Peter Heering

Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration

Objectives: To determine whether continuous venovenous hemofiltration leads to extraction of tumor necrosis factor alpha (TNFα) and cytokines from the circulation of critically ill patients with sepsis and acute renal failure and to quantitate the clearance and the removal rate of these cytokines and their effect on serum cytokine concentrations. Design: Prospective, controlled study in patients with continuous venovenous hemofiltration (24 l/24 h) using a polysulphone membrane in patients with acute renal failure. Patients: 33 ventilated patients with acute renal failure of septic (n = 18) and cardiovascular origin (n = 15) were studied. Interventions: Hemodynamic monitoring and collection of blood and ultrafiltrate samples before and during the first 72 h of continuous hemofiltration. Measurements and main results: Cardiovascular hemodynamics (Swan-Ganz catheter), Acute Physiology and Chronic Health Evaluation II score, creatinine, electrolytes, and blood urea nitrogen were recorded daily. Cytokines (TNFα, TNFα-RII, interleukin (IL) 1β , IL1RA, IL2, IL2R, IL6, IL6R, IL8, IL10) were measured in prefilter blood and in ultrafiltrate immediately preceding and 12, 24, 48, and 72 h after initiating continuous venovenous hemofiltration (CVVH). Septic patients showed elevated cardiovascular values for cardiac output (7.2 ± 2.1 l/min), cardiac index (4.2 ± 1.3 l/min per m2), and stroke volume (67 ± 23 ml) and reduced values for systemic vascular resistance (540 ± 299 dyn · s · cm− 5). All hemodynamic values normalized within the first 24 h after initiating CVVH treatment. TNFα was 1833 ± 1217 pg/ml in septic patients and 42.9 ± 6.3 pg/ml in nonseptic patients (p < 0.05) prior to CVVH. TNFα was detected in ultrafiltrate but did not decrease in blood during treatment with CVVH. There was no difference in IL 1β between septic (3.8 ± 1.9 pg/ml) and nonseptic patients (1.7 ± 0.5 pg/ml). No significant elimination of cytokines was achieved in the present study by CVVH treatment. Conclusions: These findings demonstrate that CVVH can remove TNFα and special cytokines from the circulation of critically ill patients. Cardiovascular hemodynamics seemed to improve in septic patients after induction of hemofiltration treatment, although there was no evidence that extracorporeal removal of cytokines achieved a reduction in blood levels. The study indicates that low volume continuous hemofiltration with polysulphone membranes in patients with acute renal failure is not able to induce significant removal of cytokines.

A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis

Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2, and a urine protein to creatinine ratio over 1.8 mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4 mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73 m2). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 mg/mg with all three Black patients having a mean decline of 3.6 mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary.

Restenosis after elective coronary balloon angioplasty in patients with end stage renal disease: a case-control study using quantitative coronary angiography

Objective To assess the rate of angiographic restenosis in patients with end stage renal disease after elective coronary angioplasty. Design A retrospective case-control study of 20 patients with end stage renal disease and 20 sex and age matched controls without renal disease, who had undergone primarily successful coronary angioplasty. Control coronary angiography was performed regardless of worsening or renewed incidence of anginal symptoms. Main outcome measures Group comparison of coronary morphology, as evaluated by quantitative coronary angiography, and of cardiovascular risk factors. Results The rate of angiographic restenosis was 60% in patients with renal disease and 35% in controls. In patients with end stage renal disease the following differences (mean (SD) were found versus controls: raised plasma fibrinogen (483 (101)v 326 (62) mg/dl, p < 0.001); raised plasma triglyceride (269 (163) v 207 (176) mg/dl, p < 0.01); smaller diameter of the coronary reference segment (2.59 (0.87) v 2.90 (0.55) mm, p < 0.10); smaller minimum luminal diameter of the dilated stenosis (0.77 (0.46)v 0.97 (0.27) mm, p < 0.05). Discriminant analysis showed that minimum luminal diameter before angioplasty (r = −0.79) and fibrinogen (r = +0.34) had the highest statistical association with restenosis. Conclusions The high rate of angiographic restenosis in patients with end stage renal disease seems to be related to the size of the vessel dilated and to an increased prothrombotic risk, as indicated by higher fibrinogen concentrations.

Reduced incidence of acute renal graft failure in patients treated with peritoneal dialysis compared with hemodialysis

In a case-control study performed in two centers, the incidence of delayed graft function (DGF), defined as the necessity to perform dialysis after transplantation, was analyzed according to prior treatment with continuous ambulatory peritoneal dialysis (CAPD; n = 117) or hemodialysis (HD; n = 117). The patients were matched for age, sex, HLA compatibility, and cold ischemia time. The patients were followed up for 6 months to monitor renal graft function (serum creatinine [Screa] level immediately after transplantation, at 6 weeks, at 6 months) and postoperative complications. No significant differences were found in the warm ischemia time of the graft or previous time on dialysis. DGF occurred in 27 CAPD patients (23.1%) and 59 HD patients (50.4%; P < 0.0001). The decline in Screa level after transplantation was faster in CAPD patients: the time for Screa level to decrease 50% after transplantation (T1/2Screa) was reached after 5.0 +/- 6.6 days in the CAPD group compared with 9.8 +/- 11.5 days in the HD group (P < 0.0001). A greater number of patients developed acute rejection episodes in the CAPD group (P < 0. 05), but Screa level was not different in the two groups 6 weeks and 6 months after transplantation. No differences were observed in infectious or surgical complications. This study shows that immediate renal function after transplantation is better in CAPD patients and that peritoneal dialysis should be considered as a first choice for pretransplantation therapeutic modality.

CARDIOVASCULAR RISK FACTORS AND DISEASES AFTER RENAL TRANSPLANTATION

Cardiovascular disease is a leading cause of death after renal tranpslantation (tpx), and the incidence is considerably higher than in the general population.ObjectiveTo evaluate the incidence of atherosclerotic cardiovascular complications after tpx, the prevalence of cardiovascular risk factors, prior to and following tpx, and the association between the risk factors and complications.Patients and methodsAnalysis of atherosclerotic cardiovascular diseases (coronary artery disease, cerebral and peripheral vascular disease) and cardiovascular risk factors before and after transplantation in 427 renal transplant recipients between 1987 and 1992 (mean age at transplantation 45±12 years, 58% male, 7% diabetics) with a mean post-transplant follow-up of 29±20 months.ResultsFollowing tpx 11.7% developed atherosclerotic cardiovascular diseases, the majority coronary artery disease (9.8%). The comparison of risk factors 12 months before and 24 months following transplantation showed: prevalence of systemic hypertension (from 73% to 85%), diabetes mellitus (from 7% to 16%) and obesity with a body mass index >25 kg/m2 (from 26% to 48%) had increased significantly whereas the number of smokers halved to 20%. Triglycerides decreased significantly (from235 mg/dl to 217 mg/dl). Totaland HDL cholesterol rose significantly (from 232 mg/dl to 273 mg/dl and from 47 mg/dl to 56 mg/dl, respectively). LDL cholesterol increase was significant (from 180 mg/dl to 189 mg/dl). In the univariate analysis, cardiovascular diseases were significantly associated with male gender, age over 50 years, diabetes mellitus (DM), smoking, total cholesterol ≥200 mg/dl, LDL cholesterol>180 mg/dl, HDL cholesterol ≤55 mg/dl, fibrinogen ≥350 mg/dl, body mass index>25 kg/m2, serum uric acid >6.5 mg/dl and with more than two antihypertensive agents per day. The Cox proportional hazards model revealed DM with a relative risk (RR) of 4.3, age>50 years (RR=2.7), body mass index>25kg/m2 (RR=2.6), smoking (RR=2.5), LDL cholesterol>180 mg/dl (RR=2.3) and uric acid>6.5 mg/dl as independent risk factors.ConclusionsThe high incidence of cardiovascular disease following renal transplantation is mianly due to a high prevalence and accumulation of classical risk factors before and following transplantation. Future prospective studies should evaluate the success of treatment regarding reduction of cardiovascular morbidity and mortality in this high risk population.

The use of different buffers during continuous hemofiltration in critically ill patients with acute renal failure

Objective: To determine the impact of different hemofiltration (HF) replacement fluids on the acid-base status and cardiovascular hemodynamics in patients with acute renal failure (ARF) and continuous veno-venous hemofiltration (CVVH).¶Design: Prospective, cohort study.¶Setting: Intensive Care Unit of the Heinrich Heine University Hospital, Düsseldorf, Germany.¶Subject and methods: One hundred and thirty-two critically ill patients with acute renal failure and continuous veno-venous HF were studied. Fifty-two patients were subjected to lactate-based (group 1), and 32 to acetate-based hemofiltration (group 2)while 48 (group 3) were treated with bicarbonate-based buffer hemofiltration fluid. Fifty-seven had a septic, and 75 a cardiovascular, origin of the ARF. Creatinine, blood urea nitrogen (BUN), serum bicarbonate, arterial pH, lactate and Apache II scores were noted daily.¶Main results: The mean CVVH duration was 9.8 ± 8.1 days, mortality was 65 %. No difference was present between the groups under investigation with regard to the main clinical parameters. Lactate- and bicarbonate-based hemofiltration led to significantly higher serum bicarbonate and arterial pH values as compared to the acetate-based hemofiltration. Serum bicarbonate values at 48 h after the initiation of CVVH treatment were 25.7 ± 3.8 mmol/l (p < 0.001) in group 1, 20.6 ± 3.1 mmol/l in group 2 and 23.3 ± 3.9 mmol/l (p < 0.001) in group 3. While a lack of increase in serum bicarbonate and arterial pH was correlated to poor prognosis in lactate- and bicarbonate-based hemofiltration, no such observation was made in acetate-based hemofiltration. Cardiovascular hemodynamics were superior in patients treated with lactate- and bicarbonate-based buffer solution as compared to those treated with acetate-based buffer solution.¶Conclusions: The degree of correction of acidosis during hemofiltration was determined by patient outcome in patients treated with lactate- and bicarbonate-based buffer solutions, but not in patients receiving acetate-buffered solution. Bicarbonate and lactate-based buffer solutions were found to be superior to acetate-based replacement fluid.

Effect of filtration volume of continuous venovenous hemofiltration in the treatment of patients with acute renal failure in intensive care units.

ObjectiveWe evaluated the variable Kt/V, which has become established in the therapy of end-stage renal disease in acute renal failure, to assess the influence of the filtration volume of continuous venovenous hemofiltration on Kt/V. We measured the variables of acid-base balance and uremia control. DesignProspective interventional pilot study. SettingMedical intensive care unit of a university hospital. PatientsFifty-six patients with acute renal failure and continuous venovenous hemofiltration treatment. InterventionsThe patients were consecutively treated with a filtration volume of either 1 L/hr (group 1) or 1.5 L/hr (group 2). Measurements and Main ResultsPatients with a filtration volume of 1.5 L/hr achieved a Kt/V of 0.8 per day, which was significantly higher than in the patient group treated with 1 L/hr (0.53, p < .05). The filtration volume of 1.5 L/hr led to a markedly better control of blood urea nitrogen concentrations, 69.3 ± 6.6 mg/dL vs. 52.1 ± 5.2 (p < .05), and to a much quicker and longer lasting compensation of acidosis. Both groups had acidotic pH at the beginning of therapy (group 1, 7.29 ± 0.02; group 2, 7.29 ± 0.02, nonsignificant). In group 2, a significantly higher pH value than in group 1 was measured after 24 hrs of continuous venovenous hemofiltration (p < .001; 7.39 ± 0.02 vs. 7.31 ± 0.02). The pH values in group 1 did not normalize until after 4 days. The filtration volume of 1.5 L/hr led to a quicker increase in bicarbonate concentrations after 24 hrs of therapy (group 1, 2.8 ± 3.2 mmol/L; group 2, 6.5 ± 3.1 mmol/L, p < .001). ConclusionsThe standardized urea clearance Kt/V is a valuable tool in the treatment of acute renal failure. Higher Kt/V levels were associated with a better control of uremia and acid-base balance. However, there were no differences in the clinical course, patient survival, percentage of patients with or without renal failure who were transferred from the intensive care unit, or Acute Physiology and Chronic Health Evaluation III scores.

Tubular Dysfunction following Kidney Transplantation

After transplantation the kidney is subjected to rejection and other deleterious factors including ischemic damage, acute tubular necrosis, rejection and the use of cyclosporine A (CsA) or FK506. As a result, kidney damage may be generalized with azotemia as its hallmark. These tubular syndromes may cause profound changes in the acid base balance and in the level of certain blood electrolytes and minerals. As a general rule, the renal tubular acidosis (RTA) that appears early following transplantation disappears spontaneously and is predominantly a sequela to acute renal failure. On the other hand, defects occurring in the late posttransplant period are often due to chronic rejection or CsA-induced nephrotoxicity. Secondary hyperparathyroidism, urinary tract infection and obstructive uropathy may also play a contributory urinary role in the pathogenesis of RTA. Chronic RTA following transplantation may interfere with bone metabolism and at times lead to nephrocalcinosis and nephrolithiasis. Therefore, if the condition is prolonged, a supplement of bicarbonate should be given if for no other reason that to protect the skeleton. As these patients may develop either hyperkalemia or hypokalemia, treatment with potassium supplements or potassium-sparing diuretics should be carried out with caution and under constant surveillance. Furthermore, magnesium replacement may be advisable if hypomagnesemia by decreased proximal reabsorption becomes clinically evident. Tubular dysfunction may occur following renal transplantation even in patients with maintained glomerular filtration rate and may induce a number of clinical problems including deterioration of renal graft function.

Systemic ciclosporin A in high-risk keratoplasties

Abstract• Background: It was the purpose of this study to compile the results of all high-risk keratoplasties (kp) performed in our hospital under systemic ciclosporin A (Ci A) cover from 1987 through 1994. • Methods: One hundred and thirty-one keratoplasties were performed. Ci A was administered for an average period of 9.4 months. We aimed at trough levels of 100–150 ng/ml (monoclonal RIA/TDx). The 29 kp in group A were second or third repeat kp and/or the recipient cornea had severe deep vascularization in all quadrants and/or a transplant position at the limbus was inevitable (expected risk: only immune reactions). The 40 kp in group B were threatened by severe ocular surface disorders (without severe limbal stem cell insufficiency) and by immune reactions (atopic keratopathy, keratoconus with severe endogenous eczema or chronic blepharokeratoconjunctivitis). In the 45 kp of group C resurfacing problems from severe limbal stem cell insufficiency and immune reactions were anticipated (severe burns, pseudopemphigoid or Lyell syndrome). Group D comprised 17 kp with various diagnoses (e.g. kp in newborns, rheumatic andAcanthamoeba keratitis). • Results: In group A 91% of the grafts were clear 2 years postoperatively, in group B 76%, in group C 38% and in group D 18%. In 32 of 41 failed grafts (78%), resurfacing problems were the only reason for or participated in final graft failure. Immune reactions and other causes of graft failure were of minor importance. • Conclusions: (1) Systemic Ci A cover can efficiently suppress immune reactions. (2) With the suppression of immune reactions, resurfacing disorders become the most important single cause for functional graft failure. (3) For eyes with a considerable loss of limbal stem cells, limbal stem cell transplantation should be combined with systemic Ci A cover in order to improve the long-term prognosis for penetrating keratoplasty.

Systemische Cyclosporin-A-Prophylaxe nach Keratoplastiken mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktor

Ziel: In dieser retrospektiven Studie sollte die Effektivität eines systemischen Cyclosporin-A (CsA)-Einsatzes nach Keratoplastiken mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktorüberprüft werden.Patienten und Methode: Zwischen November 1986 und Juni 1994 wurden 1121 perforierende Keratoplastiken, davon 646 Normalrisiko- und 475 Hochrisikokeratoplastiken, durchgeführt. Nur bei 130 dieser 475 Hochrisikokeratoplastiken stellte ein erhöhtes Risiko für Immunreaktionen den einzigen erhöhten Risikofaktor dar. Bei 26 dieser 130 Keratoplastiken wurde systemisches CsA eingesetzt.Ergebnisse: Mit systemischem CsA war in der Hochrisikogruppe Keratoplastik mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktor innerhalb der Nachbeobachtungszeit von bis zu 66 Monaten keine dauerhafte Transplantateintrübung zu verzeichnen (100% klare Transplantate). Ohne CsA lag der Anteil klarer Transplantate nach Kaplan-Meier 3 Jahre postoperativ in dieser Hochrisikogruppe bei nur 71,7% im Vergleich zu 86,0% bei Normalrisikokeratoplastiken. Die Unterschiede zwischen diesen 3 Gruppen waren statistisch signifikant. Mit systemischem CsA wurden in der Hochrisikogruppe Keratoplastik mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktor zwar mehr Immunreaktionen beobachtet als ohne diese Prophylaxe oder als bei Normalrisikokeratoplastiken. Das Verhältnis akuter und chronischer Immunreaktionen war mit CsA aber statistisch signifikant zugunsten der günstigen chronischen Verläufe verschoben.Schlußfolgerungen: Systemisches CsA verbessert die Ergebnisse von Keratoplastiken mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktor deutlich. Es werden zwar immer noch recht viele Immunreaktionen beobachtet, das Verhältnis akuter und chronischer Immunreaktionen ist aber deutlich zugunsten der gut zu beeinflussenden chronischen Verläufe verschoben.Background: In this retrospective study our aim was to evaluate the effectiveness of systemic cyclosporin A (CsA) after keratoplasties with an elevated risk for immune reactions as the only elevated risk factor. Patients and methods: Between November 1986 and June 1994, 1121 penetrating keratoplasties, 646 normal-risk and 475 high-risk keratoplasties were performed. In 130 out of the 475 high-risk keratoplasties an elevated risk for immune reactions was the only elevated risk factor. Twenty-six of these 130 high-risk keratoplasties were treated with systemic CsA. Results: In the high-risk group keratoplasties with an elevated risk for immune reactions as the only elevated risk factor no permanent graft failure occurred with CsA (100% clear grafts). Without CsA the percentage of clear grafts in this high risk group was only 71.7% according to Kaplan Meier 3 years postoperatively in contrast to 86.0% in normal-risk keratoplasties. The differences between these three groups were statistically significant. In the high-risk group keratoplasties with an elevated risk for immune reactions as the only elevated risk factor more immune reactions occured than without CsA or than in normal-risk keratoplasties. However, these immune reactions were mostly of the benign chronic types. Conclusions: Systemic CsA considerably improves graft prognosis after high-risk keratoplasties with an elevated risk for immune reactions as the only elevated risk factor. With CsA application we observed a significant shift from acute to chronic immune reactions, which respond much better to topical steroids.