Kidney transplantation improves survival and quality of life for patients with end-stage renal disease. Lifelong immunosuppressive therapy (IST) is required for kidney transplant (graft) survival, at an average cost of >$20,000 per year.1Tanriover B. Stone P.W. Mohan S. et al.Future of Medicare immunosuppressive drug coverage for kidney transplant recipients in the United States.Clin J Am Soc Nephrol. 2013; 8: 1258-1266Crossref PubMed Scopus (28) Google Scholar More than 10% of graft failure cases are attributed to IST nonadherence.1Tanriover B. Stone P.W. Mohan S. et al.Future of Medicare immunosuppressive drug coverage for kidney transplant recipients in the United States.Clin J Am Soc Nephrol. 2013; 8: 1258-1266Crossref PubMed Scopus (28) Google Scholar Under current US policy, Medicare IST coverage is limited to 3 years after transplantation for nondisabled recipients <65 years of age. Transplant survival rates in the United States are lower than those in developed nations that provide lifelong government-funded IST.2Gill J.S. Tonelli M. Penny wise, pound foolish? Coverage limits on immunosuppression after kidney transplantation.N Engl J Med. 2012; 366: 586-589Crossref PubMed Scopus (58) Google Scholar Patients with lifelong Medicare coverage have substantially better >3-year outcomes than those whose Medicare is limited to 3 years after transplantation,2Gill J.S. Tonelli M. Penny wise, pound foolish? Coverage limits on immunosuppression after kidney transplantation.N Engl J Med. 2012; 366: 586-589Crossref PubMed Scopus (58) Google Scholar and 51% of surveyed adult US transplant centers reported deaths or graft failures due to cost-related IST nonadherence.3Evans R.W. Applegate W.H. Briscoe D.M. et al.Cost-related immunosuppression nonadherence in among kidney transplant recipients.Clin J Am Soc Nephrol. 2010; 5: 2323-2328Crossref PubMed Scopus (79) Google Scholar Advocates for legislation to increase the duration of Medicare IST coverage contend that this would likely improve IST adherence.1Tanriover B. Stone P.W. Mohan S. et al.Future of Medicare immunosuppressive drug coverage for kidney transplant recipients in the United States.Clin J Am Soc Nephrol. 2013; 8: 1258-1266Crossref PubMed Scopus (28) Google Scholar, 2Gill J.S. Tonelli M. Penny wise, pound foolish? Coverage limits on immunosuppression after kidney transplantation.N Engl J Med. 2012; 366: 586-589Crossref PubMed Scopus (58) Google Scholar However, IST adherence has not been reported in a cohort of US transplant recipients who receive lifelong IST at no out-of-pocket cost. We studied IST adherence rates in adult US Military Healthcare System beneficiaries, who receive free lifelong IST after transplantation. This study was approved by Walter Reed National Military Medical Center’s institutional review board. Informed consent was obtained from adult (≥18 years of age) kidney transplant recipients seen in the Walter Reed National Military Medical Center nephrology or organ transplant clinics. Demographic and clinical characteristics were ascertained by an electronic medical record review. Patients were recruited consecutively and were administered the Immunosuppressive Therapy Adherence Scale (ITAS) and Beck Depression Inventory-II (BDI-II). The ITAS is a questionnaire that consists of 4 questions measuring IST nonadherence, each scored by percentage of nonadherence (0 points for >50% of the time, 1 point for 21%–50% of the time, 2 points for 1%–20% of the time, 3 points for 0% of the time).4Chisholm M.A. Lance C.E. Williamson G.M. Mulloy L.L. Development and validation of the immunosuppressant therapy adherence instrument (ITAS).Patient Educ Couns. 2005; 59: 13-20Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar ITAS scores range from 0 (score of 0 for each question) to 12 (score of 3 for each of the 4 questions). Subjects with ITAS scores of 12/12 were considered to have perfect adherence,5Cukor D. Rosenthal D.S. Jindal R.M. et al.Depression is an important contributor to low medication adherence in hemodialyzed patients and transplant recipients.Kidney Int. 2009; 75: 1223-1229Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar and were compared with subjects with ITAS scores of ≤11/12. The BDI-II is a self-report instrument that contains 21 items. BDI-II scores range from 0 to 63, with higher scores indicating the presence and severity of depressed mood.6Beck A.T. Steer R.A. Brown G.K. BDI-II: Beck Depression Inventory Manual.2nd ed. Psychological Corporation, San Antonia, TX1996Google Scholar Univariate analyses were performed with χ2 testing for categorical variables (Fisher exact test used for violations of Cochran’s assumptions) and Student’s t-test for continuous variables. To assess whether the BDI-II score is independently associated with the likelihood of perfect versus not perfect adherence, we performed exact logistic regression, adjusting for date of transplant, sex, race, and age (STATA 13 SE; StataCorp, College Station, TX). Of 40 enrolled subjects, 39 (98%) completed the ITAS. A total of 37 (95%) subjects reported ITAS scores of ≥10, with 27 subjects (69%) reporting perfect adherence. Demographic, socioeconomic, and clinical data for subjects with perfect and not perfect adherence are listed in Table 1. There were no statistically significant demographic or socioeconomic differences between the 2 groups. Donor-specific antibody was positive in 3 of 24 (13%) tested subjects with perfect adherence, compared with 6 of 9 (67%) with not perfect adherence, a significant difference (P = 0.005) (Figure 1). There were otherwise no significant differences in clinical indicators between the 2 groups. Perfectly adherent subjects had significantly lower mean BDI-II scores (6.7 ± 7.2 vs. 13.6 ± 8.8; P = 0.01), and on exact multivariable logistic regression, a 5-point BDI-II score increase was associated with a significantly lower likelihood of perfect adherence (adjusted odds ratio, 0.61; 95% confidence interval, 0.32–0.98).Table 1Demographic and clinical characteristics of study subjects, and ITAS and BDI-II resultsVariablesPerfect adherence(ITAS 12/12)(n = 27)Not perfect adherence(ITAS ≤ 11/12)(n = 12)P-valueAge at the time of study (yr)51 ± 1656 ± 120.3Gender, n (%) Male18 (67)4 (33)0.08 Female9 (33)8 (67)Race, n (%)0.8 White13 (48)4 (33) Black9 (33)5 (42) Asian3 (11)3 (25) Hispanic2 (7)0Age (yr) at transplant49.81 ± 14.1651.58 ± 11.200.7Time since transplant, n (%) <3 yr18 (67)5 (42)0.2 >3 yr9 (3)7 (58)History of prior transplant, n (%) Yes4 (15)0 (0)0.3 No23 (85)12 (100)Type of transplant, n (%) Deceased donor18 (67)11 (92)0.1 Living donor9 (33)1 (8)Prior history of rejection, n (%) Yes2 (7)4 (33)0.06 No25 (93)8 (67)Donor-specific antibody at the time of survey Positive3 (11)6 (50)0.005 Negative21 (78)3 (25) Unknown3 (11)3 (25)Serum Cr at the time of survey (mg/dl)1.90 ± 1.511.43 ± 0.420.1Spot urine protein/Cr ratio at the time of survey0.65 ± 1.600.53 ± 0.760.8Education level, n (%) ≥College degree13 (48)5 (42)0.7 $75,00014 (52)7 (58)0.9 ≤$75,0009 (33)4 (33) Unreported4 (15)1 (8)ITAS score12 ± 0.0010.42 ± 1.00<0.001BDI-II score6.7 ± 7.1713.58 ± 8.760.01Data are n (%) or mean ± SD.BDI-II, Beck Depression Inventory-II; ITAS, Immunosuppressive Therapy Adherence Scale. Open table in a new tab Data are n (%) or mean ± SD. BDI-II, Beck Depression Inventory-II; ITAS, Immunosuppressive Therapy Adherence Scale. To our knowledge, this is the first report of IST adherence in US transplant recipients who receive lifelong IST at no cost, regardless of time since transplant, age, or disability status. Subjects in our study reported high levels of adherence, irrespective of demographic or socioeconomic factors, in contrast to prior studies where non-white race7Pinsky B.W. Takemoto S.K. Lentine K.L. et al.Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression.Am J Transplant. 2009; 9: 2597-2606Crossref PubMed Scopus (258) Google Scholar, 8Dew M.D. DiMartini A.F. De Vito Dabbs A. et al.Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation.Transplantation. 2007; 83: 858-873Crossref PubMed Scopus (415) Google Scholar and low income8Dew M.D. DiMartini A.F. De Vito Dabbs A. et al.Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation.Transplantation. 2007; 83: 858-873Crossref PubMed Scopus (415) Google Scholar were associated with nonadherence. Less adherent subjects had higher BDI scores, and modest increases in BDI score associated significantly with a lower likelihood of perfect adherence. Subjects with less than perfect adherence on the ITAS were significantly more likely to have positive donor-specific antibody, emphasizing the clinical relevance of modest degrees of nonadherence. Limitations to our study include the small sample size and cross-sectional design. An alternative explanation for the association between depression and nonadherence is that the use of self-reporting to quantify adherence may have led to a positive response bias whereby subjects overestimated their IST adherence, which may have been present to a lesser degree in patients with depressed mood. Therefore, the inverse association between the BDI score and self-reported adherence should be interpreted with caution. Strengths include detailed characterization of the cohort’s broad demographic, socioeconomic, and clinical characteristics. Our results support the provision of a large, prospective, controlled study to investigate the effect of providing long-term IST at no cost to US renal transplant recipients, and highlight the importance of identifying and treating depression after kidney transplantation. The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of the Army, the Department of the Navy, the Department of Defense, or the United States government. All the authors declared no competing interests.

BACKGROUND AND OBJECTIVES:Mortality and CKD risk have not been described in military casualties with post-traumatic AKI requiring RRT suffered in the Iraq and Afghanistan wars. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:This is a retrospective case series of post-traumatic AKI requiring RRT in 51 military health care beneficiaries (October 7, 2001-December 1, 2013), evacuated to the National Capital Region, documenting in-hospital mortality and subsequent CKD. Participants were identified using electronic medical and procedure records. RESULTS:Age at injury was 26±6 years; of the participants, 50 were men, 16% were black, 67% were white, and 88% of injuries were caused by blast or projectiles. Presumed AKI cause was acute tubular necrosis in 98%, with rhabdomyolysis in 72%. Sixty-day all-cause mortality was 22% (95% confidence interval [95% CI], 12% to 35%), significantly less than the 50% predicted historical mortality (P<0.001). The VA/NIH Acute Renal Failure Trial Network AKI integer score predicted 60-day mortality risk was 33% (range, 6%-96%) (n=49). Of these, nine died (mortality, 18%; 95% CI, 10% to 32%), with predicted risks significantly miscalibrated (P<0.001). The area under the receiver operator characteristic curve for the AKI integer score was 0.72 (95% CI, 0.56 to 0.88), not significantly different than the AKI integer score model cohort (P=0.27). Of the 40 survivors, one had ESRD caused by cortical necrosis. Of the remaining 39, median time to last follow-up serum creatinine was 1158 days (range, 99-3316 days), serum creatinine was 0.85±0.24 mg/dl, and eGFR was 118±23 ml/min per 1.73 m(2). No eGFR was <60 ml/min per 1.73 m(2), but it may be overestimated because of large/medium amputations in 54%. Twenty-five percent (n=36) had proteinuria; one was diagnosed with CKD stage 2. CONCLUSIONS:Despite severe injuries, participants had better in-hospital survival than predicted historically and by AKI integer score. No patient who recovered renal function had an eGFR<60 ml/min per 1.73 m(2) at last follow-up, but 23% had proteinuria, suggesting CKD burden.

Exertional rhabdomyolysis can cause significant morbidity, including acute kidney injury (AKI),1Bosch X. PochE Grau JM. Rhabdomyolysis and acute kidney injury.N Engl J Med. 2009; 361: 62-72Crossref PubMed Scopus (894) Google Scholar, 2Landau M.E. Kenney K. Deuster P. Campbell W. Exertional rhadomyolysis: a clinical review with a focus on genetic influences.J Clin Neuromusc Dis. 2012; 13: 122-136Crossref PubMed Scopus (59) Google Scholar, 3Wald R. Quinn R.R. Luo J. et al.Chronic dialysis and death among survivors of acute kidney injury requiring dialysis; University of Toronto Acute Kidney Injury Research Group.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (555) Google Scholar which is associated with future CKD and death.3Wald R. Quinn R.R. Luo J. et al.Chronic dialysis and death among survivors of acute kidney injury requiring dialysis; University of Toronto Acute Kidney Injury Research Group.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (555) Google Scholar In the US Armed Forces, African Americans have a higher risk of exertional rhabdomyolysis than whites,4Armed Forces Health Surveillance CenterUpdate: exertional rhabdomyolysis, active component, U.S Armed Forces, 2009-2013.MSMR. 2014; 21: 14-17Google Scholar possibly related to genetic risk and enzymatic deficiencies, as has been identified in recurrent rhabdomyolysis.1Bosch X. PochE Grau JM. Rhabdomyolysis and acute kidney injury.N Engl J Med. 2009; 361: 62-72Crossref PubMed Scopus (894) Google Scholar, 2Landau M.E. Kenney K. Deuster P. Campbell W. Exertional rhadomyolysis: a clinical review with a focus on genetic influences.J Clin Neuromusc Dis. 2012; 13: 122-136Crossref PubMed Scopus (59) Google Scholar However, biomarkers that may confer increased risk for initial exertional rhabdomyolysis have not yet been investigated. During acute exertional rhabdomyolysis, CK is elevated,5Neal R.C. Ferdinand K.C. Ycas J. Miller E. Relationship of ethnic orgin, gender, and age to blood creatine kinase levels.Am J Med. 2009; 122: 73-78Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar while CoQ10 is not well described.6Joy T.R. Hegele R.A. Narrative review: statin-related myopathy.Ann Intern Med. 2009; 150: 858-868Crossref PubMed Scopus (366) Google Scholar But both primary and secondary CoQ10 deficiencies are associated with elevated CK, myopathy, and rhabdomyolysis.7Horvath R. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ10).J Inherit Metab Dis. 2012; 35: 679-687Crossref PubMed Scopus (60) Google Scholar, 8Potgieter M. Pretorius E. Pepper M.S. Primary and secondary coenzyme Q10 deficiency: the role of therapeutic supplementation.Nutr Rev. 2013; 71: 180-188Crossref PubMed Scopus (82) Google Scholar Also, CoQ10 is lower in patients with statin-induced myopathy, and some supplementation studies have demonstrated benefit.6Joy T.R. Hegele R.A. Narrative review: statin-related myopathy.Ann Intern Med. 2009; 150: 858-868Crossref PubMed Scopus (366) Google Scholar, 9Fedacko J. Pella D. Fedackova P. et al.Coenzyme Q(10) and selenium in statin-associated myopathy treatment.Can J Physiol Pharmacol. 2013; 91: 165-170Crossref PubMed Scopus (67) Google Scholar Therefore, we hypothesized that predisease CoQ10 and CK would be lower and higher, respectively, in exertional rhabdomyolysis patients versus matched controls. Because African Americans have higher exertional rhabdomyolysis risk and predisease CK,3Wald R. Quinn R.R. Luo J. et al.Chronic dialysis and death among survivors of acute kidney injury requiring dialysis; University of Toronto Acute Kidney Injury Research Group.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (555) Google Scholar we stratified by race. We performed a retrospective case-control study using Department of Defense Serum Repository (DoDSR) samples. Scr, CK, and CoQ10 in 44 military personnel prior to exertional rhabdomyolysis were compared to 120 healthy controls matched for age, sex, race, and age of serum. Detailed methodology (see Item S1) is similar to previous DoDSR studies.10Olson S.W. Owshalimpur D. Abbott K. et al.Relationship between asymptomatic proteinase 3 antibodies and future granulomatosis with polyangiitis.Clin J Am Soc Nephrol. 2013; 8: 1312-1318Crossref PubMed Scopus (20) Google Scholar Exertional rhabdomyolysis was defined as significant muscle pain or weakness following recent extreme physical exertion, with elevated CK (>5-fold above normal) and/or Scr > 2.0 mg/dL with documented evidence of heme pigment–induced AKI; patients were identified by electronic medical record. CoQ10, Scr, and CK were measured at Quest Diagnostics. Characteristics of the cases are shown in Table 1. McNemar χ2 test, Wilcoxon signed rank test, scatter plots, and conditional logistic regression analysis were performed with STATA 12.0.Table 1Characteristics of Exertional Rhabdomyolysis Cases, Stratified by Race and Disease SeverityAll Exertional RhabdomyolysisMild Exertional RhabdomyolysisSevere Exertional RhabdomyolysisAfrican American (n = 20)White (n = 24)African American (n = 10)White (n = 13)African American (n = 10)White (n = 11)Age, y27 [23-37]26 [21-35]24 [20-31]22 [19-25]31 [26-42]34 [26-39]Male sex95%100%100%100%90%100%Weight, lb187 [170-202]183 [168-200]183 [160-195]175 [168-192]201 [178-206]187 [180-209]Height, in70 [68-73]71 [68-72]69 [68-71]71 [70-72]72 [69-74]69 [67-72]BMI, kg/m226.6 [25-28.7]25.25 [23.4-28.2]26.6 [25.1-28.4]25 [22.2-27]26.8 [24-28.8]27.3 [24.4-28.7]Hospitalized95%96%90%92%100%100%Hospitalization duration, d5 [3-6]3 [2-3]4 [2-5]3 [2-3]9 [5-17]8 [5-11]Compartment syndrome5%0%0%0%10%0%Peak Scr, mg/dL2.9 [1.8-4.2]3.0 [2.0-5.6]1.8 [1.5-2.9]2.0 [1.7-2.4]4.5 [2.5-8.5]6.4 [4.5-15]Peak CK, U/L23,897 [1,942-118,000]7,459 [3,612-45,000]3,271 [1,429-8,059]4,879 [3,612-9,783]118,464 [88,601-160,000]45,000 [3,097-179,350]Ibuprofen20%21%10%30%30%18%Statin use5%0%10%0%0%0%Dialysis15%8%0%0%30%18%Intubation5%0%0%0%10%0%Note: Values for continuous variables were not normally distributed, so are given as median [interquartile range]. Open table in a new tab Note: Values for continuous variables were not normally distributed, so are given as median [interquartile range]. When comparing all cases against all healthy controls (ie, no stratification by race or disease severity), there was no difference in CoQ10, CK, or CK:CoQ10 ratio (Item S1). Among controls, African Americans had higher mean CK (186 vs 119 U/L, P = 0.003) and CoQ10 (0.67 vs 0.59 mg/L, P = 0.03) than whites. In African Americans, CK was higher in cases (predisease) than controls; the severe disease subgroup accounted for this difference. In contrast, among whites, cases did not have significantly higher predisease CK levels than controls. Among African Americans, cases had lower median CoQ10 than controls only in the severe exertional rhabdomyolysis subgroup. In whites, cases had higher CoQ10 than controls, primarily limited to the mild disease subgroup. The CK:CoQ10 ratio better distinguished African Americans at risk for future exertional rhabdomyolysis (Table 2). In African Americans, a greater percentage of severe exertional rhabdomyolysis patients had a predisease CK:CoQ10 > 460 than did controls (60% vs 7%, P = 0.002; OR, 20; 95% CI, 2.9-132). By conditional logistic regression, there were significant associations with exertional rhabdomyolysis for predisease log(CK) and log(CPK:CoQ10) in African Americans (ORs of 2.2 [95% CI, 2.9-132; P = 0.002] and 2.7 [95% CI, 1.1-6.6; P = 0.03], respectively), and for predisease log(CoQ10) in whites (OR, 5.1; 95% CI, 1.1-32; P = 0.04). Scatter plots did not show a strong correlation between CK and CoQ10 (Item S1).Table 2Comparison of Scr, CK, CoQ10, and CK:CoQ10 Ratio Prior to Exertional Rhabdomyolysis in Cases Versus Matched Healthy Controls, Stratified by Race and Disease SeverityAll Exertional RhabdomyolysisMild Exertional RhabdomyolysisSevere Exertional RhabdomyolysisCasesControlsCasesControlsCasesControlsAfrican AmericansNo.205510271028Scr, mg/dL1.07 [0.98-1.19]1.04 [0.92-1.14]1.05 [0.97-1.19]1.06 [0.94-1.18]1.10 [1.00-1.26]1.02 [0.92-1.11]CK, U/L268aP<0.05 for comparison between cases and controls within the same classification (all, mild, severe). [112-328]186aP<0.05 for comparison between cases and controls within the same classification (all, mild, severe). [89-244]231 [112-328]208 [89-245]305bP<0.025 for comparison between cases and controls within the same classification (all, mild, severe). [165-313]164bP<0.025 for comparison between cases and controls within the same classification (all, mild, severe). [80-244]CoQ10, mg/L0.62 [0.45-0.71]0.67 [0.49-0.78]0.71 [0.47-1.06]0.63 [0.50-0.78]0.53bP<0.025 for comparison between cases and controls within the same classification (all, mild, severe). [0.41-0.62]0.71bP<0.025 for comparison between cases and controls within the same classification (all, mild, severe). [0.48-0.90]CK:CoQ10528cP<0.01 for comparison between cases and controls within the same classification (all, mild, severe). [245-515]287cP<0.01 for comparison between cases and controls within the same classification (all, mild, severe). [146-387]357 [157-447]331 [199-391]699cP<0.01 for comparison between cases and controls within the same classification (all, mild, severe). [259-629]245cP<0.01 for comparison between cases and controls within the same classification (all, mild, severe). [131-387]WhitesNo.246513351130Scr, mg/dL1.01 [0.89-1.09]0.95 [0.89-1.02]1.08 [0.91-1.10]0.96 [0.85-1.08]0.94 [0.87-1.03]0.94 [0.89-0.97]CK, U/L114 [66-138]119 [65-133]111 [62-88]128 [58-146]117 [76-138]108 [56-156]CoQ10, mg/L0.69aP<0.05 for comparison between cases and controls within the same classification (all, mild, severe). [0.53-0.86]0.59aP<0.05 for comparison between cases and controls within the same classification (all, mild, severe). [0.46-0.69]0.70cP<0.01 for comparison between cases and controls within the same classification (all, mild, severe). [0.53-0.86]0.53cP<0.01 for comparison between cases and controls within the same classification (all, mild, severe). [0.41-0.69]0.68 [0.58-0.95]0.65 [0.53-0.79]CK:CoQ10185 [98-176]229 [113-228]173 [87-176]274 [131-281]199 [115-339]177 [82-178]Note: Values for continuous variables were not normally distributed, so are given as median [interquartile range].Abbreviations: CK, creatine kinase; CoQ10, coenzyme Q10; Scr, serum creatinine.a P < 0.05 for comparison between cases and controls within the same classification (all, mild, severe).b P < 0.025 for comparison between cases and controls within the same classification (all, mild, severe).c P < 0.01 for comparison between cases and controls within the same classification (all, mild, severe). Open table in a new tab Note: Values for continuous variables were not normally distributed, so are given as median [interquartile range]. Abbreviations: CK, creatine kinase; CoQ10, coenzyme Q10; Scr, serum creatinine. To our knowledge, this is the first report to show a significant difference in CoQ10 between healthy African Americans and whites.6Joy T.R. Hegele R.A. Narrative review: statin-related myopathy.Ann Intern Med. 2009; 150: 858-868Crossref PubMed Scopus (366) Google Scholar Also, our results indicate that higher CK and lower CoQ10 are associated with future severe exertional rhabdomyolysis only in African Americans. The CK:CoQ10 ratio is even more specific. These findings generate several hypotheses. Low predisease CoQ10 in African Americans may drive elevated serum CK either by increased compensatory CK activity or low-level myocyte lysis due to intracellular ATP deficiency. Conversely, in whites, higher CoQ10 found only in mild exertional rhabdomyolysis cases could be a possible compensatory response (for as-yet undocumented myocyte enzymatic or cofactor deficiencies) mitigating disease severity. The lack of strong correlation between CoQ10 and CK in our scatter plots supports a more complex pathogenicity, with possible additional exertional rhabdomyolysis risk factors and multiple required deficiencies in the same individual. While our results should not change clinical practice, they may have broad implications and could augment any identified genetic risk factors. Future exertional rhabdomyolysis research should likely include race-specific study populations and use our results to accurately power larger studies in military personnel or athletes. Statin-induced myopathy studies may also benefit from this strategy. Statins reduce CoQ10, which could contribute to myopathy.2Landau M.E. Kenney K. Deuster P. Campbell W. Exertional rhadomyolysis: a clinical review with a focus on genetic influences.J Clin Neuromusc Dis. 2012; 13: 122-136Crossref PubMed Scopus (59) Google Scholar Prior CoQ10 supplementation studies neither delineate nor analyze racial subgroups, which may account for their conflicting conclusions.10Olson S.W. Owshalimpur D. Abbott K. et al.Relationship between asymptomatic proteinase 3 antibodies and future granulomatosis with polyangiitis.Clin J Am Soc Nephrol. 2013; 8: 1312-1318Crossref PubMed Scopus (20) Google Scholar That is, a positive response in African Americans could be masked by an absent response in whites. This DoDSR study has general limitations10Olson S.W. Owshalimpur D. Abbott K. et al.Relationship between asymptomatic proteinase 3 antibodies and future granulomatosis with polyangiitis.Clin J Am Soc Nephrol. 2013; 8: 1312-1318Crossref PubMed Scopus (20) Google Scholar and lacks muscle tissue analysis. Also, serum levels may not always correlate with intracellular enzymatic and cofactor activity.8Potgieter M. Pretorius E. Pepper M.S. Primary and secondary coenzyme Q10 deficiency: the role of therapeutic supplementation.Nutr Rev. 2013; 71: 180-188Crossref PubMed Scopus (82) Google Scholar Predisease CoQ10 and CK, specifically CK:CoQ10 ratio, associate with future exertional rhabdomyolysis only in an African American cohort. This suggests multiple mechanisms of disease and may potentially inform future exertional rhabdomyolysis and statin-induced myopathy research. We appreciate the assistance of Dr Angela Cost at DoDSR. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. Contributions: research idea and study design: LKP, SWO, KCA; data acquisition: SWO, LKP, DKO, JJL; data analysis/interpretation: LKP, SWO, KCA; statistical analysis: SWO, KCA; supervision and mentorship: SWO, KCA. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. SWO takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained. Download .pdf (.4 MB) Help with pdf files Supplementary Item S1 (PDF)Detailed methods and supplementary results.

BACKGROUND AND OBJECTIVES:The subclinical pathogenesis of granulomatosis with polyangiitis (GPA) has not been completely elucidated. Proteinase 3 (PR3) antibodies are strongly associated with GPA, but have not been evaluated before disease presentation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:This was a retrospective case-control serum bank study in which PR3 antibodies and C-reactive protein (CRP) in up to three longitudinal serum samples for 27 GPA patients before diagnosis (1 day-19 years) were compared with 27 controls whose serum samples were matched for age, sex, and race. This study analyzed all patients with American College of Rheumatology criteria-confirmed disease identified in the Department of Defense electronic medical records between 1990 and 2008. RESULTS:A greater percentage of GPA patients had at least one elevated PR3 antibody level (≥6 U/ml) as well as at least one detectable PR3 antibody level (>1 U/ml) before diagnosis compared with matching controls (63% [17 of 27] versus 0% [0 of 27], P<0.001; and 85% [23 of 27] versus 4% [1 of 27], P<0.001, respectively). A greater percentage of GPA patients had a >1 U/ml per year rate of increase in PR3 antibody level compared with matching controls (62% [21 of 26] versus 0% [0 of 26], P<0.001). PR3 antibody more frequently became elevated before CRP (67% [12 of 18] versus 33% [6 of 18], P=0.04). CONCLUSIONS:Subclinical PR3 antibody presence, trajectory, and temporal relationship to CRP associates with the future diagnosis of GPA. This data set further elucidates the pathogenesis of GPA.

Introduction: In 2008, we initiated the first Guyanese comprehensive kidney replacement program, comprising hemodialysis (HD), peritoneal dialysis (PD), vascular access procedures, and living-donor kidney transplantation. The government of Guyana, US-based philanthropists, US-based physicians, and Guyanese caregivers teamed up to form a public-private partnership. This pilot program was free of cost to the patients.Methods: From July 2010 to the time of writing, we placed 17 patients with end-stage kidney disease on PD, which was used as a bridge to living-donor kidney transplantation. During the same period, we placed 12 primary arteriovenous fistulae.Results: The 17 patients who received a PD catheter had a mean age of 43.6 years and a mean follow-up of 5.3 months. In that group, 2 deaths occurred (from multi-organ failure) within 2 weeks of catheter placement, and 2 patients were switched to HD because of inadequate clearance. Technical issues were noted in 2 patients, and 3 patients developed peritonitis (treated with intravenous antibiotics). An exit-site abscess in 1 patient was drained under local anesthesia. The peritonitis rate was 0.36 episodes per patient-year. Of the 17 patients who received PD, 4 underwent living-donor kidney transplantation.Conclusions: In Guyana, PD is a safe and cost-effective option; it may be equally suitable for similar developing countries. In Guyana, PD was used as a bridge to living-donor kidney transplantation. We have been able to sustain this program since 2008 by making incremental gains and nurturing the ongoing public-private partnership. Perit Dial Int 2013; 33(2): 116-123 www.PDIConnect.com doi:10.3747/pdi.2012.00001

BACKGROUND Colonic necrosis has been reported after sodium polystyrene sulfonate (SPS)/sorbitol use, but the incidence and relative risk (RR) are not established. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 123,391 adult inpatients at a tertiary medical center. PREDICTOR Receipt of SPS prescriptions (exposed) or a prescription other than SPS (unexposed internal comparison group) between September 1, 2001, and October 31, 2010. OUTCOMES The main outcome measure was tissue-confirmed diagnosis of colonic necrosis, considered SPS-associated if SPS was prescribed 30 or fewer days before tissue accession date. MEASUREMENTS Demographics, serum chemistry test results, hospital location, and International Classification of Diseases, Ninth Revision diagnostic codes. RESULTS SPS was prescribed to 2,194 inpatients. 82 inpatient colonic necrosis cases were identified. 3 received oral SPS (1 gram per 4 milliliters of 33% sorbitol) 30 or fewer days before the colonic necrosis accession date (3.7% of inpatient colonic necrosis cases). The data were linked with 123,391 individuals who received inpatient prescriptions between the same dates. Colonic necrosis incidence was 0.14% (95% CI, 0.03%-0.40%) in those prescribed SPS versus 0.07% (95% CI, 0.05-0.08%) in those not prescribed SPS (RR, 2.10; 95% CI, 0.68-6.48; P = 0.2). The number needed to harm was 1,395 (95% CI, 298-5,100). Subgroup analysis (age >65 years; estimated glomerular filtration rate, <30 mL/min/1.73 m(2), intensive care unit admission, or surgical ward status) did not show significant associations. Sample-size analysis indicated that 4,974 SPS-treated individuals older than 65 years and a comparison group 10 times larger would be required for rigorous multivariate analysis of SPS-associated colonic necrosis risk. LIMITATIONS Individuals with colonic necrosis admitted to non-Department of Defense hospitals would not have been ascertained. Only individuals who had colonic biopsy or surgical tissue submitted for pathologic review could be ascertained as having colonic necrosis. CONCLUSIONS SPS-associated colonic necrosis is rare, and inpatient SPS/sorbitol prescription was not associated significantly with an increased RR of colonic necrosis in this retrospective cohort analysis. Multivariate analysis would require retrospective clinical cohorts from larger or more than one hospital system(s).

The pathophysiology of anti-glomerular basement membrane (anti-GBM) disease before clinical presentation is unknown. The presence of anti-GBM, anti-proteinase 3 (PR3), and anti-myeloperoxidase (MPO) antibodies associate with the disease at the time of diagnosis, but little is known about the presence of these autoantibodies before diagnosis. We used serum samples from the Department of Defense Serum Repository to conduct a case-control study involving 30 patients diagnosed with anti-GBM disease and 30 healthy controls matched for the age, gender, race, and age of the serum samples. We analyzed a maximum of three samples from each subject: the most recent sample before diagnosis, the penultimate sample before diagnosis, and the oldest sample available; the average time between the most recent sample and diagnosis was 195 days (range, 4 to 1346 days). Elevated anti-GBM levels (≥3 U/ml) were present in four patients, all less than 1 year before diagnosis but in no controls. Detectable anti-GBM antibody levels (≥1 U/ml but <3 U/ml) in a single serum sample before diagnosis were more frequent in cases than controls (70% versus 17%, P < 0.001). Only study patients had detectable anti-GBM levels in multiple samples before diagnosis (50% versus 0%, P < 0.001). Almost all patients had detectable anti-PR3 and/or anti-MPO that preceded the onset of disease. Among patients with a clear antecedent antibody, anti-PR3 or anti-MPO always became detectable before the anti-GBM antibody. In summary, our data describe the subclinical formation of autoantibodies, which improves our understanding of the pathophysiology of anti-GBM disease.

Background and objectives: Racial disparities in provision of healthcare are widespread in the United States but have not been specifically assessed in provision of chronic kidney disease (CKD) care.Design, setting, participants, & measurements: We conducted a retrospective cohort study of the clinical database used in a Department of Defense (DOD) medical system. Beneficiaries studied were DOD-eligible beneficiaries with CKD stage 3 (n = 7729) and 4 (n = 589) using the modified Modification of Diet in Renal Disease (MDRD)-estimated GFR formula but requiring manual correction for Black race. Compliance with selected Kidney Disease Outcomes Quality Initiative (KDOQI) CKD recommended targets (monitoring of recommended laboratory data, prescription of recommended medications, and referral to nephrology) was assessed over a 12-mo period, stratified by CKD stage. Logistic regression analysis was used to assess whether race (White, Black, or other) was independently associated with provider compliance with targets, adjusted for demographic factors and burden of comorbid conditions.Results: Among the targets, only monitoring of LDL cholesterol was significantly less common among Blacks. For all other measures, compliance was either not significantly different or significantly higher for Black compared with White beneficiaries. However, patients categorized as "Other" race were in general less likely to achieve targets than Whites, and at stage 3 CKD significantly less likely to achieve targets for monitoring of phosphorous, hemoglobin, and vitamin D.Conclusions: In the DOD health system, provider compliance with selected CKD stage 3 and 4 targets was not significantly lower for Black beneficiaries than for Whites, with the exception of LDL cholesterol monitoring. Patients classified as Other race were generally less likely to achieve targets than Whites, in some patients significantly so.

Until recently, it was not apparent whether apparent paradoxical associations of body mass index (BMI), lipids, and blood pressure with survival observed in hemodialysis (HD) patients, which contradict observations from the general population, also applied to peritoneal dialysis (PD) patients. Studies of survival in PD patients must account for differences in adjusted survival relative to HD patients, namely, early equivalent to superior survival, but after about 1-2 years, inferior survival. Several recent observational studies have analyzed the association between BMI and survival in PD patients from different perspectives and using different patient populations. In general, these studies found that any survival advantage associated with obesity is significantly less likely in PD than HD patients. Among PD patients, those who are obese can be said to have equivalent survival to PD patients with normal BMI. Studies of lipids and blood pressure in PD patients also yield conflicting associations with survival. Obese patients, especially if diabetic, may have increased risk of death after starting on PD compared to HD, although firm conclusions are premature given the limitations of current evidence. At present, the levels of lipids and blood pressure which are best associated with survival in PD patients are not well-defined.

Oral sodium phosphate (OSP) is a commonly used purgative before colonoscopy. There have been numerous reports of acute phosphate nephropathy attributed to the use of OSP. This study evaluated the association between the use of OSP and acute kidney injury (AKI) in an observational, retrospective, cohort study. Of 9799 patients who underwent colonoscopy and had serum creatinine values recorded within 365 days before and after the procedure, AKI, defined as > or =50% increase in baseline serum creatinine, was identified in 114 (1.16%). After adjustment for significant covariates in a multiple logistic regression model, the use of OSP was associated with increased risk for AKI (odds ratio 2.35; 95% confidence interval 1.51 to 3.66; P < 0.001) with an adjusted number need to harm of 81. Age was also independently associated with AKI in this cohort; therefore, until larger, prospective studies define the population at risk for acute phosphate nephropathy, the use of polyethylene glycol-based purgatives should be considered for older patients and possibly for those with comorbid medical conditions.

BACKGROUNDWhether the previously reported underutilization of standard-of-care medications in the management of patients with acute myocardial infarction (AMI) persists in more recent years or differs by ward of admission has not been reported.METHODSWe performed a retrospective cross-sectional study of patients hospitalized with a discharge diagnosis of incident AMI to a Department of Defense hospital (Walter Reed Army Medical Center, Washington, DC) from 2001 through 2004. Use of beta-blockers and aspirin at the time of discharge after AMI was assessed according to Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rate (eGFR) in milliliters per minute per 1.73 m2, stratified by admission to the coronary care unit (CCU) versus other wards. Adjusted odds ratios for discharge beta-blocker and aspirin therapy were calculated by using logistic regression.RESULTSAmong 431 patients, overall discharge use of beta-blockers was 86.8%, and aspirin, 86.8%, both significantly greater after CCU admission than admission to other wards (93%, aspirin use; 91.7%, beta-blocker use; P < 0.001 and P < 0.001). In logistic regression, CCU admission was the only independent factor associated with either beta-blocker or aspirin use; MDRD eGFR was not associated significantly with beta-blocker and aspirin use regardless of admission to the CCU or non-CCU.CONCLUSIONFuture studies of disparities in use of standard-of-care medications after AMI according to renal function should account for the primary site of admission, particularly CCU versus others. In addition, legitimate contraindications to the use of beta-blockers and aspirin may be subtle, including appropriate end-of-life decisions.

BACKGROUND:The impact of obesity on survival in end-stage renal disease (ESRD) patients as related to dialysis modality (i.e., a direct comparison of hemodialysis with peritoneal dialysis) has not been assessed adjusting for differences in medication use, follow-up > or =2 years, or accounting for changes in dialysis modality. METHODS:We performed a retrospective cohort study of the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Wave II Study (DMMS) patients who started dialysis in 1996, and were followed until October 31 2001. Cox regression analysis was used to model adjusted hazard ratios (AHR) for mortality for categories of body mass index (BMI), both as quartiles and as > or =30 kg/m2 vs. lower. Because such a large proportion of peritoneal dialysis patients changed to hemodialysis during the study period (45.5%), a sensitivity analysis was performed calculating survival time both censoring and not censoring on the date of change from peritoneal dialysis to hemodialysis. RESULTS:There were 1675 hemodialysis and 1662 peritoneal dialysis patients. Among hemodialysis patients, 5-year survival for patients with BMI > or =30 kg/m2 was 39.8% vs. 32.3% for lower BMI (P < 0.01 by log-rank test). Among peritoneal dialysis patients, 5-year survival for patients with BMI >/=30 kg/m2 was 38.7% vs. 40.4% for lower BMI (P > 0.05 by log-rank test). In adjusted analysis, BMI > or = 30 kg/m2 was associated with improved survival in hemodialysis patients (AHR 0.89; 95% CI 0.81, 0.99; P= 0.042) but not peritoneal dialysis patients (AHR = 0.99; 95% CI, 0.86, 1.15; P= 0.89). Results were not different on censoring of change from peritoneal dialysis to hemodialysis. CONCLUSION:We conclude that any survival advantage associated with obesity among chronic dialysis patients is significantly less likely for peritoneal dialysis patients, compared to hemodialysis patients.

Background: Studies of the use of the World Wide Web to obtain medical knowledge have largely focused on patients. In particular, neither the international use of academic nephrology World Wide Web sites (websites) as primary information sources nor the use of search engines (and search strategies) to obtain medical information have been described. Methods: Visits (“hits”) to the Walter Reed Army Medical Center (WRAMC) Nephrology Service website from April 30, 2000, to March 14, 2001, were analyzed for the location of originating source using Webtrends, and search engines (Google, Lycos, etc.) were analyzed manually for search strategies used. Results: From April 30, 2000 to March 14, 2001, the WRAMC Nephrology Service website received 1,007,103 hits and 12,175 visits. These visits were from 33 different countries, and the most frequent regions were Western Europe, Asia, Australia, the Middle East, Pacific Islands, and South America. The most frequent organization using the site was the military Internet system, followed by America Online and automated search programs of online search engines, most commonly Google. The online lecture series was the most frequently visited section of the website. Search strategies used in search engines were extremely technical. Conclusions: The use of “robots” by standard Internet search engines to locate websites, which may be blocked by mandatory registration, has allowed users worldwide to access the WRAMC Nephrology Service website to answer very technical questions. This suggests that it is being used as an alternative to other primary sources of medical information and that the use of mandatory registration may hinder users from finding valuable sites. With current Internet technology, even a single service can become a worldwide information resource without sacrificing its primary customers.

OBJECTIVESMilitary medical subspecialists consult with referring physicians, direct patient care and education, support isolated subspecialists, and maintain cohesive readiness plans. The World Wide Web appears promising in fulfilling these roles.METHODSA website providing directed resources, the Walter Reed Army Medical Center Nephrology Service website (http:@www.wramc.amedd.army. mil/departments/medicine/nephro/NEPHROLOGY/index.htm!), is described in the context of its role in military medicine and online publishing.RESULTSThe Walter Reed Army Medical Center Nephrology Service website provides educational resources for both patients and physicians worldwide. It remains the only Army internal medicine website to offer online category I continuing medical education credits free to military physicians, and it also allows online graduate medical education.CONCLUSIONSMilitary medical subspecialty programs can use the World Wide Web to provide consultation and education to distant and isolated patients and providers in a practical, feasible manner. This process can be expanded to education in operational medicine and other military-specific medical topics.

Batty, D. Scott Jr.1; Swanson, S. John III1; Polly, Shirley M.1; Oliver, J. D.2; Oliver, D. K.2; Ko, C. W.3; Kirk, Allan D.1; Agodoa, L. Y.4; Abbott, Kevin C.5 Author Information

The Military Health Services System is undergoing tremendous changes paralleling those seen in the civilian health care system. Many of the same problems and frustrations are being encountered in the military as it builds TRICARE, one of the largest managed care systems in the country. This paper describes how a team of multidisciplinary subspecialty providers established an Infusion Service for Walter Reed Army Medical Center to fulfill customer needs brought about by system changes in the medical center. Policy and operations were directed toward addressing patient and provider frustrations. Organ transplantation ward length of stay shortened significantly in association with the establishment of this Infusion Service. Peritoneal Dialysis Clinic staff productivity improved. Organizational factors and values affecting patient outcomes and health system reform are discussed. Lessons learned from this project are identified and presented as suggestions that can be used in planning and executing changes throughout the Military Health Services System.