Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.

Cardiovascular manifestations of Fabry disease: relationships between left ventricular hypertrophy, disease severity, and alpha-galactosidase A activity.

AIMS: Fabry disease is a rare X-linked deficiency of alpha-galactosidase A (alphagal), which causes glycosphingolipid accumulation. This study analysed the cardiovascular manifestations of a cohort of Fabry patients, and sought to define relationships between disease severity, alphagal activity, and cardiac abnormalities. METHODS AND RESULTS: We prospectively analysed Fabry patients (139 subjects: 92 males and 47 females) undergoing screening for potential enzyme replacement therapy. Baseline echocardiograms, electrocardiograms, and exams were obtained as part of two multinational clinical trials. Cardiovascular symptoms were present in 60.4%. By echocardiography, the mean left ventricular mass index (LVMI) was increased at 165.5 +/- 66.9 g/m(2), and 84.8% of patients displayed concentric left ventricular hypertrophy (LVH). Electrocardiographic LVH was present in >50% of adult subjects. In females, log-corrected plasma alphagal activity was inversely associated with LVMI (r = -0.45, P < 0.040). Males with extremely low alphagal activity and renal disease displayed the most LVH and cardiac symptoms, but LVH was prevalent even in females <20 years old. CONCLUSION: Concentric LVH was the predominant cardiac pathology seen in patients with Fabry disease, and was prevalent in both genders by the third decade of life. Left ventricular mass index was inversely correlated with alphagal activity, but was prevalent even in younger females.

Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors.

PURPOSE: This phase II study assessed clofarabine monotherapy in older adults (>or= 60 years of age) with untreated acute myeloid leukemia (AML) and at least one unfavorable baseline prognostic factor. PATIENTS AND METHODS: Clofarabine was administered intravenously for 5 days at 30 mg/m(2)/d during induction and 20 mg/m(2)/d during reinduction/consolidation (six cycles maximum). The primary end point was overall remission rate (ORR; ie, complete remission [CR] plus CR with incomplete platelet recovery [CRp]). RESULTS: In 112 evaluable patients who were treated (median age, 71 years; range, 60 to 88 years), the ORR was 46% (38% CR, 8% CRp). ORR by unfavorable prognostic factor was 39% for patients >or= 70 years of age; 32% for Eastern Cooperative Oncology Group (ECOG) performance status 2; 51% for antecedent hematologic disorder; 54% for intermediate karyotype; 42% for unfavorable karyotype; and 48%, 51%, and 38% for one, two, and three risk factors, respectively. The median disease-free survival was 37 weeks (95% CI, 26 to 56 weeks). Median duration of remission was 56 weeks (95% CI, 33 to not estimable). The estimated median overall survival was 41 weeks (95% CI, 28 to 53 weeks) for all patients, 59 weeks for patients with CR/CRp, and 72 weeks for patients with CR. The 30-day all-cause mortality was 9.8%. The most common non-laboratory drug-related toxicities (>or= 20% patients) were nausea, febrile neutropenia, vomiting, diarrhea, rash, and fatigue. CONCLUSION: Clofarabine is an active agent with acceptable toxicity in patients age 60 years or older with untreated AML who have at least one unfavorable prognostic factor. ORR did not seem affected by the presence of multiple unfavorable prognostic factors.

Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease.

Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

Mortality after kidney transplant failure: the impact of non-immunologic factors.

BACKGROUND: One third of cadaveric kidney transplant recipients suffer graft loss within five years of transplantation. Non-immunologic factors that predict mortality among non-transplant patients also may be potentially modifiable risk factors for mortality among patients with transplant failure. METHODS: Applying multivariate survival analysis to data from the United States Renal Data System, we determined the effect of immunologic or transplant related factors and non-immunologic factors on mortality in patients who initiated dialysis after kidney transplant failure in the United States between April 1995 and September 1998. RESULTS: A total of 4741 patients were followed for a median +/- standard deviation of 15 +/- 11 months after initiation of dialysis after transplant failure. The majority of the 1016 (21%) deaths were due to cardiac (36%) or infectious (17%) causes. Patients in the following groups had an increased risk for all-cause mortality: older patients [hazard ratio (HR) = 1.04 per year, 95% confidence interval (95% CI) 1.03-1.04], women (HR = 1.31, 95% CI 1.10-1.56), patients of white race (HR = 1.94, 95% CI 1.32-2.84), patients with diabetes (HR = 1.76, 95% CI 1.43-2.16), peripheral vascular disease (HR = 1.94, 95% CI 1.54-2.43), congestive heart failure (HR = 1.26, 95% CI 1.05-1.53), drug use (HR = 2.23; 95% CI 1.08-4.60), smokers (HR = 1.35, 95% CI 1.01-1.81), first transplant recipients (HR = 1.32, 95% CI 1.02-1.69), and patients with a higher glomerular filtration rate (GFR) at dialysis initiation (HR = 1.04 per mL/min higher, 95% CI 1.02-1.06). Those with private insurance (HR = 0.67, 95% CI 0.49-0.93) and higher serum albumin (HR = 0.73 per g/dL higher, 95% CI 0.64-0.83) had a decreased risk for all-cause mortality. Acute rejection, antibody induction, donor source, duration of graft survival and the maximum attained GFR during transplantation did not predict all-cause mortality. CONCLUSIONS: Non-immunologic factors predicted mortality among patients with transplant failure but immunologic and transplant related factors did not. Prevention, early diagnosis and treatment of co-morbid conditions and the complications of chronic kidney disease may improve the survival of patients with transplant failure.

Health care utilization among patients with chronic kidney disease.

BACKGROUND: Higher hospitalization rates among end-stage renal disease (ESRD) patients impose a substantial burden on the U.S. health care system. Early identification of patients with chronic kidney disease (CKD) and determination of factors associated with increased morbidity may lead to appropriate interventions to attenuate the complications of CKD and possibly reduce future resource utilization. METHODS: This retrospective cohort study of CKD patients in an outpatient nephrology clinic was performed to identify risk factors for hospitalization. The study population consisted of adults with elevated serum creatinine (females > or =1.5 mg/dL, males > or =2.0 mg/dL). Hospitalizations, hospital days and outpatient nephrology visits were examined. RESULTS: Among the 259 patients, 123 (47%) were hospitalized during a median follow-up of 11.4 months. The number of hospitalizations and hospital days per patient-year at risk were 0.96 and 6.6, respectively. Cardiovascular disease/hypertension accounted for the majority of hospitalizations. In a multivariate regression analysis, older age (RR 1.01, 95% CI 1.00, 1.03) and presence of cardiac disease (RR 1.91, 95% CI 1.19, 3.07) were associated with higher risk of hospitalization while higher serum albumin (RR 0.58, 95% CI 0.35, 0.95) and higher hematocrit (RR 0.92, 95% CI 0.87, 0.97) were associated with lower risk of hospitalization. Higher serum albumin (RR 0.34, 95% CI 0.21, 0.55), higher hematocrit (RR 0.87, 95% CI 0.81, 0.93) and use of ACE-inhibitors (RR 0.63, 95% CI 0.47, 0.84) were associated with lower risk of subsequent hospital days. Erythropoietin (RR 1.47, 95% CI 1.11, 1.82) use was associated with higher risk of outpatient nephrology visits. CONCLUSION: Certain potentially modifiable factors appear to be associated with increased resource utilization. It is hypothesized that attention to these factors may lead to improved outcomes in this patient population, which could result in reduced utilization.

Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury.

BACKGROUND: Traditional blood and urine markers for the diagnosis of various renal diseases are insensitive and nonspecific. Kidney Injury Molecule-1 (KIM-1) is a type 1 transmembrane protein, with an immunoglobulin and mucin domain, whose expression is markedly up-regulated in the proximal tubule in the post-ischemic rat kidney. The ectodomain of KIM-1 is shed from cells. The current studies were carried out to evaluate whether KIM-1 is present in human acute renal failure and might serve as a urinary marker of acute renal tubular injury. METHODS: Kidney tissue samples from six patients with biopsy-proven acute tubular necrosis (ATN) were evaluated by immunohistochemistry for expression of KIM-1. Urine samples were collected from an additional thirty-two patients with various acute and chronic renal diseases, as well as from eight normal controls. Urinary KIM-1 protein was detected by immunoassay and was quantified by ELISA. RESULTS: There was extensive expression of KIM-1 in proximal tubule cells in biopsies from 6 of 6 patients with confirmed ATN. The normalized urinary KIM-1 levels were significantly higher in patients with ischemic ATN (2.92 +/- 0.61; N = 7) compared to levels in patients with other forms of acute renal failure (0.63 +/- 0.17, P < 0.01; N = 16) or chronic renal disease (0.72 +/- 0.37, P < 0.01; N = 9). Adjusted for age, gender, length of time delay between the initial insult and sampling of the urine, a one-unit increase in normalized KIM-1 was associated with a greater than 12-fold (OR 12.4, 95% CI 1.2 to 119) risk for the presence of ATN. Concentrations of other urinary biomarkers, including total protein, gamma-glutamyltransferase, and alkaline phosphatase, did not correlate with clinical diagnostic groupings. CONCLUSIONS: A soluble form of human KIM-1 can be detected in the urine of patients with ATN and may serve as a useful biomarker for renal proximal tubule injury facilitating the early diagnosis of the disease and serving as a diagnostic discriminator.

Opportunities to improve the care of patients with kidney transplant failure.

BACKGROUND: Patients initiating dialysis after a failed kidney transplant are a subgroup of chronic kidney disease (CKD) patients who have not been characterized. Exposure to immunosuppressive medications differentiates these patients from the general incident end-stage renal disease (ESRD) population. METHODS: Data from the Health Care Financing Administration 2728 form were used to determine the hematocrit, erythropoietin use, serum albumin and glomerular filtration rate (GFR) among 4643 patients with failed kidney transplants who initiated dialysis between April 1995 and December 1998. RESULTS: At dialysis initiation, the mean hematocrit, serum albumin and GFR were 27.5%, 3.3 g/dL, and 8.4 mL/min/1.73 m2, respectively, and only 35% of patients had received erythropoietin. In a multivariate analysis, patients <45 years, females, patients of non-White race, non-diabetic patients, hemodialysis patients and patients with a lower serum albumin had a higher odds for hematocrit <30%. Erythropoietin use was associated with female gender, White race, increased time since transplantation, being employed, peritoneal dialysis, and higher serum albumin. Patients >/=45 years and patients with diabetes or congestive heart failure had higher odds for hypoalbuminemia, while employed patients, peritoneal dialysis patients, patients with higher hematocrit and patients who had received erythropoietin had lower odds of hypoalbuminemia. CONCLUSIONS: Despite being known to specialty physicians, patients with failed kidney transplants initiate dialysis at levels of hematocrit, serum albumin, and GFR that may be suboptimal and similar to those in the general incident ESRD population. Socioeconomic factors remain important barriers to the provision of CKD care even among these patients with established specialty physician contact. Improved CKD care could improve the outcomes of this unique subgroup of CKD patients.

Management of patients with chronic renal insufficiency in the Northeastern United States.

Comorbid conditions that develop during chronic renal insufficiency (CRI) contribute to the high morbidity and mortality among patients with end-stage renal disease (ESRD). Thus, appropriate management during CRI may lead to improved ESRD outcomes. A retrospective cohort study was performed to describe the management of patients with CRI. A total of 602 patients with CRI (creatinine > or =1.5 mg/dl for women and > or =2.0 mg/dl for men) were seen between October 1994 and September 1998 at five nephrology outpatient clinics in the Boston area. The mean (SD) age of the patients was 63 (15.5) yr, and 53% were male. At the first nephrology visit, mean (SD) serum creatinine was 3.2 (1.6) mg/dl, and mean (SD) predicted GFR was 22.3 (8.9) ml/min per 1.73 m(2). Laboratory tests for iron levels were performed in only 18% of patients, serum parathyroid hormone levels were obtained in only 15%, lipid studies were obtained in fewer than half, and among patients with diabetes, only 28% had a glycosylated hemoglobin level measured. A hematocrit <30% was present in 38%, and abnormal calcium-phosphorus metabolism was noted in 55%. Only 59% of patients who had hematocrit <30% received recombinant human erythropoietin. Among patients who received recombinant human erythropoietin, only 47% received iron. Angiotensin-converting enzyme inhibitor use was recorded for only 65% of patients with diabetes (49% of patients overall). Among patients who were known to have progressed to ESRD, only 41% had permanent access placed before initiation of dialysis. There seems to be room for improvement in the management of patients with CRI, which could result in a slower rate of progression of CRI and reduced severity of comorbid conditions.