11 results on '"Polu KR"'
Search Results
2. Clinical problem-solving. Needle in a haystack.
- Author
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Polu KR, Wolf M, Polu, Krishna R, and Wolf, Myles
- Published
- 2006
3. Stress fracture of the humerus in a collegiate baseball pitcher: a case report.
- Author
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Polu KR, Schenck RC Jr., Wirth MA, Greeson J, Cone RO III, and Rockwood CA Jr.
- Published
- 1999
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4. An open-label, sequential, dose-finding study of peginesatide for the maintenance treatment of anemia in chronic hemodialysis patients
- Author
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Besarab Anatole, Zeig Steven N, Martin Edouard R, Pergola Pablo E, Whittier Frederick C, Zabaneh Raja I, Schiller Brigitte, Mayo Martha, Francisco Carol A, Polu Krishna R, and Duliege Anne-Marie
- Subjects
Anemia ,Chronic kidney disease ,Erythropoiesis-stimulating agent ,Epoetin alfa ,Hemodialysis ,Peginesatide ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background Peginesatide is a peptide-based erythropoiesis-stimulating agent that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. The primary objective of this phase 2 dose-finding study was to determine the once-monthly peginesatide dosing strategy that would maintain hemoglobin within ±1.0 g/dL of baseline values after conversion from epoetin alfa; the safety of peginesatide was evaluated concurrently. Methods Chronic hemodialysis patients on stable regimens of epoetin alfa were sequentially assigned to cohorts that differed on (1) how the peginesatide starting dose was determined (using a single epoetin alfa–to-peginesatide dose conversion ratio or a tiered, weight-based or absolute-dose conversion table) and on (2) whether or not a 1-week erythropoiesis-stimulating agent-free interval was used. Peginesatide doses were titrated to maintain hemoglobin levels within ±1.0 g/dL from baseline. Results A total of 164 patients were enrolled and received intravenous peginesatide every 4 weeks for up to 6 doses; the duration of the study including follow-up was ≤29 weeks. Overall, the proportion of patients with hemoglobin levels within ±1.0 g/dL of baseline increased over the course of the study from 39% (Weeks 2–13) to 54% (Weeks 18–25). Cohorts that used tiered dose conversion tables trended towards having more stable peginesatide doses than did those cohorts that used a single dose conversion ratio. Moreover, cohorts that used an erythropoiesis-stimulating agent-free interval did not have the substantial initial increase in hemoglobin levels that was seen in those cohorts that did not use such an interval. In this study, the safety profile of peginesatide was consistent with those of marketed erythropoiesis-stimulating agents. Conclusions The results of this study were used to guide the dosing regimens used subsequently in phase 3 studies. Once-monthly peginesatide is feasible in hemodialysis patients. Trial registration ClinicalTrials.gov registration: NCT00228449
- Published
- 2012
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5. NPHS2 variation in focal and segmental glomerulosclerosis
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Savige Judy, Jerums George, Kaplan Bernard S, Al-Waheeb Salah, Katz Avi, Falk Ronald J, Appel Gerald B, Uscinski Andrea, Polu Krishna, Needham Alexander, Tonna Stephen J, Harmon Jennifer, Zhang Kang, Curhan Gary C, and Pollak Martin R
- Subjects
Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background Focal and segmental glomerulosclerosis (FSGS) is the most common histologic pattern of renal injury seen in adults with idiopathic proteinuria. Homozygous or compound heterozygous mutations in the podocin gene NPHS2 are found in 10–30% of pediatric cases of steroid resistant nephrosis and/or FSGS. Methods We studied the spectrum of genetic variation in 371 individuals with predominantly late onset FSGS (mean age of onset 25 years) by analysis of DNA samples. Results We identified 15 non-synonymous alleles that changed the amino acid sequence in 63 of the subjects screened (17%). Eight of these (p.R138Q, p.V180M, p.R229Q, p.E237Q, p.A242V, p.A284V, p.L327F and the frameshift 855–856 delAA) are alleles previously reported to cause FSGS in either the homozygous or compound heterozygous states, while the remaining 7 (p.R10T, p.V127W, p.Q215X, p.T232I, p.L270F, p.L312V and the frameshift 397delA) are novel alleles that have not been demonstrated previously. Twelve individuals of the 371 (3.2%) screened had two likely disease-causing NPHS2 alleles, present in either a homozygous or compound heterozygous state. We genotyped the two most common of the non-synonymous NPHS2 alleles (p.A242V and p.R229Q) identified by resequencing in participants from the Nurses' Health Study and also genotyped p.R229Q in 3 diabetic cohorts. We found that the presence of either of these variants does not significantly alter the risk of albuminuria in the Nurses' Health participants, nor does p.R229Q associate with "diabetic nephropathy". Conclusion NPHS2 mutations are a rare cause of FSGS in adults. The most common non-synonymous NPHS2 variants, p.R229Q and p.A242V, do not appear to alter the risk of proteinuria in the general population nor does p.R229Q associate with measures of kidney dysfunction in diabetic individuals. Our results help clarify the frequency of FSGS-causing NPHS2 mutations in adults and broaden our understanding of the spectrum of NPHS2 mutations that lead to human disease.
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- 2008
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6. The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses.
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Chalmers SA, Ayilam Ramachandran R, Garcia SJ, Der E, Herlitz L, Ampudia J, Chu D, Jordan N, Zhang T, Parodis I, Gunnarsson I, Ding H, Shen N, Petri M, Mok CC, Saxena R, Polu KR, Connelly S, Ng CT, Mohan C, and Putterman C
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- Animals, Female, Humans, Kidney pathology, Lupus Nephritis pathology, Mice, T-Lymphocytes pathology, Antigens, CD immunology, Antigens, Differentiation, T-Lymphocyte immunology, Cell Adhesion Molecules, Neuronal immunology, Fetal Proteins immunology, Kidney immunology, Lupus Nephritis immunology, Lymphocyte Activation, T-Lymphocytes immunology
- Abstract
T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.
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- 2022
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7. Probody therapeutics for targeting antibodies to diseased tissue.
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Polu KR and Lowman HB
- Subjects
- Animals, Antigens immunology, Humans, Immunoconjugates chemistry, Immunoglobulin G metabolism, Immunoglobulin G therapeutic use, Prodrugs metabolism, Protein Engineering, Antibodies, Bispecific therapeutic use, Immunoconjugates therapeutic use, Molecular Targeted Therapy methods, Prodrugs therapeutic use
- Abstract
Probodies are proteolytically activated antibodies engineered to remain inert until activated locally in diseased tissue. In principle, any therapeutic antibody can be converted into Probody™ form. In this perspective, we highlight the emerging therapeutic potential of the Probody approach in the form of conventional IgG-based Probodies as well as in the form of 'empowered Probody' formats such as Probody-drug conjugates.
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- 2014
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8. Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis.
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Macdougall IC, Provenzano R, Sharma A, Spinowitz BS, Schmidt RJ, Pergola PE, Zabaneh RI, Tong-Starksen S, Mayo MR, Tang H, Polu KR, Duliege AM, and Fishbane S
- Subjects
- Aged, Anemia etiology, Antibodies blood, Cardiovascular Diseases etiology, Darbepoetin alfa, Disease-Free Survival, Drug Administration Schedule, Erythropoietin adverse effects, Erythropoietin therapeutic use, Female, Hematinics adverse effects, Hemoglobins analysis, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Peptides adverse effects, Peptides immunology, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic mortality, Anemia drug therapy, Erythropoietin analogs & derivatives, Hematinics therapeutic use, Peptides therapeutic use, Renal Insufficiency, Chronic therapy
- Abstract
Background: Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peginesatide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis., Methods: In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.025 mg or 0.04 mg per kilogram of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 μg per kilogram. Doses of both drugs were adjusted to achieve and maintain hemoglobin levels between 11.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was -1.0 g per deciliter or higher. Cardiovascular safety was evaluated on the basis of an adjudicated composite end point., Results: In both studies and at both starting doses, peginesatide was noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], -0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, -0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide., Conclusions: The efficacy of peginesatide (administered monthly) was similar to that of darbepoetin (administered every 2 weeks) in increasing and maintaining hemoglobin levels. However, cardiovascular events and mortality were increased with peginesatide in patients with chronic kidney disease who were not undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00598273 [PEARL 1], NCT00598442 [PEARL 2], NCT00597753 [EMERALD 1], and NCT00597584 [EMERALD 2].).
- Published
- 2013
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9. Peginesatide in patients with anemia undergoing hemodialysis.
- Author
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Fishbane S, Schiller B, Locatelli F, Covic AC, Provenzano R, Wiecek A, Levin NW, Kaplan M, Macdougall IC, Francisco C, Mayo MR, Polu KR, Duliege AM, and Besarab A
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- Aged, Anemia etiology, Antibodies blood, Disease-Free Survival, Drug Administration Schedule, Erythropoietin adverse effects, Female, Hematinics adverse effects, Hemoglobins analysis, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Peptides adverse effects, Peptides immunology, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic mortality, Anemia drug therapy, Erythropoietin therapeutic use, Hematinics therapeutic use, Peptides therapeutic use, Renal Dialysis adverse effects, Renal Insufficiency, Chronic therapy
- Abstract
Background: Peginesatide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease., Methods: We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point--death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia--with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3., Results: In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort., Conclusions: Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].).
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- 2013
- Full Text
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10. Dose-finding study of peginesatide for anemia correction in chronic kidney disease patients.
- Author
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Macdougall IC, Wiecek A, Tucker B, Yaqoob M, Mikhail A, Nowicki M, MacPhee I, Mysliwiec M, Smolenski O, Sułowicz W, Mayo M, Francisco C, Polu KR, Schatz PJ, and Duliege AM
- Subjects
- Adult, Aged, Aged, 80 and over, Anemia blood, Anemia etiology, Biomarkers blood, Chronic Disease, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Hematinics adverse effects, Hemoglobins metabolism, Humans, Injections, Intravenous, Injections, Subcutaneous, Kidney Diseases blood, Male, Middle Aged, Peptides adverse effects, Poland, Regression Analysis, Time Factors, Treatment Outcome, United Kingdom, Anemia drug therapy, Hematinics administration & dosage, Kidney Diseases complications, Peptides administration & dosage
- Abstract
Background and Objectives: Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent. We report the first assessment of its efficacy and safety in correcting renal anemia in a population of 139 nondialysis chronic kidney disease patients., Design, Setting, Participants, & Measurements: Chronic kidney disease patients who were not on dialysis and not receiving treatment with erythropoiesis-stimulating agents in the 12 weeks before study drug administration were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (different body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and frequency of administration (every 4 or 2 weeks)., Results: Across all cohorts, 96% of patients achieved a hemoglobin response. A dose-response relationship was evident for hemoglobin increase. Comparable subcutaneous and intravenous peginesatide doses produced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions >13 g/dl tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing. The range of final median doses in the every-4-weeks dosing groups was 0.019 to 0.043 mg/kg. Across all cohorts, 20% of patients reported serious adverse events (one patient had a possibly drug-related serious event) and 81% reported adverse events (11.5% reported possibly drug-related events); these events were consistent with those routinely observed in this patient population., Conclusions: This study suggests that peginesatide administered every 4 weeks can increase and maintain hemoglobin in nondialysis chronic kidney disease patients. Additional long-term data in larger groups of patients are required to further elucidate the efficacy and safety of this peptide-based erythropoiesis-stimulating agent.
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- 2011
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11. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.
- Author
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Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, and Pollak MR
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- Adolescent, Adult, Calcium Channels genetics, Calcium Channels physiology, Cells, Cultured, Chromosomes, Human, Pair 11 genetics, Glomerulosclerosis, Focal Segmental pathology, Humans, Kidney Glomerulus pathology, Microscopy, Immunoelectron, Middle Aged, Mutation, Pedigree, TRPC Cation Channels, TRPC6 Cation Channel, Calcium Channels metabolism, Glomerulosclerosis, Focal Segmental genetics, Kidney Glomerulus metabolism
- Abstract
Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.
- Published
- 2005
- Full Text
- View/download PDF
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