Tacrolimus Therapeutic Drug Monitoring in Stable Kidney Transplantation and Individuation of CYP3A5 Genotype.

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.

De Novo Solid Tumors After Kidney Transplantation: Is It Time for a Patient-Tailored Risk Assessment? Experience From a Single Center.

BACKGROUND: Progress in immunosuppressive therapy and perioperative techniques has improved the survivals of both grafts and patients. The patient, however, is exposed to the risks of aging and side effects of immunosuppression. De novo tumors are the 2nd cause of death in the organ transplant population. The aim of this study was to evaluate whether the current accepted guidelines for the pre-transplantation study and the post-transplantation follow-up have been effective, in our kidney transplant population, regarding early detection and treatment, improving prognosis, and reducing mortality of some curable neoplastic diseases. METHODS: We considered de novo tumors in kidney transplant patients from 1995 to 2010 (n = 636) excluding hematologic and nonmelanoma skin tumors from our study. RESULTS: There were 64 de novo tumors in 59 patients out of 636 kidney transplant patients; 29.68% were urogenital cancer, 26.56% gastrointestinal cancer, 12.5% melanoma, 6.25% lung cancer, 6.25% biliopancreatic cancer, 4.68% visceral Kaposi sarcoma, 4.68% breast cancer, 4.68% thyroid cancer, 1 pleural mesothelioma, 1 meningioma, 1 merkeloma. Twenty patients died because of cancer. Ten patients had a late de novo tumor diagnosis, when the stage of tumor was advanced and not suitable for curative treatment. CONCLUSIONS: Because of the increased neoplastic risk, we consider it mandatory to carry out a meticulous screening and to implement pre-transplantation study concerning this increased neoplastic risk population to detect a subgroup of patients presenting the highest risk to improve their outcome.

Preemptive liver-kidney transplantation in von Gierke disease: a case report.

Type 1a glycogen storage disease (GSD 1a), or von Gierke disease, is a rare, autosomal-recessive disease caused by a deficiency of glucose-6-phosphatase, which leads to glycogen accumulation in the liver, kidney, and intestinal mucosa. Clinical manifestations include hypoglycemia, growth retardation, hepatomegaly, lactic acidemia, hyperlipidemia, and hyperuricemia. Long-term complications include renal disease, gout, osteoporosis, pulmonary hypertension, short stature, and hepatocellular adenomas, which may undergo malignant transformation. Herein we have described the management and the clinical course of a GSD1a patient who underwent simultaneous preemptive liver- kidney transplantation (SPLKT), which solved the liver and renal disease. We confirmed the rapid normalization of glucose metabolism, and correction of hyperlipemia after liver transplantation. In our opinion uremic patients with GSD 1a with or without adenomas must be considered for SPLKT. To our knowledge this is the fifth case of SPLKT and the first preemptive one to be described in the literature.

[Uretero-vescical anastomosis during kidney transplantation. Preliminary results of two surgical techniques]. / L'anastomosi uretero-vescicale nel trapianto di rene. Risultati preliminari di due tecniche a confronto.

AIM: The most frequent urologic complications after renal transplantation involve the uretero-vescical anastomosis (leakage, stenosis, and reflux), with a frequency of 1% to 30% in different series. METHODS: We present our results in a prospective randomized trial performed from October 2004 to September 2005, in a cohort of 36 patients, who underwent renal transplantation from cadaveric donor at our institution. A uretero-vescical anastomosis according to Lich-Gregoir was used in 18 cases (group A), whereas an anastomosis according to Knechtle was performed in other 18 patients (group B), respectively. The groups were comparable for donors and recipients characteristics. The mean donor age was 46.3 years vs 44.9 years, and the mean duration of cold ischemia was 1 086+/-296 min vs 1 100+/-381 min for group A and for group B respectively. The mean recipient age was 47.5 years vs 46.1 for group A and group B, respectively. RESULTS: No differences were evidenced between the two uretero-vescical anastomosis in term of surgical complications, infections or patient and graft survival at one year of follow-up. Stenosis and leakage involved 2 patients for each group respectively. Numbers of infections, days of antibiotic therapy were similar between the two groups. CONCLUSION: Our early experience does not evidence differences between the two types of uretero-vescical anastomosis.

Effects of successful renal transplantation on left ventricular mass.

Left ventricular hypertrophy is an independent cardiovascular risk factor in the general population and in patients with chronic renal failure. Relatively little is known about the effects of renal transplantation on left ventricular hypertrophy. The aim of this study was to determine the changes in left ventricular mass after successful renal transplantation and to evaluate the importance of some clinical, laboratory, and echocardiographic variables on the trend to left ventricular hypertrophy. Twenty-three patients with end-stage renal disease were studied by ambulatory blood pressure monitoring and echocardiography before and 2 years following renal transplantation. After 24 months of follow-up, all transplant recipients had adequate renal function (serum creatinine <2 mg/dL). At the end of the study, we observed a significant decrease in left ventricular mass and left ventricular mass index compared to the pretransplantation period. In renal transplant recipients, the prevalence of left ventricular hypertrophy significantly decreased (78% versus 44%, P < .03) after 2 years of follow-up. Systolic 24-hour blood pressure was the only predictor of left ventricular mass and of left ventricular mass index at 2 years after transplantation. In conclusion, successful renal transplantation produces a regression of left ventricular hypertrophy. This beneficial effect depends on a decrease in systolic pressure levels.

Renoprotective effect of early inhibition of the renin-angiotensin system in renal transplant recipients.

The aim of this work was to study the effect of early administration of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type-I receptors blockers (ARB) on renal function and proteinuria in renal transplant recipients with good, stable renal function and mild proteinuria. Twenty four patients started ACEI/ARB therapy within 14 months after surgery (RAS-). Before (T0) and every month for 2 years after the initiation of ACEI/ARB we evaluated creatinine clearance (CrCl), proteinuria/day (UP), UP/CrCl (FUP), arterial blood pressure, and serum lipid levels. Twenty-eight patients who never received ACEI/ARB (RAS+) were studied in the same fashion. In the RAS+ CrCl was reduced after 2 years compared with T0 (64.5 +/- 2.6 vs 75.0 +/- 3.2 mL/min, P < .003); UP and FUP were both significantly increased (666 +/- 65 vs 132 +/- 20 mg/day 8.8 +/- 1.2 vs 2.6 +/- 0.6 mg/mL x 10(3); P < .001 and .002) compared with T0. Moreover, UP (P < .04), FUP (P < .03), and the percentage reduction of CrCl (11.4% +/- 5% vs 4.6% +/- 1.8%; P < .05) were greater in RAS+ than RAS- subjects at 2 years of the study. The values of other parameters did not show significant differences between the two groups. In conclusion, this study suggested that ACEI/ARB have renoprotective effects, when used in patients with good stable renal function and mild proteinuria. These drugs may play a role to prevent chronic allograft nephropathy.

Renal allograft protection with early angiotensin-converting enzyme inhibitors administration.

Twenty renal transplant recipients (RTx) with a normal ultrasound pattern of renal artery who began angiotensin-converting enzyme inhibitor (ACEI) therapy within 14 months after surgery (ACEI(+)) were studied retrospectively to evaluate endogenous creatinine clearance/1.73 m(2) body surface area (CrCl), proteinuria (UP), UP/CrCl (FUP), mean arterial pressure (MBP), total cholesterol, LDL, HDL, and triglycerides. Before (T(0)) and every month for 2 years after initiation of ACEI. Twenty-four RTx who never received ACEI (ACEI(-)) were studied in the same fashion. No differences in the parameters were noted at T(0); all RTx had CrCl >60 mL/min, Up less than 0.5 g/d, and stable renal function for 3 months before the study. In the ACEI cohort CrCl was reduced after 2 years compared with T(0) (65.6 +/- 2.8 vs 76 +/- 3.2 mL/min, P <.004), UP and FUP were both increased (660 +/- 60 vs 130 +/- 20 mg/d, 8.9 +/- 1.3 vs 2.8 +/- 0.6 mg/mL x 10(3); P <.001 and.002, respectively). UP >0.5 g/d was present in three cases. After 2 years the ACEI(+) group showed a decrease in CrCl (68.2 +/- 3.1 vs 73 +/- 2.2 mL/min) and the increase in UP (181 +/- 21 vs 139 +/- 18 mg/d) and in FUP (3.1 +/- 0.7 vs 2.6 +/- 0.9 mg/mL x 10(3)), which were not significantly different from the values at T(0). No cases showed UP >0.5 g/d. Moreover UP (P <.04), FUP (P <.03) and the percent reduction of CrCl (11.2 +/- 2.5% vs 4.6 +/- 1.8%, P <.05) were greater among ACEI(-) than ACEI(+) patients at 2 years. ACEI(-) patients showed correlation between the percent reduction of CrCl and UP (r =.51, P <.04). The values of MBP and lipids did not reveal any significant difference between the two groups. In conclusion, this study suggests that ACEI have a renoprotective effect, when used early, and may also prevent chronic allograft nephropathy.

[Surgical complications after kidney transplantation]. / Le complicanze chirurgiche ed urologiche del trapianto di rene.

Chronic renal failure needs substitutive treatment such as haemodialysis and peritoneal dialysis for the patient to survive. Kidney transplantation (KTx) improves survival of the patient with chronic renal failure. Since the first KTx, performed by Merrill in Boston in 1959, advances in medical therapy, immunosuppressive therapy and refinements in surgical technique have improved the quality of life of the transplant patient. We present a review of the incidence, diagnosis and therapy of surgical complications after KTx reported in the literature and a retrospective analysis of 297 consecutive cadaveric donor kidney transplants done in our institution from September 1993 to September 2002. Vascular complications represent 5-10% of postoperative complications. Our experience showed an incidence of 1.7% renal artery thrombosis, 1.4% renal vein thrombosis, 1.7% renal artery stenosis, 1.4% arterial rupture due to fungal arteritis, 0.7% spontaneous graft ruptures and 12% lymphoceles. Urological complications account for 10-15% of postoperative complications. In our series we found an incidence of 7.4% urinary leakage, 2.7% urinary obstruction and 3% urinary reflux. Gastrointestinal complications represent 16% of postoperative complications. Our series showed 1% pancreatitis with an overall mortality of 33% and an incidence of 1.7% intestinal perforations. Surgical complications still represent a challenge that increments morbidity and mortality among kidney transplant recipients. Data shown may offer some guidance on how to deal with early and late post-transplant surgical complications.

[Cardiovascular disease after renal transplantation]. / La malattia cardiovascolare dopo trapianto renale.

Cardiovascular disease is the leading cause of morbidity and mortality following renal transplantation. Because many renal transplant recipients die with functioning grafts, deaths resulting from cardiovascular disease have became an increasingly important cause of graft loss, particularly after the first post-transplantation year. Moreover, a contribution of some cardiovascular risk factors to renal allograft dysfunction has been demonstrated. A number of observational studies suggest that cardiovascular disease is more common in renal transplant patients than in the general population. The excessive risk for cardiovascular disease is related to a high prevalence and accumulation of atherogenic risk factors before and after transplantation. Hypertension, post-transplantation diabetes and hyperlipidemia are well-recognized risk factors for the development of cardiovascular events after renal transplantation and are strongly associated with immunosuppressive therapy. Progressive renal dysfunction may also influence the risk of cardiovascular complications after renal transplantation. The elevated risk may also be caused by non- traditional risk factors such as anaemia, adhesion molecules, hyperhomocysteinemia, microinflammatory state, abnormal coagulation and oxidative stress. To prevent post-transplantation cardiovascular disease it is crucial to define the etiological risk factors. Some risk factors can be modified, and for some of these, there is strong evidence from studies in the general population that intervention improves survival. Given the significant morbidity and mortality of cardiovascular disease in renal transplant recipients, aggressive treatment intervention for potentially modifiable factors are strongly advocated after transplantation. In addition to treatment intervention, risk management should also involve tailoring the immunosuppressive regimen to minimize both direct and indirect cardiovascular risks. In this article we attempted to review and quantify the post-transplant risk factors for cardiovascular disease as well as offer suggestions on optimizing the therapy or treatment strategies to minimize the risk of cardiovascular complications in renal transplant patients. Reduction of cardiovascular morbidity and mortality can improve not only the life expectancy and quality of life of the transplant recipients but also their graft function and survival.

Acid production and base balance in patients on chronic haemodialysis.

Acid generation and elimination processes were compared with total base (bicarbonate plus metabolizable anions) turnover in 18 anuric patients undergoing post-dilutional haemofiltration. The study was conducted during the second haemodialysis session of the week by means of a whole-body base balance technique. The results showed that the mean rates of base loss and base gain during dialysis did not differ (i.e. the dialysis base balance approximated to zero). The concurrent mean rate of intestinal base absorption was 66+/-26 mmol/2 days, as calculated from the whole-body balance of the various inorganic cation and anion differences in a metabolic steady state. This level of intestinal base absorption would be capable of neutralizing the 59+/-21 mmol of H(+) ions/2 days that is contributed by sulphuric acid, which is the most important endogenous acid produced in anuric patients. In spite of the fact that intestinal base supply was adequate to neutralize endogenous acid production completely, our patients presented with pre-dialysis non-carbonic acidosis. The depression of plasma bicarbonate levels could not, however, be explained by increased concentrations of the anion gap and organic acids, which were within normal limits both before and after dialysis. We suggest as an alternative hypothesis that this pre-dialysis acidosis may represent an isotonic dilution acidosis that is induced by the ingestion of base-free tap water in order for plasma tonicity to be protected from the accumulation of impermeant dietary solutes, which takes place during the interdialysis period in anuric patients.

Persistent secondary hyperparathyroidism after renal transplantation.

BACKGROUND: The persistence of secondary hyperparathyroidism after renal transplantation is frequent and often complicated by overt hypercalcemia. Recent investigations have shown an effect of the different vitamin D receptor (VDR) genotypes on parathyroid hormone (PTH) secretion in both primary and secondary hyperparathyroidism. The aims of this study were (i) to assess whether persistent secondary hyperparathyroidism after renal transplantation is characterized by any change in calcium-controlled PTH secretion, and (ii) whether different VDR allelic distributions might play any role on this setting. METHODS: Eighty-one cadaveric renal transplantation recipients, followed-up for at least 12 months, were checked for PTH, other primary metabolic and clinical variables, and VDR B/b alleles (BsmI). In 22 of these the following parameters were evaluated: (a) kinetics parameters of the Ca-PTH relation curve; (b) vertebral mineral density; (c) calcitriol serum levels; (d) PTH-related peptide serum levels; and (e) urinary hydroxyproline. RESULTS: According to the stabilised PTH levels (reached by the third month), the patients were divided in two groups: group A (N = 40, PTH < 80 pg/ml) and group B (N = 41, PTH > 80 pg/ml). Group B differed from group A in that patients had higher PTH levels at the time of transplantation, were older in age, and spent more time on dialysis. Group B had increased maximal and minimal PTH levels, and higher set-point levels than Group A. The patients with the BB pattern of VDR genotype were characterized by the lowest PTH levels both at time of transplantation and after stabilization, and lower set point values than patients with Bb and bb patterns. CONCLUSIONS: Our study suggests that (i) the severity of pre-existing secondary hyperparathyroidism is the main factor determining its persistence after renal transplantation, (ii) persistent secondary hyperparathyroidism is characterized by an autonomous pattern of PTH secretion, (iii) the VDR BB genotype seems to be related to lower PTH levels.

Peritoneal clearances in hypertensive CAPD patients after oral administration of clonidine, enalapril, and nifedipine.

The authors investigated whether the reduction of arterial pressure, induced by the oral administration of clonidine (CLO), enalapril (EN), and nifedipine (NIF), has any effect on peritoneal transport rates. The study was performed in nine hypertensive patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The patients were submitted to administration of CLO, EN, and NIF, each in randomized succession for two weeks, after withdrawal of any hypotensive therapy for eight days (washout period). The nine patients underwent a four-hour dwell exchange using a 2.27 g/dL glucose two-liter bag after washout and after each hypotensive period. The following parameters were analyzed: mean arterial pressure (MAP), performed in the sitting position; net ultrafiltration; effluent/initial dialysate glucose ratio (GL D/Do); peritoneal clearance of K, BUN, creatinine (Cr), phosphate, beta-2 microglobulin (beta 2), total proteins, and the ratio between beta 2 and Cr clearance. Moreover, residual renal Cr and beta 2 clearances were analyzed. The three drugs significantly reduced MAP at a similar rate. The peritoneal transport parameters after CLO were similar to the results in the washout period. On the contrary, after EN and NIF therapy, Cr and beta 2 clearances were significantly increased, and GL D/Do decreased in comparison to the washout period. The other peritoneal transport parameters after EN and NIF were similar to the washout period. Residual renal Cr and beta 2 clearances after the three drugs were similar to those in the washout. these data suggest that after two weeks of therapy with EN and NIF, glucose, Cr, and beta 2 peritoneal transports are influenced by these hypotensive drugs irrespective of the effect on the arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

[Modifications in alpha 2 globulins, gamma globulins and in rheumatoid factor during gold salt therapy in rheumatoid arthritis]. / Modificazioni delle alpha 2 globuline, delle gamma globuline e del fattore reumatoide durante terapia con sali d'oro nell'artrite reumatoide.

A total dose of g 1.071, given as hydrosoluble salts for a 12 month period, showed a significant decrease in serum gamma globulins along with clinical improvement in 17 patients affected with rheumatoid arthritis. A decrease in alpha 2 globulins and in rheumatoid factor titre was observed too, but it was not significant. The data suggest that in rheumatoid arthritis the gold therapy might also be effective on the immunological disease mechanism.