Hindawi Journal of Tropical Medicine Volume 2017, Article ID 7868535, 12 pages https://doi.org/10.1155/2017/7868535 Research Article P. vivax Urinalysis and Clinical Correlations in Patients with or P. falciparum Malaria from Colombia AlbertoTobón-Castaño,1SebastiánBarreraEscobar,1,2andCeciliaGiraldoCastro1 1MalariaGroup,FacultyofMedicine,UniversityofAntioquia,Calle70,No.52-21,Medellin,Colombia 2FacultyofMedicine,UniversityofAntioquia,Medellin,Colombia CorrespondenceshouldbeaddressedtoAlbertoTobo´n-Castan˜o;[email protected] Received 20 December 2016; Revised 30 March 2017; Accepted 2 May 2017; Published 24 May 2017 AcademicEditor:SuklaBiswas Copyright©2017AlbertoTobo´n-Castan˜oetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttribution License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. Background. Urinalysis is a poorly reviewed diagnostic tool in malaria patients; its application can show the presence of severe malaria. Methods. Urinalysis was performed in a total of 620 patients diagnosed with malaria by thick blood smear; complications were classified according to WHO major criteria for severity and minor criteria according to the Colombian malariaguideline.Results.Severeormoderateclinicalcomplicationswerediagnosedin31.1%ofpatients,hepaticdysfunctionswere diagnosedin25.8%,anemiawasdiagnosedin9.8%,thrombocytopeniawasdiagnosedin7.7%,renaldysfunctionwasdiagnosed in 4.8%, neurological and pulmonary complications were diagnosed in 2.1% and 2.4%, hypoglycemia was diagnosed in 1.1% of patients with blood glucose analysis, and acidosis was diagnosed in 10 of 25. Bilirubinuria was found in 24.3%, associated with urobilinuria, proteinuria, and increased specific gravity; urobilinuria was found in 30.6% associated with elevated serum bilirubin and alanine aminotransferase; 39.2% had proteinuria, associated with higher blood urea nitrogen, serum bilirubin, aspartate,alanine-transaminase,hematuria,andincreasedspecificgravity.Severeormoderateliverandrenalcomplicationswere associatedwithproteinuriaandbilirubinuria.Urobilinuriawasassociatedwiththrombocytopeniaandneurologicalandhepatic dysfunction.Ketonuriawasassociatedwithneurologicaldysfunctions.Conclusions.Themostfrequentalterationsintheurinalysis werebilirubinuria,proteinuria,urobilinuria,andincreasedspecificgravity,relatedtothrombocytopeniaandliver,kidney,and neurologicalalterations. 1.Background themostcommonetiologicagentsareP.vivax(66%)andP. falciparum(34%)[1]. Malariahaslongbeenrecognizedasadiseasethatprimarily Traditionally serious cases of malaria occur in P. falci- affects tropical countries worldwide, making it a major parum infections, but recently complications caused by P. international public health problem. According to the 2015 vivax havebecomemoreprevalent[5].Earlyrecognitionof WHO World Malaria report, the annual incidence of the clinical symptoms predictive of the onset of complications disease was estimated at 214 million clinical cases with an wouldallowprompttreatmentandsupportivecaretoprevent estimatedmortalityof438,000cases,90%oftheminAfrican progressiontodeath[6]. people[1]andmostlyamongpregnantwomenandchildren As the malaria infection progresses some clinical signs undertheageof5.Itisestimatedthatin2014malariawasthe indicate the establishment of serious illness and are danger causeof7%ofglobalchildmortality[2].Althoughtherisk signs for a complicated phase of the disease [6]; the most ofacquiringmalariainLatinAmericaislow[3]inColombia frequentlyobservedarejaundice,cough,dyspnea,tachypnea, itisaseriouspublichealthproblem.Anestimated25million cyanosis, persistent vomiting, neurological disorders, and peopleareatriskin85%ofruralregions,locatedbelow1600 dark urine [7–9]. Early detection of urine alterations could metersabovesealevel,andhaveclimaticandepidemiological allow for screening of early liver or kidney damage [7]. conditionssuitablefordiseasetransmission[4].InColombia Dark urine has been associated with hemoglobinuria [10], 2 JournalofTropicalMedicine myoglobinuria[10],hematuria[7],andbilirubinuria[7,11], were in clinical and epidemiological studies conducted by all indicators of liver or kidney dysfunction [7, 12]. Other theMalariaGroupbetween1997and2007andwerepatients alterationsintheurineofmalariapatientshavebeenpoorly referred from different regions to third-level hospitals in exploredassignsofdanger. Medellin (Pablo Tobo´n Uribe and San Vicente de Pau´l Studiesonurinalysisabnormalitiesinmalariapatientsare Hospitals) between 2005 and 2010. Convenience sampling limited. A study of urinalysis abnormalities in 600 patients wasapplied. in Sudan reported albuminuria (84.9%), cylinders (71.4%), pyuria (53.8%), and hematuria (45%) in patients with a 2.2. Clinical and Laboratorial Criteria. A urine sample was positivethicksmear[13].Bilirubinandurobilinogenconcen- obtained following the instructions for processing Bayer’s trations in urine were increased in samples from Nigerian Multistixstrips.Theurinespecimenwasexaminedwithin1 patientswithmalaria,comparedtouninfectedpatients(𝑃 < hourofcollectionorwasrefrigerated(2–8∘C)andexamined 0.05)[11].Otherpublicationsdescribedproteinuria[7,14,15], within 4 hours of collection. Urinalysis was made using hematuria[14],andmyoglobinuriainmalariapatients[10]. criteriaofabnormality: Liver dysfunction, renal dysfunction, and severe ane- (1)Glucose:anypositivereading mia were reported as the most common complications in (2)Bilirubin:anypositivereading hospitalized Colombian patients in association with dark urine and jaundice [6, 7]. In malaria patients from Colom- (3)Ketones:above5mg/dL bia, hemoglobinuria (86%), urobilinuria (66%), proteinuria (4)Blood: whole or hemolyzed erythrocytes, including (54%),hematuria(43%),andbilirubinuria(39%)wereassoci- traces atedwithdarkurine;renaldysfunctionwasidentifiedinthese (5)pH:greaterthan7.4(basic)orlowerthan4.8(acid) patients[7]. Dark urine in adult malaria patients has been linked (6)Protein:≥30mg/dL tomyoglobinuriaandrhabdomyolysis[10,16,17].Although (7)Urobilinogen:≥2mg/dL rhabdomyolysis has been reported in pediatric and adult (8)Nitrites:anypositivereading patients with P. falciparum malaria [16], it is not a widely reported event in the literature; observations in Gambian (9)Leukocytes:≥70/𝜇L children show a relationship between rhabdomyolysis and (10)Specificgravity:>1.020 disease severity [18]. The pathogenic mechanism by which rhabdomyolysis develops is still not fully understood; the The presence of traces was not considered as an abnormal sequestrationofparasitizederythrocytesinthemicrovascu- testresult,exceptforhematuria.Darkyellow,orangered,or lature of skeletal muscle has been postulated as a cause of browncolorintheurinewasconsideredas“darkurine.” myocytedamageandthesubsequentmyoglobinrelease[16]. ComplicationswereclassifiedaccordingtoWHOmajor Hemoglobinuria, hematuria, and bilirubinuria have not criteria[22]forseverityandtheproposedminorcriteriafor beenassociatedwithliverorkidneydysfunctioninprevious Colombia[23]asfollows: observations in Colombia [7]. Choluria, the product of (1)Liver dysfunction: severe: total bilirubin [TB] > increased conjugated bilirubin (DB) has been described in 3mg/dLand/ortransaminases>120IU/L;mild:TB> malaria patients developing liver dysfunction as well as in 1.5–3.0mg/dLand/ortransaminases>80–120IU/L. kidneydysfunctionbythetoxicactionofbilirubinonrenal (2)Thrombocytopenia: profound: <25,000 platelets/𝜇L; epithelium[7,19,20].Bilirubinappearsinurinebeforeother severe:25–50,000platelets/𝜇L. signsofliverdysfunctionareapparent[21];thereforeitcanbe consideredtobeanearlysignofliverdamage[7]. (3)Renal dysfunction: severe: blood urea nitrogen Thisstudyaimstoanalyzetheurinealterationsinrelation [BUN]>60mg/dLand/orcreatinine>3mg/dL;mild: to the clinical status of malaria patients from low malaria BUN41–60mg/dLand/orcreatinine1.5–3.0mg/dL. endemic regions in Colombia and explore its usefulness to (4)Anemia:severe:hemoglobin[Hb]<5.0g/dL;moder- recognizeorganorsystemicinjury. ate:Hb5.0–6.9g/dL. (5)Neurologic complication: cerebral malaria: seizures/ 2.MethodsandMaterials coma;extremeweakness. 2.1.DesignandStudyPopulation. Ananalysiswasperformed (6)Pulmonary injury: acute respiratory distress syn- on clinical and laboratory records of 620 patients with drome (ARDS), pulmonary edema, or pleural effu- malariaobtainedintwopreviousanalyticalstudies[8,9]and sion from inpatient medical records from the city of Medellin. (7)Acid-basedisturbances:severeacidosis:pH<7.35and The reference population consisted of patients of all age HCO3 < 15mEq/L; acidosis: pH < 7.35 and HCO3 groups(from1to85yearsold)withsymptomssuggestiveof 15–18mEq/L. malaria and a parasitological diagnosis confirmed by thick (8)Hypoglycemia:severe:glycemia<40mg/dL;moder- bloodsmearinfirst-orsecond-levelhospitalsandhealthcare ate:glycemia40–49mg/dL. facilitiesinthemunicipalitiesofTurboandNecocl´ı(Uraba´, Antioquia), El Bagre (Bajo Cauca, Antioquia), Tumaco, The patient must have at least one clinical criterion to be Guapi, and Timbiqu´ı (Pacific Coast). The patients enrolled categorizedascomplicated. JournalofTropicalMedicine 3 (km) 0 200 400 0 100 200 300 (Miles) Alto Sinú,n=13(2,1%) Bajo Cauca,n=22(3,5%) Urabá Antioqueño,n=262(42,3%) Pacifico Chocoano,n=8(11,3%) Urabá Chocoano,n=8(1,3%) Pacifico,n=292(47,1%) Figure1:Geographicallocationsoftheregionsoforiginof618patients,obtainedandmodifiedfromtheCartographicDesignUnitofthe WorldBank,2000. 2.3. Statistical Analysis. The Kolmogorov-Smirnov test was and 103 (16.6%) with moderate complications, without sta- usedtoassessnormalityforquantitativevariables;themedian tistical differences by species of plasmodium: 129 (66.8%) valueswerecomparedwiththeMann-Whitney𝑈testwhen with P. falciparum infection, 54 (28%) with P. vivax, and variableswerenotnormal.Associationsbetweenqualitative 10 (5.2%) with mixed infections by these species (𝑃 > variableswereanalyzedwiththeChi-squaretest;OddsRatio 0.05; Chi2). The complications include hepatic dysfunction (OR) and 95% confidence interval (CI) were estimated. in 160 (38.7%), anemia in 61 (9.8%), thrombocytopenia in Spearman’srankcorrelationcoefficientwasappliedtoanalyze 48 (7.7%), renal dysfunction in 30 (4.8%), and neurological some relationships between numerical data. The adopted and pulmonary complication in 13 (2.1%) and 15 (2.4%), levelofstatisticalsignificancewas5%(𝑃<0.05).Theanalysis respectively;hypoglycemiawasdiagnosedin4of348(1.1%) wasdonewithIBM(cid:2)SPSS(cid:2)statisticsprogram,22ndversion patients with blood glucose studies and acidosis in 10 of 25 (licensedtotheUniversityofAntioquia). (40%); no increased risk of alteration in the urinalysis was identifiedinhypoglycemicpatients.Nocomplicatedmalaria 3.Results wasdiagnosedin427(68.9%)patients. Urinalysis variables are described in Table 2; the rela- Urinalysisfrom620malariapatientswasanalyzed;someof tionships between urinalysis variables and hematological the patients did not have all the urine dipstick parameters variables(Table3)wereanalyzed. recorded.Patientshadamedianageof22.8years(mean26; CI24.7–27.2);59.7%(𝑛=370)weremen.Patientscamefrom 3.1. UrineColor. Thecolorwasamberin331(79.2%)ofthe Uraba´(AntioquiaandChoco´)(43.6%),Pacific(50.5%),Bajo 418 analyzed samples, dark yellow in 64 (15.3%), orange in Cauca(3.5%),AltoSinu´(2.1%),andMagdalenaMedio(0.3%) 11 (2.6%), red in 10 (2.4%), and brown in 2 (0.5%). Dark regions (Figure 1). P. falciparum infection was diagnosed in urine was statistically related to bilirubinuria (OR 6.7, CI 419(67.9%),P.vivaxin187(30.2%),andmixedinfectionby 1.6–6.0,𝑃 < 0.001),blood(OR3.6,CI1.9–5.2,𝑃 < 0.001), thesespeciesin14(2.3%).Parasitaemiawasdistributedin8 hemoglobinuria(OR3.1,CI1.5–6.0,𝑃 = 0.001),hematuria intervals;68.6%had<10,000parasites/𝜇L.Duringthecourse (OR 2.2, CI 1.2–3.9, 𝑃 = 0.006), urobilinogen (OR 2.8, CI ofthediseasemedicationintakewasreportedasfollows:246 1.6–5.0, 𝑃 < 0.001), and proteins (OR 5.8, CI 3.5–9.7, 𝑃 < patients(39.7%)usedanalgesicoranti-inflammatorydrugs, 0.001).Darkurinewasrelatedtosevereormoderatehepatic 31 (5.0%) antibiotics, 50 (8.0%) antimalarials, and 41 (7.0%) complication (OR 3.1, CI 1.6–6.0, 𝑃 = 0.001) but not renal variousmedications(Table1). dysfunction(𝑃>0.05).SerumBUNvalues>20mg/dLwere Severe or moderate clinical complications were diag- morefrequentinpatientswithdarkurine(OR2.2,CI1.0–4.9, nosed in 193 patients, 90 (14.5%) with severe complications 𝑃=0.053). 4 JournalofTropicalMedicine Table1:Sociodemographiccharacteristics. Variable(𝑛=620) Severemalaria Uncomplicatedmalaria Totalfrequency 𝑃value Sex 0.009 Male 129(34.9%) 241(65.1%) 370(59.7%) Female 64(25.6%) 186(74.4%) 250(40.3%) ∗ Ethnicity (race) Mestizo 125(37.4%) 209(62.6%) 334(57.6%) <0.001 Afro 21(10.8%) 174(89.2%) 195(33.6%) White 14(35.9%) 25(64.1%) 39(6.7%) Amerindian 2(16.7%) 10(83.3%) 12(2.1%) ∗∗ Residence Ruralarea 98(42.2%) 134(57.8%) 232(61.9%) 0.188 Urban 53(37.1%) 90(62.9%) 143(38.1%) Ageranges 1–5years 10(40.0%) 15(60.0%) 25(4.0%) 5.1–15years 36(23.3%) 112(75.7%) 148(23.9%) 0.129 15.1–65years 140(32.5%) 291(67.5%) 431(69.5%) >65years 7(43.7%) 9(56.3%) 16(2.6%) Species P.vivax 54(28.9%) 133(71.1%) 187(30.2%) 0.004 P.falciparum 129(30.8%) 290(69.2%) 419(67.6%) Mixed 10(71.4%) 4(28.6%) 14(2.2%) ∗∗∗ Parasitemiaranges <1,000 24(22.6%) 82(77.4%) 106(18.0%) 1,000–5,000 42(24.9%) 127(75.1%) 169(28.7%) <0.001 5,001–10,000 38(29.5%) 91(70.5%) 129(21.9%) 10,001–50,000 54(34.4%) 103(65.6%) 157(26.7%) 50,001–100,000 13(61.9%) 8(38.1%) 21(3.6%) >100,000 6(100%) 6(1.0%) Previoususeofanydrug 0.052 Yes 18(46.9%) 23(56.1%) 41(6.6%) Previoususeofantimalarials <0.001 Yes 31(62%) 19(38%) 50(8.1%) Previoususeofantibiotics 0.129 Yes 13(41.9%) 18(58.1%) 31(5.0%) Useofanalgesicsand/oranti-inflammatorydrugs <0.001 Yes 101(41.1%) 145(58.9%) 246(39.7%) ∗𝑛=580;∗∗𝑛=375;∗∗∗𝑛=588. 3.2.NitritesandLeukocytes. Nitriteswerefoundin19(3.4%) alanine aminotransferase [ALT] serum values (𝑃 < 0.05). andleukocytesin84(14.9%)of564analyzedsamples;these Thepatientswithcomplicatedmalariaandspecificallywith variablesdidnotcorrelatewithclinicalcomplications. moderateorseverekidneyorliverinjuryhadagreaterrisk of bilirubinuria (Table 4). The hemoglobin values did not 3.3. pH. From 556 patients, 96.6% had a normal pH value differbetweenpatientswithorwithouturinarybilirubin(𝑃= (4.8to7.4)and19(3.4%)hadabasicpH(≥7.4);thesepatients 0.247,Mann-Whitneytest). withabasicurinarypHhadsignificantlylowerserumvalues of BUN, TB, conjugated bilirubin [DB], and unconjugated 3.5.Urobilinogen. Urobilinuriawasidentifiedin184(30.6%) bilirubin[IB](Table3)andasignificantlowerfrequencyof of 602 patients; it was associated with higher bilirubin in hepaticdysfunction(OR0.6,CI0.5–0.8)(Table4). urine and proteinuria (𝑃 < 0.05). Urobilinuria was related to increased serum BUN, BT, BD, BI, and ALT (𝑃 < 0.05) 3.4. Bilirubinuria. Present in 147 (24.3%) of 605 patients, values;themedianplateletcountwaslowerinthesepatients bilirubinuria was associated with urobilinuria, proteinuria, thaninthosewithouturobilinuria(𝑃<0.001)(Table3).The and increased specific gravity (𝑃 < 0.05). Patients with presence of urobilinogen was associated with an increased bilirubinuriahadsignificantlyhigherBUN,TB,DB,IB,and risk of severe malaria(OR 2.9, CI 1.9–4.5), specifically with JournalofTropicalMedicine 5 ∗ Table2:Urinalysistestvariablesin620patientswithmalaria . Specificgravity 1,000 1,005 1,006 1,01 1,015 1,02 1,025 1,03 (𝑛=562) 3(0.5%) 24(4.3%) 1(0.2%) 62(11%) 76(13.5%) 166(29.5%) 111(19.8%) 120(21.4%) 5.5 6.0 6.5 7.0 7.5 8.0 8.5 pH(𝑛=556) 87(15.6%) 374(67.3%) 30(5.4%) 46(8.3) 3(0.5) 15(2.7%) 1(0.2%) Traces Moderate Traces 1+ 2+ 3+ Negative Blood(𝑛=610) (notlysed) (notlysed) (lysed) (lysed) (lysed) (lysed) 428(70.2%) 83(13.6%) 17(2.8%) 7(1.1%) 15(2.5%) 17(2.8%) 43(7%) Proteins(mg/dL) 0Negative Traces 30.0 100 300 ≥2,000 (𝑛=580) 202(34.8%) 151(26%) 152(26.2%) 66(11.4%) 7(1.2%) 2(0.3%) Urobilinogen(mg/dL) 0.2,negative 1.0traces 2.0 4.0 ≥8.0 (𝑛=602) 418(69.4%) 78(13%) 17(2.8%) 51(8.5%) 38(6.3%) Leukocytes(cells/𝜇L) Negative 15traces 70 125 500 (𝑛=564) 480(85.1%) 45(8.0%) 28(5.0%) 8(1.4%) 3(0.53%) Ketones(mg/dL) 0,negative 5.0traces 15(low) 40(moderate) ≥80(high)∗∗ (𝑛=559) 432(77.3%) 79(14.1%) 19(3.4%) 15(2.7%) 14(2.5%) Glucose(mg/dL) Negative(<30.0) 100 250 500 1 (𝑛=564) 550(97.5%) 6(1.1%) 5(0.9%) 18(0.2%) 2(0.4%) Bilirubin(mg/dL) Negative(<0.2) Low Moderate High (𝑛=605) 458(75.7%) 102(16.8%) 36(6%) 9(1.5%) Negative Positive Nitrites(𝑛=564) 545(96.6%) 19(3.4%) ∗Notallpatientshavecompleteurinedipstickvariables;∗∗onlyonepatientwithketones>160mg/dL. moderate or severe complications: thrombocytopenia (OR althoughpatientswiththiscomplicationhadhigherlevelsof 2.7,CI1.3–5.3),neurologicaldysfunction(OR1.1,IC1.0–1.1), proteinuria. In 25 complicated patients with lactic acid and andhepaticdysfunction(OR2.8,CI1.7–4.5). bicarbonatemeasurements,acidosiswasdiagnosedin9and proteinuriawasthemostfrequentabnormality(78%). 3.6. Ketones. Ketonuria (𝑛 = 48, 8.6%) was associated with proteinuria and increased specific gravity (𝑃 < 0.05). 3.9.BloodinUrine. Bloodwaspresentin182(29.8%)of602 Ketonuriawasnotrelatedtohematologicalalterationsbutit analyzed samples, 82 (13.4%) classified as hemoglobinuria wasassociatedwithsevereneurologicaldysfunction(OR1.1, and 100 (16.4%) as hematuria. The presence of blood was CI1.0–1.2). associated with proteinuria (𝑃 < 0.05). There was no increasedriskofclinicalcomplicationsrelatedtothisalterat- 3.7. Glucose. Glycosuria was present in 14 of 564 (2.5%) patients;thesepatientshadahigherriskofproteinuria(𝑃 < ion. 0.05) and 9 of them had some criteria for severe malaria (OR 4.4; CI 1.4–13.2). The median blood glucose level was 3.10. Specific Gravity. This variable was increased in 231 significantlyhigherinpatientswithglycosuria(𝑃=0.02). (41.2%) of 562 patients, who exhibited an increased risk of severe or moderate renal dysfunction (OR 1.7, CI 1.0–2.7, 3.8. Proteins. 227 of 580 (39.2%) patients had proteinuria. 𝑃=0.033).Theuseofanalgesicsandanti-inflammatorywas This alteration was associated with bilirubinuria, urobilin- associated with higher specific gravity of urine (OR = 1.7; uria,blood,andincreasedspecificgravity(𝑃<0.05)andwas 1.9–2.6;𝑃=0.007). related to higher serum BUN, TB, DB, ALT, and aspartate- Some alterations in the urine dipstick were related to transaminase (AST) values and lower platelet counts. Pro- other urinary alterations. Specific gravity was related to teinuriawasrelatedtoseverethrombocytopenia(OR2.0,CI bilirubinuria(OR1.7;CI1.0–2.7;𝑃0.023),ketones(OR2.3;CI 1.1–3.8)andpulmonary(OR4.0,CI1.3–12.9)andlivercom- 1.5–3.5;𝑃0.023),andproteins(OR2.3;CI1.5–3.5;𝑃<0.001). plication(OR1.5,CI1.1–2.3);itwasnotstatisticallyassociated Blood in urine was related to proteins (OR 2.5; CI 1.7–3.6; withrenalcomplicationbutserumBUNvalues>20mg/dL 𝑃 < 0.001). Bilirubinuria was related to proteins (OR 4.2; wererelatedtoproteinuria(OR2.9,CI1.6–5.3,𝑃 < 0.001). CI2.8–6.4;𝑃 < 0.001)andurobilinogen(OR4.7;CI3.0–7.5; Proteinuria was not related to severe anemia (𝑃=0.06) 𝑃<0.001). 6 JournalofTropicalMedicine ) 0 Proteins(No/Yes) (0.95/1.0)0.29(11.28/14.42)0.000 (0.90/1.24)0.004 (0.3/0.43)0.000 (0.60/0.68)0.094 (33.0/40.0)0.028 (28.0/50.0)0.001 (11.7/11.4)0.51631,000/96,000.000 1 ( ) ria. Urobilinogen(No/Yes) (1.0/0.9)0.825(12.0/14.24)0.004 (0.9/1.55)0.000 (3.0/6.0)0.000 (0.6/0.97)0.000 (36.0/36.0)0.268(27.5/47.0)0.006 (11.6/11.8)0.75(126,500/89,0000.000 a al 0patientswithm >BasicpH(7,4)(no/yes) (1.0/0.9)0.168(12.69/9.4)0.018 (1.0/0.66)0.009 (0.36/0.20)0.013 (0.66/0.39)0.035 (37.0/28.0)0.23(31.5/31.0)0.505(11.6/10.8)0.413(109,500/131,500)0.242 2 6 nalysisfindingsin Elevatedspecificgravity(no/yes)(0.95/1.0)0.098(12.0/14.1)0.012 (0.96/1.0)0.813 (0.32/0.39)0.259 (0.63/0.65)0.475 (37.0/33.0)0.13(31.0/33.0)0.68(11.5/12.4)0.148(117,000/102,500)0.378 ri u ) he 00 n)basedont Ketones(no/yes) (1.0/0.9)0.068(12.7/11.5)0.711 (1.0/0.99)0.979 (0.33/0.36)0.537 (0.63/0.69)0.82 (37.0/37.0)0.832(32.0/32.0)0.797(11.7/10.9)0.222,000/1,050,00.844 dia (11 e m ) gicalvalues( Bilirubin(no/yes) (0.98/1.0)0.173(12/14.1)0.019 (0.9/1.35)0.00 (0.3/0.43)0.002 (0.6/0.81)0.000 (36.0/37.0)0.261(28.0/55.0)0.001 (11.5/12.1)0.2473,000/110,0000.304 milarfindings. matolo (11 atessi c mparisonofhe Glucose(no/yes) (1.0/1.1)0.46(12.3/15.0)0.13 (1.0/1.2)0.445 (0.3/0.4)0.059 (0.6/0.66)0.797 (35/58.0)6.70.06(31.5/52.0)0.302(11.5/12.5)0.38611,000/91,500)0.26 oglobinuriaindi o (1 m C he e3: 0) for Tabl ∗Blood(no/yes) (1.0/1.0)0.467(13.69/11.89)0.483 (1.0/1.0)0.972 (0.33/0.35)0.663 (0.66/0.61)0.602 (36.0/36.0)0.765(32.5/24.0)0.269(11.4/11,8)0.255(117,000/108,000.345 obinuria.Analysis gl n, L) mo Creatinine,mg/dL𝑃valueBUN,mg/dL𝑃valueTotalbilirubin,mg/dL𝑃valueConjugatedbilirubimg/dL𝑃valueUnconjugatedbilirubin,mg/dL𝑃valueASTIU/L𝑃valueALTIU/L𝑃valueHemoglobin,g/dL𝑃value𝜇Platelets(platelets/𝑃value∗Hematuriaand/orhe JournalofTropicalMedicine 7 Table4:Urinalysisvariablesaccordingtotheclinicalcomplications. pH Bilirubin Urobilinogen Ketones Proteins Severeormoderatecomplication Basic Normal Positive Negative Positive Negative Positive Negative Positive Negative ∗∗ Complicatedmalaria Yes 3 167 55 129 54 127 17 150 86 93 No 16 370 92 329 52 369 31 361 141 260 OR–CI 0.4 0.1–1.4 1.5 1.0–2.3 3.0 2.0–4.5 1.4 0.7–2.5 1.7 1.2–2.4 𝑃value 0.167∗ 0.035 0.000 0.381 0.003 Thrombocytopenia Yes 1 42 14 30 15 25 1 41 25 18 No 13 283 76 265 63 278 35 263 130 188 OR–CI 0.5 0.1–4.1 1.6 0.8–3.2 2.6 1.3–5.3 0.2 0.1–1.2 2.0 1.1–3.8 𝑃value 0.525∗ 0.163 0.006 0.114∗ 0.034 Anemia Yes 3 52 7 51 8 46 5 49 30 26 No 11 300 90 264 79 276 32 281 133 199 OR–CI 1.6 0.4–5.8 0.4 0.2–0.9 0.6 0.3–1.3 0.9 0.3–2.4 1.7 1.0–3.0 𝑃value 0.451∗ 0.031 0.217 0.828 0.06 Neurologicalcomplication Yes 0 11 1 11 6 4 4 6 6 5 No 19 526 146 447 100 491 44 505 221 348 OR–CI NA NA 0.3 0.1–2.2 7.3∗ 2.0–26.5 7.6 2.1–28.1 1.9 0.6–6.3 𝑃value NA 0.336∗ 0.001∗ 0.002∗ 0.456 Pulmonarycomplication Yes 0 13 3 10 4 6 2 11 10 4 No 19 524 144 448 102 490 46 500 217 349 OR–CI NA NA 0.9∗ 0.3–3.4 3.2 0.9–11.5 1.9∗ 0.4–9.2 4.0∗ 1.3–12.9 𝑃value NA 0.823∗ 0.145∗ 0.700∗ 0.025∗ Livercomplication Yes 1 140 50 101 48 102 14 124 72 77 No 11 202 48 199 36 210 21 194 85 140 OR–CI 0.6 0.5–0.8 2.1 1.3–3.3 2.7 1.7–4.5 1.0 0.5–2.1 1.5 1.01–2.3 𝑃value 0.032∗ 0.002 0.000 0.908 0.044 Renalcomplication Yes 0 26 5 20 8 15 1 25 14 13 No 14 316 92 283 75 299 33 296 143 206 OR–IC ND ND 0.8 0.2–2.1 2.1 0.9–5.2 0.4 0.1–2.7 1.5 0.7–3.4 𝑃value ND 0.787 0.098 0.323 0.273 ∗ ∗∗ Fisherexacttest; anycriteriaofcomplication;ND:nodata. Themalariavivaxpatientsexhibitedahigherfrequency P.vivaxorP.falciparumcaseswithoutstatisticaldifferences, ofhematuria,hemoglobinuria,andleukocytesinurinethan including thrombocytopenia, anemia, and liver and kidney theP.falciparumcases,withsignificantstatisticaldifference dysfunction, consistent with other studies in Colombian (𝑃 < 0.005, Chi-square test). In contrast, the P. falciparum patients which found liver and kidney complications and casesshowedhigherfrequencyofketonuria,proteinuria,and severeanemia[24]. urobilinuria(𝑃<0.005,Chi-squaretest). The various parameters evaluated by urinalysis may be altered by a series of factors that reflect kidney or urinary 4.Discussion tract alterations or systemic processes [12]. Proteinuria [7, 10, 13, 14], hematuria [7, 11, 13], bilirubinuria [7, 11, 13], Themostcommonurinalysisalterationsinthe620malaria hemoglobinuria[7,13,25,26],andmyoglobinuria[10,15,16] patients were increased specific gravity (41.2%), proteinuria havebeenfoundintheurinalysisofpatientswithmalaria. (39.2%), urobilinuria (30.6%), blood (29.8%), bilirubinuria (24.3%),ketones(22.7%),andleukocytes(14.86%).Eitherone 4.1.Proteinuria. Proteinuriawasfoundin39.1%ofsamples, major or minor criterion of complication was diagnosed in similar to previous findings in Colombian and Nigerian 8 JournalofTropicalMedicine malariapatients[11,15,27].InColombianpatientswithP.fal- independentfactorforkidneyinjurywitha88.2%sensitivity ciparuminfection,proteinuriawasoneofthemostcommon and62.7%specificity,comparedwiththerespectivevaluesof alterationsinurinalysis,reachingupto54%,andwasassoci- 94,1% and 90,8% for hematuria, the latter related to raised atedwithrenaldysfunction[7].Inourpatients,proteinuria BUNandcreatinine(𝑃<0.01)[14]. wasassociatedwithincreasedTBandDBserumlevels,with increased risk of liver, kidney, and lung complications, and 4.2. Bilirubinuria. The clinical manifestations of malaria otheralterationsinurinalysisincludingbilirubinuria,urobil- generally include paroxysmal episodes of fever and chills inuria,ketonuria,andglycosuria.Concurrenthematuriawas every 24–48 hours or 72 hours depending on the infecting found in 93 of 227 patients with proteinuria (40.96%) but species [38, 39], which coincide with synchronous rupture hematuriawasnotrelatedtoclinicalcomplications. of parasitized erythrocytes [3]. Circulating bilirubin levels In malaria patients with acute kidney injury, protein- increase due to hemolysis during erythrocytic schizogony; uria indicates progression to nephropathy [7, 18, 28, 29]. thishyperbilirubinemiaismildanddoesnotgenerateintense Proteinuria associated with blood in urine (hematuria or jaundice [40, 41]. Increased levels of conjugated and total hemoglobinuria) suggests glomerular disease [15, 30] and bilirubin have been reported in malaria patients [7, 11, 41, a mixed pattern of glomerular-tubular excretion has been 42], possibly due to an increased hepatic conjugation of establishedinmalariapatients[18,31].Observationsinchil- unconjugatedbilirubin[7].Significanthyperbilirubinemiais drenwithcerebralmalariainGambiashowedthat53%had an important marker of liver dysfunction with an increase a glomerular-tubular pattern of urinary protein excretion, in aminotransferases [7, 43]. Under normal conditions the while 46% had a tubular pattern [18], and postmortem bilirubinincreaseinbloodisoffsetbytheincreaseofbilirubin histological evidence of glomerular lesions by P. falciparum excretioninurinetopreventhyperbilirubinemia[44].Conju- hasbeendescribed[20,32–34].Interstitialnephritiscaused gatedbilirubiniswatersolubleandthereforemaybedetected by influx of leukocytes to renal tissue could explain such in the urinalysis, while unconjugated bilirubin, insoluble, alterations; however glomerulonephritis attributed to the cannot pass through the renal glomerulus and cannot be deposition of immune complexes is a form of glomerular detectedinthetest[12].Bothconjugatedandunconjugated injurypoorlyreportedinthemalarialpatient[19]. bilirubin are toxic to the kidney tissue [19, 45] especially Inourpatients,therewasarelationshipbetweenprotein- to renal tubular cells, hence the fact that a patient with uriaandBUN(OR2.8,𝑃 = 0.001)butnotwithcreatinine. hyperbilirubinemiahasagreaterriskoftubularnecrosis[7]. This finding is similar to observations by Hanson et al. Ahigherconjugatedbilirubinconcentrationinbloodand [35] but contrasts with observations in India that found no increasedmortalityinpatientswithimpairedrenalfunction relationshipbetweenproteinuria,serumcreatinine,andBUN infalciparummalariacasesinIndiahasbeenreported;renal [14]. In 1328 Colombian patients, aged 5 to over 60 years, function deterioration was associated with a decrease in proteinuriawaspresentin54%ofP.falciparuminfectionsand excretionofconjugatedbilirubininurine[45].Alowerrate 48%ofP.vivax,anditwasassociatedwithserumcreatinine> of bilirubin excretion in urine may lead to an increase in 1.5mg/dL(𝑃=0.013)andwithcholuriaandhemoglobinuria, conjugatedbilirubinconcentrationinblood,perpetuatinga suggestingkidneydamage[15].In40Nigerianchildrenwith cycle of renal injury and predisposing these patients with acutefalciparummalaria,thecreatinineclearancerate[CCR] renal injury to develop other complications [45] such as was significantly lower during the acute phase of infection cerebralmalaria,electrolytedisorders,jaundice,andanemia comparedtotherecoverystage;proteinuriawaspresentedin [19,20,32]. 40%ofpatientsbutwasnotassociatedwithCCR[27]. Moderate or severe liver complication was present in Increased BUN or creatinine can result from prerenal 38.7% of our patients, consistent with previous studies that azotemia[19]throughaninadequatekidneybloodflowand found up to 33% of patients with this complication [9]. In aglomerularhydrostaticpressureinsufficienttomaintainthe these patients, both proteinuria (OR 1.5, CI 1.0–2.3) and glomerular filtration rate [GFR] [36]. Long lasting prerenal bilirubinuria (OR 2.1, CI 1.3–3.3) were associated with an azotemia can produce tubular necrosis, the most common increased risk of liver complications; and both were related formofrenalinjuryinmalaria[19].Howeverthediagnosisof to renal complications (𝑃 < 0.05), suggesting a role as renaldamageistraditionallysupportedonserumcreatinine predictors of injury in these organs since kidney and liver increases (values over 1mg/dL) and these values are only dysfunction are involved in other clinical complications in apparentoncetheGFRhasfallenabout50%[37].Proteinuria malaria patients. From this evidence we could then explain maybeanearlyresultofinjurybeforeasignificantdropin theassociationbetweenproteinuriaandincreasedTBandDB theGFRandcreatininerisecanbeobserved.Inourpatients, by a complex mechanism that involves not only the direct relationbetweenproteinuriaandseverekidneyinjurywasnot toxiceffect ofbilirubinontubularcells[7,45],butalsothe found(creatinine>1,5mg/dLorBUN>40mg/dL;𝑛 = 30), effectsofprerenalazotemiawhichinmanycasescanleadto but when severe and mild kidney injury (Cr > 1mg/dL or thedevelopmentofischemicdamageoftendescribedasacute BUN > 20mg/dL; 𝑛 = 170) were pooled, a relation was tubularnecrosis[36].Themechanismsthatleadtoallofthese established between proteinuria and kidney injury (OR 1.7; alterationsinurinalysisparametersshareanaturebeyondthe CI 1.0–2.6; 𝑃 = 0.029), possibly due to the greater number localrenalcommitmentandinvolvefactorsbothwithinand of subjects included in the analysis. In the same direction, outside this organ, evidenced by the complex pathogenesis proteinuria was related to BUN > 20mg/dL (OR 2.9; CI of the establishment of acute kidney injury in the malarial 1.6–5.3; 𝑃 = 0.029). In Indian patients, proteinuria was an patient[19]. JournalofTropicalMedicine 9 4.3. Other Relations with Liver and Kidney Injury. Asso- hematological variables was found. Ketones are a product ciations were found among serum ALT and bilirubinuria ofthedecreasedmetabolismofglucoseinthepatients[12]; (𝑃 = 0.01),urobilinuria(𝑃 = 0.006),andproteinuria(𝑃 = asglucoseisoneofthemostimportantsubstratesforbrain 0.001);thiscontributestoexplainingarelationshipbetween metabolism, the neurologic complications (manifested as liver complication and bilirubinuria (OR 2.1, CI 1.3–3.3), seizure or coma) can appear. Although our patients with urobilinuria(OR2.7,CI1.7–4.5),andproteinuria(OR1.5,CI neurological complications have lower blood glucose levels 1.0–2.3). thanthosewithoutneurologicalalteration(median90versus Pyuriawasdetectedin22.9%ofoursample,aparameter 102mg%), the difference is not significant. Additionally the rarelyreportedinmalaria.In Nigeria,pyuriawasinformed lownumberofpatientswithneurologicalcomplicationand in malaria patients but without difference in the frequency blood glucose and urine ketones measurements (𝑛 = 5) with nonmalaria patients [11]. In Sudan, pyuria was found preventsexploringtheserelationships. in 140 patients, 53.8% with a positive blood smear, but the Inthisstudyproteinuriahasbeenrelatedtomoderateor differencebetweentheoccurrencesofpyuriainmalarialand severepulmonarycomplication(𝑃 = 0.025);thiscomplica- nonmalarialpatientswasnotstatisticallysignificant[13].The tionhasbeenreportedinpatientswithmalarialacutekidney presenceofleukocytesinurineishighlyspecific to urinary injury [20, 33] and has been described in 31% of malarial tractinfectionbutithaslowsensitivity;combinedwithapos- patients who required treatment in an intensive care unit itivenitritetestitisastrongindicatorofinfection.However, [55].Onepossibleexplanationforthisassociationcanbethe nitritesmaybeaffectedformanyreasonsincludingbacteria increasedbloodvolume,byeitherrenalorhydricoverload; lacking the enzyme that converts nitrates to nitrites, so a bothconditionshavebeenrelatedtopulmonarycomplication negativeresultofthelatterdoesnotexcludethepossibilityof inthemalarialpatients[56].Infacttheassociationbetween urinarytractinfection[21].Ameta-analysisaboutbacterial malaria kidney complication and pulmonary complication infectionsinchildreninfectedwithP.falciparumconcluded was evaluated in a study by Kaushik et al. in malaria vivax that these patients were at an increased risk of bacterial patients in India; they found that 14% of the patients with infectionsresultinginincreasedmortality[46]. acutekidneyinjuryalsopresentedacuterespiratorydistress While in our study the presence of leukocytes was not syndrome[57]. related to an increased risk of clinical complications, it is The relationship between analgesic and anti-inflam- worth noting this marker of urinary tract infection; this matoriesuseandtheincreasedurinarydensityisinfavorof may reflect the different immunosuppressive events that theassociationbetweenthisalterationandrenaldysfunction. occurduringmalaria.Agreatersusceptibilityofthemalaria Inadditiontomalaria,kidneyinjurymaybefavoredbythe patient to various infections during the acute disease has useofmedications.Oneinterestingfindingistheassociation been described, along with the role of hemozoin as an between urobilinogen and moderate or severe thrombocy- immunosuppressantthataffectsbothantigenprocessingand topenia;thiscanreflecttheseverityofthedisease. immunomodulatory effects in macrophages [47] as well as Darkurinewasrelatedtoproteins,urobilinogen,biliru- by inhibiting dendritic cell activity [48]; the inhibition of bin, and blood (hemoglobin or hematuria) in urine, asso- the neutrophil function has been related to the hemolysis ciated with liver dysfunction, and was more frequent in andthehemeoxygenaseoneinduction[49].Thedefenseof patientswithBUNover20mg/dL.Previousfindingsreported the urinary tract relies primarily on the innate immunity, no association between dark urine and hepatic or renal with a particular interest in the neutrophil function in the complication,concludingthatthissigncanbeusedasearly bladder [50]. In fact different polymorphism in the TLR marker of these complications [8]. Bilirubin in urine is, (Toll-Like Receptor) genes has been related to an increased almost entirely, conjugated bilirubin and evidences hepatic susceptibility to urinary tract infections[51]; as the malaria injury,inthesamewayofotherfindingsinthisstudy. parasite can inhibit the innate immune function, increased Alimitationofthestudyisthatamultivariatemodelof urinarytractinfectionsinthemalariapatientscouldappear. therelationshipsbetweenurinalysisandseveremalariawas Finally, leukocyturia in patients could be related to not obtained, probably because this outcome is due to dif- interstitialnephritis;thisalongwithhematuriacanbepresent ferentcomplications;onlybivariaterelationswereobtained. in different types of glomerulonephritis [52]; indeed the Since the pathogenesis underlying each organ injury would interstitial nephritis has been described in infections with producedistinctalterationsintheurine,animportantstatis- P.falciparuminassociationwithacutetubularnecrosisand ticalsampleofeachcomplicationwouldberequired. glomerularinjury[53,54]. This study found a relation between proteinuria and a 5.Conclusions high specific gravity (𝑃 < 0.05). Specific gravity in a urine sampledependsonboththenumberofparticlespresentin ThemostfrequentalterationsintheurinalysisinColombian the sample and their weight [21]. Increased urine specific patientswithmalariawerebilirubinuria(24.3%),urobilinuria gravitymaybeduetoincreasedsolutesinthesample,such (30.6%),proteinuria(39.2%),andhighdensity(41.2%)related as proteins, bilirubin, and ketones. Impaired renal function to liver, kidney, and neurological function and thrombo- must be considered as one of the factors that can increase cytopenia. The use of the urine dipstick facilitated rapid specificgravityinurine[12]. identificationofliverandkidneyinjuryandothersuspected Ketones was also associated with an increased risk of complicationsincludingacidosis,pulmonary,andneurologic neurologicalcomplications(𝑃 = 0.002)butnorelationwith compromise. 10 JournalofTropicalMedicine Urinalysisprovestobeanexcellenttooltodetectpatho- study, and to Esteban Mesa and Margery Sullivan for their logical changes in malaria patients. Its low cost and ease of support in translating and revising the manuscript. This application at the bedside make it a cost effective method projectwasfundedbytheUniversityofAntioquia,Colombia applicableinthefirstlevelsofcareforthetimelyrecognition (MalariaGroup,FacultyofMedicine,andViceChancellorof ofpatientsatriskallowingappropriatecaretoreducesevere Investigation). morbidityanddeaths.Therelationshipbetweenalterationsin urineandserummarkersoforgandysfunctionindicatesthat References this test is usefulto alert the clinician to the progressionof malariatoseveredisease. [1] WorldHealthOrganisation,“Worldmalariareport2014,”2014. [2] UNICEF, World Health Organization, The World Bank, and Abbreviations UnitedNations,“Level&TrendinChildMortality,”2014. [3] N.J.White,S.Pukrittayakamee,T.T.Hien,M.A.Faiz,O.A. ALT: Alanineaminotransferase Mokuolu,andA.M.Dondorp,“Malaria,”TheLancet,vol.383, AST: Aspartateaminotransferase no.9918,pp.723–735,2014. BUN: Bloodureanitrogen [4] A.E.Maestre,“Plasmodios,”inMicrobiologiadeLasInfecciones Cr: Creatinine Humanas,F.J.Diaz,S.Estrada,L.Francoetal.,Eds.,pp.340– CCR: Creatinineclearancerate 351,CorporacionparalasInvestigacionesBiologicas,Medellin, DB: Conjugatedbilirubin Colombia,1stedition,2007. GFR: Glomerularfiltrationrate [5] J.K.Baird,“NeglectofPlasmodiumvivax malaria,”Trendsin Hb: Hemoglobin Parasitology,vol.23,no.11,pp.533–539,2007. TB: Totalbilirubin [6] A. Tobo´n-Castan˜o, “Danger signs in the Malaria patient,” IB: Unconjugatedbilirubin. Biomedica,vol.29,no.2,pp.320–329,2009. [7] A. Tobo´n-Castan˜o, A. D. M. Cortina, A. F. Miranda, and S. EthicalApproval Blair Trujillo, “[Dark urine and jaundice as warning signs in PlasmodiumfalciparummalariainColombia,”RevistaCubana ThedocumentwasendorsedbytheEthicsCommitteeofthe deMedicinaTropical,vol.2,no.1,pp.28–35,2010. Medical Research Institute from the Medical School of the [8] A. Tobo´n-Castan˜o, C. Giraldo-Castro, and S. Blair-Trujillo, University of Antioquia (Minute 31, July 2002; Minute 05, “Utilityoftheclinicalandparasitologicalsignsintheprognosis June 2005). The review of retrospectively studied patients’ ofseveremalariainColombia,”Biomedica,vol.32,no.2,pp.79– medicalrecordswasapprovedbytheHospitalEthicsCom- 94,2012. mitteesfrom“HospitalPabloTobo´nUribe”and“HospitalSan [9] A.T.Tobo´n-Castan˜o,J.G.Pin˜erosJime´nez,S.Blair-Trujillo,and VicenteFundacio´n”(Letter5282,Oct.2009). J. Carmona-Fonseca, “Clinical presentation of severe malaria duePlasmodiunfalciparum.Case-controlstudyinTumacoand Turbo(Colombia),”Iatreia,vol.19,no.4,pp.339–355,2006. Consent [10] A. O’Donnell, D. J. Weatherall, A. M. Taylor, J. C. Reeder, andS.J.Allen,“Musclecellinjury,haemolysisanddarkurine Thepatientsstudiedprospectivelywereincludedaftergiving in children with falciparum malaria in Papua New Guinea,” a written informed consent to participate and publish the Transactions of the Royal Society of Tropical Medicine and results. Each adult signed the informedconsent. Forall the Hygiene,vol.100,no.9,pp.817–825,2006. children,aparentorguardianprovidedtheinformedconsent [11] E.I.UgwujaandN.C.Ugwu,“Abnormalfindingsondipstick ontheirbehalfandalsoawrittenapprovalwasrequestedfor urinalysis of out-patients with malaria in Abakaliki, Nigeria,” subjectsbetween7and17yearsofage. JournalofVectorBorneDiseases,vol.48,no.4,pp.205–209,2011. [12] G.CampuzanoMayaandM.Arbela´ezGomez,“Urineanalysis: ConflictsofInterest morethanacommontest,”MedicinayLaboratorio,vol.12,no. 11,pp.511–556,2006. Theauthorsdeclarethattheyhavenoconflictsofinterest. [13] A.E.G.KaroumOsmanandB.A.Mohammed,“Urineanalysis inMalariainKassalaTown,EasternSudan,”SauddiJournalof Authors’Contributions KidneyDiseasesandTransplantation,vol.11,no.2,pp.208–210, 2000. Alberto Tobo´n-Castan˜o participated in the study design, [14] S. S. Pati and S. K. Mishra, “Can urine dipstick tests detect datacollection,dataanalysis,andwritingofthemanuscript. renalimpairmentinPlasmodiumfalciparummalariainarural Sebastia´n Barrera Escobar contributed to data analysis and setup?”TropicalDoctor,vol.40,no.2,pp.106-107,2010. writingofthemanuscript.CeciliaGiraldoCastromadethe [15] M.Are´valo-Herrera,M.Lopez-Perez,L.Medina,A.Moreno, diagnosisofmalariaandqualitycontrolandcontributedto J. B. Gutierrez, and S. Herrera, “Clinical profile of Plasmod- dataanalysisandrevisionofmanuscript. iumfalciparumandPlasmodiumvivaxinfectionsinlowand unstable malaria transmissionsettings of Colombia,” Malaria Acknowledgments Journal,vol.14,no.1,pp.1–11,2015. [16] S. K. Mishra, S. S. Pati, K. C. Mahanta, and S. Mohanty, Thanks are due to “Malaria Group of the University of “Rhabdomyolysis in falciparum malaria—a series of twelve Antioquia” and “San Vicente de Pau´l” and “Pablo Tobo´n cases(fivechildrenandsevenadults),”TropicalDoctor,vol.40, Uribe” Hospitals, which provided data analyzed in this no.2,pp.87-88,2010.