Erik H. Strøm

Conversion of Long-Term Kidney Transplant Recipients From Calcineurin Inhibitor Therapy to Everolimus: A Randomized, Multicenter, 24-Month Study

Background. Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain. Methods. ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30–70 mL/min/1.73 m2) were randomized to everolimus with CNI elimination (n=127) or CNI minimization (n=144), or continued CNI unchanged (controls, n=123) to assess the effect on measured GFR at month 24 after randomization. Results. Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0±22.0 mL/min/1.73 m2, 46.6±21.1 mL/min/1.73 m2, and 46.0±20.4 mL/min/1.73 m2 in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m2, 95% confidence interval [CI] −3.51 to 5.76, P=0.63) and CNI minimization (0.59 mL/min/1.73 m2, 95% CI −3.88 to 5.07, P=0.79) versus controls at month 24 were nonsignificant that is, the primary endpoint was not met. No efficacy endpoint differed significantly between groups. Post hoc analyses showed that patients with baseline creatinine clearance (CrCl) more than 50 mL/min had a significantly greater increase in measured GFR after CNI elimination versus controls (difference 11.4 mL/min/1.73 m2, 95% CI 2.1 to 20.8 mL/min/1.73 m2, P=0.017). Adverse events resulted in discontinuation in 36 (28.3%) CNI elimination patients, 24 (16.7%) CNI minimization patients, and 5 (4.1%) controls (P<0.001 vs. CNI elimination; P=0.020 vs. CNI minimization). Conclusion. Conversion to everolimus with CNI elimination or minimization a mean of 5.6 years after kidney transplantation had no overall renal benefit and was associated with more frequent adverse events and discontinuations. Patients with CrCl more than 50 mL/min may benefit from a change in therapy more than 6 months after renal transplantation.

Assessment of renal allograft fibrosis by acoustic radiation force impulse quantification--a pilot study.

Chronic allograft nephropathy characterized by interstitial fibrosis and tubular atrophy is a major cause of renal transplant failure. Acoustic radiation force impulse (ARFI) quantification is a promising noninvasive method for assessing tissue stiffness. We evaluated if the method could reveal renal transplant fibrosis. In a prospective study, 30 adult renal transplant recipients were included. ARFI quantification, given as shear wave velocity (SWV), of the renal cortex was performed by two observers. SWV was compared to grade of fibrosis (0–3) in biopsies. The median SWV was 2.8 m/s (range: 1.6–3.6), 2.6 m/s (range: 1.8–3.5) and 2.5 m/s (range: 1.6–3) for grade 0 (n = 12), 1 (n = 10) and grades 2/3 (n = 8) fibrosis respectively. SWV did not differ significantly in transplants without and with fibrosis (grade 0 vs. grade 1, P = 0.53 and grade 0 vs. grades 2/3, P = 0.11). The mean intraobserver coefficient of variation was 22% for observer 1 and 24% for observer 2. Interobserver agreement, expressed as intraclass correlation coefficient was 0.31 (95% CI: −0.03 to 0.60). This study does not support the use of ARFI quantification to assess low‐grade fibrosis in renal transplants. ARFI quantification in its present stage of development has also high intra‐ and interobserver variation in renal transplants.

Carcinoid lung tumors — incidence, treatment and outcomes: a population-based study

OBJECTIVE Few published reports have examined the incidence and outcomes for patients with carcinoid lung tumors. The aim of the current study was to explore incidence, type of surgical treatment given, and outcome for patients with typical (TC) and atypical (AC) lung carcinoids in a national cohort (Norway). METHODS All lung-cancer patients diagnosed in the period 1993-2005 and who were reported to the Cancer Registry of Norway were identified. Biopsies or resection specimens were reviewed and reclassified according to the World Health Organization (WHO) 2004 classification. Surgically treated patients were staged according to the seventh edition of the pathological tumor-node-metastasis (pTNM) staging system. RESULTS Of 26665 lung cancers registered during the period, 265 (1%) had carcinoid tumors, of which 11 were diagnosed coincidentally at autopsy. In the remaining 254 patients, TCs were found in 188 cases, and ACs were found in 59 cases; seven cases had unclassifiable carcinoids. Of the 217 resected tumors, 173 (80%) were TCs. General surgeons performed 94 resections, including 11 of 17 pneumonectomies. All six bronchial resections were performed by thoracic surgeons. Of the 33 operated patients who died during follow-up, 18 had metastatic carcinoid tumors, of which 10 (56%) were ACs. In 37 non-resected patients (15 with AC and seven with unclassifiable histology), metastatic or locally advanced disease (N=21, 12 of which were ACs) was the main cause of inoperability and death. Five-year survival for all patients was 92% for TC and 66% for AC; for resected patients, the survival rates were 96% and 79%, respectively. CONCLUSIONS Carcinoids are rare malignant tumors and are, in most cases, resectable; the TC subgroup had better prognosis than the AC in univariate analyses. The main cause of death was metastasis/locally advanced tumor at presentation or recurrent disease following resection; both situations were three times more common in patients with AC.

Early versus late acute antibody-mediated rejection in renal transplant recipients.

Background Over the last decade, the diagnostic precision for acute antibody-mediated rejection (aABMR) in kidney transplant recipients has improved significantly. The phenotypes of early and late aABMR may differ. We assessed the characteristics and outcomes of early versus late aABMR. Methods Between January 1, 2005 and December 31, 2010, aABMR was diagnosed in 67 grafts in 65 kidney recipients, with a median follow-up of 3.6 years (range, 61 days–7.3 years). Recipients were stratified by early aABMR (<3 months after transplantation; n=40) and late aABMR (>3 months after transplantation; n=27). The main outcome was kidney allograft loss. Outcome of aABMR was compared with recipients with acute early (n=276) or late (n=100) non-ABMR during the same period. Results Recipients with late aABMR had significantly reduced graft survival compared with recipients with early aABMR (P<0.001, log-rank test; 40% vs. 75% at 4 years; hazard ratio, 3.72; 95% confidence interval, 1.65–8.42). Graft survival in late aABMR was also inferior to late non-ABMR acute rejections (P=0.008). At transplantation, more patients were presensitized to human leukocyte antigens (22 [55%] vs. 4 [15%] in the early vs. late aABMR group). The late aABMR group was characterized by younger recipient age (37.9±12.9 vs. 50.9±11.6 years; P<0.001), increased occurrence of de novo donor-specific antibodies (52% vs. 13%; P=0.001), and nonadherence/suboptimal immunosuppression (56% vs. 0%; P<0.001). Conclusion Compared with early aABMR, late aABMR had inferior graft survival and was characterized by young age, frequent nonadherence, or suboptimal immunosuppression and de novo donor-specific antibodies.

Recurrent lupus nephritis after kidney transplantation: a surveillance biopsy study

Objectives To determine the incidence of recurrent lupus nephritis (LN) in renal transplant recipients with systemic lupus erythematosus (SLE). Methods All patients with SLE that had undergone transplant with a functioning graft were asked in 2008 to participate in a cross-sectional study. The study included a standardised clinical examination, laboratory tests and a biopsy of the transplanted kidney. Results A total of 41 (93%) of a cohort of 44 patients with SLE with renal transplants participated. Of the biopsies, 3 were indication biopsies and 38 were surveillance biopsies. In all, 22 patients (54%) had biopsy-proven recurrence of LN. The majority of the cases were subclinical and characterised as class I/class II LN. Proteinuria (mg protein/mmol creatinine) was significantly increased in patients with recurrence, 70.6 (104.9) mg/mmol versus 11.9 (6.7) mg/mmol in patients without recurrence (p=0.038). Lupus anticoagulant was found more frequently in the patients with recurrence, nine versus two patients (p=0.033). Recurrence of LN was associated with receiving a kidney from a living donor (p=0.049). In all, 83% (34 of 41) had chronic allograft nephropathy in the transplanted kidneys with no difference between patients with recurrence or without. Conclusions Subclinical recurrence of LN is common in patients with renal transplants with SLE. The majority of the patients have chronic allograft nephropathy.

Noninvasive assessment of myocardial fibrosis in patients with obstructive hypertrophic cardiomyopathy

Objective Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging is the reference standard for non-invasive assessment of fibrosis. In hypertrophic cardiomyopathy (HCM) patients the histological substrate for LGE is still unknown. The aim of this study was to assess the ability of LGE and strain echocardiography to detect type and extent of myocardial fibrosis in obstructive HCM patients undergoing septal myectomy. Methods Thirty-two HCM patients (age 60±10) were included in this cross-sectional study and preoperatively examined by speckle-tracking strain echocardiography and LGE-CMR (n=21). Histological fibrosis was classified as interstitial, replacement and total. Results Histological fibrosis was present in 31 patients. The percentage of total, interstitial and replacement fibrosis was 15(7, 31)%, 11(5, 24)% and 3(1, 6)%, respectively. Reduced longitudinal septal strain correlated with total (r=0.50, p=0.01) and interstitial (r=0.40, p=0.03), but not with replacement fibrosis (r=0.28, p=0.14). Septal LGE was detected in 13/21 (62%), but percentage LGE did not correlate with total fibrosis (r=0.25, p=0.28). Extent of fibrosis did not differ between patients with and without septal LGE (20(9, 58)% versus 14(5, 19)% p=0.41). Patients with ventricular arrhythmias (n=8) had lower septal longitudinal strain and increased extent total and interstitial fibrosis in myectomy specimens, but no differences were demonstrated in LGE. Reduced longitudinal septal strain and increased extent of interstitial fibrosis predicted ventricular arrhythmias independently of age and gender. Conclusions In myectomised HCM patients, reduced longitudinal septal strain correlated better with interstitial and total fibrosis in myectomy specimens, and was a more powerful tool to predict arrhythmias than LGE.

Increased amount of interstitial fibrosis predicts ventricular arrhythmias, and is associated with reduced myocardial septal function in patients with obstructive hypertrophic cardiomyopathy

AIMS Reduced echocardiographic strain is associated with ventricular arrhythmias in hypertrophic cardiomyopathy (HCM) patients. The aim of this cross-sectional study was to investigate which type of histological fibrosis contributes to ventricular arrhythmias and reduced septal longitudinal strain, in obstructive HCM-patients with or without additional coronary artery disease (CAD) and/or hypertension (HT). METHODS AND RESULTS Sixty-three HCM-patients (mean age 57 ± 13 years) were included. Strain by speckle tracking echocardiography was performed prior to either percutaneous transluminal septal ablation (n = 37) or septal myectomy (n = 26). In 24 patients myectomy specimens were available (histology population) and allowed determination of %area of interstitial and replacement fibrosis. Twenty-nine (46%) patients had concomitant CAD and/or HT, and 15 (24%) experienced ventricular arrhythmias defined as documented ventricular tachycardia or arrhythmogenic suspected syncope. The patients with ventricular arrhythmias had lower septal longitudinal strain compared with those without arrhythmias (-9.0 ± 4.0 vs. -13.6 ± 5.6%, P = 0.006). In the histology population reduced septal longitudinal strain correlated to interstitial (R(2) = 0.36 P = 0.003), but not to replacement fibrosis (R(2) = 0.03 P = 0.43). By logistic regression analyses, interstitial fibrosis predicted ventricular arrhythmias (OR 1.16, 95% CI 1.02-1.32, P = 0.03), while replacement fibrosis did not (OR 1.22, 95% CI 0.93-1.59, P = 0.15). CONCLUSION Total amount of fibrosis was a marker of ventricular arrhythmias in obstructive HCM-patients. Interstitial fibrosis seemed to be more important compared with replacement fibrosis in arrhythmogenesis, and was related to reduced septal myocardial function. These findings suggest that interstitial fibrosis may play an important role as the arrhythmogenic substrate, and that strain echocardiography can help detection of patients at risk.

Associations between TS, TTF-1, FR-α, FPGS, and overall survival in patients with advanced non-small-cell lung cancer receiving pemetrexed plus carboplatin or gemcitabine plus carboplatin as first-line chemotherapy.

Introduction: Pemetrexed is effective in the treatment of non–small-cell lung cancer, mainly in nonsquamous cell carcinomas. Inhibition of thymidylate synthase (TS) is considered the key mechanism of action. Folate receptor-&agr; facilitates uptake of pemetrexed. Polyglutamation by folylpolyglutamate synthetase enhances activity and prolongs cellular retention of pemetrexed. Thyroid transcription factor-1 (TTF-1) is mainly positive in nonsquamous cell carcinoma and has been proposed as a marker for sensitivity to pemetrexed. The aim was to investigate associations between these biomarkers and survival in patients who participated in a phase III trial comparing pemetrexed plus carboplatin with gemcitabine plus carboplatin as first-line chemotherapy in advanced non–small-cell lung cancer (n = 436). In this study, there was no difference in overall survival between the two regimens. Methods: Formalin-fixed, paraffin-embedded biopsies were collected. Percentages of tumor cells positive and highly positive for the biomarkers were assessed using immunohistochemistry (IHC) and an IHC score was calculated (range, 0–200). Results: Two hundred thirty-six biopsies were analyzed (pemetrexed plus carboplatin: n = 114, gemcitabine plus carboplatin: n = 122). There was a significant difference in overall survival between those with TTF-1–positive and –negative tumors (10.4 versus 6.0 months; p < 0.001) and those with a low and a high TS IHC score (9.7 versus 6.2 months; p < 0.001). Folate receptor-&agr; and folylpolyglutamate synthetase were not significant prognostic factors. In multivariate analyses adjusting for established prognostic characteristics, TS (p = 0.002) and TTF-1 (p = 0.003) remained significant. There were no differences in survival between the treatment arms depending on biomarker scores. Conclusions: TTF-1 positivity and low TS level were associated with prolonged survival. The associations between the biomarkers and overall survival were similar for both chemotherapy regimens.

Immunoelectron microscopy on epoxy sections without deplasticizing to detect glomerular immunoglobulin and complement deposits in renal diseases

Twenty renal biopsies were studied by immunoelectron microscopy (IEM) after embedding in epoxy resin. Immunogold labeling for immunoglobulins and complement C3 was performed on the epoxy sections, which were not subjected to any kind of etching or deplasticizing prior to the immunolabeling. The concentration of accelerator, DMP‐30 (Tri (Dimethyl Amino Methyl) Phenol), was increased in the infiltration and embedding steps far beyond the values normally used to make immunolabeling of these antigens possible on epoxy sections. The sections were stained with tannic acid accompanied by uranyl acetate and lead citrate. Immunofluorescence (IF) for light microscopy was carried out on frozen sections of parallel tissue samples. Some cases with IgA‐nephritis demonstrated a higher sensitivity for IEM than IF, in the sense that smaller amounts of antigen were detectable with IEM. Ultrastructural preservation with this method was approximately the same as that usually seen on epoxy‐embedded material. By combining excellent immunolabeling with nearly optimal ultrastructural morphology in one procedure, this method is useful particularly in situations where the material available is limited, such as in studies of renal biopsies. As far as we know, this is the first time that immunoglobulins have been satisfactorily immunolabeled on epoxy sections without etching or deplasticizing.

Non-invasive assessment of renal allograft fibrosis by dynamic sonographic tissue perfusion measurement

Background Chronic allograft nephropathy (CAN) characterized by interstitial fibrosis and tubular atrophy is a major cause of renal transplant failure. The diagnosis can currently only be verified by a graft biopsy. Purpose To evaluate whether non-invasive dynamic color Doppler sonographic parenchymal perfusion measurements are different in grafts with various degrees of biopsy proven renal transplant fibrosis. Material and Methods Forty-nine adult patients were prospectively included. Four patients were excluded. Color Doppler videos from the renal cortex were recorded. Perfusion in the renal cortex was evaluated using a software package which calculates color pixel area and flow velocity, encoded by each pixel inside a region of interest of a video sequence. The software calculates parameters that describe tissue perfusion numerically. Two of these, the perfusion intensity and tissue pulsatility index, were compared to grade of interstitial fibrosis (0–3) in biopsies. Observer agreement was evaluated in a subset of 12 patients. Results Of the 45 patients analyzed, 18 patients had grade 0, 18 had grade 1, seven had grade 2 and two had grade 3 fibrosis. The mean perfusion intensity of grade 0 was significantly higher than that of grade 2 and 3 fibrosis in the proximal cortical layer (1.65 m/s vs. 0.84 m/s, P = 0.008). No significant difference was found between grade 0 and grade 1 fibrosis. Perfusion intensity was correlated to estimated glomerular filtration rate (Pearson r 0.51, P = 0.001, R2 = 0.26 and 0.46, P = 0.001, R2 = 0.22 in the distal and proximal cortex, respectively). Inter-observer agreement of the perfusion intensity, expressed as intraclass correlation coefficient was 0.69 in the proximal part of the cortex. Intra-observer agreement was 0.85 for observer 1 and 0.82 for observer 2. Conclusion Perfusion intensity assessed by dynamic color Doppler measurements is significantly reduced in allografts with grade 2 and 3 fibrosis compared to allografts without fibrosis. Further studies involving longitudinal assessment of allografts undergoing protocol biopsies would be of interest.