Immunosuppressive Agents and Bone Disease in Renal Transplant Patients With Hypercalcemia

Renal transplantation is the definitive treatment for many metabolic abnormalities of uremic patients, although it is only partially effective for renal osteodystrophy, which may interact with posttransplant renal osteopathy. Osteopenic-osteoporotic syndrome represents, together with fractures secondary to osteoporosis and osteonecrosis, the bone complication most related to renal transplantation. Several factors contribute to the pathogenesis of posttransplantation osteoporosis, particularly immunosuppressive treatment. In this study, we evaluated the prevalence of factors related to posttransplant renal osteopathy and the clinical impact of immunosuppressive protocols. We studied 24 renal transplant recipients with hypercalcemia. Glomerular filtration rate was >50 mL/min. Mean age, time on dialysis, and time from transplantation were 49.6, 5.4, and 6.9 years, respectively. We evaluated serum and urine calcium and phosphorus, calcitonin, parathormone, bone-specific alkaline phosphatase, osteocalcin, urine deoxypyridinoline, telopeptide of type 1 procollagen, 1,25-(OH)₂ and 25-OH vitamin D, parathyroid ultrasound, and computerized bone mineralometry. The combination of sirolimus and steroids resulted in the most disadvantageous outcomes regarding alkaline phosphatase and mineralometry. Calcineurin inhibitors did not significantly influence bone metabolism markers; mycophenolate mofetil evidenced no effect on bone. According to the literature, steroids account for the abnormalities found in our patients and in severe osteopenia. Several factors may contribute to the development of osteoporosis and fractures in transplantation patients, although they are overcome by the prominent effect of steroids. In patients at high risk of osteoporosis, steroid-free therapy should be considered. Everolimus is indicated for diseases with bone loss. Combined therapy with everolimus and mycophenolic acid without cyclosporine and steroids, seemed to be particularly indicated. Prophylactic treatments should be commenced early. No single marker was useful to diagnose posttransplant renal osteopathy. The definitive diagnosis should be made by bone biopsy during transplantation, and noninvasive procedures, such as densitometry and evaluation of biologic markers, may be useful during follow-up.     

Incidence of Cytomegalovirus Infections in Renal Transplant Patients Treated With Conventional or Cyclosporin Therapy

The incidence and severity of cytomegalovirus (CMV) infectionwas examined in groups of consecutive renal transplant patients:group A (50 patients) transplanted from August 1984 to October1985 received cyclosporin (from the day of transplantation)and steroid therapy; group B (50 patients) transplanted betweenJune and July 1984 received conventional therapy (azathioprineand steroids, and antilymphocyte globulin for 14 days). In groupsA and B there were respectively 5 (10%) and 14 (28%) seronegativepatients prior to transplantation (CMV antibody titre <128by ELISA); the overall incidence of CMV was 38% vs 74% (P<0.001);the incidence of primary infection was 0% (0 of 5) vs 36% (5of 14) (NS); the incidence of secondary infection was 42% (19of 45) vs 89% (32 of 36) (P<0.00001); and the total incidenceof symptomatic infection was 10% vs 26% (P< 0.04). Thus weconclude that initial cyclosporin therapy leads to a reductionin CMV infection.     

Hyperuricemia and Acute Renal Failure in Renal Transplant Recipients Treated With High-Dose Mizoribine

Background

Hyperuricemia is a common adverse event frequently found in renal transplant recipients with mizoribine (MZ). Hyperuricemia itself will be a cause of renal dysfunction, and renal dysfunction also will be a cause of hyperuricemia simultaneously. This study investigates frequency of hyperuricemia and renal failure in renal transplant recipients treated with high-dose MZ.

Ureteral Complications in Renal Transplant Recipients Successfully Treated With Interventional Radiology

Introduction

Ureteral complications in renal transplantation occur in approximately 8% of renal transplant recipients, occasionally leading to graft loss. This retrospective study presents a single-center experience in managing ureteral complications with interventional radiology as well as the long-term graft function and recipient survival.

Patients and Methods

We analyzed 21 renal transplant recipients with ureteral problems.

Results

Nine patients experienced urinary leak, six patients had ureteric obstruction, and six patients had obstruction preceded by leak. Median recipient age was 48 (range, 20-63) years; 71% (15/21) of the patients were male and 66.6% (14/21) of transplants were derived from cadaveric donors. Ureteral complications were diagnosed at a mean of 18 days (range, 12-47) after renal transplantation. Initially a percutaneous nephrostomy was performed, followed by antegrade placement of a nephroureteral stent. In cases with ureteral obstruction, ureteral balloon dilation was performed prior to placement of the stent. Median time to the procedure was 53 days, and median follow-up for the purposes of this study was 57 months. Renal graft function improved following treatment of the ureteral complication. Mean serum creatinine values prior to and after the intervention were 4.8 ± 2.12 and 1.79 ± 0.58 mg/dL, respectively (P<.0001). Functional renal grafts were observed at the first, third, and fifth posttransplantation year among 100%, 95.2% and 80.9% of patients, respectively. It should be further noted that no graft was lost due to a ureteral complication.

Conclusions

Interventional radiology was successful in treating immediate and long-term ureteral problems among renal transplant recipients with preservation of good renal function and patient survival.     

Hazards of Stroke in Renal Transplant Recipients and Patients With End-Stage Renal Disease

BackgroundSeveral comparison studies have suggested that kidney transplant (KT) could reduce stroke risk in patients with end-stage renal disease (ESRD). To avoid the selection criteria bias of using dialysis patients as control groups, we compared the risk of stroke between KT recipients and comparable propensity score-matched dialysis patients.MethodsWe used Taiwan's National Health Insurance Research Database to identify patients with newly diagnosed ESRD between 2000 and 2009. We separated them into 2 groups: a KT group and a non-KT dialysis-only group. To evaluate the stroke outcome, we compared each patient with KT to a patient on dialysis without KT using propensity score matching.ResultsIn total, 2735 KT recipients and 10,940 propensity score-matched dialysis patients were identified. The incidence rates of overall stroke were 9.1 and 23.4 per 1000 person-years in KT recipients and non-KT dialysis patients. Compared with the propensity score-matched dialysis patients, the patients who received KT exhibited significantly lower overall stroke risk, hemorrhagic stroke, and ischemic stroke, the adjusted hazard ratios were 0.37 (95% CI, 0.31–0.45), 0.19 (95% CI, 0.12–0.29), and 0.46 (95% CI, 0.37–0.56), respectively (all P < .001).ConclusionsThrough a propensity score-matched cohort, this study confirms that KT is associated with a reduced risk of stroke more than dialysis alone in patients with newly diagnosed ESRD.     

The Influence of Need‐Based,Continuous, Low‐Dose Iron Replacement on Hemoglobin Levels in Hemodialysis Patients Treated With Erythropoiesis‐Stimulating Agents

Anemia is a common and important complication of chronic kidney disease. Treatment includes the use of erythropoiesis‐stimulating agents (ESAs) and iron supplementation. However, the optimal schedule of iron supplementation remains to be defined. Thirty‐one long‐term hemodialysis patients were treated for 1 year (period 1) with ESAs and an intermittent pulse regimen consisting of 100 mg of iron sucrose administered after different dialysis sessions depending on serum ferritin and other laboratory values, but no more than once per week. During the next 3 years (period 2), patients were treated with ESAs and need‐based, continuous, low‐dose iron. Iron doses were determined on the basis of values and changes of serum ferritin and transferrin saturation every fourth week after the longest interdialysis time interval. Iron doses ranged from 10 to 60 mg of iron sucrose and were given 1–3 times per week. If grounded, we gradually reduced or even abolished the iron doses. A significant increase in the hemoglobin concentration and hematocrit during period 2 in comparison with period 1 was observed. The use of ESAs did not change significantly during period 2 in comparison with period 1, while the use of iron was significantly lower in period 2. Significantly lower values were obtained for serum ferritin, saturation of transferrin, serum iron, and total serum iron‐binding capacity during period 2. A better response to ESA therapy (increase in hemoglobin and hematocrit) is achieved with need‐based, continuous, low‐dose iron replacement.     

Serum Stem Cell Factor Level in Renal Transplant Recipients With Posttransplant Erythrocytosis

The etiology of posttransplant erythrocytosis (PTE) remains unclear, and the most frequently suggested causative factors are still a matter of controversy. We aimed to investigate serum‐soluble stem cell factor (sSCF) along with serum erythropoietin (EPO) levels in renal transplant recipients (RTRs) with PTE. Thirteen RTRs with PTE, 42 RTRs without PTE, and 42 healthy controls were included. Serum sSCF and EPO levels were determined using an enzyme‐linked immunosorbent assay kit. Expected and observed/expected EPO levels were calculated. Serum sSCF levels and observed/expected EPO were significantly higher in RTRs with PTE than both RTRs without PTE and controls. In RTRs with PTE, sSCF level was significantly correlated with hematocrit and observed/expected EPO, respectively. Significant correlation was also observed between hematocrit level and observed/expected EPO in RTRs with PTE. Increased sSCF level and inadequate suppression of EPO production seem to have a role in the pathogenesis of PTE.     

Correlation Between C2 and AUC(0-4) in Renal Transplant Patients Treated With Diltiazem

BACKGROUND: The area-under-the-curve (AUC) of cyclosporine (CsA) reflects exposure to the drug, but this monitoring strategy is time-consuming and not cost-effective. Recently, it has been suggested that the concentration at 2 hours after dosing (C2) shows the best correlation with AUC. The C2 has been replacing the trough measurement (C0) to monitor CsA therapy, but in patients receiving diltiazem there is not much information about this issue. We investigated the correlations between C2 and C0 with absorption AUC over the first 4 hours (AUC(0-4)) in renal stable transplant patients receiving CsA therapy with or without diltiazem. PATIENTS AND METHODS: Ten patients (five men) of ages 23 to 68 years and 6 to 84 months after transplantation, were randomly assigned to an 8-week initial period of either diltiazem washout or controlled treatment with diltiazem. Time-concentration curves of cyclosporine were performed at the end of this period using a specific RIA measurement of blood samples. Thereafter, a crossover of the groups was performed and after another 8 weeks, a second curve was obtained. Drugs that change the pharmacokinetics of cyclosporine or diltiazem were not allowed. RESULTS: The cyclosporine daily dose was lower with diltiazem (173 +/- 4 mg vs 213 +/- 4 mg, P = .002), but despite a dose reduction of only 19% +/- 1.5%, there was a trend to a larger AUC/dose (28 +/- 5 ng x h/mL x mg vs 17 +/- 2 ng x h/mL x mg, P = .1) and a trend to an increased C2 when treatment included diltiazem (1035 +/- 156 ng/mL vs 652 +/- 126 ng/mL, P = NS). Moreover, we confirmed that C2 showed the best correlation with AUC(0-4), (r = 0.7, P = .04), a correlation that improved with diltiazem (r = 0.9, P < .002). CONCLUSION: C2 is the point that correlates best with AUC(0-4) with or without diltiazem. C2 in the presence of diltiazem was associated with a stronger, more significant correlation with AUC(0-4).     

The Long-Term Prognosis of Renal Transplant in Patients With Systemic Vasculitis

Little information is available about the long-term outcome of renal transplantation in patients with systemic vasculitis (SV). We compared the outcomes of 19 renal transplant recipients with SV with those of 38 controls matched for time of transplantation, age, gender and source of donor. The mean post-transplant follow-up was 58 +/- 57 months for vasculitic patients and 61 +/- 49 months for controls. The actuarial 10-year patient survival was 87% in vasculitic patients and 90% in controls, death-censored graft survival were 84% and 100%, respectively. The risks of acute and chronic rejection, and arterial hypertension were not significantly different between the two groups. Infection was significantly more frequent in vasculitic patients (74% vs. 34%; p = 0.01). Seven patients (36.8%) had a recurrence of vasculitis in mean 45 months after renal transplant (0.076/patients/year). After recurrence, one patient had an irreversible humoral rejection, another died from hemophagocytosis and another restarted dialysis 1 year later. Long-term patient and renal allograft survival in vasculitic patients was good. Although graft function recovered in most relapsers after reinforcement of immunosuppression, one patient died and two lost graft function.     

Incidence and Treatment of Lymphedema in Heart Transplant Patients Treated With Everolimus

Background

Proliferation signal inhibitors are increasingly used as immunosuppressive drugs in solid organ transplantation. Among their side effects peripheral lymphedema is rarely described in literature.

Methods

All heart transplant patients treated with everolimus (de novo or maintenance) at our center (135 patients: age 50.72 ± 11.1 y, 115 male) were retrospectively analyzed. We considered the incidence of adverse events, particularly the appearance of peripheral edema (13 patients, 9.6%), and the correlation with preoperative characteristics, concomitant medications, other possible causes of edema, as well as all the measures developed for its therapeutic treatment.

Results and Conclusions

Edema appearance, especially in lower limbs, was considered to be one of the most frequent side effects in heart transplant patients treated with everolimus. In some cases its regression was possible with an adjustment of drug dosages associated with diuretics and lymphatic drainage, but more often a suspension of the drug itself was required for complete regression of the symptoms.     

Orthotopic Kidney Retransplantation in Simultaneous Pancreas Kidney Transplant Patients With Renal Failure

Traditionally transplant nephrectomy was required as a separate procedure prior to retransplantation in simultaneous pancreas kidney transplant patients. An alternative approach combining both procedures is described, during which the rejected kidney is removed and replaced orthotopically by the new allograft.     

Comparison of Hyperlipidemia in Dialysis Patients,Renal Transplant Recipients,and Steroid Treated Nonrenal Patients

Scrim lipids were studied in 25 stable renal transplant recipients 3–60 months after transplantation, 25 stable patients maintained on hemodialysis, and 16 steroid-treated patients with normal renal functions. Lipid abnormalities were found in 72% of the transplant patients and 52% of dialysis patients. The mean scrum triglyceride levels were significantly higher in the transplant and the dialysis group than age and sex matched controls, but were not significantly elevated in the steroid-treated patients with normal renal function. The mean cholesterol levels were normal for the transplant and steroid-treated groups, but significantly reduced in the dialysis group. There was a significant correlation between the triglyceride levels and the reciprocal of creatinine clearance suggestive of a possible etiologic relationship.     

Calcimimetics and Bone Mineral Density in Renal Transplant Patients With Persistent Secondary Hyperparathyroidism

Background

The persistence of secondary hyperparathyroidism plays an important role in posttransplant bone loss. Calcimimetics are efficient to control metabolic alterations associated with this problem, but there are few publications that assess their effects on bone density.

Patients and Methods

This prospective study assessed the effects of a single daily dose of cinacalcet on calcemia, phosphatemia, parathyroid hormone (PTH), and bone densitometry (femur and spine) values of 27 renal transplant patients with stable kidney function, calcium > 10.5 mg/dL, and PTH > 65 pg/mL.

Results

A preliminary study after 6 months showed decreased calcemia (11.05 ± 0.5 to 10.18 ± 0.6 mg/dL; P < .0001), reduced levels of intact PTH (iPTH; 258 ± 104 to 209.61 ± 127 pg/mL; P < .05), and increased phosphatemia (2.38 ± 0.45 to 2.54 ± 0.3 mg/dL; P < .05). We also observed an increase in femoral neck bone mass with improved T score (−1.36 ± 1.19 to −1.05 ± 0.84 g/cm²; P < .05).

Conclusions

Cinacalcet was effective in the management of posttransplant persistent secondary hyperparathyroidism, resulting in decreased calcemia and iPTH, while also improving femoral neck bone loss. Longer-term studies with control groups are needed to determine the drug's influence on overall bone mineral density.     

Renal Transplant Immunosuppression in Patients With Hemolytic Uremic Syndrome: Four Case Reports

A high rate of recurrence has been described in atypical hemolytic uremic syndrome renal transplant recipients, favored by certain immunosuppressant drugs that can induce complement activation. We present four case series in which three patients were diagnosed pretransplantation and a fourth who had onset in the very early post-transplantation period. The patients received different immunosuppression schedules, and all had improvement after more than 2-years. We suggest the need to stratify the risk of atypical hemolytic uremic syndrome recurrence using genetic studies and the available drugs as the main factors that allow graft survival improvement today.     

Successful Treatment of Hepatitis C in Renal Transplant Recipients With Direct‐Acting Antiviral Agents

The direct‐acting antivirals (DAAs) constitute an emerging group of small molecule inhibitors that effectively treat hepatitis C virus (HCV) infection, a common comorbidity in end‐stage renal disease patients. To date, there are no data to guide use of these agents in kidney transplant patients. The authors collected data from 20 consecutive kidney recipients treated with interferon‐free treatment regimens for HCV at their center: 88% were infected with genotype 1; 50% had biopsy‐proved advanced hepatic fibrosis on their most recent liver biopsy preceding treatment (Metavir stage 3 fibrosis [F3] or F4); and 60% had failed treatment pretransplantation with interferon‐based therapy. DAA treatment was initiated a median of 888 days after renal transplantation. All patients cleared the virus while on therapy, and 100% have achieved a sustained virologic response at 12 weeks after completion of DAA therapy. The most commonly used regimen was sofosbuvir 400 mg daily in combination with simeprevir 150 mg daily. However, four different treatment approaches were used, with comparable results. The DAAs were well tolerated, and less than half of patients required calcineurin inhibitor dose adjustment during treatment. Eradication of HCV infection with DAAs is feasible after kidney transplantation with few treatment‐related side effects.