Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.     

The effect of long-term intravenous high dose B-complex vitamins with or without folic acid on serum homocysteine in hemodialysis patients

BACKGROUND: Many regimens using different doses of folic acid (FA) alone or with supplementation of B-complex vitamins (BCV) have been tested for the reduction of total homocysteine (tHcy) levels in hemodialysis (HD) patients. BCV are usually administered orally and for a short period. In the present study, we assessed the effect of long-term intravenous (IV) BCV on serum tHCy levels in HD patients, and the effect produced by moderate oral supplementation with FA. METHODS: In a cohort of 37 patients under chronic HD treatment for a mean of 50.2 +/- 46.7 months, serum concentrations of tHcy, folate and vitamin B12 were determined at the end of four sequential periods: (A) three months without any FA supplementation, (B) three months with oral supplementation of 5 mg of FA three times weekly, (C) six months without FA supplementation, and (D) three months without BVC or FA supplementation. From the start of HD treatment and throughout the study until the beginning of period D, patients received a standard IV dose of BCV (B1 250 mg + B6 250 mg + B12 1.5 mg) three times per week, post-dialysis. RESULTS: At the end of period B, mean serum tHcy levels were significantly lower than in periods A and C (13.7 +/- 3.6 micromol/L vs 19.6 +/- 10.8 micromol/L and 21.3 +/- 9.4 micromol/L, respectively, p < 0.001) and mean serum folate levels were significantly higher (20.7 +/- 7.4 ng/mL vs 5.0 +/- 2.8 ng/mL and 4.5 +/- 1.4 ng/mL, respectively, p < 0.01). At the end of period D, mean serum tHcy levels were significantly higher than in all the previons periods (29.3 +/- 13.5 micromol/L, p < 0.001). Twenty-six of the 37 patients (70.2%) had normal (< 15 micromol/L) serum tHcy levels at the end of period B and only one (2.7%) had normal tHcy at the end of period D. Mean serum vitamin B12 levels at the end of periods A, B and C were 100 times the usual normal values. At the end of period D, although significantly lowered (p < 0.001), they remained above the normal range. CONCLUSIONS: Long-term high-dose BCV IV three times a week post-dialysis reduced serum tHcy levels only when combined with oral FA supplementation.     

Parathyroid hormone levels, calcium-channel blockers, and the dyslipidemia of nondiabetic hemodialysis patients

BACKGROUND: Experimental studies have shown that increased levels of parathyroid hormone (PTH) in uremia may cause elevation of intracellular calcium, predisposing to insulin resistance and lipid metabolism abnormalities. Administration of calcium-channel blockers (CCBs) in these models protects against the development of lipid profile abnormalities. This study evaluates the combined effect of intact PTH (iPTH) levels and administration of CCB on the lipid profiles of nondiabetic hemodialysis patients. METHODS: One hundred and eight non-diabetic hemodialysis patients were studied for 6 months. The population was divided into four groups, according to iPTH levels and administration of CCB: (A) iPTH<70 pg/mL, administration of CCB (n=16), (B) iPTH>300 pg/mL without administration of CCB (n=43), (C) iPTH<70 pg/mL without CCB administration (n=19), and (D) iPTH>300 pg/mL with CCB administration (n=30). Serum concentrations of total cholesterol, high-density lipoprotein (HDL), triglycerides, and albumin were measured on a monthly basis. RESULTS: All results are shown as mean SE. Total cholesterol values (in mg/ dL) were for group (A) 186 +/- 4, for group (B) 205 +/- 3, for group (C) 200 +/- 3, and for group (D) 203 +/- 4 [p NS between (C) and (D), p<.05 for all other comparisons]. Triglycerides values (in mg/dL) were for group (A) 171 +/- 9, for group (B) 199 +/- 6, for group (C) 190 +/- 6, and for group (D) 191 +/- 9 (p NS for all comparisons). HDL values (in mg/dL) were for group (A) 43.8 +/- 1, for group (B) 35.8 +/- 1, for group (C) 38.3 +/- 0.7, and for group (D) 37.2 +/- 0.7 mg/dL [p NS between (C) and (D), p<.001 for all other comparisons]. Low-density lipoprotein values (in mg/dL) were for group (A) 107.6 +/- 4.4, for group (B) 149.3 +/- 2.5, for group (C) 131.2 +/- 2.9, and for group (D) 126.8 +/- 4.1 [p NS between (C) and (D), p<.001 for all other comparisons]. Atherogenic index values, calculated as [triglycerides/HDL] ratio, were for group (A) 4.6 +/- 0.04 , for group (B) 6.2 +/- 0.04, for group (C) 4.9 +/- 0.03, and for group (D) 5.9 +/- 0.03 [p NS between (C) and (D), p<.004 for all other comparisons]. CONCLUSION: In nondiabetic hemodialysis patients, lipid profile abnormalities often accompany high levels of iPTH. The decrease in iPTH and/or the administration of CCB are accompanied by significant improvements in the main lipid profiles, including the atherogenic index.     

Conversion from cyclosporine microemulsion to tacrolimus-based immunoprophylaxis improves cholesterol profile in heart transplant recipients with treated but persistent dyslipidemia: the Canadian multicentre randomized trial of tacrolimus vs cyclosporine microemulsion.

BACKGROUND: Tacrolimus improves lipid profile in renal and liver transplant recipients. The impact of conversion from cyclosporine microemulsion (Neoral) to tacrolimus (Prograf) in a large randomized study of stable heart transplant recipients with treated but persistent mild dyslipidemia is reported. METHODS: One hundred twenty-nine long-term (>or=12 months) cyclosporine microemulsion-treated heart transplant recipients with low-density lipoprotein cholesterol >2.5 mmol/liter and/or a total cholesterol/high-density lipoprotein cholesterol ratio >4 were recruited for the study. Complete lipid profile was assessed before (baseline) and after 6 months of treatment with either cyclosporine microemulsion maintenance (n=64) or tacrolimus conversion (n=65). RESULTS: At 6 months, tacrolimus-converted patients exhibited a greater decrease in total cholesterol (from 5.51 +/- 0.16 to 4.88 +/- 1.22 mmol/liter [tacrolimus], vs 5.61 +/- 1.36 to 5.38 +/- 0.87 mmol/liter [cyclosporine]; p = 0.0078). This decrease in cholesterol was caused largely by a decrease in low-density lipoprotein cholesterol (-0.41 +/- 0.54 [tacrolimus] vs -0.13 +/- 0.55 [cyclosporine]; p=0.0018). There were no changes in high-density lipoprotein cholesterol and triglyceride levels, but apolipoprotein B therapy was reduced in tacrolimus-converted vs cyclosporine-maintained patients (p=0.0003). By 6 months, 23.7% of tacrolimus- vs 6.7% of cyclosporine-treated patients met the target lipid levels for high-risk patients (p=0.0094). Conversion from cyclosporine to tacrolimus resulted in decreases in blood urea nitrogen, creatinine, and uric acid without any changes in glucose, HbA(1C), and insulin levels. CONCLUSIONS: Conversion from cyclosporine microemulsion- to tacrolimus-based immunoprophylaxis resulted in decreased cholesterol, apolipoprotein B, urea, creatinine, and uric acid without any clinically evident perturbation of glucose metabolism in stable heart transplant recipients with treated but persistent mild dyslipidemia.     

Comparison of enteric-coated mycophenolate sodium with mycophenolate mofetil in living renal allograft transplantation

OBJECTIVE: Enteric-coated mycophenolate sodium (MPS) has been developed to decrease the GI side effects of mycophenolate mofetil (MMF). We did a retrospective analysis of 112 patients to compare the safety and efficacy of enteric coated MPS vs MMF in living renal transplantation. METHODS: Patients were divided into two groups. Group A who received MPS [Novartis, Basel, Switzerland] [1.08-1.44 g/d] included 53 patients of mean age 33.5 +/- 11.9 yrs, and M:F gender ratio 37:15 with a mean donor age of 43.2 +/- 9.9 years. Group B who received MMF [1.5-2.0 g/d] included 59 subjects of mean age 33.2 +/- 9.9 yrs and M:F gender ratio 57:6, with a mean donor age of 41.4 +/- 10.9 years. All patients received cyclosporine and prednisolone in addition to mycophenolate. Mean follow-up in the two groups was 11.6 +/- 7.0 and 12.6 +/- 8.5 months, respectively. RESULTS: There were 11 (20.7%) rejection episodes in Group A and 12 (20.3%) rejection episodes in Group B (P = NS). Incidence of CMV disease was 9.61% and 10.1%, and of other infections, 88.7% and 74.7% in Groups A and Group B, respectively [P = NS]. The incidence of GI (18.9% & 20.3%) and hematologic toxicities (9.4% & 5.1%) were similar in the groups. Patient and graft survivals in Group A were 91.9% & 86.6%, and in Group B was 91.3% & 91.3%, respectively [P = NS]. CONCLUSION: Mycophenolate sodium is an alternative immunosuppressant to mycophenolate mofetil in kidney transplant recipients with a similar efficacy and safety profile.     

Ionized serum calcium levels during acute renal failure: intermittent hemodialysis vs. Continuous hemodiafiltration

BACKGROUND: Achieving "adequacy of dialysis" includes the maintenance of normal serum ionized calcium concentrations and is an important therapeutic goal in the treatment of acute renal failure (ARF). It is unknown whether this goal is best achieved with intermittent or continuous renal replacement therapy. METHODS: We compared the effects of continuous veno-venous hemodiafiltration (CVVHDF) and intermittent hemodialysis (IHD) on serum ionized calcium concentrations using daily morning blood tests in 88 consecutive intensive care patients of which half were treated with IHD and half with CRRT. RESULTS: Mean patient age was 54 +/- 14 years for IHD and 60 +/- 14 years for CVVHDF (NS). However, patients who received CVVHDF were significantly more critically ill (mean APACHE II scores: 24.4 +/- 5.1 for IHD vs. 29.2 +/- 5.7 for CVVHDF, p < 0.003). Before treatment, the mean ionized calcium concentration was 1.177 +/- 0.03 mmol/l for IHD and 1.172 +/- 0.04 mmol/l for CVVHDF (NS), with abnormal values in 51.6% of IHD patients and in 68% of CVVHDF patients (NS). During treatment, hypocalcemia was significantly more common among CVVHDF patients (24.5% vs. 14.9%; p < 0.011) while hypercalcemia was more frequent during IHD (36.1% vs. 25.6%; p < 0.019). CONCLUSIONS: Abnormal serum ionized calcium concentrations are frequent in ARF patients before and during renal replacement. Once dialytic therapy is applied, CVVHDF is more likely to lower serum calcium concentrations, while IHD is more likely to induce hypercalcemia. Appreciation of these different biochemical effects may assist clinicians in adjusting dialytic therapy in selected patients.     

携带供者抗原的第三方树突状细胞诱导小鼠皮肤移植耐受的研究

目的 了解携带供者抗原的第三方树突状细胞(DC)是否具有与供者源未成熟DC相似的免疫功能.方法 雌性C57BL/6小鼠、BALB/c小鼠和昆明小鼠分别为皮肤移植的供者、受者和第三方.将40只BALB/c小鼠分为对照组、环磷酰胺组、供者源未成熟DC组、第三方未成熟DC组、携带供者抗原第三方DC组,每组8只.后4组大鼠皮肤移植术前4 d用环磷酰胺(200 mg/kg)预处理,对照组同法给予等量等渗盐水.后3组术前2 d用1 ml相应DC悬液(1×107个/ml)预处理,并在术后12 d重复给予1 ml DC悬液(1×107个/ml)1次;前2组于上述2个时相点同法给予等量等渗盐水.记录各组皮片平均成活时间(MST)并于术后5 d对皮片进行组织学观察.结果 与对照组(16.1±3.5)d比较,供者源未成熟DC组和携带供者抗原第三方DC组小鼠移植皮片的MST明显延长,分别为(38.3±7.7)、(34.9±7.7)d(P＜0.01);携带供者抗原第三方DC组与供者源未成熟DC组皮片的MST相近(P＞0.05),但与第三方未成熟DC组(23.7±2.7)d比较,差异有统计学意义(P＜0.05).镜下见携带供者抗原第三方DC组移植皮片结构较清楚、排列有序,与供者源未成熟DC组情况相近.结论 携带供者抗原的第三方DC与供者源未成熟DC,均可在一定程度上建立抗原特异性免疫耐受.     

Bone histology in patients with nephrotic syndrome and normal renal function

BACKGROUND: The prevalence of metabolic bone disease in patients with nephrotic syndrome (NS) at normal level of renal function remains uncertain. METHODS: To address this issue, we studied 30 patients (20 men and 10 women, mean age 27.3 +/- 11.7 years) with NS who had normal renal function (mean creatinine clearance 103 +/- 4 ml/min). We evaluated their serum calcium, phosphorus, alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), vitamin D metabolites, urinary calcium, and skeletal survey. The extent of bone mineralization was analyzed by histomorphometric analysis of iliac crest bone biopsy specimens in all patients. The findings on bone histology were correlated with biochemical parameters. RESULTS: The mean duration of NS was 35.5 +/- 26.9 months, with a protein excretion of 7.3 +/- 3.2 g/24 hr and a serum albumin of 2.2 +/- 0.8 g/dl. Total serum calcium was 7.8 +/- 0.8 mg/dl, whereas ionized calcium was 5.7 +/- 0.7 mg/dl, phosphorus 3.2 +/- 1.2 mg/dl, and alkaline phosphatase 149 +/- 48.6 U/liter. Serum iPTH levels were normal in all except two patients. The mean serum 25-hydroxyvitamin D [25(OH)D] level was 3.9 +/- 1.2 ng/ml (normal 15 to 30 ng/ml), whereas 1,25-dihydroxyvitamin D was 24 +/- 4.7 pg/ml (normal 16 to 65). There was an inverse correlation between serum levels of 25(OH)D and the magnitude of proteinuria (r = -0.42, P < 0.05). The mean 24-hour urinary calcium excretion was 82 +/- 21 mg/day. The skeletal survey was normal in all patients. Bone histology was normal in 33.3% of the patients, whereas 56.7% had isolated osteomalacia (OSM), and 10% had an increased bone resorption in association with defective mineralization. The severity of OSM measured by mineralization lag time correlated linearly with the duration (r = 0.94, P < 0.0001) and the amount (r = 0.97, P < 0.0001) of proteinuria. All patients with NS for more than three years had histological changes. Patients with OSM had lower 25(OH)D and serum albumin as compared with those with normal histology (P < 0.005). Bone mineralization had no significant correlation with serum iPTH, divalent ions, or vitamin D levels. CONCLUSIONS: OSM is a frequent finding in adult patients with NS, even at a normal level of renal function. Its severity correlates with the amount and duration of proteinuria.     

Calcium-enriched bread for treatment of uremic hyperphosphatemia.

OBJECTIVE: To assess phosphate-binding efficacy of a new food product, bread with unusually high calcium content (Ca-bread). DESIGN AND SETTING: A randomized parallel group trial in the university hospital outpatient dialysis unit. PATIENTS: Fifty-three randomly selected uremic patients who met the following inclusion criteria: (1) required maintenance hemodialysis treatment, (2) were not to receive vitamin D throughout the study, (3) were nondiabetic, and (4) were diagnosed with hyperphosphatemia. INTERVENTION: Fifty-three patients were randomized into 2 groups: control group (n = 26), which received calcium acetate as a phosphate binder throughout the study, and Ca-bread group (n = 27), which, after a 2-week washout period, received Ca-bread containing 2.5% of elemental calcium (by weight), which served as a phosphate binder. Bread was made using wheat flour, calcium carbonate, and fermented buttermilk. The amount of elemental calcium used as a phosphate binder was similar in both groups. Observation of both groups lasted 14 weeks. RESULTS: Mean serum phosphate concentration at randomization was 2.11 +/- 0.14 mmol/L in the control group and 2.20 +/- 0.13 mmol/L in the Ca-bread group. Mean serum calcium concentration at randomization was 2.12 +/- 0.21 mmol/L in the control group and 2.14 +/- 0.11 mmol/L in the Ca-bread group. The Ca-bread group patients' predialysis phosphate concentration decreased to a mean of 1.67 +/- 0.18 mmol/L (P <.05), and their mean calcium concentration increased to 2.27 +/- 0.11 mmol/L (P = NS). In the control group, neither value changed significantly from the original readings. After the hemodialysis session, the mean serum calcium concentration in the control group and the Ca-bread group increased by 7.5% and 7.9%, respectively (P = NS). Mean phosphate concentration simultaneously decreased to nearly 1/2 its original predialysis value in both groups. Ca-bread group patients saw a decrease in the mean phosphate concentration (from predialysis to postdialysis values) that was 13.8% greater than that of the control group (P = NS). CONCLUSION: A new form of calcium-containing phosphate binder was developed: Ca-bread with an elemental calcium content of 2.5%. Ca-bread allows for effective amelioration of hyperphosphatemia without inducing hypercalcemia. Furthermore, patient compliance may increase if hyperphosphatemia can be treated by consuming bread with an elevated calcium content.     

Comparison of generic cyclosporine microemulsion versus neoral in de novo renal transplant recipients managed by 2-hour postdose monitoring

INTRODUCTION: The bioequivalence of generic formulations is established by measuring pharmacokinetic parameters in healthy volunteers. Cyclosporine (CsA) absorption and exposure is known to differ between healthy volunteers and transplant recipients. Therefore bioequivalence testing may be inadequate to ensure therapeutic equivalence. We sought to compare the efficacy of generic cyclosporine (ArpimuneME, RPG Life Sciences) versus Sandimmune Neoral in de novo renal transplant recipients. METHODS: A prospective single-center, open-label study enrolled 20 de novo renal transplant patients (group 1: mean age 30.55 +/- 9.81 years, M:F 19:1, mean donor age 43.4 +/- 10.8). All patients received ArpimuneME along with azathioprine and prednisolone. The results were compared with 17 matched controls (group 2: mean age 28.1 +/- 9.5 years, M:F 13:4, mean donor age 47.8 +/- 6.8) who received Neoral and were transplanted during the same period. C(2) levels were monitored by the cloned enzyme donor immunoassay (CEDIA). RESULTS: Patient and graft survivals were 100% and 100% and 100% and 92.8% in groups 1 and 2, respectively (P = NS). Six patients (30%) experienced rejection in group 1 as compared eight patients (47.1%) in group 2. Mean CsA levels (ng/mL) during the first month were 1419.1 +/- 213.6 and 1460.5 +/- 290.7 and at 3 months, 1296.3 +/- 227.8 and 1342.4 +/- 303.4 in the two groups, respectively (P = NS). The mean serum creatinine levels (mg%) in group 1 and group 2 were 1.6 +/- 0.8 and 2.0 +/- 1.4 at discharge and 1.5 +/- 0.4 and 1.5 +/- 0.8 at 6 months, respectively (P = NS). CONCLUSION: Use of a generic microemulsion form of CsA provided safe and effective immunosuppression compared with Sandimmune Neoral when drug monitoring was performed by C(2) levels.     

Relationships among natriuresis, atrial natriuretic peptide and insulin in insulin-dependent diabetes.

Insulin-dependent diabetic patients have a large exchangeable body sodium pool, secondary to sodium retention. The pathogenesis of impaired natriuresis in insulin dependent diabetes remains to be elucidated. The present study examines the role of hyperinsulinemia, impaired atrial natriuretic release, and resistance to atrial natriuretic peptide action in determining sodium retention in normotensive and hypertensive insulin-dependent diabetic patients. Eight insulin-dependent diabetic patients had significantly higher daily sodium excretion rate (147 +/- 16 mmol/day; mean +/- SE) during conventional insulin treatment (daily plasma glucose: 11.6 +/- 1.2 mmol/liter; daily plasma insulin: 27 +/- 3 microU/ml) than during intensified insulin treatment (daily sodium excretion rate: 91 +/- 12, P less than 0.01; daily plasma glucose: 6.8 +/- 0.7, P less than 0.01; daily plasma insulin: 44 +/- 4, P less than 0.01). Daily sodium excretion rate was also significantly lower (107 +/- 13, P less than 0.01) in the same diabetic patients during intensified insulin treatment along with hyperglycemic clamp (daily plasma glucose: 12.8 +/- 0.3, NS; plasma insulin 48 +/- 4, P less than 0.01). Seven control subjects had lower extracellular liquid volume than eight insulin-dependent diabetic patients (11.0 +/- 0.8 l/1.73 m2 vs. 14.8 +/- 0.9, P less than 0.05) and also had baseline plasma atrial natriuretic peptide concentrations (18 +/- 5 pg/ml vs. 37 +/- 4, P less than 0.05). Atrial natriuretic peptide response to saline challenge was blunted in insulin-dependent diabetic patients when saline was administered on the basis of body surface area (90 mmol/1.73 m2.90 min) but not when administered on the basis of extracellular liquid volume (ECV) (8.2 mmol/liter ECV.90 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclosporine C2 monitoring improves renal dysfunction after lung transplantation.

BACKGROUND: Cyclosporine (CyA) toxicity is a potential cause of renal dysfunction, which occurs in 38% of lung transplant (LTx) recipients within 5 years. Reducing CyA to "sub-therapeutic" trough (C0) levels increases the risk of rejection. The 2-hour post-dose concentration (C2) is favored as the best single-point surrogate measure of CyA area under the curve (AUC), which reflects drug exposure. In this investigation we assess the effect of conversion to CyA C2 monitoring on renal dysfunction after LTx. METHODS: Fifteen patients (M:F = 12:3), aged 47 +/- 14 years (range 28 to 62), 3.5 +/- 2.7 (0.2 to 9.0) years post-LTx, with C0 in the therapeutic range (maintenance 100 to 200 microg/liters) (Behring/EMIT immunoassay) and abnormal renal function, were converted from C0 monitoring to C2 monitoring with dose reductions targeting C2 levels of 300 to 600 microg/liter over a 12-month period. RESULTS: CyA dose was reduced from 6.4 +/- 7.3 (1.2 to 27.9) to 3.1 +/- 2.7 (0.8 to 9.0) mg/kg/day (p = 0.04), with a reduction in C2 levels from 799 +/- 341 (299 to 1,466) to 390 +/- 148 (195 to 675) microg/liter (p < 0.001). Improvements in serum creatinine (0.20 +/- 0.07 [0.12 to 0.35] vs 0.16 +/- 0.04 [0.11 to 0.22] mmol/liter [p = 0.005]) were maintained during the study follow-up period of 1 year. Only 1 patient developed acute rejection and group mean forced expiratory volume in 1 second (FEV(1)) remained stable (2.4 +/- 1.0 [1.1 to 4.0] vs 2.4 +/- 1.2 [1.1 to 4.6] liters). CONCLUSIONS: C2 monitoring is a practical method of improving renal dysfunction that allows safe dose reductions of CyA when formal AUC monitoring is not feasible. Extended use of this strategy is associated with long-term benefits.     

Alterations in vitamin D metabolites during treatment of Paget's disease of bone with calcitonin or etidronate

We report serum 25-hydroxyvitamin D (25-OHD), 24,25-dihydroxyvitamin D [24,25-(OH)2D], and 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels in untreated Paget's disease and the effect of treatment with either calcitonin (CT) or etidronate (EHDP) on these levels. In untreated Paget's patients serum 25-OHD (73 +/- 29 nmol/liter, n = 36, mean +/- SD) and 24,25-(OH)2D (0.3-12.9 nmol/liter, median 2.2, n = 36) levels were significantly lower than in age-matched controls (94 +/- 30 nmol/liter, n = 32, p less than 0.005, and 1.3-16.4 nmol/liter, median 5.3; n = 32, p less than 0.001, respectively). Also, the 24,25-(OH)2D levels correlated with the 25-OHD levels in the untreated Paget's patients (r = 0.56, p less than 0.01) and in the controls (r = 0.39, p less than 0.05). The percentage molar ratio of 24,25-(OH)2D to 25-OHD in Paget's patients had a median value of 3.7% (range 0.4-14.3%), which was not significantly different from controls, who had a median value of 5.6% (range 2.2-18%). There was no difference between the 1,25-(OH)2D, and immunoreactive PTH (iPTH) levels of Paget's patients and control subjects. The percentage molar ratio of 1,25-(OH)2D to 25-OHD in untreated Paget's patients (0.157 +/- 0.09%) was not significantly different from controls (0.124 +/- 0.05%) despite lower 25-OHD levels in Paget's patients. There was a significant inverse correlation between the severity of Paget's disease as measured by plasma alkaline phosphatase (AP) levels and 25-OHD levels (r = 0.392, p less than 0.02); however, 24,25-(OH)2D and 1,25-(OH)2D levels were not correlated with AP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium acetate versus calcium carbonate as phosphate binders in hemodialysis patients.

We conducted a randomized unblinded parallel clinical trial to compare the effectiveness, side effects and tolerance between calcium acetate (CA) and calcium carbonate (CC) in 80 stable chronic hemodialysis patients selected on the basis of their acceptable control of serum phosphorus (P) levels with aluminum hydroxide (AH). All patients were dialyzed against the same calcium dialyzate (1.62 mmol/l). The serum analytical tests included: calcium corrected to total protein, P, PTH (intact molecule) and bicarbonate. The study was divided into the following periods: P0: baseline measurements; P1: washout (withdrawal of AH for 15 days); P2: random allocation to CA and CC treatment at doses equivalent to 75 mEq of elemental calcium, stratified according to previous doses of AH (2 months); P3: adjustment of doses until control P (2 months). CA was poorly tolerated in 7 patients and CC in 2 (NS). The changes in serum P levels between P0 and P2 periods were lower in the CA group (1.73 +/- 0.25 vs. 1.80 +/- 0.50 mmol/l; p = 0.26) than in the CC group (1.77 +/- 0.35 vs. 1.93 +/- 0.48 mmol/l; p = 0.03, paired t test). Serum calcium was hardly modified by CA (2.42 +/- 0.20 vs. 2.47 +/- 0.17 mmol/l; NS) while in the CC group, it rose significantly (2.40 +/- 0.12 vs. 2.55 +/- 0.22 mmol/l; p = 0.0004). There were no differences in the control of PTH or bicarbonate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced clinical utility of de novo cyclosporine C2 monitoring after lung transplantation.

BACKGROUND: The 2-hour post-cyclosporine (CyA) dose concentration (C2) is favored as the best single-point correlate of CyA area-under-the-concentration curve. CyA nephrotoxicity is a prominent cause of renal dysfunction that affects 38% of lung transplant (LTx) recipients at 5 years. METHODS: We assessed the utility of de novo C2 monitoring after LTx by comparing 2 sequential groups of 18 bilateral LTx recipients followed with traditional de novo trough CyA (C0) monitoring and de novo C2 monitoring, respectively. Target C0 levels were 450 microg/liter and 250 microg/liter at 1 week and 3 months (3/12). Target C2 levels were 1,200 microg/liter and 800 microg/liter. Groups were matched for anthropometrics and diagnoses. Baseline serum creatinine (Cr) was lower in the C0 group than in the C2 group (65 +/- 17 vs 81 +/- 21 micromol/liter, p = 0.02). RESULTS: At 3 months, survival for both groups was 100%, but the C0 group had a greater increase in Cr from baseline (90 +/- 54% vs 33 +/- 23%, p < 0.001) despite similar CyA dosage (6.6 +/- 3.8 vs 6.5 +/- 2.9 mg/kg/day, p = 0.94). There was no difference in forced expiratory volume in 1 second (% predicted) (71 +/- 16 vs 69 +/- 14, p = 0.68), mean acute vascular rejection score per patient (2.61 +/- 2.12 vs 1.44 +/- 1.72, p = 0.079), mean bronchial rejection score per patient (3.72 +/- 1.81 vs 2.83 +/- 1.58, p = 0.126) or rate of infection (1.85 vs 1.79 events per 100 patient-days). CONCLUSIONS: De novo C2 monitoring, which reduces both the risk of CyA toxicity and the risk of sub-therapeutic dosing, is a safe and effective technique for short-term preservation of renal function after LTx.     

Direct effect of the correction of acidosis on plasma parathyroid hormone concentrations, calcium and phosphate in hemodialysis patients: a prospective study

BACKGROUND: Metabolic acidosis contributes to renal osteodystrophy and together with hyperphosphatemia, hypocalcemia and altered vitamin D metabolism may result in increased levels of intact parathyroid hormone (iPTH) and metastatic calcifications. However, the impact of the correction of metabolic acidosis on iPTH levels and calcium-phosphate metabolism is still controversial. STUDY DESIGN: The effects of the correction of metabolic acidosis on serum concentrations of iPTH, calcium (Ca), phosphate (PO(4)) and alkaline phosphatase were prospectively studied. Twelve uremic patients on maintenance hemodialysis (HD) for 49 months (median; range 6-243 months) with serum bicarbonate levels < or =20 mmol/l were studied before and after 3 months of oral sodium bicarbonate supplementation. Predialysis serum bicarbonate, arterial pH, ionized calcium, plasma sodium, plasma potassium, serum creatinine, hemoglobin, K(t)/V, postdialysis body weight, predialysis systolic and diastolic blood pressure were also evaluated before and after correction. RESULTS: Serum bicarbonate levels and arterial pH increased respectively from 19.3 +/- 0.6 to 24.4 +/- 1.2 mmol/l (p < 0.0001) and 7.34 +/- 0.03 to 7.40 +/- 0.02 (p < 0.001). iPTH levels decreased significantly from 399 +/- 475 to 305 +/- 353 pg/ml (p = 0.026). No changes in total serum Ca, plasma PO(4), serum akaline phosphatase, K(t)/V, serum creatinine, hemoglobin, body weight, predialysis systolic and diastolic blood pressures were observed. iCa decreased significantly. CONCLUSIONS: Our study demonstrates that the correction of metabolic acidosis in chronic HD patients reduces iPTH concentrations in HD patients with secondary hyperparathyroidism possibly by a direct effect on iPTH secretion.     

20-year experience with elderly donors in living renal transplantation

PURPOSE: This study evaluates the impact of living renal donors (LD) aged 60 years and older on graft performance and patient survival in an old-for-young constellation. PATIENTS AND METHODS: We analyzed 144 consecutive LDs between January 1983 and December 2002 (19 patients 60+/125 controls). RESULTS: Mean donor age in the 60+ group was 63.7 (+/- 2.6) years and 43.7 (+/- 9.0) years for the <60 group. Mean recipient age was 42.4 (+/- 15.2) years versus 32.6 (+/- 15.3) years HLA-A, -B, and DR-mismatches were 3.16 (+/- 1.3) for the 60+ group and 3.13 (+/- 1.7) for the controls (P = NS). Rejection episodes in the first year following LD did not differ (53% versus 33%, P =.25). Mean serum creatinine for 65+ versus <65 after 1, 3, and 12 months was 1.91 +/- 1.2 versus 1.48 +/- 0.85 mg/dL (P =.16), 1.82 +/- 0.89 versus 1.29 +/- 0.35 mg/dL (P <.05) and 1.80 +/- 0.31 versus 1.37 +/- 0.38 mg/dL (P <.05) and mean creatinine clearance at 12 months 62 versus 82 mL/min (P =.06). Censored 1-, 3-, and 5-year graft survival was 100% versus 95% (P = NS), 100% versus 93% (P = NS) and 100% versus 83% (P = NS) with no significant difference in the log-rank test for Kaplan Meier. CONCLUSION: No impact of donor age was found for graft survival but function of the 65+ kidneys at 3 and 12 months was reduced. Living renal donors 60+ are acceptable for carefully allocated recipients.     

Moderate versus deep hypothermia for the arterial switch operation--experience with 100 consecutive patients.

OBJECTIVES: To evaluate the impact of moderate versus deep perioperative hypothermia on postoperative morbidity in patients receiving the arterial switch operation (ASO). METHODS: One hundred consecutive patients received the ASO from 9/98 to 4/06 using temperature-corrected full-flow moderate (M>24 degrees C, n=51) or deep hypothermic cardiopulmonary bypass (CPB) (D <20 degrees C, n=49). Complex TGA morphology was present in 33 patients (M: 27.4%, D: 38.8%, n.s.). Median age was 9 days (M) versus 10 days (D) and body weight was 3.5+/-0.7 kg (M) versus 3.6+/-0.9 kg (D) (both p=n.s.). Follow-up was 3.7+/-2.1 years. RESULTS: Lowest perioperative rectal temperature was 25.3+/-1.1 degrees C (M) versus 19.0+/-0.8 degrees C (D), p<0.001. Intraoperative blood transfusion (M: 231+/-47 ml, D: 252+/-112 ml, p=0.04) and postoperative lactate level (M: 3.2+/-1.3 mmol/l, D: 3.8+/-2.4 mmol/l, p=0.02) were lower under moderate hypothermia. One patient (D) suffered myocardial ischemia, required ECMO support and died. All other patients were safely weaned from CPB using dopamine (M: 3.0 microg/kg min, D: 3.4 microg/kg min, n.s.) and dobutamine (M: 5.6 microg/kg min, D: 6.7 microg/kg min, p=0.048). Secondary chest closure was performed in 41% (M) versus 59% (D) (p=0.04). Patients were extubated after 89 h (M) versus 126 h (D) (p=0.03). Under moderate hypothermia ICU stay (M: 8.4+/-4.7 days, D: 12.0+/-13.8 days, p=0.03) and hospital stay (M: 12.8+/-6.8 days, D: 20.7+/-15.5 days, p=0.001) were shorter. Five-year freedom from reoperation was 97.0% for simple and 85.2% for complex TGA with RVOT reconstruction in 4/6 patients. CONCLUSIONS: The ASO under full-flow moderate compared to deep hypothermia was advantageous regarding length of procedure and primary chest closure rate. Moderate hypothermia seemed to be beneficial for pulmonary recovery, length of chest tube drainage treatment and inotropic support. No worse early or long-term effects of moderate hypothermia were found.     

Elective total parathyroidectomy without autotransplant in end-stage renal disease

Ten patients are reported following parathyroidectomy (PTX). In 9 all identifiable parathyroid tissue in the neck was deliberately removed, and in the tenth (operated 14 years ago) the remnant which had been left probably did not function. Their post-operative course resembled that of patients treated conventionally, and their subsequent course was likewise uneventful with disappearance of all symptoms associated with their osteodystrophy. All patients required oral calcium supplementation but none were given vitamin D compounds after the initial period of repletion following surgery. Mean serum values were (before PTX and current) for calcium 2.63 +/- 0.14 and 2.33 +/- 0.08 mmol/liter, P = NS, for phosphorus 1.96 +/- 0.13 and 1.38 +/- 0.09 mmol/liter, P less than 0.01, and for alkaline phosphatase 713 +/- 191 and 101 +/- 14 IU, P less than 0.05. Evidence for residual parathyroid tissue was present in each case; one patient remained mildly hyperparathyroid and several were mildly hypoparathyroid by the IRMA PTH assay. Bone histomorphometry in five subjects post-PTX showed either normal or low turnover. Radiologically, striking remineralization was seen with disappearance of all erosive changes. We suggest that residual areas of parathyroid tissue are stimulated and continue to secrete hormone even when all the discrete glands have been removed. It is recommended that when indicated, and in the absence of aluminum excess, total PTX without autotransplant should be the preferred form of therapy for long-term dialysis patients.     

Effective treatment of hyperhomocysteinemia in heart transplant recipients with and without renal failure.

BACKGROUND: Elevated total plasma homocysteine (tHcy) levels have been associated with vascular disease and higher mortality in patients with coronary artery disease. Graft coronary disease is a major cause of mortality in long-term survivors of heart transplantation, and hyperhomocysteinemia may be one of its causes. The objectives of our study were to establish the effectiveness of a 3 stage homocysteine-lowering algorithm in a group of 84 heart transplant (HTx) patients and to evaluate the effect of renal function on the response to homocysteine-lowering therapy. METHODS: Prospective treatment of 84 Htx patients (64 male; mean age, 48 +/- 13 years) with tHcy > 75th percentile consisted of a 3-stage treatment algorithm: Stage 1, folic acid (FA) 2 mg + vitamin (vit) B(12) 500 mcg daily; Stage 2, addition of vit B(6) 100 mg daily; Stage 3, increase FA to 15 mg daily. Serum creatinine (Cr) and tHcy levels were measured before treatment and 21 +/- 19 weeks after each stage of treatment. RESULTS: All 3 stages of treatment significantly lowered mean tHcy from 22.4 +/- 16.3 (mean +/- SD) micromol/liter to 16.3 +/- 6.7 micromol/liter (p < 0.00001), from 17.6 +/- 6.1 micromol/liter to 15.2 +/- 5.3 micromol/liter (p < 0.0001), and from 16.8 +/- 5.2 micromol/liter to 15.6 +/- 5.3 micromol/liter (p < 0.05), respectively. The average reduction from baseline was 38%. Creatinine levels did not change significantly during the study period. Total plasma homocysteine levels decreased below the 75th percentile in 55% of patients, with Cr levels significantly lower in this group of patients (126 +/- 36 micromol/liter vs 182 +/- 65 micromol/liter, p < 0.00001). However, we found no significant relationship between % change in tHcy and baseline Cr. CONCLUSIONS: In a group of 84 heart transplant patients with tHcy levels >75th percentile, treatment with FA and vit B(6) and B(12) according to a 3-stage algorithm resulted in statistically significant declines in mean tHcy levels. Overall, tHcy levels decreased 38%, with target tHcy levels <75th percentile achieved in 55% of the patients. The % change in tHcy was not related to Cr. Further studies are needed to correlate treatment of hyperhomocysteinemia with clinical endpoints, such as the time to development of transplant vasculopathy and long-term survival, and to define the most appropriate targets for therapy.