Bernd Kutkuhn

Mycophenolate mofetil versus cyclosporin A in high risk keratoplasty patients: a prospectively randomised clinical trial

BACKGROUND/AIMS The requirement for an effective, minimally toxic immunosuppressive agent remains a major obstacle to performing high risk corneal transplantation. Although therapy with cyclosporin A (CSA) allows superior graft survival, its use is limited because of a wide range of side effects. Mycophenolate mofetil (MMF) has been shown to be a safe and effective immunosuppressive agent following renal transplantation. This prospective, randomised clinical trial was carried out to investigate the efficacy and safety of MMF in preventing corneal allograft rejection. METHODS Recipients of corneal transplants who were at high risk for graft failure were randomly assigned to either CSA or MMF immunosuppressive therapy. CSA was given in doses to achieve whole blood trough levels of 120–150 ng/ml. MMF was given in a daily dose of 2 g. Both therapy groups additionally received oral corticosteroids (fluocortolone 1 mg/kg) which were tapered and discontinued within the first 3 postoperative weeks. Patients were monitored closely for evidence of corneal graft rejection and adverse side effects. Drug efficacy was measured, primarily, by the number of patients who experienced at least one episode of clinical graft rejection. Safety analysis focused on reported adverse side effects and laboratory measurements. RESULTS 41 patients were enrolled in the study. There was no statistically significant difference between the two groups. 20 patients received CSA and 21 patients received MMF. Two patients in each group showed evidence of acute graft rejection which could be treated effectively by corticosteroids. All corneal grafts remained clear throughout the follow up. CONCLUSIONS In this study it was shown that MMF is just as effective as CSA in preventing acute rejection following high risk corneal transplantation. Mycophenolate mofetil represents a promising alternative therapeutic option in patients who are at high risk for corneal graft failure.

Development of Insulin Resistance and Elevated Blood Pressure during Therapy with Cyclosporine A

OBJECTIVES Essential hypertension and insulin resistance frequently coexist; cyclosporine A (CsA) is known to induce hypertension which has been used as a model for essential hypertension. The present study aimed to evaluate whether elevated blood pressure and insulin resistance coexist during CsA therapy to prove the similarity between essential hypertension and CsA induced hypertension. DESIGN Normotensive patients who underwent keratoplasty were investigated before and during single therapy with CsA (2-4 mg/kg body weight) in an open A-B Trial. PATIENTS Eighteen lean, normotensive patients without metabolic disorders with normal renal function and without family history of hypertension or metabolic abnormalities. MAIN METHODS Insulin sensitivity index was determined by the modified frequent sampling intravenous glucose tolerance test (FSIGT) and blood pressure was determined by indirect ambulatory blood pressure monitoring. RESULTS Mean insulin sensitivity index (S1) was significantly reduced (p < 0.03) during treatment with CsA (4.4 +/- 2.6 x 10(-4) vs 2.8 +/- 2.0 x 10(-4)/min per microU/ml), whereas mean systolic daytime blood pressure increased from 126.4 +/- 10.8 mmHg to 135.7 +/- 11.8 mmHg (p < 0.02), as well as the corresponding diastolic blood pressure from 76.8 +/- 8.7 mmHg to 82.8 +/- 9.3 mmHg (p < 0.05). CONCLUSIONS CsA therapy induces elevated blood pressure and insulin resistance as seen in patients with essential hypertension, thus CsA induced hypertension is considered to have pathophysiological similarities to essential hypertension.

Influence of betaxolol on renal function and atrial natriuretic peptide in essential hypertension.

The hypotensive action of beta-adrenoreceptor blockers is not fully understood, there being a lack of studies focusing on possible relationships between beta-blockers and the secretion of atrial natriuretic peptide (ANP). In 10 patients with essential hypertension, we investigated the influence of betaxolol, a selective beta 1-adrenergic blocking agent, on renal function and on plasma levels of ANP during exercise, volume depletion and volume expansion. Chronic therapy with betaxolol (mean 14.5 mg/day) did not alter glomerular filtration rate and renal blood flow although blood pressure was reduced. Renal vascular resistance decreased from 12795 +/- 1064 dyn/s per cm5 to 10614 +/- 833 dyn/s per cm5 (P less than 0.005). Under betaxolol, basal ANP levels increased from 39 +/- 10 pg/ml to 80 +/- 19pg/ml (P less than 0.01). ANP increased during exercise and volume expansion but was decreased during volume depletion. ANP values observed under betaxolol treatment showed significantly higher values while preserving their dynamic features. We believe that the stimulating effect of betaxolol on ANP may at least partly account for its hypotensive action.

Renin Secretion and Captopril Stimulation in Hypertensive Renal Transplant Recipients

Basal renin secretion and the diagnostic value of a captopril stimulation (captopril test) in identifying renovascular hypertension secondary to transplant renal artery stenosis was assessed in 69 patients with hypertension after renal transplantation. An increase of plasma renin activity of 260% 1 h after captopril was considered as a positive result, assuming renovascular hypertension. Six of 69 patients had a positive captopril test, of these patients 5 had transplant renal artery stenosis. These patients were treated with percutaneous transluminal angioplasty (PTA) or surgery. Based on angiographic results and blood pressure response after PTA or surgery the captopril test showed a sensitivity of 100% and a specificity of 92% in the identification of hemodynamically significant stenosis of the transplant artery. Therefore, the captopril test provides a suitable screening instrument for the differential diagnosis of hypertension following renal transplantation.

Successful treatment of renovascular hypertension has no effect on insulin sensitivity

Background  The association of insulin resistance (IR) and essential hypertension is well known, but a causal relationship has not been proven. Patients with secondary hypertension as a result of renal artery stenosis (RAS) usually do not reveal IR, but no study has addressed the effect of blood pressure reduction after successful treatment of RAS on insulin sensitivity and glucose effectiveness.

Acute Blockade of the Renin System and Differential Renal Vein Renin Determinations in the Diagnosis of Renovascular Hypertension

For validation of differential renal vein renin determinations in the diagnosis of renovascular hypertension (RVH), we investigated 102 patients suspected of suffering from RVH before and 1 h after administration of 25 mg captopril. Sensitivity, specificity and posterior probability for renin ratio (RR) and renin secretion (RS) were calculated based on 44 patients with proven RVH and 58 patients with primary hypertension (PH) using discriminant analysis. There is good (>95%) and identical specificity of both variables under all conditions, whereas sensitivity remains poor even after Captopril administration (RR 23% vs. 32%; RS 20% vs. 34%). The posterior probabilities obtained by discriminant analysis revealed a cut-off point of 2.5 for the renin ratio and of 1.9 for the renin secretion. No change is observed after ACE inhibition. We conclude that the acute blockade of the renin system by captopril in differential renin sampling yields no advantages in diagnosing RVH and that there is no difference betwee...

CellCept® — Eine neue therapeutische Option nach perforierender Hochrisiko-Keratoplastik

ZusammenfassungProblemstellungEine effektive und sichere Immunsuppression ist eine wichtige Grundvoraussetzung für eine erfolgreiche Hochrisiko-Keratoplastik. Obwohl die postoperative Prophylaxe mit Cyclosporin A (CSA, Sandimmun®) zu einem deutlich verbesserten Transplantatüberleben führt, ist diese Therapie aufgrund des Nebenwirkungsspektrums nicht bei jedem Patienten einsetzbar.Die Wirksamkeit und Sicherheit von Mycophenolatmofetil (MMF, CellCept®) zur Verhinderung der allogenen Abstoßungsreaktion nach Nierentransplantation konnte bereits in mehreren Studien nachgewiesen werden. Ziel dieser prospektiven, randomisierten klinischen Studie war es, die Effektivität und Sicherheit von MMF zur Verhinderung der Abstoßungsreaktion nach Hornhauttransplantation zu untersuchen.Patienten und MethodenPatienten vor Hochrisiko-Keratoplastik wurden durch Ziehung eines Loses der immunsuppressiven Therapie mit CSA oder MMF zugeteilt. Die post-operative Immunsuppression wurde am Operationstag begonnen und für die Dauer von 6 Monaten verabreicht. CSA wurde blutspiegeladaptiert verabreicht, MMF in einer täglichen Dosis von 2 × 1 g/Tag.ErgebnisseEs nahmen insgesamt 41 Patienten an der Studie teil. 21 Patienten wurden mit CSA, 20 Patienten mit MMF therapiert. Zwei Patienten in jeder Gruppe zeigten jeweils eine akute Abstoßungsreaktion, welche mit Kortikosteroiden wirksam behandelt werden konnte. Es kam zu keiner Transplantateintrübung in der durchschnittlichen Nachbeobachtungszeit von 11 Monaten.DiskussionMycophenolatmofetil zeigt sich als sicheres und effizientes Immunsuppressivum und ist eine vielversprechende therapeutische Alternative für Patienten nach Hochrisiko-Keratoplastik.SummaryBackgroundA beneficial effect of CellCept® (mycophenolate mofetil, MMF) on graft survival following renal transplantation has already been demonstrated in the clinical setting. This study aimed to determine the efficacy and safety of MMF in preventing allograft rejection following high-risk corneal transplantation.MethodsProspective recipients of corneal transplants who were at high-risk for postoperative graft failure were randomized to receive either Cyclosporin A (CSA) or MMF for the first six postoperative months.ResultsThe incidence of rejection was not statistically different in the 20 CSA and the 21 MMF patients (10% and 9.5% respectively). There were no graft opacifications in the follow up period of 11.6 (CSA) and 10.1 (MMF) months.ConclusionsThe safety and efficacy of CellCept® in improving the outcome of high-risk corneal transplantation was comparable to CSA.