Choices of long-term immunosuppression in renal transplantation: balancing the benefits and risks.
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Humans↗
Biomedical subjects
R A Koene
Publications and source records attributed to R A Koene.
Renal and systemic effects of atenolol and tertatolol in renal transplant recipients on cyclosporine A.
BACKGROUND: Hypertension and nephrotoxicity are well-known side-effects of cyclosporine A (CsA). CsA-induced vasoconstriction of the afferent glomerular arteriole probably plays a role in at least the nephrotoxicity. Frequently renal transplant recipients on CsA have to be treated with antihypertensive drugs and for this purpose also beta-blockers are used. Tertatolol is a new beta-blocker with specific vasodilatory properties, and thus might be particularly useful in CsA-treated transplant recipients. METHODS: We studied the systemic and renal haemodynamic effects of atenolol and tertatolol in 12 hypertensive renal transplant recipients on cyclosporine A (CsA). In a cross-over way, all patients were treated with atenolol and tertatolol for 4 weeks each, separated by a wash-out period also of 4 weeks. At the end of each period, the mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured. RESULTS: The mean arterial pressure was lower (P < 0.05) during atenolol (124 +/- 2 mm Hg) and tertatolol (125 +/- 2 mm Hg) treatment compared with washout (132 +/- 4 mm Hg). Also the heart rate was lower (P < 0.01) during atenolol and tertatolol (54 +/- 3 and 55 +/- 2 beats/min respectively) than in the wash-out period (65 +/- 3 beats/min). GFR and RPF were not changed by either beta-blocker. CONCLUSION: In CsA treated renal transplant recipients both atenolol and tertatolol effectively reduced blood pressure. In these patients we found no evidence of a specific vasodilatory effect of tertatolol. Both beta-blockers had no negative influence on renal function. Hence, these cardioprotective agents are an attractive and safe choice for the treatment of hypertension in such patients.
Adrenergic beta-Antagonists↗
Oral cyclophosphamide versus chlorambucil in the treatment of patients with membranous nephropathy and renal insufficiency.
We treated patients with idiopathic membranous nephropathy (iMGN) and renal insufficiency, using: (i) (n = 15) monthly cycles of steroids (1 g methyl-prednisolone i.v. on three consecutive days, followed by oral prednisone 0.5 mg/kg/day months 1, 3 and 5) and chlorambucil (0.15 mg/kg/day months 2, 4 and 6); or (ii) (n = 17) oral cyclophosphamide (1.5-2.0 mg/kg/day for 1 year) and steroids in a comparable dose. The groups were comparable in age, renal function and levels of proteinuria. During the 6 months preceding treatment, serum creatinine levels increased from 148 +/- 50 to 219 +/- 73 mumol/l in the chlorambucil group and from 164 +/- 86 to 274 +/- 126 mumol/l in the cyclophosphamide group. Median (range) follow-ups were: chlorambucil 38 months (8-71); cyclophosphamide 26 months (5-68) (NS). Renal function improved in both groups, but the improvement was short-lived in the chlorambucil group; 12 months after starting treatment, mean serum creatinine was 6.3 mumol/l lower in the chlorambucil group and 121 mumol/l lower in the cyclophosphamide group (p < 0.01). Four chlorambucil-treated patients developed ESRD, and five needed a second course of therapy, whereas only one cyclophosphamide-treated patient developed ESRD (p < 0.05). Remissions of proteinuria occurred more frequently after cyclophosphamide treatment (15/17 vs. 5/15; p < 0.01). Side-effects necessitated interruption of treatment in six patients on cyclophosphamide and in 11 on chlorambucil (p < 0.05). In our patients, oral cyclophosphamide was better tolerated than oral chlorambucil. The suggested greater efficacy of the oral cyclophosphamide regimen needs to be ascertained by longer follow-up.
Adult↗
Haemolysis after kidney transplantation: beware of the graft.
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Antibody Formation↗
Fixation of urinary sediment.
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Fixatives↗
[Kidney transplantation without previous dialysis: limitations, but also possibilities].
Kidney transplantation guarantees a better quality of life than dialysis and is less costly. Transplantation without preceding dialysis is an attractive option. However, transplantation long before end-stage renal failure prolongs the period of exposure to immunosuppressive therapy, thereby increasing the risk of malignancy. Transplantation at one year before dialysis-dependency is expected would seem an acceptable compromise. Unfortunately, this option is purely theoretical because there is a long waiting-list due to the existing donor shortage. Patients are usually put on the waiting-list after dialysis has already been started. Extension of the list with pre-dialysis patients is currently only justifiable in exceptional cases. These limitations do not apply to patients who have received an offer of kidney donation from a living (related or unrelated) donor. In these patients transplantation can be done as soon as the creatinine clearance has reached a level of 10-12 ml per minute. More attention should be paid to this form of transplantation, because it can help to decrease the donor shortage.
Humans↗
Recurrence of type I membranoproliferative glomerulonephritis after renal transplantation: analysis of the incidence, risk factors, and impact on graft survival.
BACKGROUND: The information in the medical literature on the incidence of recurrence of type I membranoproliferative glomerulonephritis (MPGN) after renal transplantation and its impact on graft survival is limited because most data are derived from case reports or from studies involving a small number of patients. METHODS: We analyzed the data from our transplant center. Among 1097 adult patients receiving their first allograft between 1977 and 1994, we identified 32 patients with type I MPGN. RESULTS: A recurrence was detected in 9 of the 27 recipients of a first cadaveric graft (33%). The cumulative incidence reached 48% at 4 years after transplantation when patients with graft failure from other causes were censored. All patients with recurrent MPGN had clinically significant proteinuria (>1 g/24 hr) that was first observed at a median time of 20 months (range, 1.5-42 months) after transplantation. Graft survival was significantly worse in patients with recurrence as compared with patients without recurrence. Mean duration of graft survival after the diagnosis of recurrence was 40 months. We could not detect any clinical characteristics of patients or donors that were associated with recurrent disease. However, an increased risk of recurrence was observed in patients with the HLA haplotype B8DR3. Four patients received an HLA-identical graft from a living related donor. Recurrence occurred in three patients (75%), with ensuing graft loss in two. The only patient with a haploidentical living related graft did not have a recurrence. Five patients with a recurrence in the first graft received a second transplant. Recurrence was observed in four of these patients (80%). CONCLUSIONS: Type I MPGN recurred after renal transplantation in half of the patients. The incidence may be even higher in recipients of an identical living related donor graft and in patients receiving a second transplant after having experienced a recurrence in their first graft. Recurrence of type I MPGN has a detrimental effect on graft survival.
Adult↗
Role of polymorphic Fc receptor Fc gammaRIIa in cytokine release and adverse effects of murine IgG1 anti-CD3/T cell receptor antibody (WT31).
Anti-CD3 monoclonal antibody (mAb) OKT3 is immunosuppressive, but causes severe adverse effects during the first administration ("first-dose reaction"). These adverse effects are presumably caused by cytokine release that results from T-cell activation. In vitro, T-cell activation by anti-CD3 mAb requires interaction with monocyte Fc receptors. The Fc receptor for murine IgG1, Fc gammaRIIa, is polymorphic. In some individuals, murine IgG1 anti-CD3 mAb causes T-cell proliferation and cytokine release in vitro (high responders [HR]), whereas in individuals with the low-responder (LR) phenotype it does not. We have now investigated the role of this Fc gammaRIIa polymorphism in the release of cytokines in vivo and the occurrence of adverse effects after the administration of WT31, a murine IgG1 anti-CD3/T cell receptor mAb. WT31 caused an increase of plasma tumor necrosis factor-alpha in all four HR patients and none of the five LR patients. In all HR patients except one, plasma gamma-interferon and interleukin 6 also increased, and a first-dose response was observed, whereas no cytokine release or adverse effects occurred in any of the LR patients. WT31 caused lymphopenia in all HR and none of the LR patients. FACS analysis demonstrated that in HR patients, after the initial disappearance of CD3+ cells from peripheral blood, modulation of CD3 occurred, whereas in LR patients a high degree of coating of the lymphocytes was observed. Surprisingly, WT31 also induced a marked granulocytopenia, as well as a decrease of thrombocytes, in three of the four HR patients (and in none of the LR patients). These data provide direct clinical evidence that Fc receptor interaction determines the release of cytokines and the occurrence of adverse effects after administration of anti-CD3/T cell receptor mAb. Furthermore, these data suggest that tumor necrosis factor-alpha by itself is not sufficient to induce the first-dose reaction.
Antibodies, Monoclonal↗
Accessory molecules utilized by endothelial cells for allogeneic stimulation of T-lymphocytes.
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Antigens, CD↗
Mouse glomerular epithelial cells in culture with features of podocytes in vivo express aminopeptidase A and angiotensinogen but not other components of the renin-angiotensin system.
The binding of antibodies to podocytic antigens such as the Heymann antigen or aminopeptidase A may lead to the induction of a membranous glomerulonephritis in several species. To study the possible future interactions of antibodies with antigens on these podocytes, epithelial cells from isolated mouse glomeruli were cultured. By indirect immunofluorescence, the cells were positive for cytokeratin, vimentin, desmin, and the ZO-1 protein, a component of the tight junction complex. When rat monoclonal antibodies were used, the cells were also positive for the hydrolases aminopeptidase A and dipeptidyl peptidase IV, and they stained with ASD-33, a monoclonal antibody that recognized an epitope only present on the cell membranes of mouse podocytes. They were negative for the von Willebrand factor and did not stain with a monoclonal antibody (ASD-13) that binds to endothelial cells of glomeruli and peritubular capillaries. By electron microscopy, the cells showed tight junctions but lacked Weibel Palade bodies (endothelium), desmosomes, and cilia (parietal epithelium). The mRNA expression of several components of the renin-angiotensin system was also examined, and some factors indirectly coupled to the renin-angiotensin system component angiotensin II in this podocytic culture by RT-PCR analysis. mRNA Expression for the angiotensin II degrading hydrolase aminopeptidase A and angiotensinogen was found, but this was not found for any other component of this system, such as renin, angiotensin-converting enzyme, or the angiotensin II receptors AT1a, AT1b, and AT2. Low mRNA expression for dipeptidyl peptidase IV was observed. In addition, expression of the growth factors transforming growth factor-beta and interleukin-7, and the extracellular matrix components fibronectin, laminin B2, perlecan, and collagen IV alpha 1, was observed. Given these characteristics, a glomerular epithelial cell culture with features of podocytes in vivo that will allow future studies on the interaction of anti-aminopeptidase A monoclonal antibodies and angiotensin II with aminopeptidase A was established. This is of interest in light of the observation that injection of mice with anti-aminopeptidase A antibodies causes an acute albuminuria.
Aminopeptidases↗
Urinary IgG excretion as a prognostic factor in idiopathic membranous nephropathy.
In membranous nephropathy it would be of great value to be able to identify in an early phase patients at highest risk for disease progression, since potentially toxic treatment could then be restricted to these patients only. We measured renal hemodynamics, serum proteins and urinary protein excretion in 22 patients with membranous nephropathy, nephrotic syndrome and normal renal function (endogenous creatinine clearance > 85 ml/min). These patients were followed for a mean of 56 months. Renal function deteriorated in nine patients. When using univariate analysis, deterioration of renal) function appeared to be associated with a low serum albumin and transferrin, high urinary transferrin, beta-microglobulin, and IgG excretion, but not with renal hemodynamics. A step-up procedure, used for selecting variables associated with survival, showed that IgG excretion was independently associated with renal function deterioration. In patients with membranous nephropathy and normal renal function, the urinary excretion rate of IgG predicts future renal function outcome.
Adult↗
Costs of drugs used after renal transplantation.
There are no detailed data on the relative contributions to overall health care costs of the various drugs that are commonly used in renal transplant patients. We performed a cost analysis in 122 patients, using the medical records and our hospital administration service as data sources, for all health care-related costs during the first year after renal transplantation. During the first 3 months all patients were on cyclosporine (CsA) and prednisone. Subsequently, they were randomly allocated to CsA monotherapy or to conversion from CsA to azathioprine. Cost of drugs comprised about 25% of total health care expenses. In CsA-treated patients, the following costs per patient per year were calculated: CsA, DFL 9929 (1 DFL is about US$0.60; 67.5% of total drug costs); antilymphocyte agents, DFL 2613 (17.8%); other immunosuppressive drugs, DFL 455 (3.1%); antimicrobial agents, DFL 687 (4.7%); antihypertensive drugs, DFL 467 (3.2%); remaining drugs, DFL 554 (3.8%). Conversion from CsA to azathioprine resulted in a decrease in mean drug costs for the remainder of the first posttransplant year of DFL 4597 (P < 0.01). Although the incidence of acute rejections tended to be higher after steroid withdrawal than after conversion (39% versus 26%, not significant), the costs of anti-rejection therapy, hospitalization, and laboratory services did not differ. We conclude that CsA is the main determinant of overall drug costs. When compared to CsA monotherapy, conversion from CsA to azathioprine at 3 months after transplantation may result in subsequent cost savings of about DFL 5000 per patient per year without a higher incidence of rejection or graft loss.
Adolescent↗
Analysis at the DNA level of human Fc gamma RII isoforms in relation to the polymorphic binding of murine IgG2b to human B cells.
Three classes of human leucocyte Fc gamma receptors (hFc gamma R) have been identified so far: hFc gamma RI, hFc gamma RII, and hFc gamma RIII. Previous studies have demonstrated that genetically determined differences between individuals exist both with respect to the binding of murine IgG1 (mIgG1) to hFc gamma receptors, and with respect to the binding of murine IgG2b (mIgG2b). The polymorphism in binding of mIgG1 could be ascribed to hFc gamma RIIA, an isoform of hFc gamma RII. The authors have now investigated whether one of the isoforms of hFc gamma RII is also responsible for the polymorphism in binding of mIgG2b. In these studies the authors used EBV-transformed human B cells that demonstrated either binding or no binding of mIgG2b in EA-rosetting assays. mRNA obtained from these cells was amplified by reverse transcriptase and polymerase chain reaction (RT-PCR). Hybridization experiments with the RT-PCR products revealed that the hFc gamma RIIB but not the hFc gamma RIIA isoform was present in these cells. DNA sequencing further demonstrated that the nucleotide sequence of both the extracellular part and the cytoplasmic moiety of hFc gamma RIIB was identical for all individuals tested, regardless of their ability to bind mIgG2b. These findings indicate that the polymorphic binding of mIgG2b cannot be ascribed to one of the isoforms of hFc gamma RII. Since hFc gamma RI and hFc gamma RIII are not present on the cell surface of these cells, the authors conclude that an Fc receptor different from the known hFc gamma receptors must be responsible for the polymorphic binding of mIgG2b. These data further expand the complexity of hFc gamma R.
Antigens, CD↗
Inhibition of aminopeptidase A activity causes an acute albuminuria in mice: an angiotensin II-mediated effect?
The hydrolase aminopeptidase A is an important regulator of the renin-angiotensin system, since it inactivates its most vasoactive component angiotensin II (Ang II). A single i.v. injection of a monoclonal antibody against mouse aminopeptidase A (ASD-4) induces a membranous-like glomerulonephritis in mice, characterized by an acute albuminuria, that is not dependent on complement, the coagulation system, or inflammatory cells. We hypothesized that this albuminuria is the consequence of a reduction in aminopeptidase A enzyme activity, that might subsequently lead to an increase in Ang II levels. Aminopeptidase A enzyme activity was analysed in vitro by a fluorimetric enzyme assay and in vivo by enzyme histochemistry. The role of Ang II in the induction of albuminuria in this model was studied by measuring the renal aminopeptidase A mRNA expression in our model by a competitive PCR assay as an indirect measure of Ang II levels. In addition, the role of Ang II in this model was studied by preventing the formation of Ang II with the angiotensin-converting enzyme inhibitor enalapril or by blocking of the Ang II receptor with the AT1 receptor antagonist losartan. Only antibodies that were able to inhibit the aminopeptidase A enzyme activity in vitro and in vivo induced an acute albuminuria in mice. Renal aminopeptidase A mRNA expression was increased by injection of the anti-aminopeptidase A antibody. Both enalapril and losartan treatment reduced the acute albuminuria, measured 1 day after injection of a monoclonal antibody against aminopeptidase A, by 91% and 83%, respectively. It is concluded that the induction of acute albuminuria is correlated to the enzyme-inhibiting capacity of the anti-aminopeptidase A antibodies. This impaired enzymatic activity most likely leads to an increase in the levels of Ang II, the best known substrate of aminopeptidase A. The results of our additional experiments are in keeping with our hypothesis that Ang II mediates this acute albuminuria. Whether this occurs by an increase of blood pressure or by a growth factor-like effect remains to be defined by further studies in this model.
Acute Disease↗
Survival on renal replacement therapy in Europe: is there a 'centre effect'?
OBJECTIVE: Survival is the ultimate outcome measure in renal replacement therapy (RRT) and may be used to compare performance among centres. Such comparison, however, is meaningless if the influences of comorbidity, age and early deaths are not considered. We therefore studied survival rates on RRT in seven centres in Europe after taking into account the influence of age, early deaths, primary renal diagnoses, and comorbidity. DESIGN: A retrospective survival analysis was carried out on 1407 patients who commenced RRT in seven centres across five European countries during a 7-year period. Patients were stratified into low-, medium- and high-risk groups based mainly on comorbidity and to a lesser extent on age at commencement of RRT. Kaplan-Meier survival and Cox's proportional hazards model were used to compare survival. RESULTS: Before risk stratification overall 2-year survival across the seven centres ranged from 60.2 to 85.3% (69.3-89.9%) after excluding early deaths) masking a range of survivals of 27.4% for the high-risk group with the worst survival to 100% in the low-risk group with the best survival. After excluding early deaths 2-year survival in the low risk groups (n=622) was greater than 90% in all centres. Multivariate analysis showed that the mortality risk increased four fold from low- to medium- and a further 1.6-fold from medium- to high-risk group. However, despite this adjustment for comorbidity and age there still remained a significant difference in survival among some centres, i.e. a 'centre effect' which ranked the centres. CONCLUSION: Risk stratification diminishes the variance in survival between centres but a centre effect remains despite adjusting for age and comorbidity. Multicentre prospective studies are urgently required to identify the reasons for this apparent centre effect.
Adult↗
Different mediator systems in biphasic heterologous phase of anti-GBM nephritis in mice.
BACKGROUND: After the injection of rabbit anti-mouse glomerular basement membrane (GBM) antibody into normal C57BL/6J mice severe albuminuria develops, which reaches a peak at 24 h. This early albuminuria is dependent on polymorphonuclear granulocytes (PMN) and is completely absent in the congenic beige mutant strain (C57BL/6J, bg/bg), which is genetically deficient in leukocytic neutral proteinase activity. We now studied the development of anti-GBM nephritis in beige mice during the later heterologous phase. METHODS: In untreated beige mice we assessed the albuminuria and glomerular lesions on days 1-5 after i.v. injection of anti-GBM antibody. Secondly, effector mechanisms involved in the later days of the heterologous phase were studied by substitution of whole anti-GBM antibodies by F(ab')2 fragments, by leukocyte depletion (total body irradiation), scavenging of reactive oxygen metabolites (dimethylsulfoxide treatment), and complement depletion (cobra venom factor treatment). RESULTS: In the later part of the heterologous phase (days 2-5), when there is still no sign of autologous antibody formation, i.v. injection of anti-GBM antibodies in beige mice induces nephritis with gradually increasing albuminuria, that reaches levels similar to those in non-deficient, congenic controls by day 3. This late albuminuria did not occur after injection of F(ab')2 fragments of the antibody, could be prevented by leukocyte depletion, and was greatly reduced by treatment with dimethylsulfoxide, a scavenger of hydroxyl radicals. The late albuminuria was not influenced by complement depletion with cobra venom factor. Histologic and immunohistologic studies gave no indication for a role of glomerular macrophages or lymphocytes. CONCLUSIONS: The heterologous phase in murine anti-GBM nephritis is a biphasic process, with sequential involvement of different and independent mediating systems: both phases are PMN-dependent, but only the early albuminuria depends on leukocytic neutral proteinase activity, whereas the albuminuria and the glomerular damage at later days are effected by reactive oxygen metabolites, most probably originating from PMN accumulating in the glomerulus.
Albuminuria↗
Cyclosporin does not inhibit the tubular secretion of creatinine.
BACKGROUND: The immunosuppressive drug cyclosporin is known to impair renal function. The degree of renal dysfunction is usually estimated from the clearance of creatinine (CCr). Theoretically however, a fall in CCr can be caused by a decrease of GFR, an inhibition of the tubular secretion of creatinine, or the combination of both. CsA has convincingly been shown to decrease GFR, but detailed information on the effects of CsA on tubular secretion of creatinine is lacking. METHODS: We performed two studies to investigate the influence of CsA on tubular creatinine secretion. In study A we simultaneously measured CCr and GFR (using inulin) immediately before and 4 weeks after cessation of CsA therapy in 17 renal transplant patients. In study B, the rise in serum creatinine after administration of cimetidine, which blocks the tubular secretion of creatinine, was compared in renal transplant patients treated with either CsA (in whom secretion might already be inhibited) or azathioprine. RESULTS: Study A: After cessation of CsA there was an increase of GFR (54+/-15 vs 63+/-16 ml/min/1.73 m2, PCr (71+/-21 vs 82+/-23 ml/min/1.73 m2; PCr and GFR (a measure of the relative contribution of tubular secretion to the clearance of creatinine) did not change significantly (1.33+/-0.21 vs 1. 32+/-0.30). Study B: In nine couples of patients matched for GFR the relative rises in serum creatinine after administration of cimetidine were 26+/-21% and 22+/-7% for CsA and azathioprine treated patients respectively (NS). CONCLUSION: CsA does not substantially inhibit the tubular secretion of creatinine. A rise in serum creatinine after administration of CsA can thus be attributed completely to a fall in GFR.
Adult↗
Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function.
1. The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function. 2. After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0 +/- 3.0, 11.1 +/- 3.0, 8.7 +/- 3.7 and 6.7 +/- 2.1 l h-1 (means +/- s.d.) in patients with creatinine clearances (CLcr) of > 100, 41-100, 21-40, and 8-20 ml min-1, respectively. .3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CLcr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CLcr < 40 ml min-1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups. 4. This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.
Adult↗