Cyclosporine in the treatment of azathioprine-induced red cell aplasia following renal transplantation

Azathioprine, a well-known immunosuppressive agent, is used extensively in renal transplantation. There have been several case reports of pure red cell aplasia induced by this drug following a successful kidney transplant. Previous management of azathioprine-induced red cell aplasia included reduction of azathioprine dose, or treatment with cyclophosphamide. We propose the substitution of cyclosporine for azathioprine, in this clinical setting. Not only does cyclosporine allow recovery of bone marrow function, but it maintains a level of immunosuppression which stabilizes renal function in the post-transplant patient.     

Effect of Pregnancy on Long-Term Kidney Function in Renal Transplant Recipients Treated with Cyclosporine and with Azathioprine

In order to investigate the effect of different immunosuppressive regimens and the time interval between transplantation and pregnancy on long-term outcome, we performed a case-control study in pregnant renal allograft recipients. Eighty-one pregnancies of kidney transplanted recipients were identified [cyclosporine (CYA): n = 40; azathioprine (AZA): n = 41]. Controls were matched with respect to important prognostic factors. Posttransplant follow-up was 91.3 +/- 5 months. Graft and patient survival were similar in both groups and there was no apparent effect of immunosuppression. A total of 28 recipients (33%) delivered within 2 years and 6 (8%) subjects within 1 year after transplantation, but these short transplantation-to-pregnancy intervals had no apparent adverse effect on long-term outcome. In contrast to AZA-treated patients, CYA-treated patients experienced an increase in serum creatinine postpartum (1.15 +/- 0.2 mg/dL vs. 1.61 +/- 0.1 mg/dL; p < 0.05). Whole blood CYA levels decreased transiently during pregnancy from 115.9 +/- 8 ng/mL to 80.7 +/- 7 ng/mL leading to a gradual increase in drug dose from 240 +/- 14 mg/day to 324 +/- 21 mg/day (p < 0.05). Following delivery, there was an increase in CYA concentrations to 173 +/- 5.4 ng/mL, requiring rapid dose tapering to baseline of 246 +/- 15 mg/day. Pregnancies in renal recipients do not affect long-term patient and graft survival, independent of the immunosuppression. No detrimental effect of short transplantation-to-pregnancy intervals on long-term graft function was detected.     

Fracture Risk Associated with Parkinsonism and Anti-Parkinson Drugs

We studied fracture risk associated with parkinsonism (including Parkinson’s disease) and drugs used to treat these conditions in a case-control study. Cases were all subjects with any fracture during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. Exposure was a diagnosis of parkinsonism or use of anticholinergic drugs, levodopa alone or in combination with carbidopa, and/or catechol-O-methyl transferase (COMT) inhibitors, dopamine agonists, or monoamine oxidase B (MAO-B) inhibitors and a number of other confounders. Parkinsonism was associated with a crude odds ratio (OR) of any fracture of 2.2 (95% confidence interval [95% CI] 2.0–2.5) and an adjusted OR of 1.2 (95% CI 1.0–1.4), the risk being higher especially in males younger than 75 years. Levodopa was associated with an increased overall fracture risk and an increased risk of hip fractures in high doses. Dopamine agonists, anticholinergic drugs, and MAO-B inhibitors were not associated with increased fracture risk except for hip fractures at high doses for MAO-B inhibitors and hip fractures at median doses for dopamine agonists. Neuroleptics were associated with increased risk of fractures in almost all skeletal sites and doses. In conclusion, parkinsonism was associated with increased risk of fractures, especially among males younger than 75 years, and the risk was significantly attenuated upon adjustment for confounders. Use of neuroleptics and, to some degree, levodopa was associated with increased risk of fractures.     

The Difference between Hazard and Risk in the Relation between Bone Density and Fracture

The relation between fracture risk and bone density is frequently defined in terms of a relative hazard derived from the Cox proportional hazards model. The relative hazard is a multiplicative factor representing the rise in hazard for each standard deviation fall in bone mineral density, which has a typical value of about 1.5. It is not generally appreciated that this hazard may only be equated with absolute risk when risk is very low; at higher risk and over long periods, it is inappropriate to apply a multiplicative factor to absolute risk because risk has a range of 0-1 and cannot exceed unity. Here, we show how “hazard” can be converted to risk and how misleading the current practice of equating relative hazards with relative risks can be.     

CsA与肾移植患者的低血镁症

为研究环孢素Ａ（ＣｓＡ）降低血镁的作用及其机制，探讨ＣｓＡ诱导的低血镁是否与肾移植后高血压有关，以硫唑嘌呤（Ａｚａ）治疗组为对照组，以ＣｓＡ治疗血压正常组和ＣｓＡ治疗高血压组为研究组，检查了各组血镁浓度和镁排泄分数。结果：Ａｚａ组、ＣｓＡ血压正常组、ＣｓＡ高血压组的血镁浓度分别为０８２±０．０５ｍｍｏｌ／Ｌ、０７５±０．０６ｍｍｏｌ／Ｌ、０６６±００８ｍｍｏｌ／Ｌ，两两比较有显著性差异（Ｐ＜００５）；镁排泄分数分别为：６４％±２３％、７５％±３６％、８８％±３９％，两两比较有显著性差异（Ｐ＜００５）；低镁血症发生率分别为：６７％、５５０％、８１１％，两两比较有显著性差异（Ｐ＜００５）。结果提示：ＣｓＡ能引起肾移植患者血镁显著下降，这种低血镁可能是肾性镁丢失的结果，与肾移植后高血压相关。     

Azathioprine, UV light, and skin cancer in organ transplant patients--do we have an answer?

The remarkable story of transplant medicine currently benefitsmore than 35 000 patients in the EU and US annually [1]. Patientand organ survival time has steadily increased over the years,and according to a recent analysis of 94 934 kidney transplantrecipients, the half-life for kidney transplants has nearlydoubled from 1988 to 1996 [2]. However, with increasing graft and patient survival, the focusof medical disciplines involved in the aftercare of transplantrecipients is shifting towards managing the direct and indirectconsequences of chronic immunosuppression [3,4]. The developmentof cutaneous infections and skin cancers is frequently observedin patients with impaired immunosurveillance, culminating insignificant morbidity and even mortality in organ transplantrecipients (OTR) [5]. A comprehensive study examining the US-Medicare billing claimsof more than 35 765 kidney transplanted patients showed     

Methotrexate mechanism in treatment of rheumatoid arthritis

Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple hypotheses to explain the mechanism of methotrexate efficacy in RA. These include folate antagonism, adenosine signaling, generation of reactive oxygen species (ROS), decrease in adhesion molecules, alteration of cytokine profiles, and polyamine inhibition amongst some others. Currently, adenosine signaling is probably the most widely accepted explanation for the methotrexate mechanism in RA given that methotrexate increases adenosine levels and on engagement of adenosine with its extracellular receptors an intracellular cascade is activated promoting an overall anti-inflammatory state. In addition to these hypotheses, we examine the mechanism of methotrexate in RA from the perspective of its adverse effects and consider some of the newer genetic markers of methotrexate efficacy and toxicity in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear explanation for the pathway and mechanism leading to methotrexate efficacy in RA, there may be a way to formulate more potent therapies with fewer side effects.     

Controlled Trial of Azathioprine and Cyclosporin to Prevent Anti-LHA Antibodies due to Third-party Transfusion

The beneficial effect of elective transfusion on renal allograftsurvival must be weighed against the risks of sensitisation.We report a randomised controlled trial in which patients inend-stage renal failure who were non parous and not previouslytransplanted or transfused, were entered in a transfusion protocolduring which one group received no drugs (controls), one receivedazathio prine, and one received cyclosporin. Each group wasgiven three identical transfusions of leucocyte-enriched freshblood at 2–3 week intervals. The transfused blood wasof known HLA type and donor/recipient pairs were completelymismatched. Sensitisation rates were assessed by T and B cellcross-matches between donor and recipi ents and by the screeningof all sera against lymphocytes from 40 random donors. Fifty-one patients have completed the protocol, 20 in the controlgroup, 12 in the azathioprine group, and 19 in the cyclosporingroup. The sensitisation rate in the control group was 30%,occasionally of high titre, and persistent. In the azathioprinegroup, 25% developed anti-HLA antibodies and reactivity wasof high titre and was broadly specific. Sensitisation in thecyclosporin group was 10%, was narrowly specific, reacting withonly 10% of a panel, and was transient. There was no difference in graft survival between the groups. We conclude thatcyclosporin therapy concurrent with third-party transfusionreduces the incidence, titre, and duration of sensitisation.     

Proton Pump Inhibitors, Histamine H2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture

We studied the effect of proton pump inhibitors, histamine H₂ receptor antagonists, and other types of antacid drugs on fracture risk. All cases were subjects with any fracture sustained during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of proton pump inhibitors, histamine H₂ antagonists, and other antacid drugs. Adjustments were made for several confounders, including diagnosis of an ulcer, nonsteroidal anti-inflammatory drug use, use of histamine H₁ antagonists, stomach resection, previous fracture, and use of corticosteroids. The effect of dose was examined by stratifying for cumulated dose (defined daily dose). Use of proton pump inhibitors was associated with an increase in fracture risk for use within the last year [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.12–1.43 for overall fracture risk; OR = 1.45, 95% CI 1.28–1.65 for hip fractures; and OR = 1.60, 95% CI 1.25–2.04 for spine fractures). Histamine H₂ antagonists were associated with a decreased fracture risk if they had been used within the last year (OR = 0.88, 95% CI 0.82–0.95 for any fracture, OR = 0.69, 95% CI 0.57–0.84 for hip fractures). Other antacids were not associated with overall fracture risk but were associated with hip and spine fractures. Proton pump inhibitors appeared to be associated with a limited increase in fracture risk, in contrast to histamine H ₂ antagonists, which seemed to be associated with a small decrease in fracture risk. In all cases, the changes in risk estimates were small and the clinical significance was limited.     

Monitoring of TPMT in Heart Transplant Recipients under Immunosuppressive Therapy with Azathioprine

Abstract: Azathioprine (AZA) is routinely used in double and triple immunosuppressive therapy after cardiac transplantation. In some cases it causes severe myelosuppres–sion. The interindividual differences in AZA toxicity is probably due to differences in the drug metabolism. Thi–opurine methyltransferase (TPMT) is thought to be the most important enzyme in the catabolism of AZA. A deficiency in this enzyme will presumably increase the availability of 6–mercaptopurine for the anabolic pathway thereby leading to increased cytotoxicity. A 65–year–old male underwent heart transplantation at our institution with an uncomplicated course. Immunosuppression consisted of cyclosporine, prednisolone, and AZA. Several weeks after the administration of AZA, the patient developed severe leukopenia. TPMT activity was then measured in this patient and found to be below the detection limit. Subsequently the patient died from multiorgan failure due to septicaemia. As a result of this experience, we started to screen all patients for TPMT deficiency. In 58 healthy controls, the mean activity was found to be 11. 8 nmol/h/ml of red blood cells (RBC) while in 13 patients on our waiting list, the mean activity was found to be 11. 97 nmol/h/ml of RBC. In 15 patients after heart transplantation and azathioprine treatment, the mean activity was found to be 17. 2 nmol/h/ml of RBC. We suggest screening for TPMT activity in transplant patients with leukopenia under AZA therapy. If TPMT deficiency is present, the AZA dosage should be adjusted or alternative immunosuppressive regimens should be considered.     

Cyclosporine A versus cyclosporine G: a comparative study of survival,hepatotoxicity, nephrotoxicity,and splenic atrophy in BALB/c mice

Our group has previously shown that cyclosporine A (CSA) but not cyclosporine G (CSG) causes splenic atrophy in a BALB/c mouse model. We have now extended our studies to observations of the effect of the two drugs on other parenchymal organs and on the nervous system. Groups of mice (N=30) were given 150 mg/kg per day of either CSA or CSG and were compared to two control groups. Absorption of the drugs was similar in the two groups, although CSG blood levels were slightly higher. Animals treated with CSA, but not CSG, lost up to 50% of body weight over a 3-week period. Overall mortality was much higher in the CSA group. Blood urea levels were significantly higher in both treatment groups than in controls and were significantly higher in the CSA than in the CSG group. CSA-treated animals showed marked histological changes in their kidneys, the most prominent of which was proximal tubular vacuolation. Both drugs showed some hepatotoxicity, both histologically and biochemically; the histological changes were more marked in the CSA group. There was no pancreatic toxicity at this dose, either histologically or in terms of blood-sugar concentrations. Mice treated with CSA, but not with CSG, showed marked behavioral changes, including hyperactivity and irritability. The most intriguing observation was the effect of CSA, but not CSG, on the spleen. There was atrophy of lymphoid tissue in both the B and the T cell areas, although the most prominent change was in the periarterial lymphatic sheaths. These changes may be of significance in the longterm maintenance of immunosuppression and graft acceptance. CSG appears, therefore, to be significantly less toxic overall in this model than CSA and warrants further study, both experimentally and clinically.     

骨折患者发生ARDS的危险因素分析

目的 :探讨无其他脏器严重损伤的骨折患者并发ARDS的特点、治疗及结果。方法 :分析 5例并发ARDS的骨折患者的骨折部位、治疗、并发症、转归、死因。采用的ARDS诊断标准为 :①呼吸困难甚至窘迫 ;②至少包括Qs/Qt≥ 2 0 % ,通气 -灌注指数 <2 5 0中的一项 ;③机械通气≥ 2 4hX线胸片表现为肺纹理增多 ,边缘模糊 ,斑片状或大片阴影等间质性肺泡性改变 ;④肺毛细血管压或中心静脉压 <2 0mmHg。⑤胸廓顺应性 <5 0mL /cmH2 O ;⑥X线胸片表现为肺纹理增多 ,边缘模糊 ,斑片状或大片阴影等间质性肺泡性改变。结果 :5例并发ARDS的骨折患者中 ,4例伤后出现休克 ,1例出现感染。 3例因MOF死亡。结论 :休克可能是骨折并发ARDS的最危险因素。     

环孢素与激素在大鼠小肠移植中的联合应用

报道了应用环孢素Ａ、环孢素Ａ＋强的松及不用免疫抑制剂的条件下小肠移植的大鼠存活、排斥反应情况。结果提示应用环孢素Ａ的受体较对照组大鼠存活时间明显延长；环孢素Ａ强的松联合应用较单用环孢素Ａ的最长存活时间、平均存活时间明显延长。     

Family History and Risk of Osteoporotic Fracture

The importance of family history of fractures as a risk factor for fractures is unclear. The aim of this study was to test the hypothesis that family history of fracture increased a woman's risk of hip, wrist and other osteoporotic fracture and determine whether the influence of family history is independent of low bone density. We tested this hypothesis in a prospective study of 9704 Caucasian women, age 65 years or older, by assessing family history and bone density of the radius and calcaneus at baseline; 7963 women had femoral bone density measurements two years later. Fractures occurring during an average of 7.1 years of follow-up since baseline and 5.2 years since the second examination were confirmed by radiographic report. After adjusting for age, risk of hip fracture was increased in those with a maternal (1.48; 95% CI = 1.03–2.11); sister's (1.83; 1.20–2.80) or brother's history of hip fracture (2.26; 1.16–4.42). Risk of wrist fracture was increased by maternal (1.52; 1.10–2.11) and paternal (2.41; 1.14–5.07) history of wrist fracture. Adjustment for bone density did not consistently and substantially affect the strength of the associations. Family history of hip fracture was not associated with an increased risk of wrist fracture and family history of wrist fracture did not increase the risk of hip fracture. We conclude that family history is an important risk factor for fracture that may act, at least in part, through means besides bone density. Furthermore, the effect of family history is not a general but site-specific predisposition to fracture. Received: 12 September 1997 / Revised: 6 February 1998     

Reduced Fracture Risk in Users of Thiazide Diuretics

Thiazide diuretics (TD) reduce renal calcium excretion and may increase bone mineral density. A reduced fracture risk has been reported in some but not all studies. The aim of this study was to assess fracture risk in users of TD. The study design was nationwide population-based pharmacoepidemiological case-control study with fracture in year 2000 as outcome and use of TD during the previous 5 years as the exposure variable. Individual use of TD was derived from the Danish National Pharmacological Database and related to fracture data from the National Hospital Discharge Register. These data were combined with information on use of other drugs, social status, working status, income, educational status, contacts with general practitioners and practicing specialists, and comorbidity. A total of 64,699 patients (age = 40 years) who sustained a fracture during the year 2000 were compared to 194,111 age- and gender-matched controls. After adjustment for potential confounders, current use of TD was associated with a 10% (95% confidence interval [CI], 7% to 12%) reduced risk of any fracture and a 17% (95% CI 11% to 23%) reduced risk of forearm fractures. In former TD users, the risk reduction was slightly less pronounced. Similar results were found in men and women, and in subjects younger or 65 years of age. Dose-effect analysis revealed a decreased risk of any fracture and fractures at the forearm and hip with an increased number of redeemed defined daily dosages (DDDs) of TD. Therefore, use of more than 2000 DDD was associated with a 19% (95% CI 10% to 27%) decreased hip fracture risk. We conclude that use of TD is associated with a significantly reduced fracture risk.     

Cyclosporine and Therapeutic Plasma Exchange in Treatment of Progressive Autoimmune Diseases

Abstract: Despite treatment with intensive immunosup-pressive drug regimens, the prognosis of patients suffering from severe progressive autoimmune diseases like systemic lupus erythematosus (SLE), nephrotic syndrome (NS), and Behqet's disease is poor. Side effects (infections and malignant tumors) often occur. In the present trial, 35 patients suffering from autoimmune diseases (SLE, n = 21; NS, n = 10; and Behqet's disease, n = 4) were treated for 3.7 ± 2.0 years with 2.5 ± 0.6 mg cyclosporine/kg body weightlday in addition to corticosteroids alone or in combination with azathioprine and/or cyclophosphamide. In active stages of the diseases with extremely high concentrations of anti-ds-DNA-antibodies, antinuclear antibodies, circulating immunocomplexes, and reduced complement concentrations, therapeutic plasma exchange (TPE) has been applied. Compared with previous treatment mo dalities, significantly (p < 0.05) more effective and rapid reductions of the antibodies were reached. Clinical disorders improved within 1–6 weeks. All patients reported increased performance and a better quality of life. After 1–12 months, the previously required doses of immuno-suppressive drugs and the frequency of TPE could be reduced by 40–100%. After 13.4 ± 11.8 months in 17 of 35 patients (8 with SLE, 5 with NS, 4 with Behqet's disease), cyclosporine was established as the monotherapy. No severe side effects were registered. In treating active stages of severe progressive autoimmune diseases and forms with persistent high antibody levels, the addition of TPE to conventional therapy was very effective, as observed in both clinical and laboratory parameters.     

Selective Serotonin Reuptake Inhibitors and Other Antidepressants and Risk of Fracture

Our aim was to study fracture risk in users of various antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and the group of other antidepressants including monoamine oxidase B inhibitors and drugs with effect on the norepinephrine system) and its relationship with effects on inhibition of the cholinergic and serotonin transporter system. We conducted a case-control study with 124,655 fracture cases and 373,962 age- and gender-matched controls. The exposure was use of antidepressants and a number of confounders. Among the tricyclic antidepressants, amitriptyline and clomipramine were associated with a dose-dependent increase in fracture risk, while imipramine and nortriptyline were not. Amityriptyline was associated with an increased risk of fractures at low doses, while the other tricyclic antidepressants were not. Among the selective serotonin reuptake inhibitors, citalopram, fluoxetine, and sertraline were associated with a dose-dependent increase in fracture risk, while the increase was borderline statistically insignificant for paroxetine. The group of other antidepressants was not associated with fracture risk. The increase in fracture risk was significantly associated with the pharmacodynamic effect on the serotonin transporter system but not on other signaling systems. The effect of antidepressants on the risk of fractures may be linked to their effect on the serotonin transporter system. While selective serotonin receptor uptake inhibitors were associated with an increased fracture risk, tricyclic antidepressants and the group of other antidepressants were not systematically associated with fracture risk.     

A Population-Based Study of Fracture Incidence in Southern Tasmania: Lifetime Fracture Risk and Evidence for Geographic Variations within the Same Country

Symptomatic fractures are a significant problem in terms of both morbidity and financial cost. Marked variation in both total and site-specific fracture incidence has been documented internationally but there is limited within-country data. This prospective population-based study documented the incidence of all symptomatic fractures occurring from July 1, 1997 to June 30, 1999 in adults ≥50 years of age resident in Southern Tasmania (total population ≥50 years: 64 688). Fractures were ascertained by reviewing reports from all the radiology providers within the area. There were 701 fractures in men and 1309 fractures in women. The corresponding fracture incidence in men and women was 1248 and 1916 per 100 000 person-years, respectively. Residual lifetime fracture risk in a person aged 50 years was 27% for men and 44% for women with fractures other than hip fractures constituting the majority of symptomatic fracture events. These fracture risk estimates remained remarkably constant with increasing age. In comparison to Geelong, there were significantly lower hip fracture rates (males: RR 0.59, 95% CI 0.45–0.76; females: RR 0.61, 95% CI 0.53–0.71) but significantly higher distal forearm fractures (males: RR 1.87, 95% CI 1.10–3.78; females: RR 1.31, 95% CI 1.11–1.55) and total fractures in men (RR 1.31, 95% CI 1.17–1.46) but not women (RR 1.05, 95% CI 0.98–1.13). In contrast, Southern Tasmania had lower age-standardized rates of all fractures compared with Dubbo (RR 0.28–0.79). In conclusion, this study provides compelling evidence that fracture incidence varies between different geographic sites within the same country, which has important implications for health planning. In addition, the combination of high residual fracture risk and short life expectancy in elderly subjects suggests fracture prevention will be most cost-effective in later life. Received: 27 April 2000 / Accepted: 16 August 2000     

Cyclosporine reduces basolateral,but not apical,nitric oxide secretion in medullary thick ascending limb cells

Abstract Cyclosporine (CsA) reduces nitric oxide (NO) production in medullary thick ascending limb (mTAL) cells. We postulated that CsA affected NO secretion in a vectorial manner in polarized renal epithelial cells. The experiments were performed in a model of mTAL sub‐cultured cells. The expression of iNOS in mTAL cells was confirmed by RT‐PCR. The cells were grown on a non‐permeable filter. Nitrite was measured by the modified Griess method. Transepithelial resistance was measured to ensure the integrity of the tight junction. CsA (100 ng/ml) reduced NO production by 22% in mTAL cells. The inhibitory effect was limited to the basolateral side (control: 165 ± 11; plus CsA: 93 ± 17 nM/10⁶ cells, P < 0.001) without affecting apical NO secretion. The transepithelial resistance through the epithelial monolayer remained unchanged in CsA‐treated cells. CsA reduced basolateral NO secretion without affecting apical secretion. The results suggest that CsA might affect intra‐renal hemodynamics at the peritubular level.