Cardiovascular morbidity and mortality in patients with diabetes mellitus type I after kidney transplantation: a case-control study.

BACKGROUND: The proportion of diabetics among patients requiring renal replacement therapy continues to increase in most western countries. The acceptance rate for renal transplantation varies among transplant centers and is influenced by the current opinion on the outcome of transplantation in diabetics. Controlled data on patient and graft survival in type I diabetics, however, are scarce. METHODS: We performed a retrospective case-control analysis on patient and graft survival and the cardiovascular morbidity of patients with type I diabetes after renal transplantation versus carefully matched non-diabetic transplant recipients. Match criteria were duration of previous hemodialysis, age and date of renal transplantation. Moreover, risk factors for cardiovascular disease in uremic patients were evaluated at the time of registration for renal transplantation and at the end of the observation period. RESULTS: Seventy-seven matched pairs were enclosed. Patient survival was significantly worse in the diabetic patients, graft survival was comparable in both groups, when graft loss because of patient's death was censored. In the diabetic patients, risk of death (odds ratio: 4.38) as well as the prevalence of cardiovascular morbidity (odds ratio: 4.47) were significantly higher than in the matched nondiabetic controls. Cox regression analysis showed that diabetes mellitus was an independent risk factor for patient survival; no association was found with hypertension, hyperlipidemia, hyperparathyroidism, calcium x phosphate product, body mass index and HbA1c. Cardiovascular morbidity, however, was already significantly higher in the diabetic group at the time of registration. CONCLUSIONS: Diabetes mellitus type I has a dominant impact on morbidity and mortality after renal transplantation and is associated with an approximately 4-fold higher risk of death. Cardiovascular disease accounts for the significantly worse long-term outcome of diabetic patients after renal transplantation.

Renal transplantation in older adults: is graft survival affected by age? A case control study.

BACKGROUND: The demand for kidney allografts in older patients is growing continually. Previously published data indicate that the higher rate of graft losses resulting from the age-related increased mortality in older transplant recipients is balanced by a significantly lower number of graft losses from immunological problems (acute and chronic rejection) in old patients. This single center study was performed to scrutinize these results with the methods of a case control analysis. METHODS: Ninety-one patients, 65 years and older (mean age 67), were included in the case group. Their data were compared with those obtained from two control groups, 40-55 and 18-35 years old, respectively (mean ages 48 and 29, respectively). Apart from age, the groups were matched with regard to HLA-mismatches and date of transplantation. RESULTS: The number of initially non-functioning grafts and donor age did not differ significantly between the case and the control groups. During the follow-up of 5 years, acute rejections were significantly more frequent in the older control group. In contrast to previous studies, however, graft losses caused by rejections were not significantly more frequent in younger patients than in transplant recipients over age 65 years. Thus, as a consequence of increased patient mortality, the total graft survival in the case group was significantly worse than in the control groups. CONCLUSIONS: In the presence of organ shortage, an indication for kidney transplantation in patients over 65 years has to be considered carefully because age did not prove to have a beneficial effect on graft survival. Nevertheless, patients of this age group should not be excluded from renal transplantation, because not only medical, but also ethical, issues are involved.

Antiproteinuric efficacy of fosinopril after renal transplantation is determined by the extent of vascular and tubulointerstitial damage.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors have been successfully used for treatment of proteinuria after renal transplantation (RTx). Factors possibly responsible for the great inter-patient variance of the antiproteinuric effect (APE) have not yet been investigated in renal-transplanted patients. METHODS: 28 patients after RTx with a persistent proteinuria of more than 1.25 g/d were treated prospectively with does of fosinopril (10-15 mg/d) which were not effective on systemic arterial blood pressure. Prior to initiation of fosinopril, renal graft biopsy was performed in all patients and renal graft artery stenosis was excluded by duplex ultrasound. Serum creatinine and proteinuria were measured prior to, as well as 3 and 8 months after initiation of ACE inhibition, mean arterial pressure was controlled via 24-h measurement and repeated spot measurements. Reduction of proteinuria was correlated with renal histology, serum creatinine, creatinine clearance, mean arterial blood pressure, sodium excretion before therapy and the relative changes of these parameters during therapy respectively. RESULTS: Therapy had to be stopped in 8/28 patients due to side effects including rise of serum creatinine (n = 4). Three patients were excluded due to non-compliance. In the remaining patients (n = 17) proteinuria was reduced from 2.94 +/- 1.66 to 1.82 +/- 1.39 and 2.48 +/- 3.05 g/d after 3 and 8 months respectively, in the mean +/- SD. There was a significant inverse correlation between the APE and the extent of benign nephrosclerosis, interstitial fibrosis and tubular atrophy. No correlation of the APE to any of the other parameters could be demonstrated. CONCLUSIONS: Fosinopril can be administered effectively in a subgroup of proteinuric renal transplant recipients. However, because of a high proportion of patients developing side effects, careful monitoring is obligatory. Our results show that the lesser the degree of chronic morphological injury, the greater is the antiproteinuric effect. Thus, the degree of pre-existing histologically proven damage of the graft may serve as an indicator for the antiproteinuric efficacy of ACE inhibitor therapy after RTx.

Incidence of Pneumocystis carinii pneumonia after renal transplantation. Impact of immunosuppression.

The incidence and potential risk factors of Pneumocystis carinii pneumonia (PCP) in our population of renal transplant recipients were analyzed retrospectively. Of 1427 patients who received transplants between January 1986 and June 1994, 1192 were evaluated. Four different immunosuppressive regimens were applied: (1) cyclosporine (CsA) + prednisolone (Pred), (2) CsA + azathioprine (Aza, 2 mg/kg/day) + Pred, (3) CsA + Aza + antithymocyte globulin, and (4) (after December 1, 1993, European multicenter trial) FK506 + Aza (1 mg/kg/day) + Pred. No prophylaxis against PCP was performed. Before December 1, 1993, three PCPs in 494 patients on protocol 2 or 3 occurred (0.6%). Afterward, seven PCPs in 77 patients occurred (9%): three in 38 patients on protocol 2 (7.8%) and four in 28 patients on protocol 4 (14.3%). Comparing patients with PCP on CsA and FK506, the mean Aza dose was 2.40 and 1.32 mg/kg/day, five and two patients received additional steroids, antibody treatment was used in three and no patients, and CMV infections occurred in five and two patients, respectively. The incidence of PCP with a moderate CsA-based immunosuppressive regimen is low and seems to occur only in cases of additional immunosuppressive cofactors. Despite a general increase of PCP, its incidence was highest in patients on FK506 with fewer immunosuppressive cofactors. Thus, prophylaxis against PCP after renal transplantation should be performed, if not in every renal transplant recipient, at least in case of treatment with additional steroids, antibodies, or FK506.

Induction of interleukin-1 and interleukin-1 receptor antagonist during contaminated in-vitro dialysis with whole blood.

BACKGROUND: Previous studies on the permeability of cellulosic and synthetic dialysers for bacterial-derived cytokine-inducing substances gave conflicting results. We tried to study this issue as close to the in-vivo situation as possible. METHODS: An in-vitro dialysis circuit with whole human blood present in the blood compartment of cuprophane (Cup), polysulphone (PS), and polyamide (PA) dialysers was employed; sterile filtrates derived from Pseudomonas aeruginosa cultures were added to the dialysate. We studied the induction of interleukin-1 beta (IL-1 beta) by plasma samples taken from the blood compartment as well as the induction of IL-1 beta and interleukin-1 receptor antagonist (IL-1Ra) in mononuclear cells separated from whole blood after circulation by radioimmunoassay and polymerase chain reaction. RESULTS: Plasma samples from the blood side of all dialysers induced IL-1 beta from non-circulated mononuclear cells after addition of pseudomonas filtrates to the dialysate; the maximal amount of IL-1 beta induced by samples from the blood compartment was 4.8 +/- 1.2 ng/ml for Cup, 1.9 +/- 0.5 ng/ml for PS, and 2.0 +/- 0.6 ng/ml for PA. Mononuclear cells separated after contaminated dialysis will all types of dialysers expressed increased mRNA levels for IL-1 beta and IL-1Ra. Production of IL-1Ra by cells separated after contaminated dialysis was determined after Cup and PS dialysis; there was increased production of IL-1Ra by these cells (Cup, 10.3 +/- 4.2; PS, 7.3 +/- 2.5 ng/ml) compared to cells separated after sterile dialysis (Cup, 5.6 +/- 2.1, P < 0.05; PS, 4.5 +/- 1.1 ng/ml, n.s.) or from non-circulated blood (Cup experiments, 4.7 +/- 1.5, P < 0.05; PS experiments, 4.1 +/- 1.2 ng/ml, n.s.). CONCLUSIONS: These data suggest penetration of cytokine-inducing substances through both cellulosic and synthetic dialysers. Differences between dialysers may exist regarding extent and time course of penetration. The detection of cytokine mRNA as well as the measurement of IL-1Ra synthesis is a more sensitive marker for the transfer of cytokine-inducing substances through dialyser membranes than the measurement of IL-1 beta protein synthesis.

Retention of cytokine-inducing substances inside high-flux dialyzers.

Reprocessing of dialyzers is often performed with nonsterile solutions possibly contaminated with bacterial-derived cytokine-inducing substances. We investigated the retention of cytokine-inducing substances inside the dialyzer during reprocessing in a closed loop in vitro hemodialysis system using a polyamide high flux membrane. After the first in vitro circulation of human whole blood, rinse of the blood compartment (BC) and reverse ultrafiltration (RUF) was performed with either cytokine-inducing substance-free saline or saline contaminated with filtrates from Pseudomonas cultures (6 ng/ml LAL-reactive material); subsequently, dialyzers were stored in 2% formaldehyde. Dialyzers were rinsed with approximately 15 liters pyrogen-free saline before the second circulation using blood from the same donor; the effluates were free of cytokine-inducing substances and formaldehyde. Before and after the blood circulations, peripheral blood mononuclear cells (PBMC) were separated and total production of IL-1 alpha and IL-1 beta was determined after overnight incubation. In noncirculated PBMC as well as in PBMC separated after whole blood circulation with pyrogen-free processed dialyzers, production of IL-1 beta was not detectable. After contaminated rinse of the BC, production of IL-1 beta could be observed (1,600 +/- 1,100 pg/ml, mean +/- SEM). When pyrogen-free RUF was performed after contaminated BC rinse, IL-1 beta production averaged 163 +/- 92 pg/ml when using reused dialyzers, but 1,820 +/- 880 pg/ml when using new dialyzers. After reuse with pyrogen-free BC-rinse and contaminated RUF no IL-1 beta synthesis was observed; however, when pyrogen-free BC-rinse and contaminated RUF was applied to new dialyzers, IL-1 beta synthesis averaged 1,620 +/- 1,200 pg/ml. We conclude that cytokine-inducing substances are retained inside the dialyzer, probably by adsorption to the membrane as well as to the protein layer covering the membrane and are still biologically active after sterilisation. Cytokine-inducing substances adsorbed to the protein layer can be partially removed by RUF. Finally, the protein layer on the membrane appears to reduce the convective transfer of cytokine-inducing substances from the dialysate into the blood compartment.

The role of plasma coating on the permeation of cytokine-inducing substances through dialyser membranes.

We studied the effects of coating of dialyser membranes with plasma proteins on the permeation of bacteria-derived cytokine-inducing substances (CIS). An in vitro dialysis circuit using polysulphone (PS) or modified cellulose triacetate (mCT) dialysers was used. Precoating of the dialysers was performed by recirculation of 10% normal human plasma for 30 min in the blood compartment and subsequent rinse with pyrogen-free saline. Samples from the blood compartment were tested for induction of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF alpha) at various time points after challenging the dialysate with sterile culture supernatants from Pseudomonas aeruginosa. Contamination of the dialysate resulted in the appearance of CIS in the blood compartment of both polysuphone modified cellulose triacetate (IL-1 alpha: PS, time 0: 81 +/- 11 pg/ml, time 60 min: 4747 +/- 1822 pg/ml, P < 0.05; mCT, time 0: 235 +/- 141 pg/ml, time 60 min: 1632 +/- 531 pg/ml, P < 0.05). The plasma protein layer reduced the penetration of CIS significantly only for polysulphone (IL-1 alpha: PS, time 60: 4747 +/- 1822 versus 880 +/- 525 pg/ml, P < 0.05; modified cellulose triacetate, time 60 min: 1632 +/- 531 pg/ml versus 930 +/- 326 pg/ml). Samples from the blood compartment contained < 6 pg/ml LAL-reactive material at all time points. We conclude that plasma coating of polysulphone dialysers reduces the permeability for CIS derived from Pseudomonas, either by reducing the effective pore size or by adsorption of proteins that bind CIS.(ABSTRACT TRUNCATED AT 250 WORDS)

Transesophageal echocardiographic assessment of superior vena cava thrombosis in patients with long-term central venous hemodialysis catheters.

In some patients with end-stage renal failure, arteriovenous fistulas cannot be created due to poor vessel conditions. Alternatively, hemodialysis (HD) can be performed using long-term central venous catheters. However, these dialysis catheters are associated with a presently unknown risk of superior vena cava (SVC) thrombosis. We examined 20 patients (11 female, 9 male, age 29-83 years) 1-48 (mean 15) months after transjugular insertion of a permanent single lumen silicone rubber HD catheter. All patients underwent both transthoracic (TTE) and biplane transesophageal (TEE) echocardiography. TTE visualized the catheter only when its tip was localized in the right atrium (2 patients), but did not succeed in adequate imaging of the SVC. In contrast, TEE allowed high quality imaging of the SVC in all patients and detected a SVC thrombosis in 6 patients; in 3 of them, caval thrombosis was subtotal. One additional patient showed a thrombus attached to the catheter tip alone. Dwelling time of catheters since insertion in the SVC was not significantly different in patients with and without thrombosis. Reduced blood flow during HD was observed in 5 of 7 patients with catheter-associated thrombi but also in 4 of 13 patients without evidence for caval thrombosis by TEE. It is concluded that thrombotic occlusion of the SVC is frequent in patients with long-term central venous access; it does not necessarily correlate with clinical signs but can easily be detected by TEE. Patients with long-term central venous hemodialysis catheters should undergo transesophageal echocardiography at regular intervals.

Cross-reactivity distinguishes serum and nephritogenic anti-DNA antibodies in human lupus from their natural counterparts in normal serum.

To distinguish the properties of anti-DNA antibodies in patients with lupus from those in normal individuals, we compared the ligand binding, idiotypic and charge properties of serum anti-DNA antibodies derived from: patients with active lupus; normal individuals; and among Ig eluted from the kidneys of two patients with active lupus nephritis (one with mesangial proliferation and the other with membranous nephropathy). The kidney eluate anti-DNA antibodies were the most cross-reactive; they cross-reacted with ssDNA, poly(GdC), poly(dT), poly(dG), poly(dC), ZDNA, SmRNP and the phospholipids cardiolipin and phosphatidyl serine. Lupus serum anti-DNA antibody cross-reacted with polynucleotides but not with phospholipids, whereas anti-DNA antibodies derived from normal serum reacted only with poly(dT). An anti-idiotype (anti-IdD; produced against serum anti-DNA antibodies from one patient) reacted with: anti-DNA antibodies in 8/9 lupus sera; antibodies in both kidney eluates; and anti-DNA antibodies from 5/7 normal sera. Anti-IdD did not react with Ig that did not bind to DNA. Isoelectric focusing of Ig showed that the charge of anti-DNA antibodies from lupus serum and normal serum were similar and unrestricted (pI 5.4-9.0); Ig in kidney eluates varied: membranous lupus pI 4.5-8.6; mesangial lupus pI 8.1-9.1. We conclude that idiotypically related anti-DNA antibodies in tissue lesions, lupus serum and normal serum from different individuals can be distinguished on the basis of their cross-reactive antigen-binding properties. Furthermore the cross-reactive properties of lupus auto-antibodies may influence their capacity to form glomerular immune deposits.