An evaluation of commonly used surrogate baseline creatinine values to classify AKI during acute infection

Introduction Classification of acute kidney injury (AKI) requires a premorbid baseline creatinine, often unavailable in studies in acute infection. Methods We evaluated commonly used surrogate and imputed baseline creatinine values against a “reference” creatinine measured during follow-up in an adult clinical trial cohort. Known AKI incidence (Kidney Disease: Improving Global Outcomes [KDIGO] criteria) was compared with AKI incidence classified by (1) back-calculation using the Modification of Diet in Renal Disease (MDRD) equation with and without a Chinese ethnicity correction coefficient; (2) back-calculation using the Chronic Kidney Disease–Epidemiology Collaboration (CKD-EPI) equation; (3) assigning glomerular filtration rate (GFR) from age and sex-standardized reference tables; and (4) lowest measured creatinine during admission. Back-calculated distributions were performed using GFRs of 75 and 100 ml/min. Results All equations using an assumed GFR of 75 ml/min underestimated AKI incidence by more than 50%. Back-calculation with CKD-EPI and GFR of 100 ml/min most accurately predicted AKI but misclassified all AKI stages and had low levels of agreement with true AKI diagnoses. Back-calculation using MDRD and assumed GFR of 100 ml/min, age and sex-reference GFR values adjusted for good health, and lowest creatinine during admission performed similarly, best predicting AKI incidence (area under the receiver operating characteristic curves [AUC ROCs] of 0.85, 0.87, and 0.85, respectively). MDRD back-calculation using a cohort mean GFR showed low total error (22%) and an AUC ROC of 0.85. Conclusion Current methods for estimating baseline creatinine are large sources of potential error in acute infection studies. Preferred alternatives include MDRD equation back-calculation with a population mean GFR, age- and sex-specific GFR values corrected for “good health,” or lowest measured creatinine. Studies using surrogate baseline creatinine values should report specific methodology

The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium knowlesi malaria (PACKNOW): study protocol for a randomised controlled trial

Background Plasmodium knowlesi is the most common cause of human malaria in Malaysia. Acute kidney injury (AKI) is a frequent complication. AKI of any cause can have long-term consequences, including increased risk of chronic kidney disease, adverse cardiovascular events and increased mortality. Additional management strategies are therefore needed to reduce the frequency and severity of AKI in malaria. In falciparum malaria, cell-free haemoglobin (CFHb)-mediated oxidative damage contributes to AKI. The inexpensive and widely available drug paracetamol inhibits CFHb-induced lipid peroxidation via reduction of ferryl haem to the less toxic Fe3+ state, and has been shown to reduce oxidative damage and improve renal function in patients with sepsis complicated by haemolysis as well as in falciparum malaria. This study aims to assess the ability of regularly dosed paracetamol to reduce the incidence and severity of AKI in knowlesi malaria by attenuating haemolysis-induced oxidative damage. Methods PACKNOW is a two-arm, open-label randomised controlled trial of adjunctive paracetamol versus no paracetamol in patients aged ≥ 5 years with knowlesi malaria, conducted over a 2-year period at four hospital sites in Sabah, Malaysia. The primary endpoint of change in creatinine from enrolment to 72 h will be evaluated by analysis of covariance (ANCOVA) using enrolment creatinine as a covariate. Secondary endpoints include longitudinal changes in markers of oxidative stress (plasma F2-isoprostanes and isofurans) and markers of endothelial activation/Weibel–Palade body release (angiopoietin-2, von Willebrand Factor, P-selectin, osteoprotegerin) over 72 h, as well as blood and urine biomarkers of AKI. This study will be powered to detect a difference between the two treatment arms in a clinically relevant population including adults and children with knowlesi malaria of any severity. Discussion Paracetamol is widely available and has an excellent safety profile; if a renoprotective effect is demonstrated, this trial will support the administration of regularly dosed paracetamol to all patients with knowlesi malaria. The secondary outcomes in this study will provide further insights into the pathophysiology of haemolysis-induced oxidative damage and acute kidney injury in knowlesi malaria and other haemolytic diseases

Artemether-lumefantrine versus chloroquine for the treatment of uncomplicated Plasmodium knowlesi malaria (CAN KNOW): an open-label randomized controlled trial

Plasmodium knowlesi is reported increasingly across Southeast Asia, and is the commonest cause of malaria in Malaysia. No randomized trials have assessed comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria.A randomized-controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if >10kg, parasitemia <20,000/μL, and had a negative Pf-HRP2 rapid-diagnostic-test. Diagnosis was confirmed by PCR. Patients were block randomized to AL (total target dose 12mg/60mg per kg) or CQ (25mg/kg). The primary outcome was parasite clearance at 24-hours in a modified intention-to-treat analysis.From November 2014 to January 2016, 123 patients (including 18 children) were enrolled. 24-hours after treatment 76% (95%CI 63-86; 44/58) of patients administered AL were aparasitemic compared to 60% (47-72; 39/65) administered CQ (Risk Ratio 1.3 [1.0-1.6]; p=0.061). Overall parasite clearance was shorter following AL (median 18 hours) compared to CQ (24 hours); p=0.021; with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days/1000 patients; IRR 0.86 [0.82-0.91]; p<0.001). There were no serious adverse events.AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia

Artemether-lumefantrine versus chloroquine for the treatment of uncomplicated Plasmodium knowlesi malaria (CAN KNOW): an open-label randomized controlled trial

Plasmodium knowlesi is reported increasingly across Southeast Asia, and is the commonest cause of malaria in Malaysia. No randomized trials have assessed comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria.A randomized-controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if >10kg, parasitemia <20,000/μL, and had a negative Pf-HRP2 rapid-diagnostic-test. Diagnosis was confirmed by PCR. Patients were block randomized to AL (total target dose 12mg/60mg per kg) or CQ (25mg/kg). The primary outcome was parasite clearance at 24-hours in a modified intention-to-treat analysis.From November 2014 to January 2016, 123 patients (including 18 children) were enrolled. 24-hours after treatment 76% (95%CI 63-86; 44/58) of patients administered AL were aparasitemic compared to 60% (47-72; 39/65) administered CQ (Risk Ratio 1.3 [1.0-1.6]; p=0.061). Overall parasite clearance was shorter following AL (median 18 hours) compared to CQ (24 hours); p=0.021; with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days/1000 patients; IRR 0.86 [0.82-0.91]; p<0.001). There were no serious adverse events.AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia

Plasmodium falciparum artemisinin resistance monitoring in Sabah, Malaysia: in vivo therapeutic efficacy and kelch13 molecular marker surveillance

Background Spreading Plasmodium falciparum artemisinin drug resistance threatens global malaria public health gains. Limited data exist to define the extent of P. falciparum artemisinin resistance southeast of the Greater Mekong region in Malaysia. Methods A clinical efficacy study of oral artesunate (total target dose 12 mg/kg) daily for 3 days was conducted in patients with uncomplicated falciparum malaria and a parasite count &lt; 100,000/µL admitted to 3 adjacent district hospitals in Sabah, East Malaysia. On day 3 and 4 all patients were administered split dose mefloquine (total dose 25 mg/kg) and followed for 28 days. Twenty-one kelch13 polymorphisms associated with P. falciparum artemisinin resistance were also evaluated in P. falciparum isolates collected from patients presenting to health facilities predominantly within the tertiary referral area of western Sabah between 2012 and 2016. Results In total, 49 patients were enrolled and treated with oral artesunate. 90% (44/49) of patients had cleared their parasitaemia by 48 h and 100% (49/49) within 72 h. The geometric mean parasite count at presentation was 9463/µL (95% CI 6757–13,254), with a median time to 50% parasite clearance of 4.3 h (IQR 2.0–8.4). There were 3/45 (7%) patients with a parasite clearance slope half-life of ≥ 5 h. All 278 P. falciparum isolates evaluated were wild-type for kelch13 markers. Conclusion There is no suspected or confirmed evidence of endemic artemisinin-resistant P. falciparum in this pre-elimination setting in Sabah, Malaysia. Current guidelines recommending first-line treatment with ACT remain appropriate for uncomplicated malaria in Sabah, Malaysia. Ongoing surveillance is needed southeast of the Greater Mekong sub-region

Age-related clinical spectrum of plasmodium knowlesi malaria and predictors of severity

Background:Plasmodium knowlesi is increasingly reported in Southeast Asia, but prospective studies of its clinical spectrum in children and comparison with autochthonous human-only Plasmodium species are lacking. Methods:Over 3.5 years, we prospectively assessed patients of any age with molecularly-confirmed Plasmodium monoinfection presenting to 3 district hospitals in Sabah, Malaysia. Results:Of 481 knowlesi, 172 vivax, and 96 falciparum malaria cases enrolled, 44 (9%), 71 (41%), and 31 (32%) children aged ≤12 years. Median parasitemia was lower in knowlesi malaria (2480/μL [interquartile range, 538-8481/μL]) than in falciparum (9600/μL; P &lt; .001) and vivax malaria. In P. knowlesi, World Health Organization-defined anemia was present in 82% (95% confidence interval [CI], 67%-92%) of children vs 36% (95% CI, 31%-41%) of adults. Severe knowlesi malaria occurred in 6.4% (95% CI, 3.9%-8.3%) of adults but not in children; the commenst severity criterion was acute kideny injury. No patient had coma. Age, parasitemia, schizont proportion, abdominal pain, and dyspnea were independently associated with severe knowlesi malaria, with parasitemia &gt;15000/μL the best predictor (adjusted odds ratio, 16.1; negative predictive value, 98.5%; P &lt; .001). Two knowlesi-related adult deaths occurred (fatality rate: 4.2/1000 adults). Conclusions:Age distribution and parasitemia differed markedly in knowlesi malaria compared to human-only species, with both uncomplicated and severe disease occurring at low parasitemia. Severe knowlesi malaria occurred only in adults; however, anemia was more common in children despite lower parasitemia. Parasitemia independently predicted knowlesi disease severity: Intravenous artesunate is warranted initially for those with parasitemia &gt;15000/μL

Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): An open-label, randomised controlled trial

Background: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate-mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children. Methods: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p&lt;0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p&lt;0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p&lt;0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p&lt;0·0001). One (&lt;1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug. Interpretation: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network