Ulrich Frei

Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock.

Objectives: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. Design:Prospective, randomized, double-blind, single-center study. Setting:Medical intensive care unit of a university hospital. Patients:Forty-one consecutive patients with early hyperdynamic septic shock. Interventions: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. Measurements and Main Results: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. Conclusions: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.

Immunohistochemical Detection of Hypoxia-Inducible Factor-1α in Human Renal Allograft Biopsies

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.

Plasma Levels Of Tumor Necrosis Factor (tnf) And Soluble Tnf Receptors In Kidney Transplant Recipients

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.

Cytotoxic effector molecule gene expression in acute renal allograft rejection: correlation with clinical outcome; histopathology and function of the allograft.

BACKGROUND Cytotoxic effector molecule expression in human renal allograft biopsies has been closely associated with acute rejection. Here we studied whether intragraft expression of perforin, granzyme B, and Fas ligand correlates with long-term clinical outcome of acute rejection episodes. Furthermore, we examined the relation to histopathology and function of the allograft during rejection. METHODS Twenty-two human renal biopsies were quantified for mRNA expression of perforin, granzyme B, Fas ligand, and Fas with reverse transcription-polymerase chain reaction. Expression levels were correlated with clinical outcome after 12 months, Banff rejection grades, and allograft function in the course of acute rejection. RESULTS Only Fas ligand, but not perforin or granzyme B, showed significantly higher up-regulation in seven samples with therapy-resistant acute rejections versus eight samples with therapy-sensitive acute rejection. We found no relation between cytotoxic marker expression and Banff rejection grades or serum creatinine peak levels. CONCLUSIONS Fas ligand may be useful as an early marker of therapy-resistant acute rejection. Cells that express Fas ligand but not classical soluble cytotoxic molecules might influence clinical outcome of acute rejection episodes.

Treatment of cytomegalovirus disease with valganciclovir in renal transplant recipients: a single center experience.

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<0.001). After cessation of therapy, none of patients developed relapse of CMV antigenemia/symptoms within the follow-up. VGC therapy was well tolerated in all patients and no major adverse effects occurred. This pilot trial showed VGC to be safe and highly effective in antiviral therapy after renal transplantation. However, subsequent multicenter clinical trials for treatment of CMV disease are necessary.

Improved Physical Performance after Treatment of Renal Anemia with Recombinant Human Erythropoietin

The physical performance of 12 anemic patients on renal dialysis was investigated following treatment of renal anemia with recombinant human erythropoietin (rhEPO; 40-120 U/kg, 3 times a week). Exercise intensity at a heart rate of 130 beats/min (PWC130) on a bicycle ergometer was assessed before rhEPO treatment, after reaching the target hematocrit (73 +/- 18 days), and in the maintenance phase (211 +/- 53 days). Hemoglobin concentrations measured at these time points were 7.3 +/- 1.2, 11.9 +/- 1.5, and 12.1 +/- 1.4 g/dl, respectively. PWC130 rose from 77 +/- 27 to 104 +/- 37 and 104 +/- 51 W, respectively. Aerobic threshold (i.e. blood lactic acid concentration of 2 mmol/l) shifted to higher workloads indicating improved muscle oxygen supply.

Urodilatin: a new approach for the treatment of therapy‐resistant acute renal failure after liver transplantation

Abstract A pilot study was performed in patients after liver transplantation (Ltx) to examine the effect of continuous intravenous urodilatin (URO, CDD/ANP‐95–126)‐infusion as an alternative therapy of acute renal failure (ARF) resistant to conventional therapy. Eight patients who developed ARF after liver transplantation and fulfilled requirements for haemo‐dialysis/haemofiltration were treated. After URO infusion was started, renal function improved and all patients developed a strong diuresis and natriuresis within 2–4h. The extracellular expansion due to sodium and water retention in anuric/oliguric ARF lead to an increased central venous pressure (CVP) and elevated blood pressure. During the URO infusion CVP declined and systolic, as well as diastolic, blood pressure were stable. In six patients where haemodialysis/haemofiltration could be avoided, serum creatinine (SC) and blood urea nitrogen (BUN) declined during URO treatment and creatinine clearance (CC) also improved significantly. Fluid and electrolyte disturbances changed promptly and normalized. This was in concordance with renal excretion of electrolytes. Two patients still required haemodialysis/haemofiltration. The six patients who did not require haemodialysis/haemofiltration after URO treatment normalized concerning their renal function and did well in a control period of 12 weeks. The study shows that continuous low dose URO infusion may present a new concept for treatment of postoperative acute renal failure resistant to conventional therapy.

Alterations of the immune response with increasing recipient age are associated with reduced long-term organ graft function of rat kidney allografts1

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 <0.001), more advanced morphologic evidence of chronic allograft damage (P <0.001), and greater cellular infiltration (P <0.05) and major histocompatibility complex expression (P <0.01) within grafts. Additional in vitro studies examined age-related changes in the cellular immune response by enzyme-linked immunosorbent assay, fluorescence-activated cell sorter analysis, and alloreactive enzyme-linked immunospot: splenocytes from old LEW rats produced significantly more interleukin (IL)-2 (P <0.0001), IL-4 (P <0.05), interferon (IFN)-&ggr; (P <0.0001), and tumor necrosis factor-&agr; (P <0.05). IFN-&ggr;–producing memory-type T cells were significantly elevated in older rats (P <0.0001). Moreover, they revealed significantly more alloreactive T cells directed against F344 (146±64.2 and 512±277/106 T cells; P <0.05). Double renal allografts from young donors into old recipients confirmed an independent effect of recipient age on the acceleration of chronic graft deterioration. Conclusions. The enhanced cellular immune responsiveness in elderly recipients was associated with advanced chronic graft injury. Clinically, older recipients may need a modified immunosuppression.

High mortality from urothelial carcinoma despite regular tumor screening in patients with analgesic nephropathy after renal transplantation

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 transplantations 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.

Role of excretory graft function for erythropoietin formation after renal transplantation

Abstract. To examine the role of renal excretory function for erythropoietin (EPO) formation we have determined the kinetics of plasma immunoreactive EPO (irEPO) in patients with end‐stage renal disease undergoing renal allotransplantation (RTX).