely confounded by selection and the competing risk of death and was no longer observed in recent eras, i.e. in transplants performed in the last decade. In summary, the recommendation for pre-emptive kidney transplantation for optimal patient and graft survival remains valid even in recent periods but the association of dialysis vintage after dialysis initiation with death-censored graft survival is less clear. The association of dialysis vintage with mortality after transplantation depends on the median duration of dialysis of the wait-listed population as well as acceptance rates for transplantation, and may thus be country specific. Nevertheless, it is reasonable to advocate pre-emptive kidney transplantation in all age groups. What remains unsolved is the selection issues since the reasons for longer waiting time on dialysis are difficult to capture in retrospective observational studies, and lead time as well as immortal time bias may have confounded the mortality data.

Validation of Plasma Biomarker Candidates for the Prediction of eGFR Decline in Patients With Type 2 Diabetes.

OBJECTIVE The decline of estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes is variable, and early interventions would likely be cost-effective. We elucidated the contribution of 17 plasma biomarkers to the prediction of eGFR loss on top of clinical risk factors. RESEARCH DESIGN AND METHODS We studied participants in PROVALID (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers), a prospective multinational cohort study of patients with type 2 diabetes and a follow-up of more than 24 months (n = 2,560; baseline median eGFR, 84 mL/min/1.73 m2; urine albumin-to-creatinine ratio, 8.1 mg/g). The 17 biomarkers were measured at baseline in 481 samples using Luminex and ELISA. The prediction of eGFR decline was evaluated by linear mixed modeling. RESULTS In univariable analyses, 9 of the 17 markers showed significant differences in median concentration between stable and fast-progressing patients. A linear mixed model for eGFR obtained by variable selection exhibited an adjusted R2 of 62%. A panel of 12 biomarkers was selected by the procedure and accounted for 34% of the total explained variability, of which 32% was due to 5 markers. The individual contribution of each biomarker to the prediction of eGFR decline on top of clinical predictors was generally low. When included into the model, baseline eGFR exhibited the largest explained variability of eGFR decline (R2 of 79%), and the contribution of each biomarker dropped below 1%. CONCLUSIONS In this longitudinal study of patients with type 2 diabetes and maintained eGFR at baseline, 12 of the 17 candidate biomarkers were associated with eGFR decline, but their predictive power was low.

Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft‐versus‐host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor‐specific tolerance results in improved outcomes remains unanswered. We collected follow‐up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper‐matched living‐donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72‐99) in the tolerant cohort and 118 μmol/l (IQR 99‐143) in the control group. Mixed linear‐model showed around 29% lower average creatinine levels throughout follow‐up in the tolerant group (P < .01). Our data clearly show stable renal graft function without long‐term immunosuppression for many years, suggesting permanent donor‐specific tolerance. Thus sequential transplantation might be an alternative approach for future studies targeting tolerance induction in renal allograft recipients.