Long-term renal function in heart transplant recipients receiving cyclosporine therapy

BACKGROUND: Immunosuppression with cyclosporine has improved allograft function and reduced both morbidity and mortality in organ transplantation. However, cyclosporine-induced nephrotoxicity still is a concern. The purpose of our study was to evaluate the effects of cyclosporine on renal function in orthotopic heart transplant recipients. METHODS: Thirty-nine patients who received transplants from 1985 to 1991 and had at least three yearly glomerular filtration rate measurements posttransplantation by 125I-iothalamate clearance method were included in the study. In addition, serum creatinine (before and after transplantation) and cyclosporine doses were analyzed. RESULTS: Maintenance immunosuppression at 1 year consisted of prednisone (0.1 mg/kg/day), azathioprine (2 mg/kg/day), and cyclosporine (12-hour trough level 100 to 150 ng/ml by fluorescence polarization immunoassay). The mean serum creatinine at 1 year was significantly higher than the mean pretransplantation serum creatinine (1.51 +/- 0.32 versus 1.28 +/- 0.38, p < 0.05) and stabilized after the first year. The mean glomerular filtration rate by 125I-iothalamate clearance method was 70.6 +/- 20.3 ml/min/1.73 m2 (range 32 to 105) at 1 year and remained relatively stable during the follow-up period of up to 7 years. Creatinine clearance calculated by the Cockcroft and Gault formula overestimated the true glomerular filtration rate after the third year. The mean cyclosporine dosage was significantly lower after the first-year dose of 3.9 +/- 1.8 mg/kg/day (p < 0.05). Three patients in 39 started hemodialysis at 5, 7, and 10 years after transplantation. CONCLUSION: Our data indicate that the adequacy of renal function is preserved with long-term cyclosporine therapy in heart transplant recipients.     

Accuracy of estimated creatinine clearance in obese patients with stable renal function in the intensive care unit

We compared agreement between creatinine clearance values in obese, critically ill patients calculated using three common empirically derived formulas and modifications thereof, with creatinine clearance obtained by conventional 24-hour urine collection. We selected the charts of 22 patients in intensive care units (86% medical, 14% surgical) according to the following criteria: actual body weight greater than 150% of ideal body weight; serum creatinine variation of less than 15% from the day of starting 24-hour urine collection to the day before or after the collection; presence of a urinary bladder catheter; no history of renal dialysis; and clinical indication for renal function assessment. Mean measured 24-hour urinary creatinine clearance for all patients was 72 +/- 64 ml/minute (range 8-248 ml/min). The method of estimating creatinine clearance that showed the least mean bias was the equation of Salazar and Corcoran using a corrected serum creatinine concentration (mean bias -2 ml/min); however, the corresponding 95% confidence intervals were wide (-133-129 ml/min). The narrowest range of 95% confidence intervals were seen with Jelliffe's equation (mean bias 25 ml/min, 95% confidence intervals -41-90 ml/min). In this sample, estimated creatinine clearances did not agree acceptably with measured values. Despite low mean bias values, none of the empirically derived equations that we studied had clinically acceptable 95% confidence intervals. We recommend using the 24-hour urine collection method when assessing creatinine clearance in obese, critically ill patients.     

Converting-enzyme inhibitor versus calcium antagonist in cyclosporine-treated renal transplants

The influence of antihypertensive treatment on the long-term evolution of arterial pressure and renal function was studied in a prospective controlled trial conducted in renal transplant recipients treated by cyclosporine. Within six months after transplantation, patients were randomly allocated to treatment by the angiotensin-converting enzyme inhibitor, lisinopril (ACEI, alone or associated with frusemide; N = 14), or the calcium antagonist, nifedipine (CA, alone or associated with atenolol; N = 11). Glomerular filtration rate (TcDTPA clearance) and effective renal plasma flow (hippuran clearance) as well as 24-hour urinary excretion of electrolytes and albumin were estimated at about 1 and 2.5 years of follow-up. Before initiation of antihypertensive therapy, the two groups were similar with regards to mean arterial pressure (119 +/- 2 vs. 120 +/- 4 mm Hg), effective renal plasma flow (285 +/- 26 vs. 248 +/- 33 ml/min/1.73 m2) and glomerular filtration rate (59 +/- 4 vs. 61 +/- 8 ml/min/1.73 m2 in the ACEI and CA groups, respectively). Both ACEI and CA treatments were associated with no change in renal function, a similar change in mean arterial pressure (ACEI -18 +/- 3; CA -13 +/- 5 mm Hg) and identical trough blood levels of cyclosporine. Urinary albumin excretion did not change significantly in any groups. Of interest, only in the ACEI group did filtration fraction significantly decrease (from 0.22 +/- 0.01% to 0.19 +/- 0.01% at final studies). These results indicate that in cyclosporine-treated transplant recipients, a satisfactory control of hypertension is obtained by chronic ACEI, which is as effective on arterial pressure as a combination of CA and atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Can two-, four- or eight-hour urine collections after voluntary voiding be used instead of twenty-four-hour collections for the estimation of creatinine clearance in healthy subjects?

The accuracy of creatinine clearance estimations obtained from 4-hour (16:00-20:00, 20:00-24:00, 08:00-12:00, 12:00-16:00) and 8-hour (16:00-24:00, 24:00-08:00 and 08:00-16:00) urine collections and the Cockcroft Gault formula compared with the standard 24-hour collection, as well as the cyclical variation in creatinine excretion were studied in a group of 22 healthy subjects (Serum creatinine < 1.5 mg/dl, Blood Urea Nitrogen < 50 mg/dl) after voluntary voiding. The mean 4-hour and 8-hour creatinine clearances were not significantly different from the 24-hour values. Clearance values from 8-hour collections between 24:00-08:00 and 16:00-24:00 were found to be the most accurate and gave the best correlations. Furthermore only the mean absolute percentage deviations of the 8-hour from the 24-hour clearance values were significantly less than 20%. Significant cyclical variations in creatinine clearance over 24 hours were not observed. Time intervals between 23:00-07:00 and 07:00-09:00 were chosen for the comparisons between 8-hour, 2-hour, Cockcroft Gault creatinine clearance estimations and the 24-hour values in 21 healthy subjects. The mean 2-hour and 8-hour creatinine clearances were not significantly different from the 24-hour values. However, once again only the 8-hour clearance values differed by less than 20% from the 24-hour values and they were more accurate and better correlated than the 2-hour values. As expected, in both groups of subjects, the percentage of clearance values that deviated by more than 20% from the 24-hour values decreased as the length of the collection times increased. The Cockcroft Gault formula in both groups of volunteers gave less accurate clearance estimations, smaller correlation coefficients (not statistically significant in Group I subjects) and percentage deviations from the 24-hour values greater than 20%. Undetected early stage renal insufficiency in three volunteers and the use of actual instead of normalized Scr values may have been the cause of these poor clearance estimations. In healthy subjects (Scr < 1.5 mg/dl) 24-hour creatinine clearance may be estimated from an 8-hour urine collection with voluntary voiding if a 20% deviation from the 24-hour value is considered clinically acceptable.     

Hyperlipidaemia in renal transplant patients

OBJECTIVES: The aim of study was to assess the prevalence and severity of hyperlipidaemia in renal transplant patients in a Nordic country. DESIGN: Multicentre, cross-sectional study. SETTING: Outpatients and ward inpatients registered from 23 hospitals covering all regions of the country. SUBJECTS: Renal transplant patients with a functioning graft were registered: 406 patients in all; that is, 43% of the national renal transplant population. All patients used prednisolone, 71% used cyclosporine, either with (51%) or without (20%) azathioprine. Total cholesterol values from general population were obtained from a national survey. MAIN OUTCOME MEASURES: Blood lipids and their relation to clinical parameters. RESULTS: Total cholesterol was significantly higher in transplant patients than in the general population for both genders and all age groups (P < 0.01). Female patients had higher total cholesterol (mean +/- SD: 7.49 +/- 1.61 mmol L(-1)) than males (7.01 +/- 1.55 mmol L(-1); P < 0.001), and also higher HDL cholesterol (1.55 +/- 0.43 vs. males: 1.32 +/- 0.46 mmol L(-1); P < 0.001). Triglycerides were equally elevated in both genders, and 33% had values above 2.2 mmol L(-1). Reduced creatinine clearance, a high body-mass index, female gender, hypertension, and coronary artery disease were independently associated with higher total cholesterol. Beta blockers were associated with lower HDL cholesterol and higher triglycerides, and diuretics with higher triglycerides. Blood lipid levels were not associated with cyclosporine immunosuppression. CONCLUSION: Hyperlipidaemia is prevalent after renal transplantation, and is associated with impaired graft function, hypertension, and with the use of beta blockers and diuretics, but not with the use of cyclosporine.     

Breakdown of blood pressure and body fluid homeostasis in heart transplant recipients

OBJECTIVES: This study was designed to investigate disturbances in arterial blood pressure and body fluid homeostasis in stable heart transplant recipients. BACKGROUND: Hypertension and fluid retention frequently complicate heart transplantation. METHODS: Blood pressure, renal and endocrine responses to acute volume expansion were compared in 10 heart transplant recipients (57 +/- 9 years old [mean +/- SD]) 20 +/- 5 months after transplantation, 6 liver transplant recipients receiving similar doses of cyclosporine (cyclosporine control group) and 7 normal volunteers (normal control subjects). After 3 days of a constant diet containing 87 mEq/24 h of sodium, 0.154 mol/liter saline was infused at 8 ml/kg per h for 4 h. Blood pressure and plasma vasopressin, angiotensin II, aldosterone, atrial natiuretic peptide and renin activity levels were determined before and at 30, 60, 120 and 240 min during the infusion. Urine was collected at 2 and 4 h. Blood pressure, fluid balance hormones and renal function were monitored for 48 h after the infusion. RESULTS: Blood pressure did not change in the two control groups but increased in the heart transplant recipients (+15 +/- 8/8 +/- 5 mm Hg) and remained elevated for 48 h (p < or = 0.05). Urine flow and urinary sodium excretion increased abruptly in the control groups sufficient to account for elimination of 86 +/- 9% of the sodium load by 48 h; the increases were blunted (p < or = 0.05) and delayed in the heart transplant recipients, resulting in elimination of only 51 +/- 13% of the sodium load. Saline infusion suppressed vasopressin, renin activity, angiotensin II and aldosterone in the two control groups (p < or = 0.05) but not in the heart transplant recipients. Heart transplant recipients had elevated atrial natriuretic peptide levels at baseline (p < or = 0.05), but relative increases during the infusion were similar to those in both control groups. CONCLUSIONS: Blood pressure in heart transplant recipients is salt sensitive. These patients have a blunted diuretic and natriuretic response to volume expansion that may be mediated by a failure to reflexly suppress fluid regulatory hormones. These defects in blood pressure and fluid homeostasis were not seen in liver transplant recipients receiving cyclosporine and therefore cannot be attributed to cyclosporine alone. Abnormal cardiorenal neuroendocrine reflexes, secondary to cardiac denervation, may contribute to salt-sensitive hypertension and fluid retention in heart transplant recipients.     

CD4 lymphocytopenia as a risk factor for skin cancers in renal transplant recipients

BACKGROUND: Renal transplant recipients are at increased risk of developing skin cancer. It remains difficult to establish the actual influence of overimmunosuppression in the development of skin cancers. We investigated whether lymphocyte subset count may predict the risk of developing skin cancer in long-term renal transplant recipients. METHODS: One hundred fifty long-term renal transplant recipients were followed for a mean period of 26 months. Each patient was examined at least annually by a dermatologist. Lymphocyte subsets were measured annually. RESULTS: Fifteen patients exhibited skin cancers. Patients with and without skin cancer did not differ in age, gender, transplant duration, hemodialysis duration before transplantation, immunosuppressive regimen, and serum creatinine concentration. CD4 cell counts were significantly lower in patients with skin cancers (330+/-179/mm3 vs. 503+/-338/mm3; P<0.01), whereas total lymphocyte and CD8 and CD19 cell counts were similar between the two groups. CONCLUSIONS: CD4 cell depletion is associated with skin cancer in long-term renal transplant recipients.     

Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy

BACKGROUND: Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. PATIENTS AND METHODS: Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. RESULTS: At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. CONCLUSIONS: These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.     

Low dose angiotensin converting enzyme inhibition and glomerular permselectivity in renal transplant recipients

In this study, we determined the fractional clearance of neutral polydisperse dextrans (theta D) and monodisperse dextran sulfate (theta DS) to describe glomerular size and charge selectivity in 25 renal transplant recipients with proteinuria. Thirteen were treated with low dose lisinopril for six months (group 1) and 12 patients without ACE inhibitor therapy formed group 2. Mean arterial blood pressure was stable (group 1, 112 +/- 4; group 2, 109 +/- 2 mm Hg at baseline and after 6 months) whereas creatinine clearance, glomerular filtration rate and renal plasma flow decreased nonsignificantly but were comparable at any time. Lisinopril treatment lowered filtration fraction (22 +/- 2 vs. 19 +/- 2%, P = 0.07) whereas no change was seen in group 2 (20 +/- 2%). The fractional protein excretion (mg urinary protein per day/ml creatinine clearance per day) was stable in group 1, but significantly increased in group 2. The same pattern was found for theta D larger than 56 A. theta DS was stable and consistently elevated in both groups at any time. We conclude that low dose ACE inhibitor treatment in proteinuric renal transplant recipients stabilizes glomerular size selectivity independently of its systemic hemodynamic effects.     

Diagnosis of thoracic outlet syndrome in the emergency department

Gadodiamide at a dose of 0.1 mmol/kg was administered intravenously to 10 renal transplanted patients with stable, impaired, or slowly deteriorating renal function (serum creatinine 194-362 mumol/l). The patients were referred for contrast medium enhanced magnetic resonance imaging to rule out possible graft circulation abnormalities. The excretion of gadodiamide in urine was prolonged as compared with healthy controls. After 120 h 92% of the injected dose was excreted in urine and only 0.4% in faeces. The plasma clearance of gadodiamide was 28.6 +/- (SD) 5.5 ml/min (n = 10), and the renal clearance (0-72 h) was 26.3 ml/min. The renal clearance of 125I-iothalamate for the same time period was 27.9 +/- 5.3 ml/min. Thus, gadodiamide is eliminated by glomerular filtration also in renal transplant patients with moderately to severe impaired renal function, and gadodiamide clearance may serve as an alternative marker for the determination of the glomerular filtration rate. Serum values of creatinine and beta(2)-microglobulin and creatinine clearance were unchanged by gadodiamide and neither was the urinary enzyme excretion significantly changed. These results suggest that the renal tolerance to gadodiamide is good also in renal transplant patients with impaired renal function.     

Methylprednisolone and cortisol metabolism during the early post-renal transplant period

Despite the widespread use of methylprednisolone and the well-appreciated effects of this drug on HPA suppression, little data is available which describes individual patient exposure to both methylprednisolone and cortisol following renal allograft placement. The clinical utilization of methylprednisolone during the early post-transplant period is based upon standardized dosing protocols that do not consider factors which may influence the pharmacokinetics of this drug during the post-transplant period. Therefore, this study was designed to examine the pharmacokinetics of methylprednisolone (mean dose: 28 mg) and cortisol pharmacodynamics in 9 renal transplant recipients (4 females; 5 males) who were studied during the early post-transplant period (5 to 12 days after surgery). All patients (mean serum creatinine: 1.4 +/- 0.3 mg/dl) had serial blood samples collected over a 12- to 24-hour period (depending upon the dosing schedule) which were analyzed concurrently for methylprednisolone and cortisol. A three-fold variation in drug clearance ranging from 174 to 638 ml/h/kg with a range in the volume of distribution of 0.83 to 2.24 l/kg and resultant half-lives ranging from 1.20 to 3.02 hours was noted. The cortisol response was quantitated by a 12-hour cortisol area under the curve (C-AUC12) to examine the interpatient cortisol patterns during the early post-transplant period. C-AUC12 ranged from 44.0 to 636 ng.h/ml. Significant correlations were noted between the cortisol plasma concentration at 12 hours and methylprednisolone clearance and area under the concentration versus time curve (AUC). Interpatient variability in the disposition of methylprednisolone and cortisol response noted during the early post-transplant period contradict the clinical assumptions which underlie the fixed dosing protocols currently utilized for methylprednisolone.     

Surgical removal of visceral fat reverses hepatic insulin resistance

Various cytokines and growth factors may be involved in IgA nephropathy. To clarify whether interleukin-6 was a prognostic factor for this disease, we investigated interleukin-6 positivity of renal biopsy specimens and its relationship with the prognosis. The subjects were 90 patients with IgA nephropathy (42 males and 48 females with a median age of 32.7 +/- 13.8 years). Renal biopsy specimens were stained for interleukin-6 using an enzyme-antibody method. Fifty-two of 90 patients showed glomerular positivity for interleukin-6. Among the patients positive for interleukin-6, 24-hour urinary protein excretion and serum creatinine levels were significantly higher at the time of biopsy than in the patients without interleukin-6 positivity, while creatinine clearance was significantly lower. In the interleukin-6-positive patients without steroid therapy, serum creatinine increased significantly after 1 year (Deltas-Cr; 1.04 +/- 0.45 mg/dl) and creatinine clearance decreased significantly (DeltaCcr; -11.7 +/- 3.2 ml/min) compared to the interleukin-6-negative patients without steroid therapy. Steroid therapy improved 24-hour urinary protein excretion, serum creatinine, and creatinine clearance in the interleukin-6-positive patients, while these parameters worsened without steroid therapy. On the other hand, the IL-6-negative patients showed no differences of clinical parameters irrespective of the presence or absence of steroid therapy. In conclusion, glomerular interleukin-6 positivity may be a prognostic factor and an indicator of the need for steroid therapy in IgA nephropathy.     

Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome

BACKGROUND: Hypertension and nephrotoxicity are well-known side-effects of cyclosporine A (CsA). CsA-induced vasoconstriction of the afferent glomerular arteriole probably plays a role in at least the nephrotoxicity. Frequently renal transplant recipients on CsA have to be treated with antihypertensive drugs and for this purpose also beta-blockers are used. Tertatolol is a new beta-blocker with specific vasodilatory properties, and thus might be particularly useful in CsA-treated transplant recipients. METHODS: We studied the systemic and renal haemodynamic effects of atenolol and tertatolol in 12 hypertensive renal transplant recipients on cyclosporine A (CsA). In a cross-over way, all patients were treated with atenolol and tertatolol for 4 weeks each, separated by a wash-out period also of 4 weeks. At the end of each period, the mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured. RESULTS: The mean arterial pressure was lower (P < 0.05) during atenolol (124 +/- 2 mm Hg) and tertatolol (125 +/- 2 mm Hg) treatment compared with washout (132 +/- 4 mm Hg). Also the heart rate was lower (P < 0.01) during atenolol and tertatolol (54 +/- 3 and 55 +/- 2 beats/min respectively) than in the wash-out period (65 +/- 3 beats/min). GFR and RPF were not changed by either beta-blocker. CONCLUSION: In CsA treated renal transplant recipients both atenolol and tertatolol effectively reduced blood pressure. In these patients we found no evidence of a specific vasodilatory effect of tertatolol. Both beta-blockers had no negative influence on renal function. Hence, these cardioprotective agents are an attractive and safe choice for the treatment of hypertension in such patients.     

Inhibition of Salmonella enteritidis by oleuropein in broth and in a model food system

OBJECTIVE: To compare the pharmacokinetics of methylprednisolone in renal transplant recipients on 2 occasions separated by at least 1 month during chronic immunosuppression. DESIGN: A prospective unblinded trial. PATIENTS: Ten renal transplant recipients (aged 25-62 years) evaluated in a public university-affiliated hospital clinic. INTERVENTIONS: All patients received their chronic oral dose of methylprednisolone as a 10-20-minute intravenous infusion during the 2 study periods. MAIN OUTCOME MEASURES: Serum methylprednisolone concentrations were determined by HPLC and were used to generate the pharmacokinetic parameters of the drug. RESULTS: During study 1, which ranged from 1.2 to 24 months posttransplant, the mean +/- SD methylprednisolone dose was 13.2 +/- 6.4 mg. In study 2 (2.5-38.5 mo posttransplant), the mean dose was 10.6 +/- 3 mg. During both study periods, methylprednisolone concentrations exhibited a monoexponential decline. Considerable variability in methylprednisolone clearance was observed between periods in certain patients. Four of the 10 patients demonstrated a reduction in clearance from study 1 to study 2, which ranged from a 28% to a 53% decrease. Two patients exhibited an increase in clearance of 40% and 49%. The mean +/- SD total body clearance in study 1 was 363 +/- 330 mL/min/kg, whereas the mean volume of distribution was 1.18 +/- 0.53 L/kg. The mean elimination rate constant was 0.29 +/- 0.14 h-1, with a mean serum half-life of 2.87 +/- 1.15 h during the first phase. In study 2, the mean methylprednisolone clearance was 261 +/- 150 mL/min/kg (p > 0.05) and the mean volume of distribution was 0.89 +/- 0.31 L/kg (p > 0.05). The mean serum half-life of methylprednisolone was 2.91 +/- 0.60 h (p > 0.05), with the mean elimination rate constant of 0.25 +/- 0.06 h-1 (p > 0.05). CONCLUSIONS: These data demonstrate that intrapatient variability in methylprednisolone clearance exists among certain renal allograft recipients. As a result of the observed variability, patients who are continued on the same dose of methylprednisolone during the posttransplant period of chronic immunosuppression will be subjected to a changing pattern of exogenous glucocorticoid exposure. The impact of these changing patterns requires further prospective evaluation.     

Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients

Increased circulating total homocysteine (tHcy) has been implicated as an independent risk factor for atherosclerotic disease. In cardiac transplant patients, accelerated coronary atherosclerosis is an important cause of late allograft failure; however, studies of tHcy in this at-risk group are limited. We sampled a cohort of 72 subjects 3.95+/-3.14 (mean +/- SD) years after transplantation and found that all had tHcy concentrations above our upper reference limit (15.0 micromol/L). The mean tHcy in the transplant group (25.4+/-7.1 micromol/L) was significantly greater than in our reference group (9.0+/-4.3 micromol/L; n = 457; P <0.001). We also examined the effect of age, gender, time since transplant, serum folate and cobalamin, total protein, urate, creatinine, albumin, and trough whole blood cyclosporine concentrations. In a multiple linear regression model, only creatinine (mean 144+/-52 micromol/L; P = 0.021) and trough cyclosporine concentrations (191+/-163 microg/L; P = 0.015) were independent positive predictors of tHcy, whereas serum folate (8.35+/-7.43 nmol/L; P = 0.018) and time since transplant (P = 0.049) were significant negative predictors. We conclude that hyperhomocysteinemia is a common characteristic of cardiac transplant recipients. Our analysis suggests that folate and renal glomerular dysfunction are important contributory factors; however, whole blood cyclosporine concentrations may also predict the degree of hyperhomocysteinemia in this population and therefore influence interpretation of any apparent response to treatment.     

Conversion from +Sandimmune to Neoral in kidney transplant recipients treated with cyclosporine and ketoconazole

BACKGROUND: Microemulsion cyclosporine is a new pharmaceutical form whose intestinal absorption is more constant, resulting in a better bioavailability. AIM: To assess dose adjustments and variability of blood levels after the conversion of cyclosporine to microemulsion cyclosporine in renal transplant recipients function receiving cyclosporine-ketoconazole. PATIENTS AND METHODS: Thirty four patients with more than one year after the transplantation, with stable renal function and receiving triple immunosuppression were studied. Conventional cyclosporine was changed to the microemulsion form maintaining the same daily dose. Drug serum levels, serum creatinine and blood pressure were measured within two to eight months after the conversion. Doses of microemulsion cyclosporine were adjusted to achieve serum levels of 150 +/- 40 ng/ml. RESULTS: Microemulsion cyclosporine induced a slight initial increase in blood cyclosporine levels. Afterwards, levels were more stable than with conventional cyclosporine (165-185 and 145-210 ng/ml respectively) and the dispersion of values were lower (standard deviations of 70 and 100 ng/ml respectively). Twenty three patients did not require dose adjustments, in four it was reduced and in five it was increased. There were no changes in serum creatinine or blood pressure after the conversion. CONCLUSION: More stable serum levels without adverse reactions were obtained with microemulsion cyclosporine. Doses of cyclosporine need not to be changed during the conversion.     

Sodium excretion in children with lithogenic disorders

INTRODUCTION: The causes of nephrolithisis are multifactorial and have not yet been enough investigated [1]. Hypercalciuria is the most common cause of metabolic nephrolithiasis [2-4]. Close relationship between urinary calcium and urinary sodium has been a subject of reported observations in the past, showing that high urinary sodium is associated with high urinary calcium [5-7]. Hyperoxaluria, hyperuricosuria and cystinuria are also metabolic disorders that can lead to nephrolithiasis. Recent studies have indicated that urinary elimination of cystine is influenced by urinary sodium excretion. Based on these observations it has been hypothesised that patients with high urinary sodium excretion are at high risk of urinary stone disease. The purpose of the study was to investigate sodium excretion in a 24-hour urine and first morning urine collected from children with lithogenic metabolic abnormalities (hypercalciuria, hyperoxaluria, hyperuricosuria, cystinuria), both with nephrolithiasis and without it, in order to determine its significance in urinary calculi formation. PATIENTS AND METHODS: Urinary sodium excretion was investigated in 2 groups of children: patients with lithogenic metabolic abnormalities, but without urinary stone disease (L group) and patients with nephrolithiasis (C group). Both groups were divided into 2 subgroups: patients with hypercalciuria and without it. There were 22 patients in group L (mean age 11.97 +/- 4.13 years), of whom 17 formed a hypercalciuric subgroup and 5 formed a non-hypercalciuric subgroup (3 patients with hyperuricosuria and 2 patients with hyperoxaluria). Group C consisted of 21 patients with nephrolithiasis (mean age 12.67 +/- 3.44 years), of whom 6 formed a hypercalciuric subgroup and 15 formed a non-hypercalciuric group (2 patients with cystinuria and 13 patients without lithogenic metabolic abnormalities). Control group consisted of 42 healthy age-matched children. All subjects had a normal renal function. A detailed history and clinical examination were done, and ultrasonography was performed in all patients. A 24-hour urine, first morning urine and serum specimen were analysed for sodium, potassium, calcium, uric acid, urea and creatinine. Fractional excretion of sodium, as well as urinary sodium to creatinin ratio and urinary sodium to potassium ratio, were calculated from the findings. Sodium and potassium levels were determined by flame photometry, calcium was measured by atomic absorption technique (Beckman Atomic Spectrophotometer, Synchron CX-5 model, USA), uric acid by carbonate method and creatinine by Jaffe technique. Cystine and dibasic amino acids were quantified by ion chromatography. Urinary oxalate excretion was determined by enzyme spectrophotometry. Hypercalciuria was defined by 24-hour calcium excretion greater than 3.5 mg/kg per day and/or calcium to creatinine ratio greater than 0.20 [8]. Uric acid excretion was expressed as uric acid excretion factored for glomerular filtration, according to Stapleton's and Nash's formula [9]. Normal values were lower than 0.57 mg/dl of glomerular filtration rate in 24-hour samples. Mean values were statistically analyzed by Pearson's linear correlation and analysis of variance (ANOVA). RESULTS: Urinary sodium concentration values including urinary sodium to potassium ratios, are shown in Table 1. We found that urinary sodium excretion was significantly increased in patients of both L and C groups when compared with controls (p < 0.05). Further analysis of the subgroups showed that urinary sodium excretion was significantly higher only in patients with hypercalciuria of both L and C groups in comparison to controls (p < 0.05) (Table 2). A significant positive correlation was found between 24-hour urinary sodium to creatinine ratio and urinary calcium to creatinine ratio (r = 0.31; p < 0.001) (Graph 1), as well as between urinary sodium to potassium ratio in 24-hour and first morning urine (r = 0.69; p < 0.001) (Graph 2). (A     

The significance of urinary N-acetyl-beta-D-glucosaminidase for predicting early stage diabetic nephropathy

We studied urinary N-acetyl-beta-D-glucosaminidase (NAG) in the early stage of diabetic nephropathy in 27 non-insulin-dependent diabetes mellitus (NIDDM) patients with a microalbumin level below 20 mg on 24-hour urine sample. Microalbumin and NAG excretion were measured in 24-hour urine samples collected on three separate occasions within seven days of admission. Creatinine clearance was determined simultaneously. There was a significant negative correlation between the creatinine clearance and 24-hour urinary NAG (r = -0.38, p < 0.05). Elevation of urinary NAG may indicate decreased renal function during early stage NIDDM nephropathy.     

Relation between urinary cytology abnormalities and cyclosporine A therapy in bone marrow transplant recipients

The aim of the study was to determine the relationship, if any, between abnormalities in urinary cytology and the administration of cyclosporine A in bone marrow transplant recipients. Specific attention was given to the presence of tubular cells with round inclusions (TCRI). Two bone marrow transplant recipient groups were studied: one with allogeneic bone marrow transplantation (BMT) (20 patients) who were treated with cyclosporine A, and the other with autologous BMT (12 patients) who did not receive cyclosporine A. Urinary cytology showed TCRI in 41.66% of the patients after autologous BMT and in 80% of the patients after allogeneic BMT. In the group of patients treated with allogeneic BMT, the occurrence of TCRI was associated with a high incidence of glycosuria and was followed by an increase in the blood level of cyclosporine A, an increase in the serum creatinine concentration and a decrease in the creatinine clearance. These results demonstrated that TCRI, although related to, were not found to be exclusively specific to the administration of cyclosporine A.