Superior efficacy of enteric-coated mycophenolate vs mycophenolate mofetil in de novo transplant recipients: pooled analysis.

Dose reduction and discontinuation of mycophenolate mofetil (MMF) therapy because of gastrointestinal complications has been associated with increased risk of acute rejection episodes and graft loss. Enteric-coated mycophenolate sodium (EC-MPS) delays release of mycophenolic acid (MPA), and was designed to reduce MPA-related gastrointestinal adverse events. Data comparing the efficacy of EC-MPS vs MMF in de novo renal transplant (RTx) recipients from large prospective studies are limited. Therefore, a pooled data analysis was performed based on 1891 de novo RTx recipients receiving EC-MPS (n = 1289) or MMF (n = 602) plus cyclosporine and steroid therapy in 4 prospective multicenter studies with similar entry criteria. In all trials, the initial dose of EC-MPS was 1440 mg/d, and of MMF was 2000 mg/d; both dosages deliver equimolar amounts of MPA. Induction therapy was permitted in 2 studies per center practice. Multivariate logistic regression analysis was performed, adjusting other potential explanatory variables including recipient age, sex, and race/ethnicity; induction therapy; and diabetes mellitus at baseline. In addition, propensity scores were used to explain potential bias. Mean (SD) MPA dose (EC-MPS dosage was converted to MMF equivalent) during months 0 to 12 was similar: EC-MPS, 1820 (370) mg/d, vs MMF, 1860 (290) mg/d. However, at univariate and multivariate analyses, the rates of treatment failure, biopsy-proved acute rejection episodes, and graft loss were significantly lower with EC-MPS compared with MMF at month 12. In conclusion, this pooled analysis documents a substantial improvement in efficacy in de novo RTx recipients receiving EC-MPS vs MMF with concomitant cyclosporine and steroid therapy.

Long-term administration of enteric-coated mycophenolate sodium (EC-MPS; myfortic) is safe in kidney transplant patients.

BACKGROUND: To date, there are no data on long-term use of enteric-coated mycophenolate sodium (EC-MPS; myfortic) from time of renal transplantation. We report the first long-term safety and efficacy data on EC-MPS when administered for up to 3 years post transplant. METHODS: De novo renal transplant recipients completing 1 year of treatment in a multicenter, randomized, double-blind trial of EC-MPS versus mycophenolate mofetil (MMF) were invited to take part in an open-label extension during which all patients received EC-MPS 720 mg b.i.d. Results from the period 12 - 36 months post transplant were compared to comparable data from MMF-treated patients taking part in two studies of everolimus versus MMF (RAD 201 and RAD 251). RESULTS: Of 367 patients completing the blinded core study, 247(62%) entered the open-label extension phase. During the first 24 months of the extension, the incidence, type and severity of adverse events were comparable between the newly-exposed and long-term EC-MPS patients. There were 2 deaths in the newly-exposed group and 4 among long-term EC-MPS patients, with 1 and 2 graft losses, respectively. Six patients (5%) in the newly-exposed group and 4 (3%) in the long-term EC-MPS group experienced biopsy-proven acute rejection. Cross-study comparisons indicated that the tolerability profile of EC-MPS was similar to MMF, including the incidence of adverse events, infections and malignancies, as was the incidence of efficacy events. CONCLUSION: These results demonstrate that EC-MPS with cyclosporine and steroids provides good long-term efficacy and tolerability, and confirm the safety of converting renal transplant patients from MMF to EC-MPS.

Early and late residual renal function and surgical complications in living donors: a 15-year experience at a single institution.

Living donation in the field of renal transplantation has increased over time as well as the use of laparoscopic nephrectomy. We present a 15-year experience on 162 living donors (105 women, 57 men; mean age, 46.7 years; range, 31-74 years) who underwent nephrectomy using different surgical approaches as open lombotomic nephrectomy (OLN), open transperitoneal nephrectomy (OTN), and laparoscopic hand-assisted nephrectomy (LHAN). We collected data on residual donor and recipient renal function, as well as early versus late medical and surgical complications. With a mean follow-up of about 8 years, we observed normal residual renal function in all donors and similar results of early and late graft function independent of the surgical procedure. Long-term incidence of hypertension and noninsulin-dependent diabetes in living donors was similar to the general population. OLN and OTN donors showed higher incidences of early and late complications, readmissions, and reoperations than LHAN donors. Our results confirmed that living donor nephrectomy is a safe procedure without serious side effects in terms of renal function and long-term quality of life. LHAN should be the preferred technique because of a lower incidence of early and late complications.

Pancreas retransplantation: ideal timing and early and late results.

Surgical complications are the leading cause of pancreatic graft loss among diabetic patients who undergo pancreas transplantation alone (PTA), or combined with kidney transplantations (PK) or after kidney transplantations (PAK). Therapeutic effects on secondary complications of diabetes justify pancreas retransplantation (re-PT) when the first graft is lost. However, the appropriate timing for retransplant and related problems is not known. We present our initial experience on re-PT performed on seven diabetic patients who lost their first pancreas grafts (PK) due to surgical complications (venous thrombosis in five and enteric fistula in two). Five re-PT were performed a few days after the first PT without a second course of induction therapy, while two patients received re-PT some months later with reinduction therapy. In the early re-PT group, one patient died some hours after the second surgical procedure due to pulmonary embolism, while four patients lost their second grafts due to accelerated rejection within 2 years from re-PT. In the late re-PT group, both patients have good graft function without signs of rejection. Our initial experience showed discouraging results in the group of early re-PT, due to accelerated rejection episodes leading to a high incidence of graft loss. Late re-PT accompanied by reinduction therapy seemed to have better results.

Laparosopic hand-assisted living donor nephrectomy: the Niguarda experience.

Perioperative donor morbidity, a barrier to living organ donation, may be mitigated by the laparoscopic approach. From September 2002 to September 2004, 15 living donors, of ages ranging from 36 to 59 years, underwent laparoscopic nephrectomy. We used a hand-assisted device to increase the safety of the procedure. The average operating time was 200 minutes. The average blood loss was about 100 mL. The patients resumed oral intake and started walking within 1 day. The average postoperative hospital stay was 6 days. Although laparoscopic operating times were longer than those for traditional surgery, we showed benefits to the laparoscopic donor to be less postoperative pain, better cosmesis, shorter recovery time, and faster return to normal activities. We therefore consider laparoscopic nephrectomy a good alternative to traditional surgery for selected patients. Despite a lack of strong evidence, such as large prospective randomized studies, laparoscopic donor nephrectomy is likely to become the gold standard for donor nephrectomy in the near future.

Advantages of short-time ureteric stenting for prevention of urological complications in kidney transplantation: an 18-year experience.

We retrospectively studied the incidence of urological complications in a consecutive series of 590 patients (group B) who received a kidney transplant (KT) with a ureteral stent from January 1994 to December 2002. The ureteral stent was sewn to the bladder catheter during the surgical procedure and left in situ for a mean time of 10 days (range 8 to 12 days). The results were compared to a consecutive series of 414 patients who received a KT from March 1986 to December 1993 without a ureteral stent (group A). The two groups were comparable in terms of donor and recipient gender, ischemia time, delayed graft function, and chronic rejection incidence, but differed in mean donor age (44.1 vs 36.0 years), mean recipient age (45.4 vs 39.1 years), living/cadaveric donor rate (19.8% vs 11.9%), arterial lesions and bench reconstruction rate (11.1 vs 3.5%), as well as acute rejection episodes (11.7% vs 29.2%). Complications were seen in nine patients in group B (1.5%) and 17 patients in group A (4.1%) (P < .0001). Urinary leaks presented in two patients in group B (0.3%) and 11 patients in Group A (2.6%; P < .0001), while stenosis was present in six patients in group B (1.5%) and 7 in group A (1.2%) (P = NS). Urological complications such as urinary tract infection and macroscopic hematuria were similar in both groups. Time to presentation of a leak was within 2 weeks from KT in 10 patients (92.3%), while stenosis presented early in four patients (one in group B and four in group A). Of the stenoses, 69.3% presented late (beyond 12 weeks) in five patients in group B and three in Group A. In conclusion, our data suggest that routine use of double pigtail ureteral stent significantly decreased the incidence of leaks and early stenoses, but it did not modify late stenosis incidence. In the last decade, risk factors for urological complications have been increasing over time, namely, older donors and older recipients, living donation, length of dialysis, and the use of grafts with arterial lesions. Therefore we believe that a ureteral stent should be routinely considered to afford the advantage to protect the urinary anastomosis in the early postoperative period when the incidence of complications is highest, without the need of cystoscopy for its removal.

Surgical complications are the main cause of pancreatic allograft loss in pancreas-kidney transplant recipients.

We examined surgical complications among a group of diabetic type 1 patients (IDDM) with end-stage renal disease (ESRD) who had undergone pancreas-kidney transplantations (PK). Between October 1993 and August 2004, 70 SPK were performed using bladder (n = 14) or enteric (n = 56) drainage. Donors were selected according to standard criteria (mean age, 27.6 years; range, 17-49). All patients received cyclosporine-based immunosuppression. All pancreata functioned immediately, whereas 2 patients needed postoperative dialysis. Four patients (5.7%) lost their pancreatic graft due to vascular thrombosis; both patients underwent urgent allograft pancreaectomy and pancreas retransplantation (re-PT). One of them (1.4%) experienced a venous thrombosis and died due to a pulmonary embolism at 12 hours after re-PT. The other 3 patients had uneventful postoperative courses and were discharged with good pancreatic and renal function. Three patients in the bladder group (21.4%) had an anastomotic leak, which resolved with a bladder catheter. Four patients in the enteric group (7.1%) who experienced an anastomotic leak needed a second surgical procedure but in 3 of them allograft pancreatectomy was necessary. Relaparotomy was required in the other 3 patients due to hemorrhage (1 patient) or occlusion (2 patients). Acute rejection episodes, which occurred in 16 patients (22.8%), were treated with steroid boluses. With a mean follow-up of 72 months (range, 3-129), 2 patients have died at 8 and at 36 months, respectively, after SPK due to acute myocardial infarction (2.9%). Chronic rejection was the leading cause of pancreatic failure in 5 patients (7.1%) and of renal failure in 2 patients (2.8%). Patient, kidney, and pancreas survival rates were 95.8%, 92.9%, and 81.5%, respectively. Surgical complications were the leading cause of pancreatic allograft loss in IDDM and ESRD patients submitted to SPK.

A randomized trial of steroid avoidance in renal transplant patients treated with everolimus and cyclosporine.

In this randomized trial renal transplant recipients were treated with basiliximab, everolimus 3 mg/day, low-dose CsA. At transplantation, patients were randomized to stop steroids at the seventh day (group A) or to continue oral steroids in low doses (group B). Of the 113 patients enrolled, 65 were randomized to group A and 68 to group B. All patients were followed for 2 years. During the study 28 (43%) group A patients required reintroduced corticosteroids. One patient died, in group B. The Graft survival rate was 97% in group A and 90% in group B. There were more biopsy-proven rejections in group A (32% vs 16%; P = .044). The mean creatinine clearance was 54 +/- 21 mL/min in group A vs 56 +/- 22 mL/min in group B. Mean levels of serum cholesterol tended to be lower in group A, but the difference was of borderline significance (191 +/- 91 vs 251 +/- 188 mg/dL; P = .07). Vascular thrombosis (0 vs 5) and pneumonia requiring hospitalization (2 vs 7) tended to be more frequent in group B. Only three cases of CMV infection (1 vs 2) occurred. An immunosuppressive therapy with everolimus and low-dose CsA allows one to obtain excellent renal graft survival and stable graft function at 2 years. Early interruption of steroids in patients treated with this regimen may increase the risk of acute rejection, but neither affects graft survival nor graft function, while possibly reducing the risk of hyperlipemia and vascular thrombosis. About 60% of patients given everolimus and low-dose CsA can definitively stop steroids after 1 week.

Risk of Kaposi's sarcoma and of other cancers in Italian renal transplant patients.

A follow-up study of 1844 renal transplant patients in Italy showed a 113-fold increased risk for Kaposi's sarcoma. Kaposi's sarcoma risk was higher in persons born in southern than in northern Italy. Significant increases were also observed for cancers of the lip, liver, kidney and for non-Hodgkin's lymphoma.

[Pancreas transplantation. Experience in the first 50 patients at the Niguarda Hospital of Milan: clinical outcome and open questions]. / Il trapianto di pancreas. Esperienza dell'Ospedale Niguarda sui primi 50 pazienti: dubbi e certezze.

AIM: Personal experience in 50 patients who underwent combined pancreas-kidney transplantation (PKT), with particular reference to mortality and surgical complications is reported. METHODS: Between October 1993 and December 2001, 50 adult patients (36 males and 14 females), mean age 37 years (range 25-60), with chronic renal failure, and Insulin Dependent Diabetes Mellitus (IDDM), underwent 54 pancreas transplantation (4 patients retransplanted) and 52 kidney transplantation (2 patients retransplanted). Different surgical procedures have been employed during the period of 9 years. All patients underwent the same immunosuppressive regimen; the mean length of follow-up was 49 months. During the follow-up, 30 out of 43 patients who maintained a good graft function fulfilled a questionnaire about their quality of life following the criteria of the Medical Outcome Study (MOS). RESULTS: All patients became euglycemic immediately after the surgical procedure. One patient died post-operatively due to pulmorary thromboembolism after pancreas retransplantation for acute venous thrombosis; 1 other patient died 9 months after the procedure for acute myocardial infarction. Four patients developed acute venous thrombosis. All these patients underwent pancreas retransplantation, but 3 of these patients who survived the procedure lose the graft function for chronic rejection within 1 year. Fourteen patients showed acute rejection, 7 patients CMV infection. Three patients showed hyperchloremic acidosis, 12 patients bronchopulmonar infection and 7 patients urinary infection. Among surgical complications anastomotic fistula in 6 patients was also recorded. Five patients out of 50 lose the pancreatic graft function. After 1 from PKT, 83% of patients who fulfilled a questionnaire were strongly satisfied about their quality of life. No patients developed de novo tumors following chronic immunosuppression. The 5-year survival for patient, kidney and pancreas was 95.6%, 93.4% and 84.7% respectively. CONCLUSIONS: Our experience in 50 patients submitted to PKT shows no graft loss due to acute rejection. Surgical complications (acute venous thrombosis) and chronic rejection are the most important factors leading to graft loss. A graft in "head-up" position, a short portal vein of the graft, a "no-touch technique" during pancreas retrieval can be some of the most important factors which can reduce the rate of surgical complications. Combined kidney-pancreas transplantation showed in our experience a low mortality rate and a moderate incidence of morbidity and should be considered, at the moment, the treatment of choice for patients with renal failure and IDDM.

Design of a trial comparing sirolimus plus mycophenolate mofetil versus sirolimus plus cyclosporine.

We present the study design of a prospective, multicenter, randomized trial aimed at comparing the effects of two different combinations of sirolimus. Renal transplant recipients will be allocated to receive either sirolimus and mycophenolate mofetil (group A) or sirolimus and cyclosporine (group B). The primary endpoint will be the graft function at 3, 6, 12, 24, 36, 48, and 60 months. A number of secondary endpoints will also be considered. To obtain a significant difference in the primary endpoint 180 patients will be enrolled.

Effect of familial hypertension on glomerular hemodynamics and tubulo-glomerular feedback after uninephrectomy.

Familial hypertension, glomerular hemodynamic alterations, and dysregulation of tubulo-glomerular feedback (TGFB) have all been associated with the development of chronic renal failure. In the present study we evaluated renal and glomerular hemodynamics and TGFB responses in healthy kidney donors either with or without familial hypertension, before and after nephrectomy. Para-amino-hippurate plasma clearance (CPAH) and inulin plasma clearance (CInu) were measured in 15 kidney donors before and 1 year after nephrectomy. All subjects were normotensive and were kept in a sodium-replete state. Both clearances were measured after 40 min of constant infusion of PAH and Inu, as well as 20, 30, 50, and 60 min after the intravenous administration of acetazolamide (5 mg/kg). Glomerular hemodynamics were calculated by means of the Gomez formulae. Nephrectomy caused the expected decreases in CPAH and CInu and increase in the filtration fraction (all P < .0001). The decrease in renal resistances of the remaining kidney was greater at the afferent (-24%, P = .0075) than at the efferent arteriolar level (-17%, P < .0001). The TGFB activation was not altered by nephrectomy or by familial hypertension. Effective renal plasma flow (ERPF) decrease after TGFB activation appeared earlier than glomerular filtration rate (GFR) decrease before (P = .01), but not after, nephrectomy (P = .48). The presence of familial hypertension was associated with increased glomerular pressure (P = .0004). This study suggests that uninephrectomy in healthy human subjects causes a greater decrease in afferent arteriolar resistances, but that TGFB responses are not quantitatively altered. Familial hypertension is associated with a tendency toward higher glomerular pressures.

Incidence and clinical characteristics of posttransplant lymphoproliferative disorders: report from a single center.

In the period 1973-1998, among 2139 allograft recipients treated with standard immunosuppression, posttransplant lymphoproliferative disorders (PTLD) developed in 19 patients (0.9%): one plasmacytic hyperplasia, two polymorphic PTLD, one myeloma, and 15 lymphomas. PTLD developed 1 year after transplantation (tx) in 14 patients. Five patients were diagnosed at autopsy, 2 were lost to follow up, 3 died before therapy could be instituted, and 1 patient has just started chemotherapy. Of the 8 evaluable patients, 2 received acyclovir and are alive in complete remission (CR) and 6 received chemotherapy +/- surgery. Of these 6, 4 died of lymphoma and/or infection, 1 died of unrelated causes in CR, and 1 is alive in CR. PTLD is a severe complication of tx, usually running an aggressive course which may preclude prompt diagnosis and treatment. Nevertheless, therapy is feasible and must be tailored on the histologic subtype. Seventy-four percent of patients were diagnosed with late-onset PTLD stressing the need for long-term follow up.

Medical prevention and treatment of urinary stones.

Despite revolutionary developments in minimally invasive methods for the removal of stones in the last 15 years, the medical prevention of urinary stones remains very rewarding, due to the continual increase in the prevalence of nephrolithiasis in western countries, the high recurrence rate of the disease, its complications, discomfort and the costs of lithotripsy. Medical prevention is highly effective (50-95% efficacy in different series) and cost-convenient; its basic elements are appropriate metabolic evaluation, adequate hydration, "common sense" diet, and, in selected cases, drugs of proven efficacy. Clinical-metabolic evaluation should aim at the recognition of specific types of nephrolithiasis, and sort out secondary and/or remediable cases, define urinary risk factors, assess patients' compliance and the side effects of any therapy during follow-up. Hydration has proved effective in clinical trials and population-based observational studies; "fluids" may consist of water (any kind), coffee (caffeinated or decaffeinated), tea, beer and wine; grapefruit juice appears to have an unexplained ill effect. Despite the lack of clinical demonstration that dietary manipulations reduce the recurrences of stones, biochemical and epidemiological data suggest that high sodium, animal protein and sucrose intake increase the risk. Undue reductions in Ca intake also appear to be detrimental both for stone recurrences and bone mineralisation: "adequate" Ca intake (800-1000 mg/day) should be encouraged, but only in food since supplemental Ca, as drugs, appears to increase the risk of stones. Effective drugs are available for cystine, uric acid, infected stones and several secondary causes of Ca nephrolithiasis; in "idiopathic" Ca nephrolithiasis, thiazides, allopurinol, K and K-Mg citrate and possibly neutral K phosphate have been shown to be effective, at least in specific metabolic contexts.

Is lymphocele in renal transplantation an avoidable complication?

BACKGROUND: This study evaluated the impact of surgery in the incidence of lymphocele after kidney transplantation (KTx). METHODS: A prospective randomized study was conducted during a 6-year period on a group of patients undergoing KTx and operated on by the same surgeon (CVS). A total of 280 patients undergoing KTx were randomly allocated into two groups: (1) group C (control group) was 140 patients who were submitted to KTx with standard technique: implantation of the kidney in the controlateral iliac fossa with vascular anastomoses on the external iliac vessels; and (2) group M (modified technique group) was 140 patients who underwent a modified technique with a cephalad implantation of the graft in the ipsilateral iliac fossa and vascular anastomoses in the common iliac vessels. Both groups were comparable for age, cold ischemia time, incidence of rejection episodes, presence of adult polycystic kidney disease, and source of donor graft. RESULTS: Group M showed an incidence of lymphocele production (3 patients, 2.1%) significantly lower than group C (12 patients, 8.5%). Eight patients (1 in group M and 7 in group C) required surgical treatment by peritoneal fenestration. No allograft or recipient was lost as a result of fluid collection but the hospitalization was shorter in group M than in group C. CONCLUSIONS: A cephalad implantation of the renal graft in the ipsilateral iliac fossa has been associated with a lower incidence of lymphocele, probably because vascular anastomoses on the common iliac vessels cause less lymphatic derangement than those performed on the external iliac vessels.

Effect of n-3 polyunsaturated fatty acids on cyclosporine pharmacokinetics in kidney graft recipients: a randomized placebo-controlled study.

Highly concentrated marine polyunsaturated fatty acids (n-3 PUFA), affecting the lipids and lipophilic drugs metabolism, can interfere with cyclosporine (CyA) pharmacokinetics. This prospective, randomized and placebo-controlled, double-blind study involved 42 kidney graft recipients. From day +1, 21 pts (E) received 6 g n-3 PUFA (85% EPA + DHA, Esapent, Pharmacia) and 21 pts (P) received placebo (olive oil), both reduced to 3 g from day +30 on. A quadruple immunosuppressive regimen was employed. Plasma creatinine, lipids and CyA pharmacokinetics were investigated 1, 3, 6, 9 and 12 months after graft. The two groups were comparable for age, weight, M/F ratio, hypertension prevalence and baseline lipids. Active treatment did not affect total and HDL-cholesterol, but significantly lowered triglycerides (E:120 +/- 12 vs P:166 +/- 21 mg/dl, p < 0.0001). At one year, E pts had lower creatinine than P (1.26 +/- 0.06 vs. 1.88 +/- 0.2 mg/dl, p < 0.05), comparable CyA dosage, and a larger CyA area under the curve (AUC) (n.s.), with a higher blood peak level (Cmax) (p < 0.04) and less variance in time to peak (n.s.). The larger AUC in the E group at all intervals and the better pattern of plasma creatinine, with no rise in blood pressure, provided evidence of better CyA absorption and metabolism in n-3 PUFA supplemented kidney graft recipients.