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ZUSAMMENFASSUNGMit 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.

Aus Notaufnahmen in Deutschland wird eine zunehmende Uberfullung berichtet, die die Prozesse belastet. Ziel der Studie ist es, Grunde fur die Uberfullung der Notaufnahmen sowie populationsbezogene Einflussfaktoren zu erfassen und so eine Datengrundlage fur evidenzbasierte Forschungs- und Losungsstrategien zu entwickeln. Dies ist eine „Mixed-methods“-Studie, die an zwei universitaren Notaufnahmen mit soziodemographisch unterschiedlichen Einzugsgebieten durchgefuhrt wurde (Notaufnahme Nord mit durchschnittlich niedrigem Sozialstatus der Bevolkerung und Notaufnahme Sud mit hoherem Sozialstatus). Die Methodik umfasst quantitative deskriptive Analysen eines Sekundardatensatzes von 34.333 Notfallpatienten und qualitative Fokusgruppeninterviews an beiden beteiligten Einrichtungen. Obwohl die Patienten der Notaufnahme Sud deutlich alter waren und haufiger stationar aufgenommen wurden, waren die Morbiditat und Krankenhausmortalitat der Notaufnahme Nord hoher. Die vom Personal genannten Grunde waren an beiden Einrichtungen sehr ahnlich und zeigten insbesondere externe und patientenbezogene Faktoren, die ein erhohtes Patientenaufkommen sowie einen erschwerten Patientenabfluss bedingen, auf. Es ergaben sich jedoch deutlich unterschiedliche Diskussionsschwerpunkte, die sich anhand der Patientenpopulation nachvollziehen lassen. In beiden Einrichtungen wurde ein erhohtes Mas an „Sicherheitsmedizin“ als Grund fur die Uberfullung genannt. Die wahrgenommenen Grunde fur die Uberfullung der Notaufnahmen liegen zu einem uberwiegenden Teil auserhalb des Einflussbereichs der Notaufnahmen und werden von den Charakteristika ihrer Patientenpopulation mit beeinflusst. Eine Losung des Problems erfordert daher Masnahmen, die uber Prozessoptimierungen in den Notaufnahmen selbst hinausgehen und im Sozial- bzw. dem Gesundheitssystem eingreifen.

Background & Aims Detection of hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMC) and/or hepatocytes in absence of HCV RNA in serum, designated as ‘occult HCV infection', has been a matter of controversy in recent years. We investigated for the first time the prevalence of occult HCV infection in large cohorts of chronic hemodialysis (CHD) and kidney transplant (KTx) patients. Methods We enrolled 417 CHD patients, 417 KTx recipients and 2 control groups – 25 anti-HCV (antibody against HCV)-positive and HCV RNA-positive patients with chronic hepatitis C, and 40 anti-HCV-, HCV RNA-, and HBsAg-negative healthy subjects. HCV RNA was tested in serum and PBMC using a sensitive commercial assay. Results In CHD patients, the prevalence of anti-HCV was 3.6% (15/417) and of positive serum HCV RNA 2.4% (10/417). HCV RNA was detected in PBMC in 1/407 (0.25%) HCV serum RNA-negative patients ("occult HCV infection"). In KTx recipients, prevalence of anti-HCV was 4.8% (20/417) and of positive serum HCV RNA 4.6% (19/417). Occult HCV infection was found in 2/398 (0.5%) serum HCV RNA-negative patients. On a mean longitudinal follow-up of 30months of the 3 patients with occult HCV infection, there was no clinical or virological evidence of HCV infection. Conclusions The prevalence of occult HCV infection was very low in our CHD and KTx patients, and it did not appear to be clinically relevant. Further studies in geographic populations with high HCV endemicity are required to clarify the significance of occult HCV infection in these patient groups.

Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic humoral rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications.

The Symphony study assessed whether mycophenolate mofetil (MMF)-based regimens containing reduced doses of adjunct immunosuppressants could reduce toxicity while maintaining efficacy. Here, we examined the impact of acute rejection and associated risk factors. The incidence of biopsy-proven acute rejection in the low-dose tacrolimus group was approximately half that of the standard-dose cyclosporine and low-dose cyclosporine groups, and a third of that in the low-dose sirolimus group. The low-dose cyclosporine group had more severe rejection episodes (≥grade II) compared with other groups. Acute rejection was associated with a 10 mL/min glomerular filtration rate (GFR) reduction and a 5.3% absolute increase in graft loss at 12 months. Overall, the highest GFR was found in both rejecters and non-rejecters receiving low-dose tacrolimus, both in an intent-to-treat analysis and in patients successfully treated according to the protocol. In Cox regression models, human leukocyte antigen (HLA) mismatches and expanded criteria donors increased the acute rejection risk, while recipient age, living related donor, and MMF dose were associated with a reduced risk. Acute rejection was associated with worse outcome but did not entirely explain the differences among the treatment groups. The 2 g MMF plus low-dose tacrolimus combination appears to be the most efficient of all regimens examined regardless of acute rejection.

BACKGROUND: The increasing age of organ donors and the transplantation of older recipients have become clinical practice. Age-adapted immunosuppressive protocols considering these changes are currently not established. This study analyzed the age-dependent immune response after human kidney transplantation. METHODS: One hundred renal allograft recipients were prospectively evaluated from 2004 to 2005. Patients older than 65 years of the European Senior Program receiving kidneys from donors older than 65 years were compared with recipients younger than 65 years receiving kidneys from donors younger than 65 years. Age-dependent modifications of the immune response were evaluated before transplantation and 7 days and 6 months after grafting by flow cytometry analysis of lymphocyte surface markers in peripheral blood. The cytokine pattern was determined by Cytometric Bead Array, T-cell alloreactivity by enzyme-linked immunospot analysis. RESULTS: There were no differences between the groups regarding patient survival, graft survival, and function at 6 months after transplantation. Before transplantation, 7 days and 6 months thereafter recipients older than 65 years demonstrated significantly elevated numbers of memory T-cells while counts for naive T-cells were significantly reduced. Numbers of activated cytotoxic cells were elevated with increasing age before and 7 days after transplantation. T-cell alloreactivity was more pronounced in older recipients at all time points. Seven days after transplantation tumor necrosis factor-alpha (TNF-alpha) levels were significantly higher, whereas TNF-alpha and interleukin-10 (IL-10) concentrations were significantly reduced after 6 months in older recipients. CONCLUSIONS: Our data demonstrate an initially pronounced immune response in elderly recipients receiving grafts from elderly donors. This observation supports the concept of a donor and recipient age-adapted immunosuppression.

Preconditional activation of HIF with specific prolyl-hydroxylase inhibitors (PHD-I) attenuates proximal tubular injury, induced by warm ischaemia/ reperfusion (Bernhardt, JASN, 2006). Distal tubular damage occurs in humans with acute kidney injury (AKI), in experimental contrast media-induced nephropathy (CIN), as well as in cell-free isolated perfused kidneys (IPKs). Since in the IPK distal tubular damage inversely correlates with HIF activation (Rosenberger, KI, 2005), we explored the potential of PHD-I to improve morpho-functional outcome in this model.Male SD rats were randomly given the synthetic PHD-inhibitor FG-4497 (FibroGen, 50 mg/kg IV) or its vehicle (CTR, n = 10 per group). Six hours later, the right kidney was perfused for 90 min with cell-free oxygenated medium and subsequently perfusion-fixed for morphologic assessment. The left kidney was used for HIF immunostaining.As compared with CTR kidneys, at 6 h after FG-4497 HIF-alpha isoforms were markedly up-regulated in all renal zones: HIF-1alpha in tubules and in papillary interstitial cells (IC), HIF-2alpha in IC and vascular endothelial cells. FG-4497 treatment resulted in a higher perfusate flow rate (P0.04, ANOVA). Tubular injury to medullary thick ascending limbs (mTALs) was significantly attenuated in the treatment versus control group (38.9 +/- 7.4% versus 62.7 +/- 4.9% of mTALs in the mid-inner stripe (P0.02); 23.8 +/- 6.8% versus 45.6 +/- 7.4% in the innermost zone of the inner stripe (P0.05).These findings illustrate that PHD-I preconditioning attenuates hypoxic distal tubular injury produced in the IPK in the same fashion in which it protects proximal tubules. mTAL conservation may be related to the stabilization of cellular HIF, as well as to preserved endothelial function and microcirculation.

Amino-acid-based peritoneal dialysis (PD) fluids have been developed to improve the nutritional status of PD patients. As they may potentially exacerbate acidosis, an amino-acid-containing solution buffered with bicarbonate (Aminobic) has been proposed to effectively maintain acid-base balance. The aim of this study was to evaluate the mesothelial biocompatibility profile of this solution in comparison with a conventional low-glucose-based fluid. Omentum-derived human peritoneal mesothelial cells (HPMC) were preexposed to test PD solutions for up to 120 min, then allowed to recover in control medium for 24 h, and assessed for heat-shock response, viability, and basal and stimulated cytokine [interleukin (IL)-6] and prostaglandin (PGE(2)) release. Acute exposure of HPMC to conventional low-glucose-based PD solution resulted in a time-dependent increase in heat-shock protein (HSP-72) expression, impaired viability, and reduced ability to release IL-6 in response to stimulation. In contrast, in cells treated with Aminobic, the expression of HSP-72 was significantly lower, and viability and cytokine-producing capacity were preserved and did not differ from those seen in control cells. In addition, exposure to Aminobic increased basal release of IL-6 and PGE(2). These data point to a favorable biocompatibility profile of the amino-acid-based bicarbonate-buffered PD solution toward HPMC.

Background. Tubular toxicity and renal ischaemia have been implicated in the pathogenesis of radiocontrast media induced nephropathy (CIN), but their respective role remains unclear. Aims. In order to evaluate changes in renal blood flow in response to intra-arterial contrast media administration, we aimed to continuously measure renal arterial perfusion by means of renal blood flow velocity (RBFV) during left ventricular and coronary angiography and subsequent coronary intervention in patients with chronic kidney disease (CKD). Patients and Methods. Ten patients (7 males, 63.4 +/- 11.7 years) with serum creatinine (SCr) >1.5 mg/dl participated in the study. The first five patients received low-osmolar iopromide and the others iso-osmolar iodixanol contrast medium. RBFV was measured using a 0.014-inch Doppler guide wire, which was inserted through a separate contralateral femoral sheath via a 5 F Cobra diagnostic catheter into the renal artery. Data were recorded at 500 Hz to allow beat-to-beat analysis of RBFV and pressure. All patients were pre-treated with acetylcysteine and hydration. Results. Immediately after left ventricular angiography no significant changes in RBFV were detected. Over time, however, following repeated administration of the additional contrast medium into the coronary arteries, RBFV decreased significantly from baseline until the end of the investigation, 28.4 (19.1/42.7) to 22.9 (16.9/30.6) cm/s (median and quartiles; P = 0.005), in the absence of significant changes in systemic arterial blood pressure. In individual patients the reduction in RBVF varied from 3.7% to 39.5%. On average the decline in RBFV was more pronounced in patients receiving iopromide (from 41.6 cm/s to 29.3 cm/s) than in those receiving iodixanol (from 19.3 to 17.8 cm/s; P = 0.008 for the difference of relative decline). However, in the iopromide treated patients, coronary intervention was more frequently performed (5/5 versus 2/5) and the median duration of the procedure tended to be longer [85 (32-150) min versus 38 (27-110) min; P > 0.2]. Conclusions. The administration of non-ionic low-osmolal contrast media has no immediate effect on renal perfusion in patients with CKD. However, during the course of coronary angiography a gradual decline in renal blood flow may occur, the extent of which varies, presumably depending on individual pre-disposition as well as on the amount of the contrast medium.

Although it generally is accepted that renal hypoxia may occur in various situations after renal transplantation, direct evidence for such hypoxia is lacking, and possible implications on graft pathophysiology remain obscure. Hypoxia-inducible factors (HIF) are regulated at the protein level by oxygen-dependent enzymes and, hence, allow for tissue hypoxia detection. With the use of high-amplification HIF-1alpha immunohistochemistry in renal biopsies, hypoxia is shown at specific time points after transplantation with clinicohistologic correlations. Immediately after engraftment, in primarily functioning grafts, abundant HIF-1alpha is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1alpha score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1alpha induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1alpha, with the only exception being clinical/subclinical rejection. HIF-derived transcriptional adaptation to hypoxia may counterbalance, at least partly, the negative impact of cold preservation and warm reflow injury. Transient hypoxia at 2 wk may be induced by hyperfiltration, hypertrophy, calcineurin inhibitor-induced toxicity, or a combination of these. Lack of detectable HIF-1alpha at 3 mo and beyond suggests that at this time point, graft oxygen homeostasis occurs. The strong correlation between hypoxia and clinical/subclinical rejection in long-term grafts suggests that hypoxia is involved in such graft dysfunction, and HIF-1alpha immunohistochemistry could enhance the specific diagnosis of acute rejection.

The increasing use of high-flux membranes for hemodialysis (HD) has raised concerns that these membranes may confer a higher risk of exposure to cytokine-inducing, bacterial substances (CIS) in the dialysate. Several studies, however, reported higher transfer of CIS through low-flux cellulosic than high-flux synthetic membranes. This surprising paradox was explained by adsorption of CIS to certain high-flux membranes. In order to investigate flux and membrane type independently, we studied two synthetic Polyflux (PF) membranes of the same type but with different flux properties and compared them to a cellulosic membrane (Cuprophan). Three different approaches were employed: (1) cytokine induction in whole blood during in vitro HD contaminated with bacterial filtrates, (2) removal of recombinant C5a, and (3) transfer of purified lipopolysaccharide (LPS). After 90 min recirculation of whole blood, the appearance of IL-6-inducing substances on the blood side was lowest with high-flux PF (1.1 ± 0.2 ng/ml), slightly higher with low-flux PF (1.9 ± 0.7 ng/ml) and highest with Cuprophan (4.1 ± 1 ng/ml). Recombinant C5a added to plasma on the blood side was markedly removed by high-flux PF (by 83%), to a lesser degree and only in the presence of ultrafiltration with low-flux PF (by 54%) and not significantly with Cuprophan (by 11%). Significant transfer of purified LPS from the dialysate onto the blood side was only observed with the cellulosic membrane. We conclude that in contrast to cellulosic membranes, certain synthetic membranes do not permit transfer of LPS. Cytokine induction on the blood side is further reduced by the use of high-flux membranes due to removal of activated complement factors.

Die nekrotisierende Fasziitis durch Streptococcus pyogenes ist eine relativ seltene Erkrankung, die aufgrund des fulminanten Verlaufs jedoch mit einer hohen Mortalitat assoziiert ist. Die mogliche rasche Entwicklung eines toxischen Schocksyndroms erfordert eine fruhzeitiges und aggressives chirurgisches Management mit begleitender intensivmedizinischer Behandlung und adaquater antimikrobieller Therapie. Wir berichten uber die erfolgreiche Behandlung eines 60-jahrigen Patienten mit schwerem Multiorganversagen als Komplikation einer nekrotisierenden Fasziitis des Beines.

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 Charite´ , 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).

Hypertension increases expression of growth factors and MHC II in chronic allograft nephropathy.BackgroundHypertension of the recipient is strongly associated with chronic allograft nephropathy. It is unclear, however, whether hypertension is the cause or the consequence of chronic allograft nephropathy.MethodsThe present study was performed in the Fisher to Lewis rat kidney transplant model. Transplanted rats (N = eight in each group) received either no treatment or were made hypertensive by administration of deoxycorticosteron acetate (DOCA) and salt. Proteinuria and systolic blood pressure was measured monthly, grafts were harvested at 3 and 6 months for semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and for immunohistology.ResultsSystolic blood pressure was markedly elevated in rats receiving DOCA/salt. Allografts of hypertensive animals contained significantly more cells expressing the proliferating cell nuclear antigen compared to isografts and to allografts from normotensive animals (P < 0.05). Histologic staining and mRNA expression of major histocompatibility complex (MHC) II was markedly increased in allografts of hypertensive animals compared to all other groups (P < 0.05). Expression of mRNA for platelet-derived growth factor-B (PDGF-B), transforming growth factor-β (TGF-β) and collagen was higher in allografts than in isografts and was highest in hypertensive animals.ConclusionWe conclude that hypertension augments the expression of growth factors in the allograft possibly aggravating the intimal hyperplasia observed in chronic allograft nephropathy. By increasing the expression of MHC II antigens, hypertension may render the allograft more susceptible to alloantigen-dependent damage. Hypertension and alloantigen-dependent factors appear to exert additive or synergistic effects on inflammatory pathways leading to graft injury.

Background. Chronic kidney disease is characterized by increased synthesis and inhibited destruction of collagenous and non-collagenous matrix proteins. Elevation of collagen fragments has been demonstrated in the serum and urine of patients with renal disease, but the dynamics of renal matrix deposition remain difficult to determine. Methods. To obtain a further insight into renal matrix metabolism we have assessed whether serum and urine concentrations of the non-collagenous protein, tenascin, and of the tissue inhibitor of metalloproteinases 1 (TIMP-1) are altered in association with renal disease. Serum and urine concentrations of both proteins were determined using a newly developed magnetic particle enzyme immunoassay and were compared with levels of N-terminal procollagen III-peptide (PIIINP) and related to the degree of renal failure and proteinuria. Results. Circulating levels of tenascin and TIMP-1 were moderately, but significantly, higher in patients with chronic renal disease (n = 54: mean creatinine clearance, 62 ml min) than in healthy controls (n = 176). Urine concentrations per mg creatinine of tenascin and TIMP-1 were significantly lower than serum levels, but were on average six- and 18-fold higher, respectively, in patients with renal disease than in controls. Urinary concentrations increased with progressive reduction in renal function, but were unrelated to proteinuria. TIMP-1 concentrations in urine correlated with tenascin, which is compatible with the impact of TIMP-1 on the accumulation of matrix proteins. The concentrations of proteins measured did not differ depending on the aetiology of renal disease. Conclusion. Urinary concentrations of tenascin and TIMP-1 are elevated in association with renal disease and may reflect specific aspects of renal fibrosis.

Einleitung: Bei Patienten mit einer terminalen Leber- und Nierenerkrankung ist die kombinierte Transplantation dieser Organe die einzig mogliche Therapie. Hierbei ist eine Differenzierung zwischen chronischer und akuter Niereninsuffizienz wichtig, denn akute Nierenversagen sind nach erfolgreicher Lebertransplantation haufig reversibel. In dieser Studie untersuchten wir die Indikationen und Ergebnisse dieses Verfahrens. Patienten und Methoden : Wir berichten retrospektiv uber 27 kombinierte Leber- und Nierentransplantationen. Die zugrundeliegenden Erkrankungen waren Virushepatitiden (n = 12), polycystische Leber- und Nierenerkrankungen (n = 9), primare Hyperoxalurie (n = 4) und kryptogene Lebercirrhose (n = 2) mit terminaler Niereninsuffizienz bei Glomerulonephritis, diabetischer Nephropathie oder chronischer Cyclosporintoxizitat nach Lebertransplantation und Transplantatinsuffizienz. Neun Patienten hatten vor Transplantation positive lymphocytotoxische Antikorper und 5 Patienten wurden bei einem positiven Crossmatch transplantiert. Ergebnisse: Ein Patient verstarb an rezidivierenden intraabdominellen Blutungen, 2 Patienten verloren das Nierentransplantat fruh-postoperativ aufgrund einer initialen Nichtfunktion und technischer Probleme. Keiner der Patienten mit einem positiven Crossmatch oder lymphocytotoxischen Antikorpern entwickelte eine hyperakute Abstosung des Nierentransplantats. Die Incidenz akuter und steroidresistenter Abstosungen des Lebertransplantats war 60 % und 20 % bei Patienten mit einem positiven und 32 % und 14 % bei Patienten mit einem negativen Crossmatch. Nur 2 Patienten hatten eine akute Rejektion des Nierentransplantats (3,7 %). Das Langzeitpatienten- und Transplantatuberleben war bei Patienten mit einem positiven Crossmatch nicht beeintrachtigt. Das aktuelle 1- und 5-Jahresuberleben der kombiniert transplantierten Patienten betrug 97 % und 93 % verglichen mit 91 % und 83 % bei nur lebertransplantierten Patienten. Schlussfolgerungen: Die kombinierte Leber- und Nierentransplantation ist ein sicheres Verfahren in der Therapie terminaler Leber- und Niereninsuffizienzen. Ein positives Crossmatch ist keine Kontraindikation fur das kombinierte Vorgehen.

Pancreas transplantation is still the best option to achieve normoglycaemia and insulin independence in patients with type I diabetes. As a result of improvements in surgical techniques, immunosuppression and patient selection, one year survival rates of 95, 83, and 88% for patient, pancreas, and kidney survival, respectively, are reported for patients with simultaneous pancreas and kidney transplantation. The main goals for the future are to reduce postoperative morbidity, to identify the relevant indications for single pancreas transplantation, to adopt the best surgical technique for individual patients' needs (bladder versus enteric drainage with or without portal venous delivery of insulin), and to develop immunosuppressive strategies with low nephrotoxic and diabetogenic potential.

Grundproblematik und Fragestellung: Die akute Entzundungsreaktion spielt wahrscheinlich eine wichtige Rolle in der Pathogenese aber auch der Diagnosefindung und Prognoseeinschatzung des akuten Koronarsyndroms. Es fehlen Daten zur Frage, ob hochsensitive Messungen des C-reaktiven Proteins (CRP) zusatzliche Aussagen zum etablierten Risikomarker Troponin T (TnT) ermoglichen.¶Patienten und Methodik: Wir untersuchten 50 Patienten mit akutem Koronarsyndrom (59,4 SD 13,9 Jahre) innerhalb einer Stunde nach Aufnahme und im Intervall von 4–24h in Hinblick auf TnT (Elecsys®, Roche Diagnostics) und CRP (biokit, modifizierter Quantex CRP plus, analytische Sensitivitat 0,02mg/dL). 50% der Patienten wurden retrospektiv als instabile AP klassifiziert. Alle Patienten wurden bis 6 Wochen nach Entlassung hinsichtlich des primaren Endpunktes Tod oder erneutes akutes Koronarsyndrom beobachtet.¶Ergebnisse: Die kumulative Ereignisrate lag bei Patienten mit positivem CRP und TnT 42 Tage nach Entlassung bei 62,5% im Vergleich zu 35,3% der TnT positiven und CRP negativen Patienten. Die TnT negativen und CRP positiven Patienten erreichten in 33,3% der Falle den primaren Endpunkt. Fur die TnT und CRP negativen Patienten wurden in 28,8% der Falle Ereignisse beobachtet. Die logistische Regression hinsichtlich des primaren Endpunktes mit TnT und CRP (jeweils nach 4–24h), Alter, Geschlecht und Diagnose ergab einen unabhangigen Einfluss von TnT (Cutoff 0,1μg/L, p=0,048, Odds Ratio=7,5) und CRP (Cutoff 0,862mg/dL, p=0,026, Odds Ratio=5,3). Sensitivitat/Spezifitat fur die Diagnose AMI waren 69,6%/75% fur TnT bzw. 12%/72% fur CRP in der ersten Stunde und 91,3%/68,2% fur TnT bzw. 68%/72% fur CRP im 4–24h Verlauf.¶Folgerungen: Hochsensitive CRP- Bestimmungen sind neben Troponin T fur die akute Infarktdiagnostik wenig hilfreich. Die Einschatzung der Prognose der Patienten durch TnT wird jedoch mittels CRP 4–24h nach Aufnahme signifikant unabhangig erganzt und damit wesentlich verbessert.

Purpose. We attempted to model and test the pattern of effects of prognostic factors on renal graft survival during theposttransplantation time course. Patients and methods. Patients who received a cadaveric kidney-only transplant between January 1990 and December 1995 in Eurotransplant, 7 who received cyclosporine as induction therapy, and who had a complete follow-up at the time of analysis were included in the study (n=10614). An index summarizing all covariate information was calculated and used for modeling the time-dependent effects with relation to graft failure. Results. The immunological factors (HLA mismatch and % panel-reactive antibody) were seen to have a slowly decreasing negative effect on renal graft survival. The cold ischemic trauma (>24 hr) exerted a permanent detrimental effect on the grafts. The use of organs obtained from old donors was associated with a constant higher risk of graft loss. Conclusions. An analysis of determinants of human allograft dysfunction should also study the interaction between the effects and time. Nonimmunological factors had a constant detrimental effect on graft failure, whereas the impact of the immunological factors—although remaining important for late graft loss—very slowly decreased. In the context of marginal transplants, clustering of unfavorable factors should be avoided to prevent late graft losses.

patients are of questionable value for risk stratification, most probably due to unspecific elevations. Background. Moderate elevations of cardiac troponin ( Tn) T, up to levels presumably diagnostic for minor Key words: haemodialysis; outcome; renal disease; tromyocardial damage, are suspected to be false positive ponin T; troponin I in nearly 0.3 of end-stage renal disease ( ESRD) patients undergoing haemodialysis (HD). It is not clear whether cardiac TnI is superior to TnT in those patients, if diVerences between ESRD and pre-ESRD occur, and Introduction what the prognostic meaning of these troponin elevations might be. Cardiac troponins have recently been utilized in the Subjects and methods. We examined 40 chronic renal- diagnosis of acute coronary syndromes (ACS) and disease patients [56.4 SD 13.9 years; 22 male, 18 provide major advantages compared to conventional female) without evidence of an acute coronary syn- markers such as CK and CKMB [1]. Troponin T, C drome (ACS ) for at least 28 days prior to the investi- and I are part of the troponin‐tropomyosin complex gation. Cardiac status was determined by history, of the contractile apparatus in myocytes [2]. TnI physical examination, ECG and echocardiography. (26 550 Da) and T (39 000 Da) are coded by diVerent Patients were divided into subgroups with HD (n=20) genes in skeletal and cardiac muscle, and therefore the and without HD (n=20). Patients without HD had a development of cardiospecific antibodies is possible. mean creatinine clearance (CC ) of 13.45 ml/min. Tn To overcome the lack of specificity of the conventional were measured by immunoassay techniques. TnT was cardiac markers (creatine kinase, myoglobin), troponin compared to two diVerent TnI tests (TnID, TnIB), T [3,4] and troponin I tests [5‐10] were developed and CK/CKMB activity and myoglobin (MYO) concentra- specificity for cardiac muscle was shown. tions. In all patients, a 9-month follow-up for acute The clinical value of cardiac troponin measurements myocardial infarction, re-hospitalization, and death were evaluated in large populations with acute was completed. myocardial infarction [5,11‐13] with and without conResults. None of the troponins significantly predicted comitant skeletal muscle damage [14,15]. Reference patient outcome. Tn did not correlate with CC values of troponin T and I are very low, mostly below (r

The aim of the present study was to differentiate acute rejection, chronic rejection, and tacrolimus nephrotoxicity with color and power Doppler imaging of renal transplants. One hundred examinations were obtained from 45 patients. Pulsatility and resistive indices were calculated from color Doppler images. The grade of renal vascularization was quantified using computer-assisted pixel analysis in a rectangular region-of-interest. The percentage of vessel-covered renal parenchyma (POV) was calculated using a histogram that discriminated renal vessels from renal parenchyma via power Doppler images. Furthermore, the distance from the most peripherally located vessels to the renal capsule (PVD) was measured. A reduced POVor = 55% proved to be the best discriminator when chronic rejection was suspected (sensitivity 79%, specificity 87%). Tacrolimus nephrotoxicity showed not only a moderate elevation of the Doppler signal but also an increased PVDor = 3.9 mm and a normal POV. We conclude that the evaluation of renal vessels by power Doppler images improves diagnostic accuracy for patients with renal allografts.

Severe liver dysfunction may lead to impairment of renal function without an underlying renal pathology. This phenomenon is called hepatorenal syndrome (HRS), which is associated with a poor prognosis showing a median survival of less than 2 months if renal replacement therapy is necessary. Liver transplantation is the best therapeutic option to regain renal function, but because of poor survival, these patients often die before transplantation. Herein we report a 37-year-old patient with ethyl-toxic liver cirrhosis who underwent hemodialysis due to HRS type I for more than 8 months. After living donor liver transplantation, diuresis immediately resumed, renal function soon recovered, and intermittent hemodialysis was stopped at 18 days after transplantation. Renal function was stable with a serum creatinine

Aims Cardiac troponin T is an established marker of cardiovascular risk in patients with severe angina pectoris. Data are scarce on patients admitted to a coronary care unit with low grade or atypical angina pectoris to rule out myocardial infarction. Methods and Results We investigated 106 patients (57·4 SD 11·6 years) with low grade (Braunwald class I) or atypical symptoms out of 702 patients admitted to the coronary care unit with suspected acute myocardial infarction. Serum concentrations of troponin T were measured at admission and 4h later. In hospital cardiovascular events including acute myocardial infarction, life threatening cardiac arrhythmias, congestive heart failure, and death were recorded. Patients were additionally observed after 3 and 6 months post-discharge regarding acute myocardial infarction, unstable angina, rehospitalization for cardiac causes and death. The patients were divided into a troponin T positive (≥0·2μg.l−1at admission or 4h later; n=11) and a troponin T negative group. The mean value of troponin T 4h after admission in the positive group was 0·58μg.l−1. Of the troponin T positive patients, 0·82 (0·95 CI: 0·48–0·98) had a cardiovascular event during their stay in hospital vs 0·41 (0·95 CI: 0·31–0·52) of troponin T negative patients ( P

Das Zusammentreffen von Nebennierenrinden- und Schilddruseninsuffizienz wird in der Literatur als Schmidt-Syndrom bezeichnet. Bei 2/3 dieser Patienten findet man einen koexistenten Diabetes mellitus Typ I.

Background. A microemulsion formulation of cyclosporine, Neoral, has been developed to overcome the problems associated with the poor and variable absorption of the traditional oil-based oral formulation, Sandimmune. The present study was conducted to compare the safety and tolerability of Neoral versus Sandimmune in maintenance renal transplant recipients over 1 year, and to assess the number of dose adjustments necessary to maintain trough cyclosporine concentrations within the desired therapeutic range. Methods. Patients on Sandimmune were randomized to be converted to Neoral (n=373) or remain on Sandimmune (n=93) for 12 months. Results. The proportion of patients needing dose increases to maintain cyclosporine trough levels within the desired range was significantly higher in the Sandimmune group during the first 3 months of the study, whereas the number of patients needing dose reductions was similar in both groups throughout the study period. There were no differences between the groups in terms of changes in blood pressure, serum creatinine levels, or other laboratory parameters. No significant differences in the incidence of adverse events known to be related to cyclosporine were observed between the treatment groups. More adverse events were causally related to Neoral than to Sandimmune by the investigators. However, overall, there were no clinically relevant differences between the treatment groups in the main safety and tolerability variables. Conclusions. The results of this study in maintenance renal transplant patients suggest that the improved pharmacokinetic characteristics of the microemulsion formulation of cyclosporine, Neoral, may facilitate the clinical management of cyclosporine immunosuppression, compared with the traditional formulation, Sandimmune. Furthermore, there is no evidence that the average improved bioavailability of Neoral has a negative impact on the main safety and tolerability variables, as no significant differences in graft function, the incidence of rejections, and most adverse events were seen.

Biocompatibility and buffers: Effect of bicarbonate-buffered peritoneal dialysis fluids on peritoneal cell function. Background Conventional peritoneal dialysis fluids (PDF) have been shown to compromise the function of both leukocytes and human peritoneal mesothelial cells (HPMC). Various in vitro studies have identified the low initial pH in combination with high lactate content, as well as the hyperosmolality and high glucose concentration present in currently used solutions as the primary determinants of their bioincompatibility. Bicarbonate buffered PDF (at neutral pH) display improved in vitro biocompatibility as compared to conventional, lactate buffered PDF. However, little information is currently available regarding the potential impact of PDF on the function of human peritoneal fibroblasts (HPFB), the major cell population present in peritoneal interstitium. Methods The current study compares the effect of bicarbonate and lactate buffered PDF in a model system of resting peritoneal mesothelial cells and fibroblasts cultured from human omentum. Interleukin-1β-stimulated IL-6 release from HPMC and HPFB was used as the cell functional parameter. Results While short (30min) pre-exposure to lactate buffered PDF significantly reduced the IL-1β-stimulated IL-6 release from HPMC during a subsequent recovery period (24 hr), a significant decrease in HPMC IL-6 secretion with bicarbonate buffered PDF was only observed after prolonged (≥60min) exposure. In contrast, no significant IL-6 inhibition was detected with HPFB pre-exposed to PDF for up to 90minutes. A significant suppression of HPFB IL-6 secretion was only observed in coincubation experiments (24 hr) with dilutions of both types of PDF. Conclusions These results indicate that ( i ) bicarbonate buffered PDF are less inhibitory to peritoneal cell function as compared to conventional, lactate buffered PDF; and ( ii ) HPFB may be more resistant than HPMC to bioincompatible PDF.

leukin-6; tumour necrosis factor; biocompatibility; in vitro study Background. Conventional lactate-buffered peritoneal dialysis fluids containing glucose as the osmotic agent have been shown to compromise important peritoneal host defence functions. The current study employed Introduction an in vitro model using activated peripheral blood mononuclear leukocytes (PBMC ) for the preclinical The continuous absorption of glucose from the peritonbiocompatibility assessment of a novel bicarbonate- eal cavity of patients treated with continuous ambulatbuffered peritoneal dialysis fluid containing 1.0% ory peritoneal dialysis may lead to the development of amino acids as the osmotic agent. obesity and hyperdyslipidaemia [1,2] whereas at the Methods. PBMC (5◊106/ml ) were pre-exposed same time, loss of amino acids and proteins into the ( 10‐30 mm, 37°C ) to bicarbonate-buffered 1% amino- peritoneal dialysate may contribute to negative nitroacid solution, bicarbonate- or lactate-buffered 1.5% gen balance and malnutrition [3,4]. An elegant way to glucose fluid, or control medium (RPMI ). The cells ameliorate both problems could be the substitution of were then washed and stimulated for 2 h at 37° Ci n glucose by amino acids as the osmotic agent. Indeed, RPMI containing 100 ng/mI E.coli endotoxin from earlier studies using a lactate-buffered amino-acid solustrain O55:B5. The cytokines IL-6 and TNFa in cell tion have shown its clinical feasibility and efficacy supernatants were assessed using specific enzyme [5‐10]. immunoassays, cytokine mRNA expression by reverse In addition to these clinical considerations, the transcription polymerase chain reaction. potential bioincompatibility of current dialysis fluids Results. Short, i.e. 10 min, exposure to conventional, has gained increasing interest of researchers in the lactate-buffered glucose fluid resulted in a significant field of peritoneal dialysis. The background of these and time-dependent inhibition of cytokine release and thoughts is the fact that the composition of convenmRNA expression by activated PBMC, whereas the tional peritoneal dialysis fluids is clearly unphysiologicytokine response was improved even following pro- cal: (i) in order to achieve water ultrafiltration their longed (up to 2 h) exposure to bicarbonate-buffered osmolality is increased to 360‐511 mOsm/kg by addi1% amino-acid solution or bicarbonate-buffered 1.5% tion of high glucose concentrations (15.0‐42.5 g/l ), glucose fluid. and (ii) their pH is buffered to 5.2‐5.5 with high Conclusions. Our results suggest that very short, i.e. lactate concentrations ( 35‐40 mmol/l ) in order to prepotentially clinically relevant, exposure to conventional vent glucose caramelization during the industrial heat dialysis fluid impairs the cytokine response by activated sterilization process. In the past years several studies leukocytes. In this respect, the use of bicarbonate- have therefore used in vitro experimentation for the buffered solutions containing 1.0% amino acids or evaluation of potential adverse effects of these dialysis 1.5% glucose may result in improved biocompatibility fluids on various cell populations (for reviews see properties. [11,12]). Among other things it has been shown that current dialysis fluids impair the capacity of leukocytes

Patients with chronic hepatitis run the risk of developing progressive liver disease during immunosuppressive therapy after kidney transplantation. To determine the impact of chronic hepatitis C on morbidity and mortality we analyzed 162 anti-HCV positive of 1241 renal-grafted patients (prevalence 13.1%; 84.9% HCV RNA positive) regularly surveyed in our outpatient clinic between 1992 and 1994. The mean age at transplantation was 44.5 (6-69) years, and follow-up after grafting was 7.4 (0.1-23.9) years. The immunosuppressive regimen and frequency of rejection episodes in HCV-infected patients were comparable to the total population. Only 4.3% (5/117) of the anti-HCV positive, HBV negative patients living with functioning grafts developed a markedly compromised liver function. Fifteen (9.3%) of the HCV-infected patients died, but none suffered from posthepatitic cirrhosis. An additional retrospective analysis of causes of death after transplantation prior to 1992 revealed that liver disease had only been responsible for 2% of the deaths (7 of 324) in the HBsAg negative population (n= 1901). In contrast, the predominant cause of death in the HBsAg positive population (n=76) was posthepatitic cirrhosis in 58% (15 of 26). Thus, kidney transplantation in patients with replicative hepatitis C and normal liver function appears to be justified because of low early and late morbidity and mortality due to chronic liver disease. HBV infection and hemosiderosis substantially increase the risk of chronic liver disease in renal transplant recipients with hepatitis C.

Patients with end-stage renal failure due to analgesic nephropathy have an increased risk of developing a urothelial carcinoma. To determine the impact of renal transplantation on the frequency of urothelial carcinomas, we analyzed 2072 patients who underwent 2371 renal transplantation between 1968 and 1993, including 78 (3.8%) with clinically proven analgesic nephropathy. Before and after transplantation a regular tumor screening was performed in patients with analgesic nephropathy by urine cytology and abdominal sonography. In 11 of the 78 patients with analgesic nephropathy (14.1%; age 51-66 years, 40-108 months after initiation of dialysis treatment, 5-77 months after transplantation), a urothelial carcinoma of the native urinary tract, especially the kidneys, was diagnosed. Therapy comprised nephroureterectomy (n = 6), transurethral resection (n = 6) and/or cystectomy (n = 2). Seven patients died due to tumor progression 16.3 (4-33) months postoperatively and one patient died due to a perioperative complication. Despite regular tumor screening after transplantation, the diagnosis of a urothelial carcinoma was made very late, leading to a high tumor-related mortality. As a consequence, we suggest that a bilateral nephroureterectomy should be performed prophylactically in patients with proven analgesic nephropathy. In addition, a cystoscopy with lavage cytology testing of the bladder should be performed twice a year.

Recent data suggest valganciclovir (VGC) to be as effective as ganciclovir for cytomegalovirus (CMV) prophylaxis. The objective of this study was to analyze the effect of oral valganciclovir in renal transplant patients with symptomatic CMV infection. Twenty-one patients with symptomatic CMV infection received VGC in doses adjusted to renal function until resolution of CMV antigenemia. The patients were followed for a mean of 5.5 months. During therapy, CMV antigenemia dropped in all patients from pretreatment positive levels of 5.2 +/- 3.7 to negative values of 0.25 +/- 0.2 positive cells/10,000 PBMC (P

Hypoxia-inducible factor (HIF)-1alpha and -2alpha are key regulators of the transcriptional response to hypoxia and pivotal in mediating the consequences of many disease states. In the present work, we define their temporo-spatial accumulation after myocardial infarction and systemic hypoxia. Rats were exposed to hypoxia or underwent coronary artery ligation. Immunohistochemistry was used for detection of HIF-1alpha and -2alpha proteins and target genes, and mRNA levels were determined by RNase protection. Marked nuclear accumulation of HIF-1alpha and -2alpha occurred after both systemic hypoxia and coronary ligation in cardiomyocytes as well as interstitial and endothelial cells (EC) without pronounced changes in HIF mRNA levels. While systemic hypoxia led to widespread induction of HIF, expression after coronary occlusion occurred primarily at the border of infarcted tissue. This expression persisted for 4 wk, included infiltrating macrophages, and colocalized with target gene expression. Subsets of cells simultaneously expressed both HIF-alpha subunits, but EC more frequently induced HIF-2alpha. A progressive increase of HIF-2alpha but not HIF-1alpha occurred in areas remote from the infarct, including the interventricular septum. Cardiomyocytes and cardiac stromal cells exhibit a marked potential for a prolonged transcriptional response to ischemia mediated by HIF. The induction of HIF-1alpha and -2alpha appears to be complementary rather than solely redundant.

We describe a young woman whose initial presentation was dominated by acute diarrhoea. Life-threatening multiorgan failure rapidly ensued and necessitated mechanical ventilation and dialysis treatment. An initially elongated activated partial thromboplastin time prompted further coagulation tests that led to the detection of positive lupus anticoagulant, a highly elevated IgG-anticardiolipin (aCL) antibody titre, and prolonged dilute Russell's viper venom time. Histological examination of samples obtained during endoscopy revealed widespread intestinal thrombotic microangiopathy. In view of these serologic and histologic features, a diagnosis of the malignant variant of the antiphospholipid syndrome (APS), also termed 'catastrophic APS', was established. In spite of this syndrome's grim prognosis, the patient recovered following intensive anticoagulation and adjunct treatment with steroids and immunoglobulins.

Tumor necrosis factor-alpha is elevated in plasma during kidney transplant rejection. However, the measurement and biological activity of TNF alpha is influenced by inhibitory soluble TNF receptors. We therefore determined plasma levels of TNF alpha and the 2 soluble TNF receptors, the 55-kDa TNF receptor (TNF-sR55) and the 75-kDa TNF receptor (TNF-sR75), by immunoassays in 25 patients before and daily after kidney transplantation. Plasma samples were retrospectively assigned to 3 groups: (1) patients with well-functioning grafts (n = 14); (2) patients with biopsy-proven graft rejections (n = 7 patients with 10 rejections); and (3) patients with episodes of CsA nephrotoxicity (n = 4 patients with 9 samples). On the day of biopsy-proven graft rejection, TNF alpha increased from 8.6 +/- 0.9 pg/ml to 14.8 +/- 3.5 pg/ml (P < 0.02), TNF-sR55 from 6.6 +/- 1.3 ng/ml to 9.0 +/- 1.2 ng/ml (NS), and TNF-sR75 from 10.3 +/- 1.0 ng/ml to 15.3 +/- 2.0 ng/ml (P < 0.01). During episodes of CsA toxicity, TNF alpha levels did not change, TNF-sR55 increased from 5.2 +/- 0.5 ng/ml to 10.5 +/- 0.5 ng/ml (P < 0.01), and TNF-sR75 increased from 10.2 +/- 0.8 ng/ml to 17.5 +/- 0.9 ng/ml (P < 0.01). There was a strong correlation between serum creatinine and plasma TNF-sR55 (r = 0.7, P < 0.001) and TNF-sR75 (r = 0.7, P < 0.001), but not with TNF alpha. Therefore, levels of TNF-sR55 and TNF-sR75 were corrected for serum creatinine. An index expressing TNF alpha over actively released soluble receptors (index = TNF alpha/(corr.TNF-sR55 + corr.TNF-sR75)) detected rejection episodes with a sensitivity of 70-80% and a specificity of 89%. We conclude that the measurement of plasma TNF alpha in combination with its soluble receptors is superior to isolated TNF alpha determinations in discriminating acute graft rejection from episodes of CsA toxicity in kidney transplant recipients.

Over recent years an association between cardiovascular events and inflammation has been reported by several groups and this now finally appears to be well established. Baseline levels of C-reactive protein (CRP) in apparently healthy individuals represent an independent risk factor for cardiovascular events including myocardial infarction and peripheral artery disease w1–3x. Moreover, the rise in CRP after myocardial infarction, or during unstable angina pectoris, predicts outcome w4x. It has been suggested that the inflammatory process may not merely be an epiphenomenon but rather a pathogenetical factor in the genesis of atherosclerosis w5x. Cardiovascular mortality is greatly increased in haemodialysis patients. For instance, the risk of dying from cardiovascular causes is 100-fold higher for a 40-year-old dialysis patient compared to the normal population w6x. Besides other explanations (hypertension, hyperlipidaemia), one reason may be the chronic inflammation observed in patients with renal failure, as indicated by elevated plasma levels of acute phase proteins such as CRP w7x and elevated levels of cytokines such as interleukin-6 (IL-6) w8x. Moreover, the capacity of monocytes from patients with renal failure to produce cytokines appears to be augmented. Indeed, even in dialysis patients, plasma levels of CRP and IL-6 are strong predictors Correspondence and offprint requests to: Dr R. Schindler, Department of Nephrology and Intensive Care Medicine, Charit-Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany. Email: ralf.schindler@charite.de 17 Nephrol Dial Transplant (2002) 17: Editorial Comments

COL4A5 splice site mutation and α5(IV) collagen mRNA in Alport syndrome. Mutations affecting the COL4A5 gene encoding the α5 chain of type IV collagen, are involved in the pathogenesis of X-linked Alport syndrome. We used denaturing gradient gel electrophoresis (DGGE) to screen PCR amplified exons of COL4A5 for point mutations in a set of 18 Alport patients previously characterized by Southern blotting. One sequence variant was identified in the exon 38 region of a male Alport patient. Sequence analysis revealed a G to C trans version in the 5′ intron splice donor site downstream from exon 38 (GT to CT). To determine the effect of the mutation on mRNA splicing, α5(IV) cDNA was generated from total RNA of peripheral blood lymphocytes. Subsequent cDNA PCR yielded a product 81 base pairs shorter in the affected Alport patient, compared to normal controls. The absence of exon 38 from the α5(IV) cDNA was confirmed by sequence analysis. The results demonstrated that the mutation leads to skipping of exon 38 in the processing of α5(IV) pre-mRNA. The shortened transcript lacked 27 codons encoding a Gly-X-Y-repeat sequence with a preserved reading frame, enabling the translation of codons further downstream. Clinically, the patient presented with juvenile onset Alport syndrome, end-stage renal failure, and deafness. He had no ocular lesions. Typical ultrastructural changes of the glomerular basement membrane (GBM) were shown on electron microscopy. The patient developed anti-GBM antibodies after renal transplantation, however, renal function deteriorated only moderately.

P>Regional transplant practices may affect clinical outcomes within multinational studies. This study evaluated whether the overall results from the Symphony study can be generalized to the participating countries. De novo adult renal transplant recipients (n = 1645) were randomized to receive standard-dose cyclosporine, or daclizumab induction plus low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus, all in addition to mycophenolate mofetil and steroids. Data for the highest patient-recruiting countries, Spain (n = 275), Germany (n = 316) and Turkey (n = 258), were compared. Patient transplant characteristics were different among the country subsets; only deceased donors in Spain, more expanded criteria donors in Germany, and mainly living donors in Turkey. Efficacy results for the three countries were consistent with that of the overall study - renal function and biopsy-proven acute rejection (BPAR) rates were superior with low-dose tacrolimus. Turkey had higher mean calculated glomerular filtration rate across all treatment groups (60.6-72.2 ml/min) compared with that of Spain (51.1-57.5 ml/min) and Germany (51.3-62.9 ml/min). Spain and Turkey had lower BPAR rates across the four treatment groups compared with the overall study; Germany had much higher rates (21.0-54.2%). These findings confirm the general applicability of the Symphony study results and highlight the importance of inclusion of patients from different geographic origins in randomized clinical trials. (Less)

To determine the impact of long-term immunosuppression on serum lipids in stable renal graft recipients we measured serum lipids and apolipoprotein B concentrations in 20 patients receiving therapy with cyclosporin (CsA) and low-dose prednisolone (CsA/P) and in 18 patients on therapy with azathioprine and maintenance steroids (Aza/P). The patients were matched for age, body mass index, primary renal disease and dose of prednisolone, but not for the duration in transplantation and serum creatinine concentration. Triglyceride concentrations were significantly higher in the CsA/P group than in Aza/P-treated patients: 2.62 +/- 0.35 vs 1.62 +/- 0.23 mmol/l (P less than 0.05). Similarly, total cholesterol (C) levels were significantly more elevated in the CsA/P recipients than in the other group: 7.44 +/- 0.32 vs 5.84 +/- 0.25 (P less than 0.02). CsA/P patients had higher serum levels of LDL-C (4.79 +/- 0.20 vs 3.43 +/- 0.19 mmol/l (P less than 0.001) and apolipoprotein B concentrations (191 +/- 13 vs 128 +/- 9 mg/dl: P less than 0.001). CsA/P and Aza/P recipients had similar concentrations of HDL-C (1.73 +/- 0.13 vs 1.52 +/- 0.09 mmol/l: NS). We conclude that in stable renal graft recipients with good transplant function long-term immunosuppression with CsA/P is associated with a more atherogenic lipid status than therapy with Aza/P.

Purpose Previous studies suggest that high levels of bilirubin exert cytotoxic, neurotoxic and encephalopathic effects that themselves may lead to further deterioration of liver function and multiorgan failure. Although extracorporeal BA is not a causal therapy, there are case reports of clinical benefits of BA. The present retrospective study investigated the clinical utility and effectiveness of BA in 23 patients with liver failure. Methods Twenty-three patients (61±11 years) with excessive hyperbilirubinemia (>25 mg/dL) after liver transplantation (n=7), partial liver resection (n=12) and others (n=4) were treated with BA (3.6 liters plasma per BA, BR350, Asahi) and followed for 45±8 days. Results A mean of 6.6 treatments (3–16) were performed per patient. On average, a single BA treatment reduced bilirubin-levels from 31±12 to 23.7±9 mg/dL (pConclusions BA is able to stabilize or decrease bilirubin levels in patients with liver failure. Our experience suggests that BA is a safe and promising short-term treatment option for patients with acute deterioration of hepatic function.

While some studies clearly demonstrated transfer of cytokine-inducing substances (CIS) through dialysis membranes, other authors were unable to reproduce such a transfer. This inconsistency may have been caused by marked differences in experimental design. We performed a systematic evaluation of cytokine induction in whole blood and from separated peripheral blood mononuclear cells (PBMC) using either purified lipopolysaccharide (LPS) or culture supernatants from various bacterial strains. An in vitro hemodialysis circuit with whole blood in the blood compartment was employed; the dialysate was contaminated with sterile filtrates from Pseudomonas aeruginosa cultures. Addition of plasma samples from the blood side to PBMC readily induced interleukin (IL)-1β and IL-6 after contamination of the dialysate, while the same samples failed to induce cytokine production in whole blood. In experiments using direct incubation, purified P. aeruginosa LPS induced more IL-1β and IL-6 in whole blood compared to PBMC. In contrast, bacterial filtrates from Escherichia coli, Enterobacter cloacae and especially P. aeruginosa induced significantly less cytokines in whole blood compared to PBMC. Addition of erythrocytes but not granulocytes decreased cytokine induction by bacterial filtrates as well as by LPS, probably by adsorption of these substances. The addition of 30% plasma increased cytokine induction by LPS but decreased cytokine induction by P. aeruginosas filtrates. Our results suggest that cellular and plasmatic components of whole blood interact with bacterial CIS altering their pyrogenic activity. The detection of CIS depends on the test system used; whole blood cultures are not as sensitive for the detection of CIS from bacterial filtrates as PBMC cultures.

The hepatorenal syndrome (HRS) is characterized by renal vasoconstriction leading to deterioration of renal function in patients with liver disease. A possible role of endothelin-1 (ET-1) in the pathogenesis of HRS has been suggested, but a correlation between ET-1 plasma levels and the development of HRS as well as the recovery from HRS following OLT has not been shown yet. We performed longitudinal measurements of ET-1 plasma levels in four groups of patients, 5 patients with HRS before and after orthotopic liver transplantation (OLT), 10 patients without HRS undergoing OLT, 20 patients with chronic renal failure but without liver disease, and 12 healthy controls. Before OLT, plasma levels of ET-1 were higher in patients with HRS (19.5 +/- 8.6 ng/l, P < 0.001; n = 5) compared to patients without HRS (4.9 +/- 1.1 ng/l; n = 10), normals (1.2 +/- 0.18 ng/l; n = 12), and patients with chronic renal failure (2.4 +/- 0.4 ng/l; n = 20). Patients with HRS compared to patients without HRS had higher levels for creatinine (2.42 +/- 0.6 vs. 0.89 +/- 0.05 mg/dl, P < 0.05), creatinine clearance (107 +/- 9 ml/min vs. 44.6 +/- 5.5 ml/ min, P < 0.001), and bilirubin (11.4 +/- 3.8 vs. 3.7 +/- 1 mg/dl, P < 0.05) before OLT. Within one week after OLT, there was a rapid decrease in ET-1 levels in patients with HRS while creatinine and bilirubin levels decreased slower. Regression analysis revealed a weak correlation between serum creatinine and ET-1 (r = 0.192, P = 0.04) and a significant correlation between serum bilirubin and ET-1 (r = 0.395, P < 0.001). The means of the ET-1 levels decreases rapidly with improvement of liver function after OLT. Levels of ET-1 correlate with excretory liver function assessed by bilirubin. The fall in ET-1 levels preceding improvement of renal function further strengthens the concept of ET-1 being a causative factor in HRS.

Simultaneous pancreas kidney transplantation is currently the state of the art therapy for patients with type 1 diabetes mellitus and diabetic nephropathy. Up to 30% of patients loose the pancreas with a kidney graft that continues to function. Under those conditions, isolated pancreas retransplantation can be indicated. We compared the outcome of these patients with the outcome of patients undergoing primary pancreas after kidney transplantation. From 1998 to 2005, we performed 205 pancreas transplantations. Three patients were considered for isolated pancreas retransplantation; to date, two have received a new organ. One was retransplanted twice. In two cases, the reasons for the initial graft loss in the retransplantation group were pancreatitis with hemorrhagic bleeding and in the third case severe rejection. After retransplantation two of three patients lost their graft owing to bleeding and venous thrombosis. One of three organs was successfully transplanted and the patient does not require insulin. During the same time, three pancreas after kidney transplantations were performed; all are doing well und are free of insulin. The study despite the small number of cases shows a high complication rate after pancreas retransplantation. Nevertheless, pancreatic retransplantation should be considered in selected patients.