Ulrich Frei

ZUSAMMENFASSUNG: Mit SARS-CoV-2 (Schweres Akutes Respiratorisches Syndrom Coronavirus 2) wurde die Welt von einer Pandemie erfasst, auf die weder die Nephrologie noch alle anderen Bereiche des Gesundheitswesens oder des gesamten gesellschaftlichen Lebens vorbereitet waren. Im öffentlichen Gesundheitswesen zeigte sich ein gravierender Personalmangel sowie Engpässe bei Intensivkapazitäten und Material. Föderaler Eigensinn und schwere Defizite in der Digitalisierung sowie mangelnde Laborkapazität traten zutage. Die Nephrologie ist in der Pandemie besonders gefordert, weil sie zum einen eine Hochrisikopopulation zu behandeln hat und zum anderen ein hoher Anteil der intensivpflichtigen Patienten ein akutes Nierenversagen entwickelt und eine Nierenersatztherapie benötigt. Die Belastung der pflegerischen und ärztlichen Mitarbeiter war und ist immens, viele waren selbst an COVID-19 (COVID-19: Coronavirus Disease 2019) erkrankt. Die Entwicklung neuer, wirksamer Impfstoffe in so kurzer Zeit war eine herausragende Leistung. Nur die Impfung ist der Weg aus der Pandemie. Völlig unverständlich ist, dass die hoch vulnerablen Dialysepatienten nicht in die höchste Prioritätsstufe aufgenommen wurden. Die Politik sollte die Erkenntnisse der Wissenschaft zielstrebig umsetzen. Für die Zukunft ist zu lernen, dass es notwendig ist, finanzierte Reserven vorzuhalten.

Anaemia is common in patients with chronic kidney disease (CKD) and can be managed by therapy with erythropoiesis-stimulating agents (ESAs). Epoetin delta (DYNEPO^®, Shire plc) is the only epoetin produced in a human cell line. The aim of this study was to demonstrate the safety and efficacy of subcutaneously administered epoetin delta for the management of anaemia in CKD patients (predialysis, peritoneal dialysis or haemodialysis) This was a 1-year, multicentre, open-label study. Patients had previously received epoetin subcutaneously and were switched to epoetin delta at an identical dose to their previous therapy. Dose was titrated to maintain haemoglobin at 10.0–12.0 g/dL. The primary endpoint was mean haemoglobin over Weeks 12–24. Secondary analyses included long-term haemoglobin, haematocrit and dosing levels. Safety was assessed by monitoring adverse events, laboratory parameters and physical examinations. In total 478 patients received epoetin delta, forming the safety-evaluable population. Efficacy analyses were performed on data from 411 of these patients. Mean ± SD haemoglobin over Weeks 12–24 was 11.3 ± 1.1 g/dL. Mean ± SD weekly dose over Weeks 12–24 was 84.4 ± 72.7 IU/kg. Haemoglobin levels were maintained for the duration of the study. Epoetin delta was well tolerated, with adverse events occurring at rates expected for a CKD patient population; no patient developed anti-erythropoietin antibodies. Subcutaneously administered epoetin delta is an effective and well-tolerated agent for the management of anaemia in CKD patients, irrespective of dialysis status. http://www.controlled-trials.com ISRCTN68321818

Introduction: Hyperglycemia is associated with negative outcomes in various settings of critical illness; infectious complications, especially, seem to be increased. On the other hand, intensive insulin therapy (IIT) has been shown to improve outcome in clinical trials. Whether normoglycemia itself or the application of insulin is responsible for the observed findings is unknown. We therefore tested the effect of glucose and insulin on various immune functions in vitro. Methods: Human peripheral blood mononuclear cells (PBMCs) were incubated ex vivo with low doses of lipopolysaccharide (LPS). PBMCs were incubated with various osmotic agents, insulin, or a combination of both. Interleukin (IL)-6 and IL-1 cytokine response was measured by enzyme-linked immunosorbent assay. In addition, we investigated the effects of glucose on phagocytosis and oxidative burst in human granulocytes. Results: Increasing concentrations of both glucose and mannitol significantly enhanced LPS-induced cytokine production. Insulin alone did not alter cytokine production and had only a minor influence in combination with glucose. Phagocytosis and oxidative burst were significantly reduced with increasing concentrations of glucose and mannitol. Conclusion: Hyperglycemia may lead to inflammation by enhancing cytokine production via the direct effects of hyperosmotic stress. Impaired phagocytosis and oxidative burst under hyperglycemia may weaken defense mechanisms of the host. Our in vitro findings may help to explain the beneficial effects of IIT not only in diabetic but also in critically ill patients.

A new source of organs became available following the first successful transplantation of a kidney from a living donor half a century ago. Since then, expanding the living donor pool has been a priority. This appraisal of strategies used to increase the number of living kidney donors focuses on transplantation across ABO and HLA barriers, and extending selection criteria to include elderly and obese donors, and those with hypertension. Renal transplantation is the optimal treatment for patients of all ages with end-stage renal disease. Life expectancy of the population in general is increasing consistently, as is the age of the dialysis population. Consequently, the average ages of kidney donors and recipients are rising. The combination of a growing number of patients with end-stage renal disease and a shortage of organs poses a significant challenge to the transplant community. Donor shortage is associated with unfavorable consequences (e.g. prolonged waiting time, and compromised graft and patient survival). As such, multidirectional efforts are required to expand the donor pool. Increasing the frequency of living donation seems to be an efficient solution. Living donation is associated with superior results for the recipient, and relatively benign long-term outcomes for donors. Reluctance to use organs from living donors whose eligibility was previously considered marginal (e.g. elderly donors) is declining. Although increased donor age is associated with reduced graft survival rates, this should not preclude use of older living donors; transplantation is definitely superior to remaining on dialysis. Thorough, standardized evaluation and careful screening for premorbid conditions in both elderly donors and elderly recipients are essential. Here, we present various options for expanding the living donor pool, with emphasis on the utilization of elderly living donors and transplantation in elderly recipients.

In the present healthcare system, the physician directly involved in patient care faces developments that are difficult to reconcile with his daily medical activity. He must face that the free choice of a doctor is undermined by access restriction and regulation. The focus of his activity shifts from classical medical examination to documentation and administration of the patients. His professional freedom of action is reduced by economic constraints. The thinning of the political responsibility has the consequence that he is left alone in communicating negative developments to the patients. The culture of clinical research is also increasingly under the pressure of economic constraints. While it must be demanded that physicians adapt to new developments, this must not completely undermine the basic principles of the medical profession.

The population of patients with end-stage renal disease is growing worldwide. In most of the western countries, the median age of patients on dialysis is now ∼65 years. Although transplantation is considered the treatment of choice in the elderly as compared with dialysis treatment, so far it has not been offered to elderly patients in an adequate way. To address the topic of ‘Renal transplantation in the elderly’ in depth, a 2 day satellite symposium was organized in Weimar by the Nephrology Department of the University Hospital Charité, Campus Virchow-Klinikum, Berlin, Germany. Twenty internationally renowned experts in the field of aging and kidney transplantation discussed and shared their experience with 80 transplant clinicians from all over the world. The main topics of discussion were the following: anatomy, physiology and immune responses of the aging kidneys, experimental models of rejection, single-centre experiences and views from databases on outcome of transplantation in the elderly. The aim of the symposium was to advance treatment and improve care in elderly end-stage renal failure patients by promoting ‘old-for-old kidney allocation’ (harvesting of kidneys from ≥65-year-old donors into ≥65-year-old recipients).

Erste Berichte über die Dialysetherapie bei Diabetikern zeigten extrem schlechte Ergebnisse. Ebenso waren erste Versuche der Nierentransplantation als Behandlungsmöglichkeit enttäuschend wegen ihrer hohen Empfängermortalität. In den 80er Jahren kam es zu einer Verbesserung des Patientenüberlebens. Dennoch blieb das Problem einer diabetischen Stoffwechsellage nach der Transplantation weiter bestehen. Die ersten Versuche, die simultane Pankreas- und Nierentransplantation als primäre Behandlungsmodalität einzuführen, waren mit schweren Komplikationen belastet. Erst nach einer langen Periode der Weiterentwicklung kann die simultane Pankreastransplantation heute als Routineprozedur für die meisten Fälle betrachtet werden. Anhand von zwei Fallbeispielen soll demonstriert werden, welche Verbesserungen die Transplantationsbehandlung von Diabetikern inzwischen erreicht hat:

Markers of an acute phase reaction, such as C-reactive protein (CRP) or interleukin-6 (IL-6), are predictive for cardiovascular morbidity and mortality in normal subjects and in hemodialysis (HD) patients. Le-vels of acute phase proteins (APP) may vary with time even in the absence of an acute illness and this may weaken the relationship between APP and clinical outcome. We investigated the intra- and inter-individual patterns of several inflammatory markers in HD patients. Plasma levels of CRP, IL-10, RANTES, TNF-RI, leptin, ferritin and albumin were measured weekly for 12 weeks after the long inter-dialytic interval by ELISA in ten stable HD patients with no clinical signs of infection. Considerable variability was observed. Intra-individual differences were largest for RANTES (coefficient of variation - CV - 80%, followed by CRP (51%), and low for albumin (11%) and ferritin (12%). Inter-individual variability was highest for IL-10 (135%) followed by CRP (88%). The present data suggest that single point measurements of APP, particularly CRP, may not be sufficient to assess the cardiovascular risk in HD patients. Even in patients with no apparent signs of infection, there is considerable variability in plasma levels of APP and repeated measurements are recommended to identify patients at high cardiovascular risk.

Since the sixties kidneys have been transplanted successfully at the 2 predecessors of today's transplant center at the Charité. So far, 1,290 kidneys were transplanted resulting in 89.8% overall graft survival at one year and 78.6% at 5 years. Several factors were associated with these results. Ischemia times were very short (11.9 +/- 7.3 hours). Patients with diabetic nephropathy were rarely transplanted without combined pancreas transplantation. Combined with a pancreas transplantation, kidney grafts fared even better than those of non-diabetic patients. The share of living donation is still rising and is associated with a better outcome than cadaveric grafts. In contrast, the effect of HLA mismatches was not very pronounced. Zero- and one-mismatch transplantations had a clear benefit over those with 2-3 mismatches, but higher numbers of mismatches did not lead to worse results. To expand the donor pool with kidneys from old donors (> 64 years) we participate in the Eurotransplant Senior Program (ESP) where these kidneys are allocated locally to recipients aged 65 years and older without HLA matching. The ischemia times for ESP kidneys were shorter (7.3 +/- 3.0 hours) but transplants were less well matched (4.2 +/- 2.1 mismatches). Graft survival was not different from controls aged 60 years and older who received a kidney from a donor under age 65. The ESP patients do not require prolonged hospitalization for transplantation (30.6 +/- 14.6 days versus 35.3 +/- 26.0 days in patients below 60 years). With the introduction of the ESP the number of transplantations in recipients aged 60 years and above have risen considerably.