Plasma Levels Of Cyclosporine Research Articles

Real-Life Data of Cyclosporine (CsA) Tapering in Patients with Very/ Severe Aplastic Anemia (v/sAA) Treated with Horse Anti-Thymocyte Globulin (hATG/CsA) Suggest Higher Risk of AA Relapse at Cyclosporine Plasma Levels below 100 Nanogram per Milliliter

Introduction: Aplastic anemia (AA) is an acquired bone marrow failure syndrome (BMFS) mediated by autoreactive T-cells. In adults with severe (s) or very severe (vs) AA >40-50 years or ineligible for transplant for other reasons immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), cyclosporine A (CsA) and Eltrombopag (Epag) has recently become the actual standard of care. With CsA treatment maintained for 6 to 24 months followed by CsA tapering hematologic response is achieved in 60-70 % of AA patients (pts.), while 30-40 % are primary refractory. Approximately 40% of pts. relapse during CsA tapering and most relapsed AA pts. remain CsA dependent. In vitro data indicate a dose dependent inhibition of T cell activity induced by CsA, suggesting the presence of a therapeutic CsA threshold around 100 ng/mL (Flores et al. Front Immunol 2019). Pts. with CsA related side effects such as renal insufficiency would benefit from an established lowest efficient CsA plasma level preventing relapse and reducing CsA related toxicity. As data about correlation of CsA plasma levels and the occurrence of relapse during tapering are sparse, we analyzed data from our registries including CsA plasma levels of 20 s/vsAA pts. with and without relapse during CsA tapering after treatment with horse ATG/CsA. Methods: Descriptive retrospective analysis of 20 AA pts. (17 sAA/ 3 vsAA) from the AA-BMF/Basel AA registry treated with horse ATG/CsA and sufficient clinical data during CsA tapering. Results are given as mean ± standard deviation. Mean age of the 13 female and 7 male pts. was 53 ± 19 years. Follow-up data over 59 ±17 months were compiled between 2010 and 2023. Results: All 20 pts. achieved a hematological response i.e. partial (PR) or complete remission (CR) (as defined in Peffault de Latour et al., 2022) at 3/6/9 months after ATG as follows: PR 90%/ 75%/ 55% and CR 0%/ 20%/ 45%. Relapse of AA occurred in 60 % (12 pts.) at 24 ± 11 months after ATG, while 40 % (8 pts.) remained relapse-free during a follow up period of 59 ±17 months. In the 8 pts. without relapse, dose reduction was initiated 14 ± 6 months after ATG at a hematological response of CR in 4 pts. and PR in 4 pts. In two pts. with PR, early decrease of CsA was required due to renal insufficiency (1 month after ATG) or CsA related adverse drug reaction (4 months after ATG), respectively. The average time of CsA maintenance was 32 ± 13 months. In pts. with relapse (60%, 12 pts.), dose reduction was started after reaching best hematological response i.e. CR (9 pts.) or PR (3 pts.) at 11 ± 7 months after ATG. Relapse i.e. recurrent thrombocytopenia occurred 12 ± 9 months after start of tapering at CsA plasma levels of 44.0 ± 29.2 ng/mL and a daily CsA dosage of 1.01 ± 0.70 mg/kg. In one case, relapse occurred one month after stopping CsA. No patient with CsA levels continuously > 100 ng/mL relapsed, whereas thrombocytopenia was observed with a latency of 2.8 ± 1.6 months after first decrease below 100 ng/mL CsA in pts. with relapse. While 58% (7 pts.) of the relapsed pts. responded to salvage-therapy with CsA+Epag (age 58 ± 16 years), 42 % (5 pts.) required a second course of ATG/CsA, or transplant (age 44 ± 22 years). Conclusion: In s/vsAA pts. with hematological response to ATG/CsA, closer monitoring for relapse is recommended reaching CsA plasma levels <100 ng/mL, as CsA <100 ng/mL was associated with higher risk of relapse during CsA tapering in line with previous reported in vitro data. Pending prospective validation, CsA plasma levels >100 ng/mL might serve as threshold in pts. requiring accelerated tapering due to renal insufficiency or CsA related side effects.

T1912 Calcineurine Inhibitors Accelerate Microvascular Thrombus Formation In Vivo

Thrombotic microangiopathy (TMA) is a fatal complication that occurs after combined pancreaskidney transplantation leading to allograft dysfunction and graft loss. Immunosuppressive drugs, such as calcineurin inhibitors, have been implicated in the development of nonimmune TMA. Tacrolimus has been shown to be associated with decreased NO-production, thus contributing to thrombus formation. ADMA acts as an endogenous NO-synthase inhibitor and is considered to be a marker of endothelial dysfunction. Aim of this study was to analyse the influence of different immunosuppressants on microvascular thrombus formation in vivo and to further examine the underlying endothelial function. Using the skin fold chamber in C57BL/6J mice, microvascular thrombus formation was induced photochemically and was quantitatively analyzed by intravital fluorescence microscopy. Mice were treated with tacrolimus (TAC: 10 mg/kg/d; n = 7), cyclosporine (CYA: 5 mg/kg/d) or sirolimus (RAPA: 1,5 mg/kg/d ip) on 3 consecutive days. Control mice received NaCl 0,9 % (10 ml/kg/d ip; n = 5). Drug plasma levels were examined to ensure therapeutic doses. Additionally, the systemic circulation of sPand sE-selectin as well as ADMA plasma levels were measured by ELISA. Application of immunosuppressants produced clinically relevant plasma levels (TAC: 8 ± 2 ng/ml, CYA: 214 ± 16 ng/ml; RAPA: 9 ± 1 ng/ml). Microvascular thrombus formation was significantly accelerated in mice receiving TAC compared to control mice (arteriolar and venular occlusion: 251 ± 101s and 179 ± 27 s vs. control 818 ± 221 s and 749 ± 231 s; p < 0,05). Application of CYA significantly increased thrombus formation only in venules (276 ± 49s; p < 0,05 vs. control), whereas RAPA had no significant effect on thrombosis induction. Plasma concentrations of sP-Selectin and sE-selectin were slightly reduced after TAC and CYA application. ADMA-levels however were significantly increased in mice receiving TAC (1,28 ± 0,16 μmol/l vs. control: 0,74 ± 0,13 μmol/l; p < 0,05). The present results show that clinically relevant plasma levels of cyclosporine enhanced thrombus formation only in venules whereas tacrolimus significantly accelerates thrombus formation in arterioles and venules. This effect could be explained by increased ADMA-levels in plasma resulting in impaired NO-bioavailability and increased thrombogenicity, thus presenting a new molecular mechanism in the development of transplant-thrombosis.

No Kinetic Interaction Between Levetiracetam and Cyclosporine: A Case Report

Levetiracetam is a new antiepileptic drug reported to be effective and well-tolerated in adults and children affected by epilepsy. Its lack of hepatic cytochrome metabolism is the theoretic basis for the absence of interactions with other drugs that follow this pathway. We present a 14-year-old girl who underwent orthotopic heart transplantation, followed by antirejection therapy including cyclosporine. Symptomatic occipital lobe epilepsy developed that was successfully treated with oxcarbazepine, but cyclosporine plasma levels decreased to below the antirejection threshold. Oxcarbazepine was replaced by levetiracetam. Levetiracetam did not affect the metabolism of cyclosporine, and cyclosporine plasma levels have remained in the therapeutic range up to now. The patient is still seizure-free and does not complain of any side effects after a 1-year follow-up. Further studies are necessary to confirm the lack of interactions between these drugs, which would make levetiracetam a useful therapeutic option in managing seizure control during antirejection therapy with cyclosporine.

Drug‐Drug Interaction After Single Oral Doses of the Furanocoumarin Methoxsalen and Cyclosporine

Furanocoumarins increase the bioavailability of drugs that are CYP3A4 substrates. A possible interaction of methoxsalen with cyclosporine was evaluated in 12 healthy volunteers following oral administration of 40 mg methoxsalen, 200 mg cyclosporine, or a combination of both in a randomized crossover study. Methoxsalen increased area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of cyclosporine by 29% (range, -20% to 172%; P < .05) and 8% (range, -10% to 26%; P < .05), respectively, compared to cyclosporine alone. The AUC geometric means ratio (95% confidence interval) for cyclosporine plus methoxsalen/cyclosporine alone was 1.14 (1.02, 1.27), and treatments were therefore not bioequivalent. Methoxsalen causes a clinically significant interaction with cyclosporine in some susceptible individuals. The reasons for susceptibility and the clinical implications for chronic cyclosporine administration have not been established. Caution is recommended in combination therapy, and more frequent monitoring of cyclosporine plasma levels and clinical monitoring is advised.

Combined Therapy of Prednisone and Cyclosporine as Treatment Option for Refractory Coeliac Disease and Clonal T Cell Receptor (TCR) Gene Rearrangement

Effective therapy of refractory coeliac disease is still under debate. The necessity for such treatment is underlined by the potential risk of the development of an enteropathy-associated T-cell lymphoma. We report of a male patient with coeliac disease first diagnosed in 1991. Under subsequent gluten-free diet, clinical symptoms of the disease necessitated only intermittent treatment with prednisone. A recent deterioration was treated with azathioprine which had to be stopped because of side effects. When we first saw the patient in August 2004, he had experienced a weight loss of 16 kg within 14 months and suffered from diarrhea, hypoalbuminia and impaired nutritional state. The diagnostic work-up (blood/stool/x-ray/CT) did not result in any other diagnoses explaining the clinical symptoms. GI endoscopy showed intraepithelial lymphocytosis, villous atrophy with crypt hyperplasia and ulcerative lesions in the small bowel. All biopsies (duodenum/jejunum/ileum/bone marrow/liver/lymph node) but not blood were characterized by monoclonal T-cell receptor-gamma gene rearrangement. Total parenteral nutrition resulted in a weight gain of 14 kg but administration of prednisone at different doses (20–60mg iv/die) was not associated with improved enteral resorption. Therefore, cyclosporine (initially 5mg/kg iv/die) was added to prednisone (60mg iv/die). Consequently, a stepwise reduction of parenteral nutrition was feasible. Within 4 months, the patient gained another 8 kg. A shift from parenteral to oral drug administration was successful under cyclosporine plasma levels between 65 and 96ng/ml (limitation of daily cyclosporine dosage to 2mg/kg because of developing renal insufficiency). The histological analysis of duodenal/jejunal biopsies did not show any change in the modified Marsh classification (IIIb). Conclusion: The combined administration of prednisone plus cyclosporine represents a clinically effective treatment option in patients with refractory celiac disease who are unresponsive to steroids alone and do not tolerate azathioprine.

Sirolimus Improves Renal Function in Cardiac Transplantation

In kidney and liver transplantation, sirolimus therapy has been shown to be comparable to cyclosporine in a head-to-head comparison, but it results in better preservation of renal reserve. In heart transplantation, information about the use of sirolimus is limited. We present the results of the progressive conversion from cyclosporine to sirolimus in a series of 8 heart transplant patients in whom renal dysfunction developed. The baseline creatinine level was 2.4 ± 0.5 mg/dL, and plasma levels of cyclosporine were within the therapeutic range. After the introduction of sirolimus, the creatinine level fell within the first month to 1.76 ± 0.2 mg/dL, or mean decrease of 0.6 ± 0.25 mg/dL ( P < .05). After 3 ± 2.2 months the improvement continued (1.69 ± 0.2 mg/dL). In 1 patient sirolimus was withdrawn during the first 24 hours, because of gastric intolerance. No patient developed an opportunist infection, allograft rejection, or important hematologic disorder. We conclude that sirolimus appears to be effective in heart transplant patients to improve renal function.

Cyclosporine toxicity in renal transplant recipients detected by nailfold capillaroscopy with Na-fluorescein

Cyclosporine represented a major advance in the medical management of patients with organ transplantation, but its use is limited by the frequent occurrence of hypertension and renal toxicity diagnosed by invasive renal biopsy. Renal histology shows a specific arteriolopathy. It was hypothesized that cyclosporine may also induce subclinical microvascular changes in the skin that might be detected noninvasively by a combination of dynamic capillaroscopy [capillary blood cell velocity (CBV)] with and without intravenous Na-fluorescein (NaF) injection and laser Doppler fluxmetry (LDF). The nailfold skin microcirculation was evaluated in 112 consecutive renal transplant recipients (54 +/- 11 years old; 70 males and 42 females) receiving cyclosporine. The investigation was made the same day as a routine renal biopsy performed in all patients more than two years after transplantation. Renal biopsies were blindly classified as positive (N = 33) when significant specific signs of cyclosporine toxicity were clearly observed (AH2-AH3) and were otherwise negative (AH0-AH1, N = 79) according to the Banff classification. Time to fluorescence peak after NaF injection (tpNaF) was significantly longer in patients with positive biopsies than in patients with negative biopsies (13.9 +/- 8.1 vs. 17.5 +/- 9.4 sec, P = 0.009). All patients but three with negative biopsies (93%) had a tpNaF less than 10 seconds (sensitivity 91%, negative predictive value 93%). On the other hand, CBV, LDF, plasma levels of cyclosporine, and endothelin were similar in the two groups. Nailfold fluorescence capillaroscopy is an accurate and simple mean to rule out cyclosporine toxicity in renal transplant recipients. A normal test could avoid invasive renal biopsy in about 40% of the patients. Renal biopsy would, however, still be indicated when the test is abnormal.

Influence of felodipine on left ventricular hypertrophy and systolic function in orthotopic heart transplant recipients:: Possible interaction with cyclosporine medication

Background: Concentric left ventricular (LV) hypertrophy develops early in orthotopic heart transplant (OHT) recipients. To compare the effects of a calcium channel blocker, felodipine, versus diuretics on LV hypertrophy and LV systolic function repeated magnetic resonance imaging studies were performed in OHT recipients. Cyclosporine levels and neurohormones were also measured to explore potential interactions with treatment. Methods Twenty-two patients were randomized at baseline (2 months after OHT) to receive felodipine or diuretic treatment. Before and after 4 months of treatment ( n = 19), LV dimensions and LV mass (Simpson’s rule) were measured. The relationship between circumferential fiber shortening (two-shell cyclindrical model) and end-systolic wall stress was used as a measure of load-independent LV contractility. Neurohormones were measured at the beginning and end of the treatment period, and cyclosporine levels and blood pressures were additionally measured during treatment. Results At baseline, the felodipine and diuretic groups did not differ in LV mass, wall stress, and fiber shortening. During felodipine treatment LV mass decreased ( p < 0.01) and tended to increase during diuretics treatment ( p = 0.06). Afterload-corrected fiber shortening did not change during felodipine treatment, but decreased ( p < 0.01) with diuretics. Changes in LV mass were positively correlated with cyclosporine levels ( r = 0.70) in the diuretics group, but not in the felodipine group. Conclusions In OHT recipients during diuretic treatment, progression of LV hypertrophy occurs in relation to cyclosporine plasma levels and is accompanied by impairment of systolic contractile function. Felodipine induces regression of LV hypertrophy, while systolic contractile function is preserved. During felodipine treatment, regression of LV hypertrophy is unrelated to cyclosporine levels. Thus, felodipine seems to attenuate the hypertrophic effect of cyclosporine on transplanted hearts.

A prospective study in heart and lung transplant recipients correlating persistent Epstein-Barr virus infection with clinical events.

A 2-year prospective study was set up with 30 cardiothoracic transplant recipients to study Epstein-Barr virus (EBV) infection and immunity and their correlation with clinical events. Regression assays were used to measure EBV-specific cytotoxic T lymphocyte (CTL) function. Tissue culture, immunoblotting, and polymerase chain reaction were used for EBV detection and isolate variation studies. CTL activity was significantly lower in pretransplant seropositive patients than in healthy controls (P<0.001). CTL response was undetectable in all patients during the first 6 months after transplantation, but returned at levels significantly lower than pretransplant and control levels during the second posttransplant year (P<0.001). Return of CTL function was directly correlated with time of last treated rejection episode (P<0.003) and duration of high plasma levels of cyclosporine (over 400 ng/ml; P<0.003). Significantly higher levels of EBV were detected in peripheral blood during the first 6 months than in pretransplant or control samples (P<0.05). Excretion of EBV in throat washings was significantly lower during the first 3 months when all patients were receiving acyclovir than in pretransplant and control samples (P=0.02). An increase in virus shedding was noted 3-6 months after transplantation, which was significantly higher than in pretransplant patients and controls (P<0.05). Comparison of recipients' and donors' virus isolates in 11 cases showed that seropositive recipients retained their original EBV isolate and did not acquire the donor virus. Immunosuppression decreased EBV-specific host immune function, which in turn favored increased EBV load in peripheral blood and increased excretion in the oropharynx. The transfer of donor virus to the seropositive recipients was not observed.

Possible interaction between cyclosporine and glibenclamide in posttransplant diabetic patients.

The possible occurrence of a kinetic interaction between cyclosporine A and glibenclamide was assessed by reviewing data of six posttransplant diabetic patients who received the two drugs concurrently. Coadministration of the two drugs resulted in a 57% increase in the steady-state plasma cyclosporine levels despite normal hepatic and renal functions in the patients. This elevation in cyclosporine level is possibly due to an interaction between the two drugs resulting from an inhibition of CYP3A4-mediated metabolism of cyclosporine by glibenclamide. This observation calls for a closer monitoring of cyclosporine plasma levels during concomitant administration of these two drugs in this group of patients.

EVIDENCE FOR INCREASED NITRIC OXIDE PRODUCTION AFTER LIVER TRANSPLANTATION IN HUMANS

To evaluate the role of in vivo-produced nitric oxide (NO) after orthotopic liver transplantation, nitrate, a stable end product of spontaneous NO conversion in blood, was assayed in plasma samples of 32 patients. In 31 patients, nitrate increased from 36 +/- 2 microM to 137 +/- 8 microM within the first 6 postoperative days. In 11 out of 12 patients with an uneventful early postoperative course, nitrate increased from 33 +/- 2 microM to 70 +/- 8 microM, and returned to baseline levels within 2-3 days. In the remaining 20 patients with episodes of rejection and/or infection, the nitrate peak was augmented and prolonged. Ten patients suffering from these events in the later postoperative course showed a second nitrate elevation. In 31 patients, effective plasma levels of cyclosporine were reached 4-5 days after OLT. The patient without significant elevation in plasma nitrate had effective levels already at day 1. After liver resection or coronary bypass grafting, the median nitrate level remained at 21 microM (range 15-36 microM; healthy persons: median 24 microM, range 18-32 microM). After kidney transplantation nitrate was elevated in the early postoperative course. Thus, NO formation appears to be increased after solid organ transplantation, but not after other surgeries. After OLT, the increase appears to occur (a) in response to rejection and/or infection, and (b) 4-6 days after surgery in the absence of overt complications. In the latter case, NO might be involved in subclinical rejection and its production is possibly dependent upon the effectiveness of the immunosuppressive therapy.

Modulation of vinblastine resistance with cyclosporine: A phase I study

Tumor cell resistance is a major cause of failure to cure advanced malignancies. Multidrug resistance is thought to be an important mechanism of such resistance. Our aims were to identify doses of cyclosporine that would achieve blood levels effective in modulating multidrug resistance to vinblastine and to evaluate the toxicities and maximum tolerated dose of cyclosporine when administered in conjunction with vinblastine. We conducted a phase I trial of vinblastine and escalating doses of cyclosporine. Cyclosporine was given by continuous intravenous infusion over 120 hours and vinblastine was administered by continuous infusion from hour 12 to hour 108. Sixty-two patients entered the trial, of whom 60 were evaluable. Cyclosporine was escalated from 1 to 15.6 mg/kg/day. Vinblastine doses were reduced to 1.6 and then 1.2 mg/m2/day because of increasing vinblastine toxicity at higher cyclosporine doses. The maximum tolerated dose of cyclosporine at 1.2 mg/m2/day vinblastine was 12.5 mg/kg/day; at this dose level, mean blood cyclosporine level was 1.25 +/- 0.41 mumol/L. Significant nephrotoxicity was observed at higher cyclosporine doses in two of four patients. Nephrotoxicity was not significant at doses at or lower than this maximum tolerated dose and was not cyclosporine dose dependent. Myelosuppression, neurotoxicity, and transient hyperbilirubinemia were observed and were cyclosporine dose dependent. CONCLUSIONS. Cyclosporine by continuous infusion may be safely given in high doses concurrently with continuous-infusion vinblastine. Plasma levels of cyclosporine > or = 1 mumol/L can be sustained during vinblastine administration. No sustained effect on T-cell subsets was observed. Vinblastine toxicity is enhanced by cyclosporine in a dose-dependent fashion and correlates with cyclosporine-induced hyperbilirubinemia.

EFFECTS OF SMS 201–995 ON THE PHARMACOKINETIC PROFILE AND CELLULAR IMMUNE AND TOXIC EFFECTS OF CYCLOSPORINE IN MALE WISTAR RATS

The immunosuppressant cyclosporine and the long-acting somatostatin analog SMS 201-995 (octreotide acetate) may have to be given simultaneously in diseases such as pancreatic transplantation. The aim of the study was to evaluate the effects of SMS 201-995 on the pharmacokinetics of cyclosporine, and to assess whether the addition of SMS 201-995 altered some of the cellular immune and toxic (renal, hepatic, glucose tolerance) effects of cyclosporine. Male Wistar rats were treated with cyclosporine 10 mg/kg/day, SMS 201-995 100 micrograms/kg b.i.d., a combination of the two drugs, or the vehicle alone. The addition of SMS 201-995 delayed the peak plasma levels of cyclosporine without affecting the through levels, and did not alter the effects of cyclosporine on the mononuclear cell subsets. This combination caused significant increases in plasma creatinine and hepatic enzymes, suggesting renal and hepatic toxicity, and severe glucose intolerance. If present in humans, the appearance of severe glucose intolerance with combined administration of SMS 201-995 and cyclosporine for pancreatic transplantation could be misinterpreted as rejection and lead to inappropriate interventions.

Cyclosporine plasma levels six hours after oral administration. A useful tool for monitoring therapy.

Clinical evolution and cyclosporine (CsA) monitoring of 65 transplanted patients (55 kidneys, and 10 kidneys and pancreases) treated with CsA were analyzed retrospectively (45 patients) and prospectively (34 patients). Our results showed the following: (1) nephrotoxicity is not uncommon even with low trough plasma levels of CsA; (2) the T6 value of a CsA pharmacokinetic plasma curve (6 hr after oral drug administration) is a valid expression of a full pharmacokinetic study; (3) when T6 was used prospectively as a monitoring tool and dose adjustments made disregarding concomitant serum creatinine levels, the latter decreased when CsA dose adjustments were made to correct toxic (greater than 350 ng/ml) or subtherapeutic (less than 100 ng/ml) T6, P less than 0.01. At present, serum creatinine for all our patients is 180.2 +/- 8 mumol/L, and no patient has needed to be switched to conventional treatment. The validity of trough plasma levels in patients under CsA oral administration once or twice a day seems questionable, and T6 proved to be more useful. Thus nephrotoxicity and CsA undertreatment may be avoided. This new monitoring tool (T6) will allow the utilization of lower doses of CsA and thus contribute to improved long-term graft function.

T-lymphocyte subsets in renal allograft recipients treated with cyclosporine and azathioprine.

Thirty-nine renal allograft recipients were prospectively studied to determine the quantitative effects of different immunosuppression protocols on T-cell subsets (total lymphocytes [T3], helper/inducer [T4] and suppressor/cytotoxic [T8]). Eighteen patients were initially immunosuppressed with only azathioprine and prednisone but required subsequent treatment for rejection by the addition of antithymocyte globulin (ATG) (Upjohn, Kalamazoo, MI) or conversion to cyclosporine. Three of these patients had ATG-resistant rejections and were treated with the monoclonal antibody ORTHO OKT3 (ORTHO Pharmaceuticals, Raritan, NJ). Twenty-one patients were treated only with cyclosporine and prednisone. Plasma levels of cyclosporine, as determined by high-performance liquid chromatography, were kept in the range of 50-100 ng/mL (mean: 78.1 +/- 52.1). One patient had a lymphoma, two patients had failed grafts, and three patients converted their cytomegalovirus titers. The results demonstrate that the immunosuppressive agents, azathioprine, prednisone, and cyclosporine, have an additive effect in depressing the T-lymphocytes and their subsets. In addition, ATG and cyclosporine had a more selective ablation of the T4 subset, resulting in a reversal of the T4/T8 ratios. This depression was independent of the plasma level of cyclosporine. Finally, the pan T-cell monoclonal antibody OKT3 led to severe depletion of all T-cell subsets but resulted in a normal T4/T8 ratio. In conclusion, immunosuppressive agents have a variable effect on T-lymphocytes and their subsets that cannot be adequately characterized by the T4/T8 ratio alone, but which should be quantitatively assessed by examining all subsets.

Renal Interstitial Fibrosis and Vascular Changes

Histologic examinations of kidney biopsy specimens from six patients with relapsing polychondritis (n = 1), Behçet's syndrome (n = 3), and chronic uveitis (n = 2) were performed after four to 36 months of treatment with cyclosporine. Five of the patients had a variable degree of focal interstitial fibrosis and tubular atrophy, with and without minimal interstitial inflammation. Arteriolar hyalinization was noted in four and glomerular sclerosis in two patients. These renal lesions could not be attributed to underlying autoimmune disease or previous drug therapy but were similar to those recently reported in kidney and heart recipients receiving long-term cyclosporine. The initial cyclosporine doses were 15 mg/kg body weight in one patient and 10 mg/kg in the others. The maintenance cyclosporine doses ranged from 2.5 to 7.5 mg/kg with appropriate trough cyclosporine plasma levels (60 to 130 ng/mL). A rough correspondence between the extent of the histologic renal changes and the cumulative cyclosporine was seen, whereas serum creatinine increase or the development of hypertension during treatment did not predict the degree of interstitial fibrosis or the presence of arteriolar changes. Neither did a rapid fall in the serum creatinine level after withdrawal of cyclosporine exclude focal irreversible renal lesions. Since the histopathologic changes found in the kidneys are potentially progressive, we believe that, until more is known, long-term cyclosporine treatment should be reserved for situations where more established immunosuppression has failed to control an autoimmune process threatening the function of vital organs.