HMG-CoA reductase inhibitors in chronic kidney disease.

The incidence of chronic kidney disease (CKD) is on the rise in the USA. Cardiovascular events are the leading cause of death in this patient population, therefore reducing the risk of these events has become a major focus. The aim of this review is to assess current literature on the use of statins in CKD and end-stage renal disease. Cholesterol reduction is important in preventing the development and progression of coronary heart disease and its negative effects. Statins have been widely studied and proven to reduce cardiovascular risk in the general population. The information gained from trials has been extrapolated to special populations, including CKD, despite these patients often being excluded. However, recent studies have begun to focus on CKD, hemodialysis, and transplant patients and the use of cholesterol-lowering agents and the potential association with decreased cardiovascular events. In addition, due to the unique pharmacokinetic and pharmacodynamic changes that occur in these patients, choosing the appropriate cholesterol-lowering agent becomes important for both safety and efficacy. The complexity of CKD patients is an important consideration when choosing cholesterol-lowering medication. Patients with CKD are often on medications that may interact with many of the cholesterol-lowering agents. Ensuring drug interactions are minimized is essential to the prevention of adverse events from the medications.

Preserved endocrine function in a pancreas transplant recipient with pancreatic panniculitis and antibody-mediated rejection.

Pancreas transplantation is an effective treatment option for patients with complicated diabetes mellitus. Pancreas allograft recipients are followed with laboratory markers such as serum amylase, lipase and glucose levels. Hyperglycemia may indicate severe acute rejection and has recently been associated with antibody-mediated (humoral) rejection. In this report, we describe a unique case of a pancreas-after-kidney (PAK) transplant recipient with the rare presentation of pancreatic panniculitis, biopsy-proven severe acute cellular and antibody-mediated pancreas allograft rejection and surprisingly well-preserved endocrine function despite treatment with high dose steroids. We discuss the clinicopathologic features of antibody-mediated pancreas rejection, including the importance of correlating pancreas allograft biopsy, C4d staining and donor specific antibodies, to diagnose antibody-mediated rejection and initiate the correct treatment.

Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.

Contemporary epidemiology and outcomes of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients are not well described. From March 2004 through September 2007, proven and probable IFIs were prospectively identified in 17 transplant centers in the United States. A total 429 adult SOT recipients with 515 IFIs were identified; 362 patients received a single and 67 patients received >or=2 organs. Most IFIs were caused by Candida species (59.0%), followed by Aspergillus species (24.8%), Cryptococcus species (7.0%), and other molds (5.8%). Invasive candidiasis (IC) was the most frequently observed IFI in all groups, except for lung recipients where invasive aspergillosis (IA) was the most common IFI (P<0.0001). Almost half of IC cases in liver, heart, and lung transplant recipients occurred during the first 100 days post transplant. Over half of IA cases in lung recipients occurred >1 year post transplant. Overall 12-week mortality was 29.6%; liver recipients had the highest mortality (P=0.05). Organ damage, neutropenia, and administration of corticosteroids were predictors of death. These results extend our knowledge on the epidemiology of IFI in SOT recipients, emphasizing the occurrence of IC early after non-lung transplant, and late complications with molds after lung transplant. Overall survival appears to have improved compared with historical reports.

Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry.

BACKGROUND: With use of data from the Prospective Antifungal Therapy (PATH) Alliance registry, we performed this multicenter, prospective, observational study to assess the epidemiologic characters and outcomes of invasive fungal infection (IFI) in hematopoietic stem cell transplant (HSCT) recipients. METHODS: Sixteen medical centers from North America reported data on adult HSCT recipients with proven or probable IFI during the period July 2004 through September 2007. The distribution of IFIs and rates of survival at 6 and 12 weeks after diagnosis were studied. We used logistic regression models to determine risk factors associated with 6-week mortality for allogeneic HSCT recipients with invasive aspergillosis (IA). RESULTS: Two hundred thirty-four adult HSCT recipients with a total of 250 IFIs were included in this study. IA (59.2%) was the most frequent IFI, followed by invasive candidiasis (24.8%), zygomycosis (7.2%), and IFI due to other molds (6.8%). Voriconazole was the most frequently administered agent (68.4%); amphotericin B deoxycholate was administered to a few patients (2.1%). Ninety-three (46.7%) of 199 HSCT recipients with known outcome had died by week 12. The 6-week survival rate was significantly greater for patients with IA than for those with invasive candidiasis and for those with IFI due to the Zygomycetes or other molds (P < .07). The 6-week mortality rate for HSCT recipients with IA was 21.5%. At 6 weeks, there was a trend toward a worse outcome among allogeneic HSCT recipients with IA who received myeloablative conditioning (P = .07); absence of mechanical ventilation or/and hemodialysis (P = .01) were associated with improved survival. CONCLUSIONS: IA remains the most commonly identified IFI among HSCT recipients, but rates of survival in persons with IA appear to have improved, compared with previously reported data. Invasive candidiasis and IFI due to molds other than Aspergillus species remain a significant problem in HSCT recipients.

Use of the PATH Alliance database to measure adherence to IDSA guidelines for the therapy of candidemia.

Candidemia is an increasing complication of the care of complex patients. Adherence to Infectious Diseases Society of America (IDSA) guidelines for the treatment of candidemia was investigated to assess the impact of compliance on outcomes of therapy. Data on the epidemiology, diagnosis, and treatment of patients with invasive fungal infections (IFIs) was extracted from the PATH Alliance registry, a prospective, multicenter, observational database of invasive fungal infections. Patients with proven candidemia were evaluated for adherence to the IDSA guidelines in terms of choice, dosage, and duration of antifungal therapy. Removal of central venous catheters and time to treatment initiation were assessed. Four-week survival data were compared. Of the 418 patients with candidemia who were included in the study, 361 patients with the necessary data sets were identified, of whom 262 (72.6%) were treated within the IDSA guidelines for the treatment of candidemia (IDSA group); the remaining 99 (27.4%) patients received treatment different from the guidelines (non-IDSA group). Kaplan-Meier (KM) survival analysis for patients in the IDSA and non-IDSA group showed mortality rates of 21.9 and 13.6%, respectively; the difference between the two groups was not statistically significant (P = 0.093). Following the exclusion of patients requiring mechanical ventilation or acute cardiac support, the modified survival KM curves were similar between the two groups. Significantly more patients in the IDSA group required mechanical ventilation and tunneled central catheters, had a concomitant IFI, and received caspofungin. The duration of treatment and inappropriate dosing did not appear to have had a significant impact on survival. Most of the deviations from IDSA guidelines were due to the inappropriate duration and dosing of therapy. No significant difference in mortality was noted between the IDSA and non-IDSA groups. The basis of these differences merit further study.

Cardiovascular events following renal transplantation: role of traditional and transplant-specific risk factors.

Cardiovascular mortality is increased in transplant recipients. However, studies including non-fatal events are critical to assess the burden of disease and to identify novel risk factors. We described the incidence of fatal and non-fatal events, and explored associations and interactions among traditional and transplant-specific risk factors and cardiovascular events (CVE) in a cohort of 922 patients transplanted between 1993 and 1998. One hundred and seventy-six patients experienced 201 CVE (111 cardiac, 48 cerebrovascular, 42 peripheral-vascular). Most CVE were non-fatal. Factors associated with cardiac events were (adjusted hazard ratios) tobacco (3.53; P<0.001), obesity (2.92; P<0.001), diabetes (2.63; P<0.001), multiple rejections (2.19; P=0.008), prior CVE (2.0; P=0.004), dialysis >1 year (1.91; P=0.007), and overweight status (1.68; P=0.04); with cerebrovascular events: diabetes and peritoneal dialysis (11.95; P<0.001), age >45 (6.77; P<0.001), diabetes (4.87; P<0.001), prior CVE (3.73; P<0.001), creatinine >141 micromol/l (3.16; P=0.001), peritoneal dialysis (3.06; P=0.027), and obesity (0.32; P=0.046); with peripheral-vascular events: diabetes (8.48; P<0.001), tobacco and cytomegalovirus (3.88; P<0.001), age >45 (2.31; P=0.019), and prior CVE (2.25; P=0.016); with mortality: tobacco and deceased-donor (3.52; P<0.001), age >45 (1.81; P=0.002), diabetes (1.76; P=0.002), pulse pressure (1.64; P=0.029), prior CVE (1.52; P=0.04), and dialysis >1 year (1.47; P=0.04). The majority of CVE post-transplant were non-fatal. Previous CVE was strongly associated with CVE post-transplant. Interactions among transplant-specific and traditional risks impacted significantly the incidence of CVE. Modifiable factors such as duration of dialysis, deceased-donor transplantation, and acute rejection should be viewed as cardiovascular risks.

Late mortality after orthotopic liver transplantation.

BACKGROUND: Mortality within the first year after orthotopic liver transplantation (OLTx) is usually due to infection or allograft failure. Late complications leading to death after OLTx have not been extensively evaluated. The aim of this study was to determine the incidence of late mortality and to identify the most common causes and risk factors associated with late mortality after OLTx. METHODS: A total of 479 OLTx were performed in 459 patients (320 males, 139 females; mean age 47 years, range 13 to 69) between September 1991 and April 2000. All patient deaths among liver transplant recipients who survived more than 1 year after transplantation (follow-up mean 3.4 years, median 3, range 1 to 8.6) were reviewed. RESULTS: In all, 122 allografts (24%) were lost in 109 patients during the study period (24%). Seventy-five allografts were lost in 69 patients by 1 year (15%). Forty-seven allografts were lost in 40 patients who survived at least 1 year (9.6%). Actuarial survivals at 2 years, 5 years, and 9 years were 95%, 85%, and 80%, respectively (based on 100% survival at 1 year). The causes of the late mortality were malignancy (9 patients), disease recurrence (8), late infection (6), renal failure complications (5), cardiovascular complications (4), chronic rejection (3), gastrointestinal hemorrhage (2), medication noncompliance (1), and unknown (2). CONCLUSIONS: Malignancy and disease recurrence are the major causes of late mortality among adult OLTx recipients. Pharmacologic immunosuppression is associated with many of the causes of late mortality. Advances in immunosuppression with less toxicity may improve long-term survival after OLTx.

Use of basiliximab and daclizumab in kidney transplantation.

Kidney transplantation represents a major medical victory in patients with whom dialysis and medical therapy have failed. To increase survival rates and optimize the use of limited organs, both patient care and immunosuppression therapy must be improved. Reduction in rejection episodes or severity of rejection may ultimately improve long-term allograft survival. Traditional engineered monoclonal antibodies have been associated with severe cytokine release reactions and an increased risk of opportunistic infections. Basiliximab and daclizumab are chimeric and humanized monoclonal antibodies which inhibit thymus-dependent lymphocyte proliferation. Interleukin-2 also affects the proliferation of natural killer cells, macrophages and monocytes, bursa-equivalent lymphocytes, epidermal dendritic cells, and lymphokine-activated killer cells. Interleukin-2 receptor antagonists have been shown to reduce the incidence of acute rejection without increasing the incidence of opportunistic infections or malignancy. Further studies are needed to evaluate the overall effect of these agents on long-term patient and allograft survival.

Treatment of progressive hepatitis C recurrence after liver transplantation with combination interferon plus ribavirin.

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is common, although the majority of cases are mild. A subset of transplant recipients develops progressive allograft injury, including cirrhosis and allograft failure. Minimal data are available on the safety and efficacy of antiviral treatment in this group of patients. The aim of this study is to review our experience in the treatment of moderate to severe HCV recurrence with combination interferon-alpha2b and ribavirin (IFN/RIB). Between October 1993 and October 1999, a total of 197 patients underwent OLT for HCV-related liver failure. This study describes 12 transplant recipients with moderate to severe recurrence treated with IFN/RIB. All patients met at least 1 of the following inclusion criteria: (1) moderate to severe inflammation (grade III to IV) on allograft biopsy, (2) bridging fibrosis on allograft biopsy, or (3) severe cholestasis attributable solely to HCV recurrence. Two patients had undergone re-OLT for allograft cirrhosis secondary to HCV recurrence and now had evidence of progressive HCV in their second allografts. Appropriate dose reductions of both IFN and RIB, as well as initiation of granulocyte colony-stimulating factor (G-CSF), for marked leukopenia were recorded. IFN/RIB therapy was started 60 to 647 days post-OLT, and duration of therapy ranged from 39 to 515 days. Seven patients were administered G-CSF to successfully treat leukopenia. Six of the 12 patients (50%) became HCV RNA negative by polymerase chain reaction. One of these 6 patients (no. 1) was HCV RNA negative at 6 months but chose to discontinue therapy because of intolerable side effects, experienced a relapse, and was HCV RNA positive at 12 months. Two of the remaining 5 patients were HCV RNA negative at 2 and 9 months off therapy. For the entire group, there was a statistically significant decrease in serum biochemical indices assessed at initiation of therapy and 1, 3, and 6 months into therapy. Most patients required dose reductions of both IFN and RIB. Five patients died; 3 patients died of liver-related complications that included severe intrahepatic biliary cholestasis, severe HCV recurrence, and chronic rejection with profound cholestasis. In the subset of HCV-positive liver transplant recipients with moderate to severe recurrence, combination IFN/RIB therapy resulted in complete virological response (serum RNA negative) in 6 of 12 patients ( approximately 50%). However, only 1 of 12 patients (8.3%) had sustained virological clearance after cessation of IFN/RIB therapy. Dose reductions of both IFN and RIB were required in most patients. The use of G-CSF (sometimes preemptively) allowed correction of leukopenia and full-dose antiviral therapy. Multicenter trials using combination therapy to identify factors predictive of response are needed in the subset of patients with progressive allograft injury.

Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies.

Cyclosporine and tacrolimus reduce allograft rejection, improve allograft half-life and patient survival. Ironically, the nephrotoxicity of these agents may adversely affect allograft survival in renal transplant recipients or cause end-stage renal diseases in other solid organ and bone marrow transplant recipients. Acute dose-dependent and chronic non-dose-dependent nephrotoxicity has been reported in both transplant recipients and patients with autoimmune disorders. Preliminary evidence suggests that drug therapeutic monitoring has little value in the diagnosis or management of nephrotoxicity associated with calcineurin inhibitors. Although the exact mechanism of nephrotoxicity is not fully understood, several factors have been implicated in the pathogenesis of immunosuppressive-induced nephrotoxicity. Renal and systemic vasoconstriction, increased release of endothelin-1, decreased production of nitric acid and increased expression of TGF-beta are the major adverse pathophysiologic abnormalities of these agents. Reducing the dose of a calcineurin inhibitor, or using protocols without calcineurin inhibition may ultimately minimize the risk of drug toxicity and improve allograft and patient survival. New experiences with non-nephrotoxic agents and protocols including mycophenolate and sirolimus allow for early calcineurin inhibitor reduction or elimination without increasing the risk of allograft rejection.

Effect of grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant patients.

Cyclosporin A (CsA) is an important immunosuppressant that is prone to numerous drug interactions. Grapefruit juice has been investigated, as a possible adjunct to CsA dosing in adult renal transplant recipients, to decrease CsA metabolism and reduce dosages. This study investigated this combination in pediatric renal transplant patients. Six stable pediatric renal transplant patients were entered into an open-label, four-period cross-over study in which patients were given their current CsA dose as either an oral solution (CsA-Sol) or a microemulsion (CsA-ME). In addition, drugs were administered concurrently with water or grapefruit juice. Steady-state pharmacokinetic profiles were taken during each of the four periods. Following the concurrent administration of grapefruit juice, CsA whole-blood 12-h trough levels were significantly increased during CsA-Sol dosing. Furthermore, the CsA elimination rate constant was significantly reduced during the same period. After CsA-ME dosing, no differences in CsA pharmacokinetics were found between concurrent water or grapefruit ingestion. Grapefruit juice co-administration reduced the production of CsA metabolites, AM1 and AM9, during CsA-Sol dosing. No changes in CsA metabolite production were found when patients were given CsA-ME with grapefruit juice as compared with water. Hence, alterations in CsA absorption and elimination occur with concurrent grapefruit juice ingestion when stable pediatric renal transplant patients are taking the oral CsA solution, but not the microemulsion formulation. These changes may be mediated by alterations in intestinal or hepatic metabolism, or drug absorption. The effect of grapefruit juice on CsA absorption is not readily predictable in these patients.

Renal toxicity of protease inhibitors.

Introduction of several classes of antiviral agents for the treatment of immunodeficiency virus has led to increased survival and improved quality of life for patients with HIV infection. Protease inhibitors have become the mainstays of current therapy in patient with AIDS. Renal intolerance of indinavir is a rare but important complication in HIV positive patients. The renal function of patients receiving indinavir should be closely monitored. Benign and asymptomatic crystalluria occurs in 4-13% of HIV positive patients. Several cases of acute renal failure, renal atrophy and interstitial nephritis have also been reported. A hydration protocol consisting of one to two liters of fluid should be initiated three hours after each indinavir dose. If significant renal insufficiency persists, temporary indinavir withdrawal or switching to another protease inhibitor should be considered.

Association of fungal infection and increased mortality in liver transplant recipients.

BACKGROUND: Invasive fungal infection is associated with increased morbidity and mortality following orthotopic liver transplantation (OLTx). Understanding the risk factors associated with fungal infection may facilitate identification of high-risk patients and guide appropriate initiation of antifungal therapy. OBJECTIVES: The aim of this study was to determine the incidence of fungal infections, identify the most common fungal pathogens, and determine the risk factors associated with fungal infections and mortality in OLTx recipients. METHODS: Medical records from 96 consecutive OLTx in 90 American veterans (88 males, 2 females; mean age 48 years, range 32 to 67) performed from January 1994 to December 1997 were retrospectively reviewed for fungal infection in the first 120 days after transplantation. Infection was defined by positive cultures from either blood, urine (<105 CFU/mL), cerebrospinal or peritoneal fluid, and/or deep tissue specimens. Superficial fungal infection and asymptomatic colonization were excluded from study. All patients received cyclosporine, azathioprine, and prednisone as maintenance immunosuppressive therapy. Fungal prophylaxis consisted of oral clotrimazole (10 mg) troches, five times per day during the study period. RESULTS: Thirty-five patients (38%) had documented infection with one or more fungal pathogens, including Candida albicans (25 of 35; 71%), C torulopsis (7 of 35; 20%), C tropicalis (2 of 35; 6%), non-C albicans (2 of 35; 6%), Aspergillus fumigatus (4 of 35; 11%), and Cryptococcus neoformans (1 of 35; 3%). The crude survival for cases with or without fungal infection was 68% and 87%, respectively (P <0.0001). The median intensive care unit stay and overall duration of hospitalization were significantly longer for patients with fungal infection (P <0.01). The mean time interval from transplantation to the development of fungal infection was 15 days (range 4 to 77) with a mean survival time from fungal infection to death of 21 days (range 3 to 64). Fungal infections occurred significantly more often in patients with renal insufficiency (serum creatinine >2.5 mg/dL), biliary/vascular complications, and retransplantation. CONCLUSIONS: Fungal infections were associated with increased morbidity and mortality following OLTx, with Candida albicans being the most common pathogen. Treatment strategies involving antifungal prophylaxis for high-risk patients and earlier initiation of antifungal therapy in cases of presumed infection are warranted.

Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future.

The calcineurin inhibitors cyclosporin A (CsA) and tacrolimus (FK506) are associated with dose- and efficacy-limiting adverse events, including nephrotoxicity, which may diminish their overall benefits for long-term graft survival. Nephrotoxicity is difficult to distinguish from chronic allograft rejection and is a particular problem in the setting of renal transplantation. Minimizing immunosuppressant-induced nephrotoxicity could improve long-term renal allograft survival. However, to obtain significant long-term improvement in renal allograft outcomes, it may be necessary to adopt new immunosuppressive regimens that rely less on calcineurin inhibitors. Recipients of other transplanted organs, as well as patients with autoimmune diseases who require immunosuppressant therapy, could also benefit from this change in immunosuppressive drug strategy because their healthy, native kidneys are particularly susceptible to the nephrotoxic effects of CsA and FK506. CsA- and FK506-sparing regimens, which use reduced doses of CsA and FK506 in combination with other nonnephrotoxic immunosuppressants, may be the best current option for reducing nephrotoxicity. The chemical immunosuppressant mycophenolate mofetil (MMF) has been used as part of CsA- and FK506-sparing regimens that provide improved renal function while maintaining adequate immunosuppression. Such regimens should reduce patient morbidity and mortality. Also, because immunosuppressant-induced nephrotoxicity has been associated with significant financial costs, CsA- and FK506-sparing regimens should result in substantial savings in health care costs.

Immunosuppressant-induced nephropathy: pathophysiology, incidence and management.

Immunosuppressant-induced nephrotoxicity, in particular chronic progressive tubulointerstitial fibrosis/arteriopathy induced by the calcineurin inhibitors cyclosporin and tacrolimus, has become the 'Achilles heel' of immunosuppressive agents. The use of calcineurin inhibitors as primary immunosuppressants in hepatic and cardiac transplantation has led to end-stage renal disease and dialysis. Calcineurin inhibitor-induced acute renal failure may occur as early as a few weeks or months after initiation of cyclosporin therapy. The clinical manifestations of acute renal dysfunction are caused by vasoconstriction of renal arterioles, and include reduction in glomerular filtration rate, hypertension, hyperkalaemia, tubular acidosis, increased reabsorption of sodium and oliguria. The acute adverse effects of calcineurin inhibitors on renal haemodynamics are thought to be directly related to the cyclosporin or tacrolimus dosage and blood concentration. However, new clinical data indicate that calcineurin inhibitor-induced chronic nephropathy can occur independently of acute renal dysfunction, cyclosporin dosage or blood concentration. Several strategies have been evaluated to attenuate cyclosporin-induced nephropathy, but their efficacy remains unknown. Cytokine release syndrome associated with the use of muronomab-CD3 (OKT-3) can also contribute to the pathogenesis of transient acute tubular necrosis and renal dysfunction following renal transplantation. Continued research and clinical experience should provide information regarding the aetiology of cyclosporin-induced chronic progressive tubulointerstitial fibrosis/arteriopathy and its potential treatment.

Fatal fulminant hepatitis associated with bromfenac use.

OBJECTIVE: To report a case of fulminant hepatic failure associated with the use of bromfenac, a new analog of the phenyl acetate class of nonsteroidal antiinflammatory drugs. CASE SUMMARY: A 60-year-old white woman with liver failure who had no known history of chronic liver disease was transferred to the liver transplant unit for evaluation. For three months preceding her illness, the patient was treated with bromfenac 25 mg po qid for arthritic pain. Prior to the initiation of bromfenac, her liver function test results were normal. Etiologic evaluation at presentation was unremarkable. The patient's condition continued to deteriorate, with the development of hepatic encephalopathy and worsening liver function test results while awaiting liver transplantation. Progressive hepatic and renal dysfunction along with respiratory decompensation ensued, and the patient died 48 days after initial presentation. CONCLUSIONS: Fulminant hepatic failure associated with the prolonged use of bromfenac appears to be an idiosyncratic response consistent with experience with other agents of its class. This case along with other cases of serious hepatotoxicity associated with the use of this agent ultimately resulted in bromfenac's removal from the market.