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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.

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

Strategies to increase expanded criteria donor (ECD) transplantation are needed. We quantified the extent to which ECD kidneys provide recipients with a lifetime of allograft function by determining the difference between patient survival and death-censored allograft survival (graft survival). Initial analyses compared 5-year outcomes in the Eurotransplant Senior Program (European) and the United States Renal Data System. Among European recipients ≥65 years, patient survival exceeded graft survival, and ECD recipients returned to dialysis for an average of 5.2 months after transplant failure. Among United States recipients ≥60 years, graft survival exceeded patient survival. Although patient survival in elderly recipients in the United States was low (49% at 5 years), the average difference in patient survival at 10 years in elderly recipients in the United States with an ECD versus non-ECD transplant was only 7 months. The probability of patient survival with a functioning allograft at 5 years was higher with ECD transplantation within 1 year after activation to the waiting list than with delayed non-ECD transplantation ≥3 years after activation to the waiting list. Subsequent analyses demonstrated that ECD transplants do not provide a lifetime of allograft function in recipients

Background Whole blood choline (WBCHO) concentrations reflect phospholipase D activation pathways involved in coronary plaque vulnerability and platelet activation suppressed by glycoprotein IIb/IIIa receptor (GP IIb/IIIa) inhibitors, but it is unknown whether this treatment affects serial WBCHO levels. Methods We performed a retrospective matched pairs analysis of 32 patients with acute coronary syndrome treated either with standard therapy alone or with tirofiban plus standard therapy with serial measurements of WBCHO. Results The median level of choline decreased after 4 to 6 hours in the tirofiban group (21.2 μmol/L) while the median level in the group without tirofiban increased (29.3 μmol/L) and WBCHO was significantly lower in tirofiban treated patients ( P =0.039). Over time, the decrease of WBCHO was significant in the tirofiban group only ( P =0.006). Conclusions Our results suggest that in patients with acute coronary syndrome, tirofiban treatment is associated with a significant reduction of WBCHO concentration.

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.

Stress hormones, tissue-plasminogen activator (t-PA) antigen, left-ventricular diastolic function and mood immediately before and after listening to three different kinds of music (a waltz by J. Strauss, a piece of modern classic by H. W. Henze, and meditative music by R. Shankar) were measured in 20 healthy persons (10 women, 10 men; mean age 25 [20-33] years) and 20 hypertensives (8 women, 12 men; mean age 57.5 [25-72] years). To recognise haemodynamic effects, mitral flow by Doppler ultrasound was used as a measure of left-ventricular diastolic function. Atrial filling pressure (AFF) was calculated from the flow integral (VTI) of the early E and the late A waves. The Zerssen scale was used to estimate the immediate mood of the subjects. In hypertensives the levels of cortisol (74 vs 78 ng/ml; P < 0.05) and t-PA antigen (4.3 vs 4.5 ng/ml; P < 0.05) were lower after than before the Strauss waltz. The muscle by Henze lowered the concentrations of cortisol (70 vs 84 ng/ml; P < 0.05), noradrenaline (203 vs 224 ng/l; P < 0.05) and t-PA antigen (4.1 vs 4.6 ng/ml; P < 0.05). After listening to the piece by Shankar the concentrations of cortisol (71 vs 78 ng/ml; P < 0.05), adrenaline 14.5 vs 24.5 ng/ml; P < 0.05) and t-PA antigen (4.2 vs 4.3 ng/ml; P < 0.05) were lower. In healthy subjects AFF (29 vs 26%; P < 0.05) rose after the Strauss music, VTI-E fell (69 vs 73 mm; P < 0.05, while natriuretic peptide rose (63 vs 60 pg/ml; P < 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged >/=65 years to recipients >/=65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age >/=65, n = 446) or recipient age (any to old, [A/O], recipient age 60-64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5-10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors.

Chronic infection with hepatitis C virus (HCV) is an important global health problem. The prevalence of HCV is significantly higher in haemodialysis and kidney transplant patients, as compared to the general population. In spite of the relatively milder liver disease activity reported in HCV-infected haemodialysis patients, HCV infection adversely affects survival. Likewise, HCV has a detrimental effect on both patient and graft survival after kidney transplantation. However, patient survival is significantly better with kidney transplantation compared to remaining on dialysis; therefore, HCV infection alone should not be a contraindication to transplantation. Combination antiviral therapy with pegylated interferon-alpha and low-dose ribavirin is currently evolving in haemodialysis patients. Interferon-alpha (standard/pegylated) is relatively contraindicated after kidney transplantation because of an increased risk of allograft rejection. Therefore, antiviral treatment of transplant candidates while on dialysis remains the best option and may avoid the risk of HCV-associated liver and renal disease after transplantation. Large multi-centre clinical trials are required in HCV-infected haemodialysis and kidney transplant patients in order to define optimal therapeutic strategies before and after transplantation. Copyright © 2007 John Wiley & Sons, Ltd.

Sound data about the prevalence of acute renal failure (ARF) among patients with severe sepsis and septic shock are lacking. Further, it is not known whether ARF is an independent risk factor for mortality in septic patients or merely an indicator of disease severity.A prospective cross-sectional one-day prevalence study was carried out in a representative sample of German ICUs, divided into five strata (200 beds; 201-400 beds; 401-600 beds;600 beds; university hospitals). 3877 patients were screened of whom 415 had severe sepsis and septic shock.Fourteen patients (3.4%) had chronic dialysis-dependent RF and were excluded from analysis. Of the remaining 401 patients, 166 (41.4%) had ARF, as defined by a rise in creatinine above twice the upper limit of normal and/or a drop in urine output to0.5 ml/kg bodyweight. Median APACHE II score was 22 in patients with ARF and 16 in patients without ARF (p0.0001). Patients with severe sepsis/septic shock had an overall hospital mortality of 55.2%. Hospital mortality in patients with ARF was 67.3% and without ARF 42.8% (p0.0001). After adjustment for APACHE II score and age, ARF remained a significant independent risk factor for death [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.27-3.52]. Mortality in septic patients was not associated with pre-existing, non-dialysis-dependent chronic kidney disease, whereas in dialysis-dependent patients with sepsis mortality increased to 86%.In this representative survey in patients with severe sepsis/septic shock, prevalence of ARF is high with 41.4%. ARF represents a significant independent risk factor for mortality in these patients.

Background. Indirect evidence suggests that hypoxia contributes to the pathophysiology of rhabdomyolysis-induced acute kidney injury (AKI). However, the cellular location and kinetics of hypoxia, as well as potential hypoxia adaptation are unclear. Methods. Rhabdomyolysis was induced in rats by IM glycerol (GLY) injection, which largely recapitulates the full clinical syndrome. Additional rats received IV myoglobin (MYO), in order to assess the contribution of MYO per se. We performed immunohistochemistry for hypoxia markers [pimonidazole (PIM) adducts and hypoxia-inducible factors (HIFs)] and the cell-protective HIF target gene heme oxygenase-1 (HO-1). Furthermore, we sought a potential negative feedback loop to terminate HIF activation, driven by HIF prolyl-hydroxylase-2 (PHD-2). Results. In GLY, progressive tubular injury, mainly of proximal tubules (PT), developed over time, but its extent was heterogeneous. PIM, HIFα and HO-1 were all absent in controls, but strongly positive in GLY, with a specific spatiotemporal pattern. In PT, (a) PIM was detectable throughout the study with a maximum at 6 h, (b) HIF was activated only at 3 h and (c) HO-1 and PHD-2 appeared at 6 h and persisted at a lower level at 24 h. Apart from tubular cast formation, MYO did not cause overt tissue damage, but led to strong activation of HIFs, in a pattern similar to 3 h of GLY. Conclusions. Our data suggest that renal hypoxia occurs in rhabdomyolysis, and that MYO, at least partly, contributes to hypoxia generation. Since in the most affected tubules transcriptional hypoxia adaptation is transient and inhomogeneous, pharmacologic HIF enhancement holds the potential to improve outcome in rhabdomyolysis-induced AKI.

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.

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 analysis of the hemodynamics accompanying correction of renal anemia by rhEPO shows that--although they behave qualitatively as in nonuremic anemic patients--cardiac output and peripheral resistance may change inadequately and thereby cause a rise of blood pressure. The underlying mechanisms are not yet fully understood but to a great part may be related to preexisting pathology due to a history of longlasting hypertension. In some patients the development of hypertension may only represent a temporary phenomenon of hemodynamic dysregulation. To avoid cardiovascular complications the following should be considered: Patients with a history of hypertension, even if they are normotensive in the anemic state, are at a higher risk of developing hypertension during therapy with rhEPO. Hypertensive complications may be rare events when anemia is corrected slowly. In case of the development or aggravation of hypertension a reduction of the target hematocrit is indicated.

Background: Hyperlipidemia is highly prevalent in kidney transplant recipients, but the prognostic significance for mortality and allograft survival in these patients has not been established sufficiently. Methods: We prospectively enrolled 733 kidney transplant recipients between 1996 and 1998. Clinical information was collected and blood was drawn for laboratory evaluation. Information on the previous transplantation procedures and organ donor were obtained from the Eurotransplant Foundation database. We used the Austrian Dialysis and Transplantation Registry for follow-up. Using multivariate proportional hazard regression, independent relations of fasting plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels to risk for death from any cause and risk for kidney allograft loss were examined. Results: During a median follow-up of 6.1 years, 154 patients died and 260 kidney allografts were lost. After careful multivariate adjustment, there were no significant associations between TG and TC levels and patient mortality. Patients in the highest quartile of TG and TC levels had no difference in risks for mortality compared with patients in the lowest quartile of these parameters (hazards ratio, 0.81; 95% confidence interval, 0.51 to 1.28; hazards ratio, 0.68; 95% confidence interval, 0.42 to 1.10, respectively). Similarly, no associations were found with allograft loss. Further analysis of associations between high-density lipoprotein cholesterol or low-density lipoprotein cholesterol categories and patient mortality or kidney allograft loss did not show associations. Conclusion: Elevated levels of TC or its subfractions and elevated TG levels are not associated with increased risk for patient mortality or allograft loss in these kidney transplant recipients.

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.

To investigate the effect of low-dose hydrocortisone on time to shock reversal, the cytokine profile, and its relation to adrenal function in patients with early septic shock.Prospective, randomized, double-blind, single-center study.Medical intensive care unit of a university hospital.Forty-one consecutive patients with early hyperdynamic septic shock.After inclusion and a short adrenocorticotropic hormone test, all patients were randomized to receive either low-dose hydrocortisone (50-mg bolus followed by a continuous infusion of 0.18 mg/kg body of weight/hr) or matching placebo. After shock reversal, the dose was reduced to 0.06 mg/kg/hr and afterward slowly tapered. Severity of illness was estimated using Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score.Time to cessation of vasopressor support (primary end point) was significantly shorter in hydrocortisone-treated patients compared with placebo (53 hrs vs. 120 hrs, p.02). This effect was more profound in patients with impaired adrenal reserve. Irrespective of endogenous steroid production, cytokine production was reduced in the treatment group with lower plasma levels of interleukin-6 and a diminished ex vivo lipopolysaccharide-stimulated interleukin-1 and interleukin-6 production. Interleukin-10 levels were unaltered. Adverse events were not more frequent in the treatment group.Treatment with low-dose hydrocortisone accelerates shock reversal in early hyperdynamic septic shock. This was accompanied by reduced production of proinflammatory cytokines, suggesting both hemodynamic and immunomodulatory effects of steroid treatment. Hemodynamic improvement seemed to be related to endogenous cortisol levels, whereas immune effects appeared to be independent of adrenal reserve.

The transcription factor HIF-1alpha has been identified as a key regulator in the cellular and systemic response to hypoxia. Because hypoxia is frequently associated with acidosis, like in ischemia or tumour growth, we studied the impact of acidosis on the expression of the HIF-1alpha and HIF-2alpha proteins and that of the three HIF target genes carbonic anhydrase-9 (CA-9), glucose transporter-1 (Glut-1) and erythropoietin (EPO). Since the HIF-prolyl hydroxylases (PHD) modulate cellular HIF-alpha protein levels we also investigated changes in PHD mRNA expression under hypoxia and acidosis. HIF-1alpha immunoblots revealed, depending on the cell line investigated, a moderate induction of HIF-alpha protein levels by acidosis in normoxia (Hep3B cells) or hypoxia (HeLa cells). Concordantly, the activity of HIF-driven luciferase reporters was slightly enhanced at pH 7.0. In contrast, HIF target genes exhibited divergent responses to acidosis: basal and hypoxia-induced CA-9 mRNA levels were further increased, whereas hypoxic EPO mRNA induction was attenuated, and Glut-1 mRNA levels were not altered by acidosis. Except from a small increase of hypoxia-induced PHD3 mRNA levels in HeLa cells, there was also no significant effect of acidosis on PHD expression. In conclusion, albeit HIF protein levels slightly induced by acidosis and the inconsistent regulation of HIF target genes under acidosis suggest additional, yet unidentified pH-sensitive factors to be involved in the regulation of these genes.

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).

BACKGROUND Clinically, an increasing number of older recipients are listed for transplantation. We examined recipient age-associated alterations of the immune response and their effects on graft function. METHODS Three- and 18-month-old Lewis (LEW) rats received kidneys from 3- and 18-month-old Fischer 344 (F344) rats (1.5 mg/kg/d cyclosporine A for 10 days; n=6/group) and were observed for 180 days. In additional groups, double kidney transplantations were performed to determine the impact of nephron mass and recipient age on graft outcome. RESULTS All young recipients but only 66% of old recipients survived the observation period. Increasing recipient age resulted in a significant decrease in renal allograft function (P

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.

Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes. A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis. In vitro, the oxygen-regulated subunits HIF-1alpha and -2alpha are expressed in inverse relationship to oxygen tensions in every cell line investigated to date. The characteristics and functional significance of the HIF response in vivo are largely unknown. High-amplification immunohistochemical analyses were used to study the expression of HIF-1alpha and -2alpha in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (0.1% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia). These treatments led to marked nuclear accumulation of HIF-1alpha and -2alpha in different renal cell populations. HIF-1alpha was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli. Staining for HIF-1alpha colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1. HIF-2alpha was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts. The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1alpha and HIF-2alpha is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles. The expression of HIF-2alpha in peritubular fibroblasts suggests a role in erythropoietin regulation.

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.

The von Hippel-Lindau (VHL) tumor suppressor gene targets hypoxia-inducible transcription factors (HIFs) for proteasomal degradation. Erythrocytosis due to inappropriate production of erythropoietin (EPO), one of the HIF target genes, is a classic albeit rare finding in patients with renal cancer. We report the clinical to molecular analysis in a patient in whom a thrombotic myocardial infarction was the first manifestation of a clear cell renal carcinoma associated with an elevated serum EPO level (109 U/L) and erythrocytosis (hemoglobin 200 g/L [20 g/dL]). The tumor strongly expressed EPO messenger RNA and the 2 regulatory subunits HIF-1α and HIF-2α. Sequence analysis of tumor tissue identified a point mutation of the VHL gene (nucleotide 701 T>C) with a predicted amino acid exchange (Leu163Pro). This structural change, although located at distance to the HIF-binding region, was found to inhibit binding of HIF-1α to VHL, thus leading to accumulation of HIF, which drives EPO production.

Background: The immunosuppressants used in transplantation medicine significantly elevate the incidence of neoplasia, particularly in the skin. The cumulative incidence of non-melanocytic skin cancer (NMSC) in renal transplant recipients was 20.5% in a study carried out in German centers. Data on more than 35 000 renal transplant recipients in the USA document a cumulative NMSC incidence of over 7% after 3 years of immunosuppression. Methods: The authors selectively review publications obtained by a PubMed search to discuss the incidence of, and major risk factors for, skin tumors and infectious diseases of the skin in immunosuppressed patients. Results: The main risk factors for skin tumors are age at the time of transplantation, light skin color, previous and present exposure to sunlight, and the type and duration of immunosuppressive treatment. Squamous-cell carcinoma (SCC) is the most common kind of skin tumor in immunosuppressed patients. Human herpesvirus 8 and Merkel-cell polyoma virus also cause neoplasia more often in immunosuppressed patients than in the general population. Surgical excision is the treatment of choice. Actinic keratosis markedly elevates the risk that SCC will arise in the same skin area (odds ratio 18.36, 95% confidence interval 3.03–111). Patients with multiple actinic keratoses can be treated with photodynamic therapy or with acitretin. To lower the skin cancer risk, organ transplant recipients should apply medical screening agents with a sun protection factor of at least 50 to exposed skin areas every day. 55% to 97% of organ transplant recipients have skin infections; these are treated according to their respective types. Conclusion: Squamous-cell carcinoma of the skin adds to the morbidity and mortality of transplant recipients and is therefore among the major oncological challenges in this patient group. Structured concepts for interdisciplinary care enable risk-adapted treatment.

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.

renal perfusion may result from a reduction of mean Background. Changes in renal blood flow are considered to arterial blood pressure (MABP) or decreased cardiac outplay a significant role in the induction and maintenance of put or may be due to renal vasoconstriction. The combinakidney failure, but are difficult to monitor with currently availtion of moderately reduced perfusion pressure and inable techniques. The objective was to validate renal flow measurements with Doppler guidewires and to apply this technique creased renal vascular resistance (RVR) is believed to to assess dose and time dependency of the renal vascular effects promote renal failure in patients with sepsis [2] or hepatoof norepinephrine (NE). renal syndrome [3]. The adverse effects of several “nephMethods. In 10 anesthetized pigs, flow velocity in renal arter- rotoxic” agents, including contrast media, on kidney ies (FVart) and veins (FVvein) and volumetric renal blood function are also considered to be partially due to a flow (VBF) were measured before and after intravenous bolus application of incremental doses of NE (2 to 200 mg). temporary reduction in RBF [1]. Some studies have indiResults. FVart curves exactly reflected the changes in VBF. cated that a reduction in RBF persists during the course Beat-to-beat analysis revealed a strong linear correlation over of ARF [4, 5], while others have reported that RBF is a mean VBF range of less than 0.05 to 0.35 L/min (median not an important determinant of the glomerular filtration correlation coefficient with FVart, r 5 0.998), and significant rate (GFR) depression during the maintenance phase of but less close relationships were also found between VBF and FVvein. Ten seconds after the administration of 200 mg NE, postischemic ARF [6, 7]. Therefore, in different clinical FVart dropped from 71 to 6 cm/sec and was 90% reversible situations, monitoring of renal perfusion may be releafter 48 seconds. Similarly, the renal vascular resistance tempo- vant, not only to characterize further the association rarily rose from 988 to 13711 mm Hg · min/L. In contrast, between changes in renal hemodynamics and GFR, but NE-induced increases in systemic vascular resistance were on average a maximum of 1.5-fold but persisted for more than 60 also to identify and prevent ischemic insults to the seconds. kidney. Conclusions. Doppler flow measurements in the renal artery Currently available methods for the measurement of provide an excellent surrogate of volumetric blood flow, which RBF in humans have been useful to detect RBF abnormay be useful for continuous monitoring of renal hemodynammalities in various settings, but are characterized by sevics. The renal vasculature is more sensitive when compared with the systemic vasculature, but also appears to evoke more eral methodological problems that limit their accuracy efficient counter-regulatory mechanisms in response to NE. and applicability. The urinary clearance of p-aminohippurate (PAH) [8] cannot be applied to oligo-anuric subjects, and in postischemic renal failure, PAH extraction A reduction in renal blood flow (RBF) commonly is severely impaired so that the PAH clearance markedly occurs in association with renal dysfunction and can cause underestimates renal plasma flow [6]. Dye dilution techkidney failure. In acute renal failure (ARF), renal hypo- niques require the simultaneous catheterization of the renal artery and vein and allow only bolus measurements [9]. For isotope techniques, the need for external count

Leukocyte accumulation during peritonitis is believed to be controlled by chemotactic factors released by resident peritoneal macrophages or mesothelial cells. Recent data indicate, however, that in many tissues fibroblasts play a key role in mediating leukocyte recruitment. We have therefore examined human peritoneal fibroblasts (HPFBs) for the expression and regulation of C-X-C and C-C chemokines. Quiescent HPFBs secreted monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 constitutively. This release could be dose-dependently augmented with the pro-inflammatory cytokines IL-1β and tumor necrosis factor-α. Stimulated IL-8 production reached a plateau within 48 hours while MCP-1 continued to accumulate throughout 96 hours. Induction of IL-8 and MCP-1 synthesis by HPFBs was also triggered by peritoneal macrophage-conditioned medium. This effect was partly related to the presence of IL-1β as demonstrated by IL-1 receptor antagonist inhibition. Pretreatment of HPFBs with actinomycin D or puromycin dose-dependently reduced cytokine-stimulated IL-8 and MCP-1 secretion, which suggested de novo chemokine synthesis. Indeed, exposure of HPFBs to IL-1β and tumor necrosis factor-α produced a significant up-regulation of IL-8 and MCP-1 mRNA. This effect was associated with the rapid induction of nuclear factor-κB binding activity mediated through p65 and p50 subunits, and with a transient increase in the mRNA expression for RelB and inhibitory protein κB-α proteins. These data indicate that peritoneal fibroblasts are capable of generating large quantities of chemokines under a tight control of nuclear factor-κB/Rel transcription factors. Thus, peritoneal fibroblast-derived chemokines may contribute to the intraperitoneal recruitment of leukocytes during peritonitis.

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.

Background The bioincompatibility of peritoneal dialysis fluids (PDF) in current use has been partially attributed to the presence of glucose degradation products (GDPs), which are generated during heat sterilization of PDF. Several of the GDPs have been identified and we have recently demonstrated that these GDPs per se may impair the viability and function of human peritoneal mesothelial cells (HPMC) in vitro. It is also possible that GDP-related toxicity is further exacerbated by the milieu of PDF. We review the current literature on GDP and present the results of experiments comparing the impact of heat- and filter-sterilized PDF on the viability and function of HPMC. Methods Peritoneal dialysis fluids with low (1.5%) and high (4.25%) glucose concentrations were laboratory prepared according to the standard formula and sterilized either by heat (H-PDF; 121°C, 0.2 MPa, 20 minutes) or filtration (F-PDF; 0.2 μ). The buildup of GDP was confirmed by UV absorbance at 284 nm. Confluent HPMC monolayers were exposed to these solutions mixed 1:1 with standard M199 culture medium. After 24 hours, cell viability was assessed with the MTT assay, and interleukin-1β–stimulated monocyte chemotactic protein-1 (MCP-1) release with specific immunoassay. Results Exposure of HPMC to H-PDF resulted in a significant decrease in cell viability, with solutions containing 4.25% glucose being more toxic than 1.5% glucose-based PDF (27.4% ± 3.4% and 53.4% ± 11.0% of control values, respectively). In contrast, viability of HPMC exposed to F-PDF was not different from that of control cells. Moreover, treatment with H-PDF impaired the release of MCP-1 from HPMC to a significantly greater degree compared to F-PDF (17.4% and 24.9% difference for low and high glucose PDF, respectively). Conclusions Exposure of HPMC to H-PDF significantly impairs cell viability and the capacity for generating MCP-1 compared to F-PDF. This effect is likely to be mediated by GDPs present in H-PDF but not in F-PDF.

Objectives: To compare cortisol levels during "low-dose" hydrocortisone therapy to basal and ACTH-stimulated endogenous levels and to assess whether clinical course and the need for catecholamines depend on cortisol levels and/or pretreatment adrenocortical responsiveness. Design and setting: Prospective observational study in a medical ICU of a university hospital. Patients: Twenty consecutive patients with septic shock and a cardiac index of 3.5 l/min or higher, started on "low-dose" hydrocortisone therapy (100 mg bolus, 10 mg/h for 7 days and subsequent tapering) within 72 h of the onset of shock. Measurements and results: Basal total and free plasma cortisol levels ranged from 203 to 2169 and from 17 to 372 nmol/l. In 11 patients cortisol production was considered "inadequate" because there was neither a response to ACTH of at least 200 nmol/l nor a baseline level of at least 1000 nmol/l. Following the initiation of hydrocortisone therapy total and free cortisol levels increased 4.2- and 8.5-fold to median levels of 3587 (interquartile range 2679–5220) and 1210 (interquartile range 750–1846) nmol/l on day 1, and thereafter declined to median levels of 1310 nmol/l and 345 nmol/l on day 7. Patients with "inadequate" steroid production could be weaned from vasopressor therapy significantly faster, although their plasma free cortisol concentrations during the hydrocortisone treatment period did not differ. Conclusions: (a) During proposed regimens of "low-dose" hydrocortisone therapy, initially achieved plasma cortisol concentrations considerably exceed basal and ACTH stimulated levels. (b) Cortisol concentrations decline subsequently, despite continuous application of a constant dose. (c) "Inadequate" endogenous steroid production appears to sensitize patients to the hemodynamic effects of a "therapeutic rise" in plasma cortisol levels.

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.

It was suggested recently that cardiac troponins are released as T-I-C complexes and then further degraded to T and I-C. It is not known whether the various affinity to the T-I-C and I-C complex of different troponin I test systems influence the diagnostic and prognostic value of the test results in clinical practice. We studied 162 patients (61.3 S.D. 11.1 years) with suspected acute myocardial infarction (AMI) in a single center study. AMI was confirmed in 109 patients. Blood samples were taken at admission, after 1, 2, 4, 8, 12 and 24 h. Troponin I (TnI) was measured using the OPUS plus (TnI-O, cut-off 1.6 microg/l) and the Stratus II (TnI-S, cut-off 1.5 microg/l) analyzers. TnI-O has high affinity to the binary (I-C) and TnI-S to the ternary (T-I-C) troponin complex. A 6-month follow-up with respect to death and recurrent AMI was performed. The sensitivity (SE) and specificity (SP) for AMI diagnosis were 82.6 and 86.8% for TnI-S; 75.2 and 92.5% for TnI-O 0-2 h after admission. The ROC analysis showed a slightly better curve for TnI-S at 4 h (P0.05). Logistic regression analysis shows prediction of 6 months outcome by 0-24 h serial TnI-S measurements (odds ratio 5.21, P=0.0356), and serial TnI-O measurements (odds ratio 4.92, P=0.0186). High affinity to the ternary troponin complex enhances the diagnostic but not the prognostic value of a test system. Indeed, the resulting differences are small but underline the need for standardization of biochemical markers.

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