David A Goodkin

Arbor Research Collaborative for Health, Ann Arbor, Michigan, United States

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Publications (61)404.91 Total impact

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    Full-text · Dataset · Dec 2015
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    Full-text · Dataset · Dec 2015
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    Full-text · Dataset · Dec 2015
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    ABSTRACT: Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX140-B, a selective inhibitor of C-C chemokine receptor type 2 (CCR2), could further reduce albuminuria when given in addition to standard care, including ACE inhibitors or ARBs. In this randomised, double-blind, placebo-controlled clinical trial, we recruited patients from 78 research centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. We enrolled patients with type 2 diabetes aged 18-75 years with proteinuria (first morning void urinary albumin to creatinine ratio [UACR] 100-3000 mg/g), estimated glomerular filtration rate of 25 mL/min per 1·73 m(2) or higher, and taking stable antidiabetic treatment and ACE inhibitors or ARBs, for at least 8 weeks before study entry. Patients were stratified based on baseline UACR and renal function (estimated glomerular filtration rate), and then randomly assigned (1:1:1) via an interactive web response system with a minimisation algorithm to oral placebo, 5 mg CCX140-B, or 10 mg CCX140-B once a day. The 12-week dosing period in the initial protocol was extended to 52 weeks by protocol amendment. The primary efficacy measure was change from baseline in UACR during 52 weeks in the modified intention-to-treat population (all patients with uninterrupted dosing, excluding patients who stopped dosing at week 12 either permanently under the original protocol, or temporarily because of delay in approval of the protocol amendment). We did safety analyses on all randomly assigned patients who received at least one dose of study drug. According to a prespecified analysis plan, we analysed the primary endpoint with one-sided statistical testing with calculation of upper 95% confidence limits of the differences between active and control. This trial is registered with ClinicalTrials.gov, number NCT01447147. The study ran from Dec 7, 2011 (first patient enrolled), until Aug 4, 2014. We enrolled 332 patients: 111 were assigned to receive placebo, 110 to 5 mg CCX140-B, and 111 to 10 mg CCX140-B. Of these, 192 were included in the modified intention-to-treat population. UACR changes from baseline during 52 weeks were -2% for placebo (95% CI -11% to 9%), -18% for 5 mg CCX140-B (-26% to -8%), and -11% for 10 mg CCX140-B (-20% to -1%). We recorded a -16% difference between 5 mg CCX140-B and placebo (one-sided upper 95% confidence limit -5%; p=0·01) and a -10% difference between 10 mg CCX140-B and placebo (upper 95% confidence limit 2%; p=0·08). Adverse events occurred in 81 (73%) of 111 patients in the placebo group versus 71 (65%) of 110 patients in the CCX140-B 5 mg group and 68 (61%) of 111 patients in the CCX140-B 10 mg group; there were no renal events during the study. Our data suggest that CCR2 inhibition with CCX140-B has renoprotective effects on top of current standard of care in patients with type 2 diabetes and nephropathy. ChemoCentryx. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Aug 2015
  • David A Goodkin · Brian Bieber

    No preview · Article · Jun 2015 · American Journal of Nephrology
  • David A Goodkin · George R Bailie
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    ABSTRACT: Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
    No preview · Article · Jun 2015 · Kidney International
  • David A. Goodkin · George R. Bailie

    No preview · Article · Mar 2015 · American Journal of Kidney Diseases
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    ABSTRACT: Intravenous (IV) iron is required for optimal management of anemia in the majority of hemodialysis (HD) patients. While IV iron prescription has increased over time, the best dosing strategy is unknown and any effect of IV iron on survival is unclear. Here we used adjusted Cox regression to analyze associations between IV iron dose and clinical outcomes in 32,435 HD patients in 12 countries from 2002 to 2011 in the Dialysis Outcomes and Practice Patterns Study. The primary exposure was total prescribed IV iron dose over the first 4 months in the study, expressed as an average dose/month. Compared with 100-199 mg/month (the most common dose range), case-mix-adjusted mortality was similar for the 0, 1-99, and 200-299 mg/month categories but significantly higher for the 300-399 mg/month (HR of 1.13, 95% CI of 1.00-1.27) and 400 mg/month or more (HR of 1.18, 95% CI of 1.07-1.30) groups. Convergent validity was proved by an instrumental variable analysis, using HD facility as the instrument, and by an analysis expressing IV iron dose/kg body weight. Associations with cause-specific mortality (cardiovascular, infectious, and other) were generally similar to those for all-cause mortality. The hospitalization risk was elevated among patients receiving 300 mg/month or more compared with 100-199 mg/month (HR of 1.12, 95% CI of 1.07-1.18). In light of these associations, a well-powered clinical trial to evaluate the safety of different IV iron-dosing strategies in HD patients is urgently needed.Kidney International advance online publication, 30 July 2014; doi:10.1038/ki.2014.275.
    Full-text · Article · Jul 2014 · Kidney International
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    ABSTRACT: Introduction and Aims: In clinical practice it has been reported that hypomagnesaemia is associated to low mineral density. On the other hand in vitro studies have shown that magnesium (Mg) decreases calcification in vascular smooth muscle cells. But the effects of increasing Mg levels on bone homeostasis are poorly understood. Here we elucidate the effects of elevated Mg on the osteogenic differentiation of rat MSC and hence on bone metabolism. Methods: MSC were differentiated to osteoblasts by incubation with dexamethasone, β-glycerol phosphate and ascorbic acid at different Mg concentrations. Mineralization capacity and osteoblastic markers were measured. Involvement of canonical Wnt and Notch signaling pathways in this process was analyzed by immunofluorescence. Inhibition of Mg channel TRPM7 with 2-aminoethoxydiphenyl borate (2-APB) was also studied. Results: Elevated Mg increases matrix mineralization, alkaline phosphatase activity and FGF-23 production in rat MSC. Further, the expression of osteoblast master genes such as Runx2, Osterix and Osteocalcin was augmented (Table 1). No significant differences on nuclear translocation of β-catenin were observed. However, translocation of Notch1 intracellular domain (NICD) into the nuclei increased significantly in osteoblasts cultured with rising Mg concentrations. Further, Mg promoted proliferation indicated by increasing CyclinD1 and PCNA levels. 2-APB administration decreased nuclear NICD, alkaline phosphatase activity, osteoblast master genes and proliferation marker expression. Conclusions: Our data strongly suggest that Mg directly enhances osteogenesis in rat MSC. View larger version: In this window In a new window Download as PowerPoint Slide
    Full-text · Article · May 2014 · Nephrology Dialysis Transplantation
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    ABSTRACT: Background: Although potassium-binding sodium-based resins (K resins) have been prescribed to treat hyperkalemia for 50 years, there have been no large studies of their effects among hemodialysis (HD) patients. Methods: Data from 11,409 patients in the Dialysis Outcomes and Practice Patterns Study in Belgium, Canada, France, Italy, and Sweden (nations where ≥5% of patients were prescribed a sodium- based K resin; seven other countries had <5% use) between 2002 and 2011 were analyzed. Linear mixed models examined associations between K resin use and interdialytic weight gain (IDWG) and serum electrolyte concentrations. Mortality was analyzed using Cox regression. An instrumental variable approach was used to partially account for unmeasured confounders. Results: The K resin prescription rate was 20% overall. As hypothesized, patients prescribed a K resin had greater IDWG and higher serum bicarbonate, phosphorus, and sodium (but not calcium) concentrations. Patients prescribed a K resin had higher serum K levels, but serum K levels were lower in an instrumental variable analysis limiting treatment by indication bias. K resin use was not associated with mortality risk. Conclusion: We report the first large study of K resin use and associated laboratory and clinical outcomes in HD patients. The prescription rate of K resins varied dramatically by country and dialysis center. The results suggest that K resin use may effectively lower serum K, although at the expense of somewhat higher phosphatemia and greater IDWG, and had no clear association with mortality. Further study is warranted to elucidate the optimal role for K resins in modern dialysis care.
    No preview · Article · Mar 2014 · American Journal of Nephrology
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    ABSTRACT: Background: Hepatitis C virus (HCV) infection is associated with increased mortality among hemodialysis (HD) patients. Guidelines from Kidney Disease: Improving Global Outcomes recommend that infected HD patients awaiting renal transplantation be treated for HCV and that clinicians decide whether to treat other infected patients on a case-by-case basis. We evaluated the extent and outcome of HCV therapy among HD patients. Methods: The Dialysis Outcomes and Practice Patterns Study is an observational study; 49,762 HD patients in 12 nations enrolled between 1996 and 2011. We reviewed HCV status, use of interferon or ribavirin, and survival over a median 1.4 years per study phase. Results: 4,735 patients (9.5%) were HCV+. Only 48 (1.0%) of the 4,589 HCV+ patients with prescription data were receiving antiviral medication. Among the subset of 617 HCV+ patients also known to be on a waiting list for renal transplantation, only 3.7% were receiving treatment. After restricting to HCV+ patients with overlapping propensity for antiviral treatment, 4 (9.5%) of 42 treated patients and 638 (21.0%) of 3,037 untreated patients died. The hazard ratio for adjusted mortality comparing treated patients with untreated patients was 0.47 (95% CI, 0.17-1.26). Conclusions: HD patients with hepatitis C infection very rarely receive antiviral therapy. Increased intervention might prolong survival for some patients and in particular might improve the prospects for those awaiting renal transplantation.
    No preview · Article · Oct 2013 · American Journal of Nephrology
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    ABSTRACT: To examine patterns of intravenous (IV) iron use across 12 countries from 1999 to 2011. Trends in iron use are described among 32 192 hemodialysis (HD) patients in the Dialysis Outcomes and Practice Patterns Study. Adjusted associations of IV iron dose with serum ferritin and transferrin saturation (TSAT) values were also studied. IV iron was administered to 50% of patients over 4 months in 1999, increasing to 71% during 2009-11, with increasing use in most countries. Among patients receiving IV iron, the mean monthly dose increased from 232 ± 167 to 281 ± 211 mg. Most countries used 3 to 4 doses/month, but Canada used about 2 doses/month, Italy increased from 3 to almost 6 doses/month and Germany used 5 to 6 doses/month. The USA and most European countries predominantly used iron sucrose and sodium ferric gluconate. A significant use of iron dextran was limited to Canada and France; iron polymaltose was used in Australia and New Zealand; and Japan used ferric oxide saccharate, chondroitin polysulfate iron complex and cideferron. Ferritin values rose in most countries: 22% of patients had ≥800 ng/mL in the recent years of study. TSAT levels increased to a lesser degree over time. Japan had much lower IV iron dosing and ferritin levels, but similar TSAT levels. In adjusted analyses, serum ferritin and TSAT levels increased signifcantly by 14 ng/mL and 0.16%, respectively, for every 100 mg/month higher mean monthly iron dose. IV iron prescription patterns varied between countries and changed over time from 1999 to 2011. IV iron use and dose increased in most countries, with notable increases in ferritin but not TSAT levels. With rising cumulative IV iron doses, studies of the effects of changing IV iron dosing and other anemia management practices on clinical outcomes should be a high priority.
    No preview · Article · Oct 2013 · Nephrology Dialysis Transplantation
  • David A Goodkin · Bruce M Robinson
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    ABSTRACT: Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
    No preview · Article · Mar 2013 · Kidney International
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    ABSTRACT: Aims: Treatment of renal anemia with erythropoietic stimulating agents sometimes increases blood pressure. It is uncertain whether this is due to direct vasoconstriction and/or increased red blood cell mass. Materials and methods: We conducted a post-hoc analysis of 160 critically ill patients in the EARLYARF trial with elevated urinary γ-glutamyltranspeptidase and alkaline phosphatase, indicating acute kidney injury. Patients received 2 doses of intravenous (i.v.) epoetin (500 U/kg), 24 hours apart, or placebo, in a randomized, double-blind study design. Hourly intra-arterial mean arterial pressure (MAP), and norepinephrine equivalent dose (NED: determined using equipotency conversion factors for doses of epinephrine, vasopressin, phenlyephrine, or dopamine) were extracted from clinical records. The differences between baseline and maximum MAP and NED (ΔMAP and ΔNED) over 4, 24, 72-hour, and 30-day periods following study drug administration were compared between groups. Results: At baseline, MAP was 78 ± 14 mmHg in the epoetin group and 81 ± 15 mmHg in the placebo group (p = 0.22). There were no differences between groups in ΔMAP (6 ± 14 versus 7 ± 14 mmHg; p = 0.53), in ΔNED, or in ΔMAP adjusted for ΔNED at 4 hours, or at any time points. A subgroup analysis of only those patients not requiring vasopressor support (n = 71) also showed no differences between epoetin and placebo for all outcomes. Conclusion: We concluded that intravenous high dose epoetin does not acutely increase blood pressure, suggesting no acute vasoconstrictor effect in this setting.
    No preview · Article · Jan 2013 · Clinical nephrology
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    ABSTRACT: KDOQI practice guidelines recommend predialysis blood pressure <140/90 mm Hg; however, most prior studies had found elevated mortality with low, not high, systolic blood pressure. This is possibly due to unmeasured confounders affecting systolic blood pressure and mortality. To lessen this bias, we analyzed 24,525 patients by Cox regression models adjusted for patient and facility characteristics. Compared with predialysis systolic blood pressure of 130-159 mm Hg, mortality was 13% higher in facilities with 20% more patients at systolic blood pressure of 110-129 mm Hg and 16% higher in facilities with 20% more patients at systolic blood pressure of ≥160 mm Hg. For patient-level systolic blood pressure, mortality was elevated at low (<130 mm Hg), not high (≥180 mm Hg), systolic blood pressure. For predialysis diastolic blood pressure, mortality was lowest at 60-99 mm Hg, a wide range implying less chance to improve outcomes. Higher mortality at systolic blood pressure of <130 mm Hg is consistent with prior studies and may be due to excessive blood pressure lowering during dialysis. The lowest risk facility systolic blood pressure of 130-159 mm Hg indicates this range may be optimal, but may have been influenced by unmeasured facility practices. While additional study is needed, our findings contrast with KDOQI blood pressure targets, and provide guidance on optimal blood pressure range in the absence of definitive clinical trial data.
    No preview · Article · Jun 2012 · Kidney International

  • No preview · Conference Paper · May 2012
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    No preview · Article · Jul 2011 · Blood Purification
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    David A Goodkin · Maria Larkina · Bruce M Robinson

    Preview · Article · Jul 2011 · Nephrology Dialysis Transplantation
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    ABSTRACT: INTRODUCTION AND AIMS: Higher residential altitude has been associated with greater erythropoietin response and longer survival in ESRD patients. It has been hypothesized that persistent activation of hypoxia-inducible factors (HIF) at higher altitude may explain these associations. Animal models have shown that inactivation of prolyl-hydroxylases - regulators of HIF - suppresses mammary gland proliferation in vitro, with similar findings in lung, brain, and hematopoietic cancer lines. Thus, HIF activation may also affect cancer incidence in vivo. No studies have evaluated the association between altitude and cancer incidence. METHODS: We studied incident ESRD patients (1996-2006) who had no diagnosis of cancer prior to initiation of chronic dialysis. We required 2 medical claims with a cancer diagnosis (except for non-melanoma skin cancer) to define incident cancer. We also used previously validated algorithms to ascertain six specific malignancies: breast, lung, gastric, and colorectal cancer, leukemia and lymphoma. Patients were stratified by residential altitude (<250 ft./76 m.; 250-1999 ft./76-609 m., 2000-3999 ft./610-1218 m., 4000-5999 ft./1219-1828 m., ≥6000 ft./1829 m.). Cox regression was used to study the univariate and adjusted (for demographics, comorbidities, laboratories) associations among residential altitude and these incident cancer outcomes. RESULTS: The Medical Evidence Report forms of 928965 incident ESRD patients indicated no diagnosis of cancer and 118878 (12.8%) patients were found to have any cancer during follow up. Univariate analyses revealed a monotonic decrease in cancer incidence with higher altitude (p<0.001), which was only slightly attenuated after full adjustment. Compared with patients residing near sea level (<250 ft.), the adjusted relative risks of cancer decreased by 5% (95% CI: 3-6%), 9% (4-13%), 13% (8-19%), and 14% (1-24%) among patients living at 250-1999, 2000-3999, 4000-5999, and ≥6000 ft., respectively (see metric conversion above). Using only the six validated cancer algorithms above, the associations were even more pronounced. CONCLUSIONS: Higher residential altitude among ESRD patients was associated with lower cancer incidence despite adjustment for a large number of factors. While causality cannot be inferred from our study, our findings corroborate in vitro studies showing reduced cancer cell growth with prolyl-hydroxylase inhibition.
    No preview · Article · Jun 2011 · CKJ: Clinical Kidney Journal
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    ABSTRACT: A small percentage of hemodialysis patients maintain higher hemoglobin concentrations without transfusion or erythropoietic therapy. Because uncertainty exists regarding the effects of higher hemoglobin concentration on mortality and quality of life among hemodialysis patients, studying this group of patients with sufficient endogenous erythropoietin may provide additional insights. The prospective, observational Dialysis Outcomes and Practice Patterns Study provides an opportunity to investigate this group. Among 29,796 patients in 12 nations, 545 (1.8%) maintained hemoglobin concentrations >12 g/dl for 4 months without erythropoietic support. This subset tended to be male, to have a longer duration of end-stage renal disease, and to not dialyze via a catheter. Cystic disease as the underlying cause of renal failure was over-represented in this group but was present in only 25%. Lung disease, smoking, and cardiovascular disease were associated with increased likelihood of naturally higher hemoglobin concentration. Quality-of-life scores were not higher among this subset compared with the other patients. Unadjusted mortality risk for patients with hemoglobin >12 g/dl and no erythropoietic therapy was lower than for the other patients, but after thorough adjustment for case mix, there was no difference between groups (relative risk, 0.98; 95% CI 0.80 to 1.19). These data show that naturally occurring hemoglobin concentration >12 g/dl does not associate with increased mortality among hemodialysis patients.
    Full-text · Article · Feb 2011 · Journal of the American Society of Nephrology

Publication Stats

6k Citations
404.91 Total Impact Points

Institutions

  • 2008-2015
    • Arbor Research Collaborative for Health
      Ann Arbor, Michigan, United States
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 2011
    • University of Toronto
      Toronto, Ontario, Canada
  • 2010
    • Universidade Federal da Bahia
      Bahia, Bahia, Brazil
  • 2004
    • Renal Research Institute
      New York, New York, United States
  • 2002-2004
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2003
    • Wakayama Medical University
      Wakayama, Wakayama, Japan
  • 1997-2002
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1999
    • University of Michigan
      Ann Arbor, Michigan, United States