Background: Ensovibep is a multi-specific DARPin (designed ankyrin repeat protein) therapeutic in clinical development for treatment of COVID-19. In Part A (Phase 2) of the EMPATHY study, ensovibep treatment demonstrated greater viral load decline versus placebo (Pbo), and a relative risk reduction for hospitalization, ER visits and death. We report the sustained clinical recovery data from Phase 2 of EMPATHY. Methods: Patients (pts) were eligible for EMPATHY (NCT04828161) when presenting ≥2 mild-to-moderate COVID-19 symptoms (onset within 7 days) and a positive SARS-CoV-2 rapid antigen test on day of dosing. 407 pts were randomised (1:1:1:1) to ensovibep (600, 225 or 75mg) or Pbo as single, IV infusion. The FDA COVID-19 symptom questionnaire was used (daily to Day 15, and on Days 22, 29) to assess time to sustained clinical recovery (secondary endpoint). Results: Ensovibep treatment was associated with a shorter time to sustained clinical recovery versus Pbo (Fig 1). The median time to sustained recovery were 23 days, 15 days, 14 days, and 29 days in 600mg, 225mg, 75mg, placebo arms, respectively. The cumulative proportion of patients with sustained clinical recovery by Day 15 were 44%, 54%, 55% and 36% in 600mg, 225mg, 75mg, and placebo arms, respectively. Conclusions: Ensovibep administration was associated with earlier sustained clinical recovery versus placebo.

Kovarik, J. M.; Tedesco-Silva, H.; Lien, B.; Toselli, L.; Vitko, S.; Peeters, P.; Soergel, M. Author Information

BACKGROUND:In earlier registry analyses, cyclosporine at doses of < 3 mg/kg/d at 1 year post-renal transplantation has been associated with significant graft loss or reduction in renal function. Improvements in cyclosporine formulation with increased bioavailability, plus the use of more efficient comedications, may now confer better outcomes. To determine the effect of the 1-year cyclosporine microemulsion (CsA-ME) dose on renal allograft function at 5 years, we analyzed data collected from 2889 patients with documented graft survival to year 5 in a prospective, multinational, observational study-Neoral MOST. RESULTS:Glomerular filtration rate (GFR) at year 1 was 63 +/- 20 mL/min and 59 +/- 22 mL/min at year 5. The multivariate analysis including year 1 CsA-ME dose as factor and GFR at 1 year as covariate revealed the most significant factors affecting GFR at year 5 were 1-year GFR, donor age > 60 years, and CsA-ME dose at 1 year. Risk factors associated with reduction in 5-year GFR (<65 mL/min) included donor or recipient age >60 years, delayed graft function, cadaveric donor, previous graft, and acute rejection. CsA-ME dose <3 mg/kg/d was found to protect GFR. Analysis of GFR at each year posttransplantation (Wilcoxon model) found 1-year CsA-ME (cutoff 3 mg/kg/d) had a significant effect at each time point. CONCLUSIONS:Compared to higher doses, CsA-ME <3 mg/kg/d at year 1 posttransplantation is associated with increased preservation of renal allograft function at year 5.

BACKGROUND:Delayed graft function (DGF) is a common complication after renal transplantation, and may affect graft function. The aim of this analysis was to evaluate risk factors for DGF, as well as parameters and events influencing graft function after DGF. We analyzed data collected in an ongoing international, prospective; observational study, the Neoral-MOST (Multinational Observational Study in renal Transplantation), and included in the analysis all patients with cadaveric kidney transplants for whom renal function at 1 year posttransplantation was documented (N = 8950). Logistic regression was used to evaluate the risk factors for DGF occurrence, and multifactorial analysis of variance (ANCOVA) to assess the relevance of different factors for GFR at 1 year.RESULTS:Higher donor age, longer CIT, male recipients, Caucasian recipients, high recipients body mass index, and PRA were all associated with a higher risk for DGF. Renal function of former DGF kidneys at 1 year was lower in kidneys of elder donors, or which had experienced rejection or CMV infection. Variations of the maintenance regimen at 1 year posttransplantation were not associated with better graft function. Multifactorial analysis showed donor age and acute rejection as significant independent factors.CONCLUSIONS:Most factors increasing the risk for DGF or having a negative impact on renal function at 1 year in grafts with DGF are predetermined. Additional posttransplant damage by acute rejection was associated with further reductions in GFR. Preventing acute rejection is an important step in achieving optimal function of DGF grafts.

O12 Aims: With the aim of optimizing Neoral cyclosporine (CsA) therapy, we analyzed allograft outcomes in a large group of patients with delayed graft function. We merged the data from two, prospective, multicenter trials (MO2ART and CONCERTO) with very similar study protocols involving de novo kidney transplant recipients. Methods: Both studies employed the same maintenance regimen of C2 monitored CsA with essentially the same targets (1.6–2.0 μg/mL during the first month, with stepwise reductions in subsequent months), mycophenolate mofetil and steroids per center practice. For one of the trials (CONCERTO), the study protocol included induction with anti-IL2 (basiliximab), while for the other (MO2ART) no inductin was required; in both, antibody use during DGF was per center practice. Analysis was limited to recipients of kidney allografts from cadaveric donors. Delayed graft function was defined in both protocols as the need for dialysis or the failure of serum creatinine (sCr) to fall by at least 20% from baseline in the first three days post-transplantation. CsA C2 levels and doses, as well as sCr and Nankivell GFRs were evaluated, and results presented as medians. Kaplan-Meier estimates of patient and graft survival were also determined. Patients were divided into two cohorts, one that received antibody therapy (C2+Ab) and one that did not (C2–Ab). Results: There were 117 patients who met the criterion for DGF, 98 of whom completed the six months on study therapy. The numbers of patients in the C2+Ab vs. C2–Ab cohorts were 68 vs. 49. Overall, at 6 months post-transplant, the patient and death-censored graft survivals were 98.3% and 91.5% respectively. Only one of the ten graft losses, however, was in the C2+Ab subgroup, with the C2+Ab group showing better graft survival, 98.5% vs. 81.6% (p<0.01). The Table below shows data pertaining to the rate of recovery of renal function, with relatively good serum creatinine by Day 28 post-transplantation. The Table also reveals the tendency of study investigators to use lower cyclosporine doses and C2 levels when using antibody therapy in this DGF population, even though 95% of the patients started Neoral by Day 2.FigureConclusions: The results suggest that C2 monitored Neoral with reduced levels can be introduced early during DGF with resultant good recovery in renal function. The excellent graft survival and outcomes in the C2+Ab cohort may be due to a better balance between adequate immunosuppression and reduced nephrotoxicity. Transplantation, Volume 78, Number 2, July 27, 2004

To assess the prevalence and characteristics of physiological circadian (24-hour) and ultradian (12-, 8-, and 6-hour) rhythms of mean arterial blood pressure (BP) and heart rate (HR), we analyzed 24-hour ambulatory BP profiles from 938 healthy school children aged 5 to 18 years. Cosine harmonics were fitted by Fourier analysis, and an amplitude and acrophase (time of peak) were calculated for each rhythm. Ninety percent of children displayed circadian rhythmicity of BP, independent of age, whereas circadian HR rhythmicity decreased with puberty from 96% to 87% (P<0.0001). Puberty had marked effects on the prevalence of ultradian rhythmicity: 12- and 6-hour rhythms increased for BP (27% to 47%, P<0.0001; 18% to 25%, P=0.01) and HR (36% to 47%, 17% to 31%, both P=0.001), whereas 8-hour BP rhythms decreased (34% to 23%, P=0.002). Median amplitudes were 10.1, 5.9, 5.6, and 5.2 mm Hg for the 24-, 12-, 8-, and 6-hour BP rhythms, respectively, and 13.4, 7.7, 6.8, and 6.4 bpm for HR. The acrophase occurred at approximately 14:00 hours, 8:00 hours, 5:30 hours, and 2:00 hours (military time) for the four BP rhythms, and at 13:30 hours, 08:30 hours, 01:50 hours, and 02:00 hours for HR. For the combined curve, the peak-trough difference was 25.9 mm Hg and 35 bpm for BP and HR, respectively, with the peaks occurring at 13:50 hours and 13:10 hours. There was marked association between BP and HR rhythms, both for prevalence (P<0.0001 for coupling of BP and HR rhythms of the same period length) and timing, with a median time lag of BP after HR acrophase of only 21, 16, 13, and 5 minutes for the four rhythms, respectively.

Impairment of adrenocortical function and other adverse effects have to be considered whenever corticosteroids are applied for a prolonged period of time. We hypothesized that the assessment of adrenal function with adrenocortiocotropin (ACTH) stimulation reflects the sensitivity to corticosteroids and would predict the development of side-effects in pediatric patients on triple immunosuppression after renal transplantation.

Background: Glucocorticoids are still a cornerstone in immunosuppressive regimens in pediatric patients after renal transplantation (Tx). Due to the side effects, steroid withdrawal may significantly improve the appearance and growth of children with renal grafts, but bears a substantial risk for late rejections. Aim of the study: To investigate whether exclusion of subclinical acute rejection by renal histology in combination with a prolonged steroid withdrawal period is predictive of a successful outcome. Patients and methods: Ten children (5 females) with a median age of 12.3 (range 7.9 - 20.9) years and 1.8 (0.7 - 7.5) years after Tx with a stable graft function and a median calculated creatinine clearance (C-Cr) of 71 (60.5 - 99.7) ml/min/1.73 m(2) were included. All patients showed steroid toxicity signs. Immunosuppressive regimen included low-dose steroids (median 2.72 mg/m(2)) in all patients, in addition to cyclosporin A (CsA) and azathioprine in 8, CsA on its own and CsA combined with mycophenolate mofetil in one patient each. A graft biopsy was performed in 8 patients prior to the start of steroid withdrawal, which was done over a median period of 6 months. Renal function was calculated as creatinine clearance using the Schwartz formula. Results: None of the biopsied grafts showed histologic signs of rejection. Cyclosporin A dosage and trough levels were not significantly different before and after steroid withdrawal. While steroid side effects improved in most of the patients after withdrawal, C-Cr decreased significantly within a median observation time of 42 (11.4 - 49.3) months. This decrease was due to loss of renal function in 4 patients who had biopsy-proven rejection episodes at 21.6 (8.1 - 29.9) months after the start of steroid withdrawal. Conclusion: Slow steroid withdrawal in pediatric Tx patients using conventional immunosuppression reduces side effects, but bears a high risk of late rejection. A pre-withdrawal renal biopsy was not useful for the prediction of successful steroid withdrawal.

Inhibition of the angiotensin-converting enzyme (ACE) exerts a renoprotective effect in adult patients with chronic kidney disease. We evaluated prospectively changes in blood pressure (BP), protein excretion and renal function after administration of the long-acting ACE inhibitor ramipril as monotherapy during 6 months in 14 moderately hypertensive children aged 5–18 years with various nephropathies. Four patients initially had a decreased glomerular filtration rate (GFR below 60 ml/min/1.73 m2). BP was evaluated by ambulatory 24-h monitoring. After 2 weeks of treatment by oral ramipril (1.5 mg/m2 once daily), mean values of systolic and diastolic 24-h ambulatory BP fell by more than 5 mmHg in nine patients. In eight patients the dose was doubled. At the end of the study systolic BP was below the 95th percentile in 9 and diastolic BP in 13 patients. The initially reduced nocturnal dip increased significantly. Of 11 patients with an increased albumin excretion (median 1.3 g/g creatinine), 6 responded to ramipril by a median reduction of 78% (range 24–83%), whilst in 5 albuminuria increased (median +19%). GFR was well preserved and no other adverse effects from the drug were noted. The study demonstrates that ramipril is an efficacious antihypertensive agent in children with renal hypertension. It is well tolerated, even in mild renal insufficiency. In addition, the drug has a persistent antiproteinuric action in about half of the patients contributing to conserve renal function.

Medikamente müssen vor ihrer Zulassung umfangreiche Prüfungen durchlaufen, die Untersuchungen zu Dosisfindung, Pharmakokinetik, Sicherheit, Wirksamkeit und Qualität des Medikaments umfassen. Mehrere Studien aus England haben gezeigt, dass viele Medikamente, die Kindern während einer stationären Behandlung verordnet werden, entweder nicht zugelassen (unlicensed) sind oder außerhalb der in der Zulassung festgelegten Bedingungen (off-label) verordnet werden [6, 12, 13]. Obwohl international – vor allem in den Vereinigten Staaten und England – ein großes Interesse an der Problematik der fehlenden Zulassung von Medikamenten für Kinder und der damit verbundenen Frage der Wirksamkeit und Sicherheit der pädiatrischen Pharmakotherapie besteht, liegen für Deutschland keine aktuellen Informationen über den Umfang der Off-label- oder Unlicensed-Medikamentenanwendung bei Kindern vor. Dass dieser aber bedeutend ist, hat bereits eine eigene Erhebung auf einer pädiatrischen Intensivstation vor 20 Jahren gezeigt. Um aktuelle Daten über Ausmaß und Art dieser Medikamentenanwendung bei Kindern in den verschiedenen Altersgruppen während einer stationären Behandlung zu erhalten, haben wir die vorliegende Studie durchgeführt. Sie ist Teil einer multizentrischen, europäischen Studie zur Arzneimittelanwendung in der Pädiatrie [5].

The long-term consequences of cardiac alterations in children with chronic renal failure (CRF) and after renal transplantation (TX) are largely unknown. Studies in adults with end-stage renal disease (ESRD) assume that the fate of many pediatric patients is determined by a high cardiovascular morbidity and mortality. This review describes clinical manifestations, pathophysiology, cardiac function and structure, and management of heart disease in children with CRF and post transplant. Echocardiography and Doppler ultrasonography allow differentiation of three functional disturbances: hypercirculation, systolic left ventricular (LV) dysfunction, and diastolic LV dysfunction, in addition to analysis of LV size and myocardial mass. From adult studies LV hypertrophy is recognized as an early prognostic marker of cardiovascular disease. It is present in about half of children with ESRD and after TX. It may regress, at least in part, by control of hypertension, hypervolemia, and anemia. Experimental studies have shown that, independent of these hemodynamic complications, uremia is associated with structural abnormalities of the heart, which were also described in adult patients with ESRD. These lesions consist mainly of hypertrophy of cardiomyocytes, interstitial fibrosis, and vascular changes (rarefied capillaries, thickened arteriolar walls). Cardiac complications in children with CRF and after TX deserve regular clinical and echocardiographic monitoring in order to minimize later cardiovascular morbidity by appropriate treatment.

Key words: end-stage renal disease; G20210A mutation; biopsy showed interstitial nephritis with marked interthrombophilia stitial fibrosis.More than 50% of the cortical tubulointerstitial compartment was involved and marked tubular atrophy was found.There were no signs of immune complex glomerulonephritis as found in shunt patient was given daily low-molecular-weight heparin

Ambulatory blood pressure (ABP) monitoring is increasingly used to evaluate the blood pressure of children and adolescents. The upper normal ABP values in the pediatric age group are still unknown, because reference values based on a sufficiently high number of healthy children have not yet been published. In this multicenter trial, we pooled ABP records of 1141 healthy children and adolescents with a body height between 115 and 185 cm. The study was carried out by seven centers according to a common protocol. The 50th percentile for 24-hour systolic ABP increased moderately with height, from 103 to 113 mm Hg in girls and from 105 to 120 mm Hg in boys. The 50th percentile for diastolic 24-hour means was 66 +/- 1 mm Hg, irrespective of height or gender. Diastolic daytime means were 73 +/- 1 mm Hg, which is remarkably high compared with reference values for casual blood pressure. The mean nocturnal systolic and diastolic ABP (midnight to 6 AM) was 13% +/- 6% and 23% +/- 9% lower compared with the daytime means (8 AM to 8 PM), respectively. This multicenter study provides well-based limits of normal ABP in mid-European children.