Cytomegalovirus infection and disease in renal transplant patients treated with cyclosporin

In this prospective study, the incidence of cytomegalovirus (CMV) infection and CMV disease was determined in 175 renal transplant recipients on cyclosporin and low-dose prednisone. CMV infection occurred in 51.4% of the patients, CMV disease in 13.7%. The major manifestations of CMV disease were fever of unknown origin and leukopenia. In the group with CMV infection, there was an increased occurrence of rejection (60% in infected vs 27% in noninfected patients). In most patients (41/54), the rejection preceded the CMV infection. CMV infection did not lead to a decreased graft survival. There was no close time relationship between the onset of clinical symptoms of CMV disease and the laboratory confirmation of CMV infection. A subgroup of patients at risk for the development of severe CMV disease could not be identified.     

The effect of cyclosporin on lower limb blood flow in renal transplant recipients

Abstract. We investigated the effect of electively converting stable renal allograft recipients from cyclosporin A (CyA) to prednisolone and azathioprine on limb blood. We used a non-invasive method designed to measure the hyperaemic blood flow to the lower limb following a standard ischaemic insult. The hyperaemic blood flow was greater during CyA therapy - median 14 ml/100 ml tissue per minute (95% confidence limits 10.5–16.5) - than that after conversion - median 11 ml/100 ml tissue per minute (8.3–13.8; P < 0.01). By increasing peripheral vascular resistance and reducing limb blood flow, CyA may have caused an increase in the degree of ischaemia, so resulting in a greater hyperaemic response.     

The effect of cyclosporin on lower limb blood flow in renal transplant recipients

We investigated the effect of electively converting stable renal allograft recipients from cyclosporin A (CyA) to prednisolone and azathioprine on limb blood. We used a non-invasive method designed to measure the hyperaemic blood flow to the lower limb following a standard ischaemic insult. The hyperaemic blood flow was greater during CyA therapy-median 14 ml/100 ml tissue per minute (95% confidence limits 10.5–16.5)-than that after conversion-median 11 ml/100 ml tissue per minute (8.3–13.8;P<0.01). By increasing peripheral vascular resistance and reducing limb blood flow, CyA may have caused an increase in the degree of ischaemia, so resulting in a greater hyperaemic response.     

Viral hepatitis in HBsAg-positive renal transplant patients treated with cyclosporin and steroids

This study reports clinical, serological and immunomorphological observations on viral hepatitis in 14 HBsAg-positive renal transplanted patients treated with cyclosporin and steroids. Eleven patients who were HBsAg positive before transplantation developed signs of hepatitis. This was due to HBV in six cases and progressed into a mild chronic disease. The remaining five subjects lacked signs of HBV reactivation. The hepatitis, attributed to non-A non-B agents, recovered completely. Two more patients became HBsAg positive after transplantation both developed acute hepatitis, respectively drug and HBV related. Transition into chronicity occurred only in the latter case. The results seem to indicate: (1) the possibility of a high incidence of non-B virus hepatitis in HBsAg-positive transplanted patients under cyclosporin treatment; (2) a good prognosis in non-B hepatitis as compared to hepatitis B for the same patient group; and (3) a mild degree of disease activity in cases who develop chronic hepatitis.     

Cardiovascular risk factors in renal transplant patients: cyclosporin A versus tacrolimus

The hypertensive and hyperlipidemic effects of cyclosporin A (CsA) may contribute to the high cardiovascular morbidity in renal transplant patients and to the development of chronic transplant nephropathy. Tacrolimus is reported to have less effect on BP and lipids, but steroids, other drugs, and renal function may confound this. This study assessed 24-h BP and lipid profile in stable renal transplant recipients (n = 17) while they were receiving CsA, after 4 wk of receiving tacrolimus, and again after 4 wk of receiving CsA. Antihypertensives were stopped at least 3 wk before. A few patients used low-dose steroids and lipid-lowering drugs, which were not changed during the study. Mean daytime BP decreased from 149 +/- 12 and 95 +/- 8 mmHg to 138 +/- 13 and 87 +/- 9 mmHg (P: < 0.001) after patients were switched to tacrolimus. Mean nighttime BP also decreased, from 140 +/- 12/86 +/- 7 mmHg to 132 +/- 17/79 +/- 10 mmHg (P: < 0.05). Total and low-density lipoprotein cholesterol decreased from 6.1 +/- 0.7 and 3.84 +/- 0.79 mmol/L to 5.1 +/- 0.8 and 2.98 +/- 0.75 mmol/L (P: < 0.001). Return to CsA caused an increase in BP and cholesterol to values similar as during the first CsA period. The conclusion is that tacrolimus has fewer unfavorable effects on BP and lipids than does CsA. Elective conversion from CsA to tacrolimus in stable renal transplant recipients may lead to attenuation of cardiovascular morbidity and chronic transplant nephropathy in the long term.     

Colchicine myopathy in renal transplant recipients on cyclosporin

Few data are available about the muscle status in renal transplant recipients. Moreover, the list of myotoxic drugs is growing longer and some of them are likely to be prescribed in renal transplant patients. These conditions may act as confounding factors in case reports of both cyclosporin and colchicine myopathies. Moreover no study has evaluated the frequency of myopathy in patients on both colchicine and cyclosporin. We conducted a retrospective study including all renal transplant recipients followed in our unit in whom colchicine was prescribed since January 1994. Clinical and biological data of patients on both colchicine and cyclosporin were analysed. Secondly case subjects were compared with matched controls not receiving colchicine but cyclosporin. Ten patients received colchicine in association with cyclosporin. Five patients (50%) experienced muscular symptoms and when performed, muscular histology showed vacuolar myopathy. All five patients improved after colchicine withdrawal. Cases with and without muscular symptoms did not differ in age, transplant duration, and serum creatinine level. Mean duration of colchicine therapy was 12.2±4.4 months in cases with muscular symptoms and 6.8±5.6 months in cases without muscular symptoms (P <0.05). No control complained of either muscular pain nor weakness (P <0.0005). Only one patient (3.3%) had elevated serum creatine phosphokinase concentration (P <0.0005). We conclude that myopathy is very frequent in patient on both colchicine and cyclosporin. Muscular symptoms improve in all patients after colchicine withdrawal. Key words: biological data; colchicine; cyclosporin; drug effects; muscle; myopathy      

Increased incidence of benign breast disease in female renal transplant patients receiving cyclosporin

Background : Unlike other cancers, breast cancer does not occur at increased frequency in renal transplant patients but fibroadenomata may be more common as a result of exposure to cyclosporin. In order to determine the incidence of benign breast disease in renal transplant patients at Monash Medical Centre, current female patients were studied. Methods : The study was divided into two parts: (i) a retrospective review of those who presented with clinically detectable breast lumps; and (ii) mammographic screening of current female transplant patients who had been transplanted for more than 1 year. Results : In the retrospective study there were 11 patients with 16 breast lumps among a total of 85 patients. All were confirmed by biopsy. The mean age at diagnosis of breast lumps was 41.5 years (range 25–70 years). The mean time to presentation was 3.5 years after transplantation. Nine out of 11 patients had benign breast disease including fibroadenoma (six patients), fibrocystic disease (two patients) and intraductal papillomatosis (one patient). Two patients had breast cancer. Five of the patients with fibroadenoma had multiple lumps and a recurrent course. All patients with fibroadenomata had received cyclosporin. In the second part, 54 patients were further screened. The mean duration of transplantation was 6.4 years (range 1.25–18.5 years). Eighty‐seven per cent of the patients had received cyclosporin, and 80% had a negative (normal) study. Seven of 54 had abnormalities including cysts and calcification, of whom two patients had fibroadenomata. Four patients had ‘dense mammograms’, all of whom received cyclosporin as a part of their immunosuppression. No breast cancer was detected during the study. Conclusion : The incidence of benign breast disease in the female transplant patients studied was far greater then the general population. The increase in fibroadenomata, in particular, may relate to the use of cyclosporin.     

Acute effect of cyclosporin on renal function following the initial changeover to a microemulsion formulation in stable kidney transplant patients

Potential differences in the acute effect of cyclosporin on renal function when dosed orally as the current market formulation or following a milligram-to-milligram conversion to a new microemulsion formulation were investigated in 14 stable kidney transplant patients. The study consisted of three sequential periods of 2 weeks duration each. Patients entered (period I) and completed (period III) the investigation with the market formulation and received the microemulsion formulation in period II; individualized cyclosporin doses remained unchanged throughout the study. Over one steady-state dosing interval at the end of each study period, whole blood cyclosprin pharmacokinetic profiles were assessed in parallel with endogenous creatinine clearances over sequential 1-to 2-h intervals. The rate and extent of cyclosporin absorption were significantly greater (P<0.01) from the microemulsion formulation with average increases of 73% in peak concentration and 44% in area under the curve compared to the market formulation. Sequential creatinine clearances exhibited a transient decrease with the nadir occurring on average between 4 and 6h post dose followed by a rapid return to baseline. Specifically in period I on the market formulation, clearances decreased from a baseline of 71.7±20.6 to a minimum of 51.1±17.9 ml/min per 1.73 m² (similar values in period III) and from 76.8±24.8 to 53.5±17.5 ml/min per 1.73 m² in period II on the microemulsion. Neither the baseline nor minimum clearances were significantly different among the study periods. Hence, the pharmacokinetic differences between the formulations did not acutely influence the pattern of glomerular filtration rate following the initial milligramto-milligram changeover in stable renal transplant patients.     

Early proteinuria in renal transplant recipients treated with cyclosporin

PURPOSE: To establish the risk profile for the development of proteinuria in the first months after renal transplantation and to disclose the prognostic significance of this finding. DESIGN: We conducted an observational historic cohort study. SETTING: We conducted the study in a tertiary care hospital renal transplantation unit covering a potential population of approximately 2 million. We made extensive use of suboptimal donors. POPULATION: In our unit, 560 cadaveric renal transplants were performed between January 1988 and June 1997, under Cyclosporine immunosuppression, with a minimum follow up of 1 year. METHOD: The risk profile analysis explored early clinical factors reported to be related to the late course of renal transplantation. The study of the prognostic significance of proteinuria included survival analysis and correlation with late markers of graft dysfunction, taking into consideration the intensity and persistence of early proteinuria. A multivariate approach was used in all cases. RESULTS: Early proteinuria was strongly associated with delayed graft function (odds ratio [OR] 1.03/day of dialysis), acute rejection (OR 1.7 for steroid-sensitive and 6.2 for steroid-resistant rejection), renal transplant to a hypersensitized recipient (OR 2.5), and pediatric (<5 years)(OR 4.1) or older (>60 years)(OR 3.0) donors. The predictive model for persistency of proteinuria was very similar, whereas transient proteinuria could not be adequately modeled. Increasing intensity of proteinuria was strongly associated with poor patient and graft survival. Persistent, but not transient, proteinuria supported this relationship. CONCLUSIONS: Proteinuria appearing early after renal transplantation is strongly associated with delayed graft function, acute rejection, and the use of pediatric or older donors. Whatever its background, proteinuria is a strong predictor of poor patient and graft survival. This effect is directly related to the intensity and persistence of the disorder.     

Gastrointestinal perforations in renal transplant recipients immunosuppressed with cyclosporin

Gastrointestinal perforations frequently represent a lethal complication of immunosuppression. Of 325 renal transplant recipients treated with cyclosporin (CsA), 4 patients (1.2%) developed gastrointestinal perforation: 1 from gastric ulcer and 3 from colonic diverticula. All patients underwent operative treatment and all survived without complications. Three patients maintained a well-functioning allograft. In comparison to azathioprine, CsA does not seem to greatly affect the immune response to bacterial infections, thus representing a considerable advantage in the management of serious gastrointestinal complications.

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Resumen Las complicaciones gastrointestinales no son raras en pacientes con transplante renal bajo inmunosupresión con azatioprina-prednisona, especialmente las perforaciones de úlcera péptica o de enfermedad diverticular del colon, las cuales frecuentemente vienen a significar una complicación letal de la inmunosupresión. El manejo de estas complicaciones que ponen en peligro la vida del paciente, comprende descontinuar la inmunosupresión con abandono del injerto. Sinembargo el nuevo agente inmunosupresor, la ciclosporina (CsA), un endecapéptido fungal de novedosa estructura química, exhibe una acción inmunosupresiva más específica sobre las células T que la azatioprina, dejando casi intacta la respuesta de células B a la infección bacteriana. Estos factures deben hacer que las perforaciones gastrointestinales en pacientes bajo CsA sean eventos menos desastrosos. De 325 pacientes receptores de transplante renal tratados con CsA, 4 (1.2%) desarrollaron perfora ción: 1 por úlcera gástrica y 3 por divertículos colónicos. Todos fueron sometidos a tratamiento quirúrgico y todos sobrevivieron sin complicaciones. Tres mantuvieron su aloinjerto funcionando bien. En comparación con la azatioprina, la CsA no parece afectar mayormente la respuesta inmune a las infecciones bacterianas, lo cual representa una ventaja de significación en el manejo de complicaciones gastrointestinales serias.

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Résumé Les perforations digestives représentent souvent une complication fatale de l'immunosuppression. Chez 325 transplantés rénaux traités par la cyclosporin A (CsA), 4 (1.2%) ont présenté une perforation digestive; 1 cas de perforation d'ulcère gastrique, 3 cas de perforation de diverticule colique. Les 4 malades furent opérés avec succès. Trois d'entre eux ont gardé une fonction rénale normale. Par comparaison avec l'Azathioprine la CsA ne paraît pas affecter considérablement la réponse immunitaire à l'infection bactérienne et de ce fait elle présente un avantage considérable pour traiter les complications gastro-intestinales sérieuses.

     

Fenoldopam reverses cyclosporine-induced renal vasoconstriction in kidney transplant recipients.

Cyclosporine causes renal vasoconstriction and reduced renal blood flow that may contribute to chronic nephrotoxicity. This effect has not been consistently reversed by available pharmacologic agents. The efficacy of orally administered fenoldopam, a dopamine-1 (DA-1) agonist with renal vasodilator properties, was evaluated in six patients whose condition was stable 3 to 6 months following renal transplantation. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate (PAH) clearances, respectively, at baseline, after the acute oral administration of 100 mg of fenoldopam, and following 3 weeks of chronic oral fenoldopam therapy (100 mg thrice daily). Mean ERPF increased from 3.15 +/- 0.17 mL/s/1.73 m2 (189 +/- 10 mL/min/1.73 m2) at baseline to 3.48 +/- 0.17 mL/s/1.73 m2 (209 +/- 10 mL/min/1.73 m2) 4 hours after acute administration of fenoldopam (P = 0.04). Urine flow rate and fractional excretion of sodium also increased after acute administration, but not significantly. Mean systolic (SBP) and diastolic blood pressure (DBP) decreased maximally by 18 and 6 mm Hg, respectively, and mean pulse rate increased maximally by 8 bpm between 75 and 90 minutes after both acute and chronic administration. GFR was unchanged following both acute and chronic administration. The increase in ERPF was not maintained to the end of the dosing interval during chronic administration, probably due to the short half-life of fenoldopam. However, the renal vasodilatory response was still observed 3 to 4 hours after readministration of the drug following 3 weeks of oral dosing. Thus, fenoldopam significantly reverses the renal vasoconstriction caused by cyclosporine in renal transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term renoprotective effect of candesartan in renal transplant patients

Background

The renoprotective effects of angiotensin II type 1 receptor blockers (ARBs) have been demonstrated in a number of clinical studies, but there are few evaluations of long-term ARB treatment. We measured blood pressure, urine protein, and estimated glomerular filtration rate (eGFR) among patients under long-term (up to 9 years) treatment with candesartan cilexetil to evaluate its safety and effectiveness to protect renal graft function.

Methods

This study of 41 patients (31 male and 10 female) who presented with proteinuria and hypertension (blood pressure >140/90 mm Hg) after receiving a renal graft. Their serum creatinine level at baseline was 1.51 ± 0.53 mg/dL. Cyclosporine or tacrolimus were concomitantly prescribed for 18 (43.9%) and 22 (53.7%) subjects, respectively. The ARB treatment period was ≥12 months (up to 9 years, mean 4.8 years). Combination with other antihypertensive drugs (calcium antagonists) was necessary in 14/41 subjects (34.1%).

Results

Significant declines in blood pressure were observed during the treatment period; blood pressure reduction target (blood pressure <130/80 mm Hg) was met in 56.1% for systolic and 68.3% for diastolic pressure. No significant increase in serum creatinine level or eGFR was observed. Urinary protein was reduced to negative or marginal in 63.4% of the subjects, demonstrating a significant decrease.

Conclusions

Candesartan cilexetil was considered to be safe even for long-term treatment in renal transplant patients, and effective to protect renal graft function.     

Pronounced renal vasoconstriction and systemic hypertension in renal transplant patients treated with cyclosporin A versus FK 506

This prospective study investigated hypertension and renal vasoconstriction developing during the 1st year after renal transplantation in patients randomly allocated to treatment with FK 506 (n = 28) or CyA (n = 13). Starting doses were 0.2–0.3 mg/kg per day for FK 506 and 5–8 mg/kg per day for CyA; doses were subsequently adjusted to trough levels (5–15 ng/ml for FK 506 and 100–150 ng/ml for CyA). We compared 24-h ambulatory blood pressure measurement, antihypertensive treatment, serum creatinine, and resistance index (RI), measured by Doppler ultrasound at the level of the interlobar artery. Until month 2 of treatment, FK 506-treated patients had a significantly lower RI (8 %) and better renal graft function, as evidenced by significantly lower serum creatinine values. Some 13 % of FK 506-treated patients, compared to 70 % of CyA-treated patients (P < 0.01), needed additional antihypertensive drugs after transplantation to keep blood pressure stable. FK 506 treatment, at the above-mentioned dosages, was associated with a significantly higher number of infections (urinary tract infection, pyelonephritis, and pneumonia). We conclude that CyA produces greater renal vasoconstriction and systemic hypertension than FK 506, as reflected in higher renal interlobar artery RI values and a greater need for antihypertensive treatment. After 2 months of treatment and a reduction in CyA trough levels, the renal effects (i. e., lower RI and lower creatinine values), but not the systemic hypertensive effects, disappear. Received: 25 March 1997 Received after revision: 25 September 1997 Accepted: 8 October 1997     

Pneumocystis carinii pneumonia in renal transplant recipients treated with cyclosporin

Four cases of pneumocystis carinii pneumonia occurred among 38 renal transplant recipients. Diagnosis was confirmed by cyst concentration technique in 2 cases. The other 2 cases were clinically, from the rapid improvement of fever, pulmonary infiltrates and hypoxia following a therapeutic trial of high dose sulfamethoxazole-trimethoprim. All patients responded to treatment with high dose sulfamethoxazole-trimethoprim. Three patients survived pneumocystis carinii pneumonia, but i died due to aspergillosis. One patients showed serological evidence of concomitant cytomegalovirus infection.     

Need for reduction of cyclosporin dosage in renal transplant patients with hypertriglyceridemia but not hypercholesterolemia

Currently there is a paucity of data regarding the influence of high serum triglyceride levels on cyclosporin A (CyA) levels and dosing. We therefore undertook a retrospective study to determine the relationship of serum lipid levels to CyA levels and CyA dosages. Renal transplant patients at a 0.5-to-3-year post-transplant stage, with a stable CyA dosage, who were not on medications that affect CyA metabolism or renal function, were entered into the study. The CyA dosage was adjusted by clinicians to maintain whole blood. 12-h CyA trough levels between 200 and 250 ng/ml (monoclonal TDX method, which measures the parent compound). Fortyfour patients qualified for the study. The data clearly indicated that high cholesterol levels (>300 mg/dl and with normal triglyceride levels) did not influence the CyA levels or the dosages. Conversely, high triglyceride levels (>500 mg/dl) significantly reduced the amount of CyA required. A decreased clearance of CyA in the presence of hypertriglyceridemia led to high CyA levels in some patients. Reducing the CyA dosage to achieve levels between 200 and 250 ng/ml improved renal allograft function and decreased other side effects attributed to CyA toxicity. These studies indicate that high triglyceride levels, but not high cholesterol levels, increase CyA levels, which can lead to CyA toxicity.     

The calcineurin activity profiles of cyclosporin and tacrolimus are different in stable renal transplant patients

Cyclosporin and tacrolimus remain the cornerstone immunosuppressive drugs in organ transplantation. Dosing and monitoring these drugs is based on pharmacokinetic protocols, but measuring a pharmacodynamic parameter, calcineurin phosphatase (CaN) activity, could be a valuable supplement in determining optimal doses. Forty stable renal transplant patients were investigated three times in a 6-month period. Blood samples were drawn at 0, 1, 2, 3 and 4 h after oral intake of tacrolimus (FK) or cyclosporin at days 1 and 180. At day 90, one blood sample at trough level (FK) or C2 level (cyclosporin A, CsA) was drawn. CaN activity was determined in whole blood as the release of 32P from a phosphorylated peptide. Activity of the 32P was quantitated by liquid scintillation and results converted to Units CaN, utilizing a calibration curve with CaN. We demonstrated that calcineurin activity profiles at days 1 and 180 were the same for both drugs. Furthermore, we found that patients treated with tacrolimus or cyclosporin displayed different calcineurin activity profiles. We found that cyclosporin displayed greater calcineurin inhibition than tacrolimus. We have demonstrated that the two drugs exert significantly different effects on calcineurin activity in renal transplant patients with stable, well-functioning grafts and that tacrolimus-treated patients can maintain good, stable graft function with minimal CaN inhibition.     

Effect of cyclosporin on lung diffusing capacity in renal transplant patients

A prospective lung function study pre- and postrenal transplantation was performed on 21 patients in order to evaluate whether cyclosporin decreased the lung diffusing capacity due to lung toxicity. Initial inclusion criteria were absence of respiratory symptoms and normal findings in both chest X-ray and pulmonary function tests. Participants had to be nonsmokers. We determined spirometry including lung volumes, arterial blood gases, carbon monoxide diffusing capacity by the single breath method (D_LCO_SB), and rate of CO uptake per unit of lung volume (KCO) before and 3, 6, and 12 months after transplantation. Immunosuppression consisted of prednisone and cyclosporin, maintaining total blood levels between 100 and 250 ng/ml. Spirometric and blood gases data remained within reference levels during the follow-up. Hemoglobin (Hb) pretransplant concentrations remained low, returning to their normal levels posttransplantation. Pretransplant D_LCO_SB levels were slightly decreased but fell within the therapeutic range after correction for Hb concentration, unlike the mean KCO levels which remained slightly diminished despite their correction. In post-transplant controls, the values obtained for both D_LCO_SB and KCO were significantly higher at the different post-transplant intervals (P<0.005) than pretransplantation but only when compared without Hb correction. No significant differences for D_LCO_SB were found when corrected values were compared, and an improvement in the KCO appeared to be significant at 12 months posttransplantation. Based on these findings, we feel that when serum levels are within the therapeutic range, cyclosporin fails to alter the respiratory function or the pulmonary diffusing capacity of the lung.