Pub Date : 2025-05-01DOI: 10.1016/j.semnephrol.2025.151615
Nicholas M. Anstey MBBS, FRACP, PhD , Matthew J. Grigg MBBS, PhD , Timothy William MBBS, FRCP , Giri S. Rajahram MD, MSc, FRCP , Daniel J. Cooper MBChB, MRCP, PhD , Bridget E. Barber MBBS, FRACP, PhD
Acute kidney injury (AKI) complicates non-falciparum malaria, particularly that from Plasmodium knowlesi. AKI (any KDIGO stage) is present in 20-30% of hospitalized patients with knowlesi malaria, with age >45 years having a sixfold risk of AKI. WHO-defined severe AKI (creatinine >265μmol/L) is found in ∼2.5% of adult knowlesi hospitalizations and 60% of deaths, with pathogenesis linked with intravascular hemolysis, endothelial activation, glycocalyx degradation and acute tubular necrosis (ATN). Paracetamol may have a renoprotective effect in severe knowlesi AKI, including reductions in medium-term proteinuria. WHO-severe AKI has been estimated by meta-analysis as occurring in 0.01% of combined hospital inpatient and outpatients with P. vivax malaria with unexplained geographic heterogeneity and incomplete systematic exclusion of comorbidities. Despite a paucity of community-based P. vivax KDIGO-defined AKI studies, one such study identified AKI in 10% of adults and children with vivax malaria, almost all KDIGO stage 1. AKI pathogenesis in vivax malaria is not well characterized; an exception is 8-aminoquinoline drug-induced acute hemolysis and ATN in patients with G6PD deficiency. AKI risk in malaria from P. malariae and P. ovale is poorly characterized and may be underrecognized. Long-term outcomes of AKI, including CKD and cardiovascular disease, are unknown in non-falciparum species, and longitudinal studies are needed.
{"title":"Acute Kidney Injury in Non-falciparum Malaria","authors":"Nicholas M. Anstey MBBS, FRACP, PhD , Matthew J. Grigg MBBS, PhD , Timothy William MBBS, FRCP , Giri S. Rajahram MD, MSc, FRCP , Daniel J. Cooper MBChB, MRCP, PhD , Bridget E. Barber MBBS, FRACP, PhD","doi":"10.1016/j.semnephrol.2025.151615","DOIUrl":"10.1016/j.semnephrol.2025.151615","url":null,"abstract":"<div><div>Acute kidney injury (AKI) complicates non-falciparum malaria, particularly that from <em>Plasmodium knowlesi</em>. AKI (any KDIGO stage) is present in 20-30% of hospitalized patients with knowlesi malaria, with age >45 years having a sixfold risk of AKI. WHO-defined severe AKI (creatinine >265μmol/L) is found in ∼2.5% of adult knowlesi hospitalizations and 60% of deaths, with pathogenesis linked with intravascular hemolysis, endothelial activation, glycocalyx degradation and acute tubular necrosis (ATN). Paracetamol may have a renoprotective effect in severe knowlesi AKI, including reductions in medium-term proteinuria. WHO-severe AKI has been estimated by meta-analysis as occurring in 0.01% of combined hospital inpatient and outpatients with <em>P. vivax</em> malaria with unexplained geographic heterogeneity and incomplete systematic exclusion of comorbidities. Despite a paucity of community-based <em>P. vivax</em> KDIGO-defined AKI studies, one such study identified AKI in 10% of adults and children with vivax malaria, almost all KDIGO stage 1. AKI pathogenesis in vivax malaria is not well characterized; an exception is 8-aminoquinoline drug-induced acute hemolysis and ATN in patients with G6PD deficiency. AKI risk in malaria from <em>P. malariae</em> and <em>P. ovale</em> is poorly characterized and may be underrecognized. Long-term outcomes of AKI, including CKD and cardiovascular disease, are unknown in non-falciparum species, and longitudinal studies are needed.</div></div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"45 3","pages":"Article 151615"},"PeriodicalIF":2.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-01DOI: 10.1016/j.semnephrol.2025.151617
Tryphena Adams MPhil , Anthony Batte MMED , Rafael Polidoro PhD , Regina Joice Cordy PhD
Malaria caused by the protozoan parasite Plasmodium is associated with vast morbidity and mortality worldwide. Among the serious clinical complications of this disease are acute kidney injury (AKI) and acute kidney disease (AKD), characterized by a decline in kidney function measurable by changes in serum creatinine. Research using nonhuman primates (NHPs) has revealed commonalities between NHPs and humans in malaria pathogenesis. Here, we perform a reanalysis of serum creatinine data from published studies on P. knowlesi malaria infections of long-tailed (natural host) and rhesus (nonnatural host) macaques to assess AKI and AKD. In rhesus macaques, despite receiving antimalarial treatment to reduce parasitemia, delayed onset of AKD occurred days to weeks post-treatment, showing a disconnect between parasitemia and AKD. While the high mortality of rhesus macaques prohibited a prolonged experimental design, the use of long-tailed macaques, naturally resistant to P. knowlesi, enabled longer time series studies and revealed more details about disease progression. Most long-tailed macaques, despite having a natural ability to control parasitemia, also exhibited a delayed onset of AKD in the period following peak parasitemia. Altogether, this study shows that both rhesus and long-tailed macaques exhibit a delayed onset of AKD during malaria, as has been reported in humans.
{"title":"Analysis of Serum Creatinine Data from Long-tailed and Rhesus Macaques to Assess Malaria-associated Acute Kidney Injury","authors":"Tryphena Adams MPhil , Anthony Batte MMED , Rafael Polidoro PhD , Regina Joice Cordy PhD","doi":"10.1016/j.semnephrol.2025.151617","DOIUrl":"10.1016/j.semnephrol.2025.151617","url":null,"abstract":"<div><div>Malaria caused by the protozoan parasite <em>Plasmodium</em> is associated with vast morbidity and mortality worldwide. Among the serious clinical complications of this disease are acute kidney injury (AKI) and acute kidney disease (AKD), characterized by a decline in kidney function measurable by changes in serum creatinine. Research using nonhuman primates (NHPs) has revealed commonalities between NHPs and humans in malaria pathogenesis. Here, we perform a reanalysis of serum creatinine data from published studies on <em>P. knowlesi</em> malaria infections of long-tailed (natural host) and rhesus (nonnatural host) macaques to assess AKI and AKD. In rhesus macaques, despite receiving antimalarial treatment to reduce parasitemia, delayed onset of AKD occurred days to weeks post-treatment, showing a disconnect between parasitemia and AKD. While the high mortality of rhesus macaques prohibited a prolonged experimental design, the use of long-tailed macaques, naturally resistant to <em>P. knowlesi</em>, enabled longer time series studies and revealed more details about disease progression. Most long-tailed macaques, despite having a natural ability to control parasitemia, also exhibited a delayed onset of AKD in the period following peak parasitemia. Altogether, this study shows that both rhesus and long-tailed macaques exhibit a delayed onset of AKD during malaria, as has been reported in humans.</div></div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"45 3","pages":"Article 151617"},"PeriodicalIF":2.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute kidney injury (AKI) is increasingly recognized in pediatric severe malaria, but an understanding of contributory mechanisms is lacking. We evaluated potential hemodynamic contributors to AKI in children with cerebral malaria. Structural AKI was defined using urine neutrophil gelatinase–associated lipocalin (uNGAL) values >125 ng/mL. We included 62 patients (median age 53.5 [31, 71] months), and 38 (61%) had AKI at hospital admission. Blantyre Coma Score <2 (aOR 9.1, 95%CI 1.8-43, P = .003), a low-flow phenotype on transcranial doppler ultrasound (TCD) (aOR 2.3, 95%CI 1.1-7.7, P = .05), and thrombocytopenia <75,000 × 106/L (aOR 4.2, 95%CI 1.3-12.8, P = .03) were associated with AKI. Cardiac index (CI) was lower (P = .01) and systemic vascular resistive index (SVRI) higher (P = .03) in children with AKI compared to those without. AKI was associated with poor outcome (sequelae or death: OR 5.7, 95%CI 1.5-19, P = .01). AKI is common in children with cerebral malaria. Hemodynamic measurements suggest increased vascular tone contributes to AKI.
{"title":"Chasing the Mystery of the Etiology of Acute Kidney Injury in Pediatric Severe Malaria","authors":"Doreen Thandiwe Phiri MD , Solomon Ngwira BSc , Hunter Wynkoop MD , Karl Seydel MD, PhD , Nicole F. O’Brien MD","doi":"10.1016/j.semnephrol.2025.151618","DOIUrl":"10.1016/j.semnephrol.2025.151618","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is increasingly recognized in pediatric severe malaria, but an understanding of contributory mechanisms is lacking. We evaluated potential hemodynamic contributors to AKI in children with cerebral malaria. Structural AKI was defined using urine neutrophil gelatinase–associated lipocalin (uNGAL) values >125 ng/mL. We included 62 patients (median age 53.5 [31, 71] months), and 38 (61%) had AKI at hospital admission. Blantyre Coma Score <2 (aOR 9.1, 95%CI 1.8-43, <em>P</em> = .003), a low-flow phenotype on transcranial doppler ultrasound (TCD) (aOR 2.3, 95%CI 1.1-7.7, <em>P</em> = .05), and thrombocytopenia <75,000 × 10<sup>6</sup>/L (aOR 4.2, 95%CI 1.3-12.8, <em>P</em> = .03) were associated with AKI. Cardiac index (CI) was lower (<em>P</em> = .01) and systemic vascular resistive index (SVRI) higher (<em>P</em> = .03) in children with AKI compared to those without. AKI was associated with poor outcome (sequelae or death: OR 5.7, 95%CI 1.5-19, <em>P</em> = .01). AKI is common in children with cerebral malaria. Hemodynamic measurements suggest increased vascular tone contributes to AKI.</div></div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"45 3","pages":"Article 151618"},"PeriodicalIF":2.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-01DOI: 10.1016/j.semnephrol.2025.151619
Flora Olcott MD , Cesc Bertran-Cobo MSc , Praveen K. Sahu PhD , Sameer Maharana BSc , Jabamani Bage MPharm , Akshaya K. Mohanty BSc , Angelika Hoffmann MD , Sanjib Mohanty MD , Samuel C. Wassmer PhD
Severe malaria is associated with kidney and brain injury, yet potential mechanisms linking both complications remain understudied. We investigated the associations between kidney and brain injuries in a cohort of Indian adults and children with severe Plasmodium falciparum malaria. We found that acute kidney injury was prevalent in both adults (64.4%) and children (71.4%). We also found that plasma levels of the structural kidney injury biomarker neutrophil gelatinase-associated lipocalin (NGAL) were strongly associated with acute kidney injury severity (P < .0001) and negatively correlated with whole brain magnetic resonance imaging apparent diffusion coefficient values in cerebral malaria (r = –0.6, 95% confidence interval, –0.8 to –0.3). Low apparent diffusion coefficient values indicate cytotoxic edema, a form of hypoxic brain injury mediated by parasite sequestration and inflammation. Severe cytotoxic edema has been shown to be associated with increased mortality in severe malaria. In our cohort, there was a 5.5-fold greater risk of this form of brain injury (prevalence risk ratio, 5.5, 95% confidence interval, 2.3-13.2) in patients with high NGAL levels (>300 ng/mL). These results suggest that plasma NGAL may play a critical role in structural kidney injury and could serve as a predictive marker for hypoxic brain injury in the context of severe malaria.
{"title":"Plasma Neutrophil Gelatinase-Associated Lipocalin as a Biomarker of Kidney Injury and Potential Predictor of Hypoxic Brain Injury in Severe Plasmodium falciparum Malaria: Insights From India","authors":"Flora Olcott MD , Cesc Bertran-Cobo MSc , Praveen K. Sahu PhD , Sameer Maharana BSc , Jabamani Bage MPharm , Akshaya K. Mohanty BSc , Angelika Hoffmann MD , Sanjib Mohanty MD , Samuel C. Wassmer PhD","doi":"10.1016/j.semnephrol.2025.151619","DOIUrl":"10.1016/j.semnephrol.2025.151619","url":null,"abstract":"<div><div>Severe malaria is associated with kidney and brain injury, yet potential mechanisms linking both complications remain understudied. We investigated the associations between kidney and brain injuries in a cohort of Indian adults and children with severe <em>Plasmodium falciparum</em> malaria. We found that acute kidney injury was prevalent in both adults (64.4%) and children (71.4%). We also found that plasma levels of the structural kidney injury biomarker neutrophil gelatinase-associated lipocalin (NGAL) were strongly associated with acute kidney injury severity (<em>P</em> < .0001) and negatively correlated with whole brain magnetic resonance imaging apparent diffusion coefficient values in cerebral malaria (<em>r</em> = –0.6, 95% confidence interval, –0.8 to –0.3). Low apparent diffusion coefficient values indicate cytotoxic edema, a form of hypoxic brain injury mediated by parasite sequestration and inflammation. Severe cytotoxic edema has been shown to be associated with increased mortality in severe malaria. In our cohort, there was a 5.5-fold greater risk of this form of brain injury (prevalence risk ratio, 5.5, 95% confidence interval, 2.3-13.2) in patients with high NGAL levels (>300 ng/mL). These results suggest that plasma NGAL may play a critical role in structural kidney injury and could serve as a predictive marker for hypoxic brain injury in the context of severe malaria.</div></div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"45 3","pages":"Article 151619"},"PeriodicalIF":2.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute kidney injury (AKI) is a common, life-threatening clinical complication of severe malaria in children associated with increased short- and long-term mortality. Malaria remains a leading cause of child mortality in Africa, where most severe malaria cases and deaths occur, and a few countries account for most of the global disease burden. While some children who develop severe malaria-associated AKI may require dialysis during hospitalization, survivors may require long-term care for chronic kidney disease, including maintenance dialysis and kidney transplant. There are variations in the availability and type of dialysis services offered across malaria-endemic African countries with major barriers to accessing kidney transplants. Access remains challenging among countries with dialysis services because these centers are usually located in selected specialized urban hospitals far from most patients. The limited number of available pediatric nephrologists in the region further impacts the delivery of specialized nephrology care. This review provides an overview of the magnitude of malaria-associated AKI in selected malaria-endemic countries, country-specific perspectives on dialysis availability and access, and kidney transplant services availability for children who develop chronic kidney disease.
{"title":"Kidney Replacement Therapy for Children With Acute Kidney Injury Due to Severe Malaria: A Review of Available Services in Selected African Countries","authors":"Folake M. Afolayan MBBS, MSc, FMCPaed , Nicole O'Brien MD , Pepe Mfutu Ekulu MD, PhD , Francis F. Furia MD , Chisambo Mwaba BSc, MBChB, MMed, MPhil , Olanrewaju Timothy Adedoyin MBBS, FWACP, FRCP, MD , Olayinka Ibrahim MBBS, MSc, FMCPaed , Judith Caroline Aujo MBChB, MMed, MPhil , Jessica Dalsuco , Quique Bassat MD, MSc, PhD , Anthony Batte MBChB, MMED","doi":"10.1016/j.semnephrol.2025.151621","DOIUrl":"10.1016/j.semnephrol.2025.151621","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a common, life-threatening clinical complication of severe malaria in children associated with increased short- and long-term mortality. Malaria remains a leading cause of child mortality in Africa, where most severe malaria cases and deaths occur, and a few countries account for most of the global disease burden. While some children who develop severe malaria-associated AKI may require dialysis during hospitalization, survivors may require long-term care for chronic kidney disease, including maintenance dialysis and kidney transplant. There are variations in the availability and type of dialysis services offered across malaria-endemic African countries with major barriers to accessing kidney transplants. Access remains challenging among countries with dialysis services because these centers are usually located in selected specialized urban hospitals far from most patients. The limited number of available pediatric nephrologists in the region further impacts the delivery of specialized nephrology care. This review provides an overview of the magnitude of malaria-associated AKI in selected malaria-endemic countries, country-specific perspectives on dialysis availability and access, and kidney transplant services availability for children who develop chronic kidney disease.</div></div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"45 3","pages":"Article 151621"},"PeriodicalIF":2.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-01DOI: 10.1016/j.semnephrol.2025.151620
Michael Lintner-Rivera MD , Adnan Bhutta MD , Ruth Namazzi MBChB, MMed , Caitlin Bond MPH , Andrea L. Conroy PhD , Anthony Batte MBChB, MMed
Severe malaria remains an important global cause of mortality, particularly in sub-Saharan Africa, where the majority of deaths occur in children under 5 years of age. Hyperkalemia in severe malaria has not been very well reported but is associated with increased mortality. Severe malaria has several features that predispose patients to hyperkalemia, including acute kidney injury, hemolysis, metabolic acidosis, and severe anemia requiring blood transfusion. Our objective is to discuss the epidemiology of hyperkalemia in severe malaria, provide an overview of potassium homeostasis, and discuss risk factors for elevated potassium levels in severe malaria, as well as management strategies considering the resource-limited settings where malaria is endemic.
{"title":"Hyperkalemia in Pediatric Severe Malaria","authors":"Michael Lintner-Rivera MD , Adnan Bhutta MD , Ruth Namazzi MBChB, MMed , Caitlin Bond MPH , Andrea L. Conroy PhD , Anthony Batte MBChB, MMed","doi":"10.1016/j.semnephrol.2025.151620","DOIUrl":"10.1016/j.semnephrol.2025.151620","url":null,"abstract":"<div><div>Severe malaria remains an important global cause of mortality, particularly in sub-Saharan Africa, where the majority of deaths occur in children under 5 years of age. Hyperkalemia in severe malaria has not been very well reported but is associated with increased mortality. Severe malaria has several features that predispose patients to hyperkalemia, including acute kidney injury, hemolysis, metabolic acidosis, and severe anemia requiring blood transfusion. Our objective is to discuss the epidemiology of hyperkalemia in severe malaria, provide an overview of potassium homeostasis, and discuss risk factors for elevated potassium levels in severe malaria, as well as management strategies considering the resource-limited settings where malaria is endemic.</div></div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"45 3","pages":"Article 151620"},"PeriodicalIF":2.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-01DOI: 10.1016/j.semnephrol.2025.151613
Anthony Batte, Ruth Namazzi, Andrea L. Conroy
{"title":"Acute Kidney Injury in Severe Malaria: A New Dawn","authors":"Anthony Batte, Ruth Namazzi, Andrea L. Conroy","doi":"10.1016/j.semnephrol.2025.151613","DOIUrl":"10.1016/j.semnephrol.2025.151613","url":null,"abstract":"","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"45 3","pages":"Article 151613"},"PeriodicalIF":2.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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