Efficacy of cyclosporin in difficult-to-treat idiopathic membranous nephropathy

SUMMARY: Poor tolerance and the potential long-term toxicity have limited the widespread use of corticosteroids and cytotoxic drugs in the treatment of idiopathic membranous nephropathy (IMN). Cyclosporin A (CyA) has been proven to be a less toxic alternative, but its efficacy needs further confirmation. Cyclosporin A (2–3mg/kg per day) in combination with low-dose methylprednisolone (4mg/day) was given to 28 nephrotic patients with IMN who had failed to respond, or tolerate, or to complete treatments with steroids and/or cytotoxic drugs. the mean duration of treatment was 11 ± 7 months. Seven patients (25%) showed a complete remission of proteinuria, 17 (60%) a partial one, and four (15%) did not respond at all. the average time to achieve optimal remission was 4.2 ± 1.4 weeks following the initiation of therapy. In those who responded completely or partially, plasma creatinine (Per) did not change significantly from pre CyA levels during follow up (1.0 ± 0.3 vs 1.2 ± 0.3mg/dL, P =NS). the remaining four patients who had renal insufficiency already before CyA (mean Per: 2.1 ± 0.8mg/dL), showed a rapid deterioration of renal function after the initiation of CyA (mean Per: 3.1 ± 1.5 mg/dL, P <0.01), and as a consequence, the drug was discontinued. A mul-tivariate analysis on the clinical and histological features demonstrated that the degree of renal function impairment ( P <0.02), the percentage of obsolete glomeruli ( P <0.01), and the severity of interstitial fibrosis ( P <0.005) independently predicted the response to therapy. Low dose CyA is an effective and safe alternative treatment for patients with IMN and normal renal function. However, the drug should be given with caution to patients with established renal insufficiency.     

Supraventricular tachycardia after heterotopic heart transplantation

Heterotopic cardiac transplantation where the recipient heartremains in tandem with the donor heart^[1] has a one-year survivalof approximately 80%^[2]. Rhythm disturbances after heterotopiccardiac transplantation have rarely been described^[3] and theirpotential influence on the patients symptoms and prognosis isunclear. We report a case of supraventricular tachycardia ofthe recipient heart in a patient following heterotopic hearttransplantation recorded during ambulatory electrocardiographicmonitoring.     

Macrophages and HLA-DR(+) cells in acutely rejecting kidney transplants, predict subsequent graft survival, even after reversal of the acute episode

Renal graft biopsies from 19 selected patients with acute cellular rejection (ACR) were analysed using a panel of monoclonal antibodies. All patients had only one episode of ACR, which was completely reversible. In 11 patients (group 1) graft function slowly deteriorated over a period of 14 (±17) months after the episode. In the remaining eight (group 2) graft function remained stable over a similar period of observation. In group 1 there was a significantly increased inflitrate of glomerular and interstitial monocytes/macrophages (MM) when compared with group 2. Also, the expression of HLA-DR antigen by the tubular cells were stronger in group 1, while T-cells in the glomeruli and the interstitium were equally distributed in both groups. We conclude that large numbers of MM and HLA-DR expressing cells (glomerular, interstitial and tubular) in rejecting kidneys predict a more rapid decline of follow-up renal function despite reversal of the acute episode. This may suggest that subclinical ongoing injury continues in some patients and perhaps more intense immunosuppression is necessary to prevent graft loss.     

Antiplatelet effects of prasugrel vs. double clopidogrel in patients on hemodialysis and with high on‐treatment platelet reactivity

Summary. Background: High on‐treatment platelet reactivity (HTPR) is frequent in patients on hemodialysis (HD) receiving clopidrogel. Objectives: The primary aim of this study was to determine the antiplatelet effects of prasugrel vs. high‐dose clopidogrel in patients on HD with HTPR. Patients/Methods: We performed a prospective, single‐center, single‐blind, investigator‐initiated, randomized, crossover study to compare platelet inhibition by prasugrel 10 mg day^?1 with that by high‐dose 150 mg day^?1 clopidogrel in 21 patients on chronic HD with HTPR. Platelet function was assessed with the VerifyNow assay, and genotyping was performed for CYP2C19*2 carriage. Results: The primary endpoint of platelet reactivity (PR, measured in P2Y12 reaction units [PRU]) was lower in patients receiving prasugrel (least squares [LS] estimate 156.6, 95% confidence interval [CI] 132.2–181.1) than in those receiving high‐dose clopidogrel (LS 279.9, 95% CI 255.4–304.3), P < 0.001). The LS mean differences between the two treatments were ? 113.4 PRU (95% CI ? 152.9 to ? 73.8, P < 0.001) and ? 163.8 PRU (95% CI ? 218.1 to ? 109.2, P < 0.001) in non‐carriers and carriers of at least one CYP2C19*2 allele, respectively. HTPR rates were lower for prasugrel than clopidogrel, in all patients (19% vs. 85.7%, P < 0.001) and in non‐carriers (25.7% vs. 80%, P = 0.003). All carriers continued to show HTPR while receiving high‐dose clopidogrel, but none showed it while receiving prasugrel. Conclusions: In HD patients exhibiting HTPR following standard clopidogrel treatment, prasugrel 10 mg day^–1 is significantly more efficient than doubling the clopidogrel dosage in achieving adequate platelet inhibition. Neither effect seems to be influenced by carriage of the loss‐of‐function CYP2C19*2 allele.     

Preferred QT Correction Formula for the Assessment of Drug‐Induced QT Interval Prolongation

Drug‐Induced QTc Interval Assessment. Introduction: There is debate on the optimal QT correction method to determine the degree of the drug‐induced QT interval prolongation in relation to heart rate (ΔQTc). Methods: Forty‐one patients (71 ± 10 years) without significant heart disease who had baseline normal QT interval with narrow QRS complexes and had been implanted with dual‐chamber pacemakers were subsequently started on antiarrhythmic drug therapy. The QTc formulas of Bazett, Fridericia, Framingham, Hodges, and Nomogram were applied to assess the effect of heart rate (baseline, atrial pacing at 60 beats/min, 80 beats/min, and 100 beats/min) on the derived ΔQTc (QTc before and during antiarrhythmic therapy). Results: Drug treatment reduced the heart rate (P < 0.001) and increased the QT interval (P < 0.001). The heart rate increase shortened the QT interval (P < 0.001) and prolonged the QTc interval (P < 0.001) by the use of all correction formulas before and during antiarrhythmic therapy. All formulas gave at 60 beats/min similar ΔQTc of 43 ± 28 ms. At heart rates slower than 60 beats/min, the Bazett and Framingham methods provided the most underestimated ΔQTc values (14 ± 32 ms and 18 ± 34 ms, respectively). At heart rates faster than 60 beats/min, the Bazett and Fridericia methods yielded the most overestimated ΔQTc values, whereas the other 3 formulas gave similar ΔQTc increases of 32 ± 28 ms. Conclusions: Bazett's formula should be avoided to assess ΔQTc at heart rates distant from 60 beats/min. The Hodges formula followed by the Nomogram method seem most appropriate in assessing ΔQTc. (J Cardiovasc Electrophysiol, Vol. 21, pp. 905‐913, August 2010)     

Macrophages and HLA-DR(+) cells in acutely rejecting kidney transplants, predict subsequent graft survival, even after reversal of the acute episode

SUMMARY: Renal graft biopsies from 19 selected patients with acute cellular rejection (ACR) were analysed using a panel of monoclonal antibodies. All patients had only one episode of ACR, which was completely reversible. In 11 patients (group 1) graft function slowly deteriorated over a period of 14 (± 17) months after the episode. In the remaining eight (group 2) graft function remained stable over a similar period of observation. In group 1 there was a significantly increased inflitrate of glomerular and interstitial monocytes/macrophages (MM) when compared with group 2. Also, the expression of HLA-DR antigen by the tubular cells were stronger in group 1, while T-cells in the glomeruli and the interstitium were equally distributed in both groups. We conclude that large numbers of MM and HLA-DR expressing cells (glomerular, interstitial and tubular) in rejecting kidneys predict a more rapid decline of follow-up renal function despite reversal of the acute episode. This may suggest that subclinical ongoing injury continues in some patients and perhaps more intense immunosuppression is necessary to prevent graft loss.     

Protoporphyrinogen oxidase and ferrochelatase in porphyria variegata

Protoporphyrinogen oxidase activity and ferrochelatase activity were measured in leucocytes from patients with porphyria variegata. The mean activity of protoporphyrinogen oxidase (PPO) in porphyria variegata (PV) was about 50% of normal (P less than 0.05). The mean activity of ferrochelatase with 59Fe2+ sulphate and protoporphyrin as substrates (in the presence of ascorbic acid) was reduced by 40% (P less than 0.009). The mean activity of ferrochelatase with 59Fe3+ chloride and protoporphyrin as substrates (in the presence of reduced glutathione) was increased by 65% (P less than 0.005). Both are statistically highly significant. The findings are interpreted as follows: (a) The occurrence of a low level of protoporphyrinogen oxidase in PV is confirmed. (b) The findings indicate a concurrent structural change in ferrochelatase (this may be structurally related to (a) but no evidence of this is at present available).