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Kidney Injury Biomarkers in Leptospirosis

ABSTRACT

Leptospirosis is a zoonotic infection with a global distribution, though it has a greater impact on marginalized rural agricultural and urban communities in developing countries. Kidney injury, which can lead to severe and lethal infections, is the most frequent complication associated with leptospirosis. Novel biomarkers are being studied as tools for assessing kidney injury in different pathological processes to improve early detection. This review aimed to gather information on the use of novel kidney biomarkers for human leptospirosis. A search of the literature was carried out in September 2021 using the parameters “((kidney) OR (renal) OR (chronic kidney disease) OR (acute kidney injury)) AND ((biomarker) OR (marker)) AND ((Leptospira) OR (leptospirosis))”. The review identified 11 original studies that evaluated the performance of 15 kidney biomarkers related to leptospirosis. Assessment of the evidence for biomarker utility was limited because of the small number of studies and sample sizes. Although some biomarkers were associated with kidney disease, no specific biomarker appeared to be ready for clinical practice, and more research in this field is necessary.

Keywords:
Leptospira; Leptospirosis; Biomarkers; Acute kidney injury; Kidney disease

INTRODUCTION

Leptospira is a genus of highly mobile spirochaete bacteria comprising both pathogenic and saprophytic species. The interaction between a pathogenic species and susceptible host can lead to leptospirosis. Human leptospirosis is a reemerging zoonosis with a global distribution, presenting an average of 1.03 million cases and 58,900 deaths each year11. Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, et al. Global Morbidity and Mortality of Leptospirosis: A Systematic Review. PLoS Negl Trop Dis. 2015;9(9):1-19.. Leptospirosis ranges from mild or asymptomatic to deadly. The kidney is one of the main targets of pathogenesis in Leptospira-host interaction, and during acute disease, renal impairment is common, and bacterial persistence within the kidney leads to fibrosis22. Srisawat N, Sitprija V. Leptospirosis and the Kidney: An Overview. Leptospirosis Kidney. 2019;7:1-9..

Acute kidney injury (AKI) is one of the most frequent complications of leptospirosis, with a reported occurrence varying between 10% and 88% of leptospirosis cases33. Daher EDF, Abreu KLS de, Silva Junior GB da. Leptospirosis-associated acute kidney injury. Braz J Nephrol. 2010;32(4):408-15.. Chronic kidney disease (CKD) may result after a resolved episode of acute leptospirosis, secondary to damage associated with the acute phase and/or due to the persistence of Leptospira in the kidney44. Yang HY, Chang CH, Yang CW. Leptospirosis and Chronic Kidney Disease. Leptospirosis Kidney. 2019;7:27-36.. Herath et al. identified CKD after leptospirosis-related AKI in 9% of the patients in a two-year prospective study55. Herath NJ, Kularatne SAM, Weerakoon KGAD, Wazil A, Subasinghe N, Ratnatunga NVI. Long term outcome of acute kidney injury due to leptospirosis? A longitudinal study in Sri Lanka. BMC Res Notes. 2014;7:398..

Chronic kidney disease of unknown etiology (CKDu) has emerged as a cause of CKD in agricultural communities in warm tropical regions, with toxins, infectious agents, and heat-related kidney stress proposed as probable causes66. Johnson RJ, Wesseling C, Newman LS. Chronic Kidney Disease of Unknown Cause in Agricultural Communities. N Engl J Med. 2019;380(19):1843-52.. Among the different explanations for CKDu, some authors suggest Leptospira could play a role in the etiology, as the bacteria have kidney tropism and regional hotspots are located in areas in which both diseases overlap77. Yang CW. Leptospirosis Renal Disease: Emerging Culprit of Chronic Kidney Disease Unknown Etiology. Nephron. 2018;138(2):129-36.,88. Murray KO, Fischer RSB, Chavarria D, Duttmann C, Garcia MN, Gorchakov R, et al. Mesoamerican nephropathy: a neglected tropical disease with an infectious etiology? Microbes Infect. 2015;17(10):671-5..

Kidney damage results in diminished function and is classified according to the time of establishment and the degree of function reduction99. Duarte DB, Lacerda MCSR, Ribeiro YJP, Ribeiro MZD, Frederico M de A, Oliveira MJC. Kidney biomarkers in tropical infections: an update. Pathog Glob Health. 2020;114(6):302-8.. Damage that is established in a matter of hours or a few days results in AKI, which constitutes a medical emergency and can lead to fatal illness1010. International Society of Nephology. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2(1):1.. CKD is established over time and implies more than three months of altered function that generally involves structural changes within the kidney. Individuals with CKD may not present symptoms until the advanced stages of the disease1111. International Society of Nephology. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1)..

Assessing kidney damage by quantifying renal function using traditional biomarkers such as serum creatinine (SCr), the derived estimated glomerular filtration rate (eGFR), or blood urea nitrogen (BUN) is an insensitive approach, as significant kidney injury may have already occurred prior to any change in these measures of kidney function. In contrast, the levels of kidney injury biomarkers that are produced by the pathological mechanism of injury may increase before kidney function is altered1212. Meneses GC, da Silva GB, Tôrres PPBF, de Castro VQ, Lopes RL, Martins AMC, et al. Novel kidney injury biomarkers in tropical infections: a review of the literature. Rev Inst Med Trop São Paulo. 2020;62.. Consequently, kidney injury biomarkers have emerged as a promising tool in the diagnosis, prognosis, and monitoring of kidney disease, such as for the detection of AKI, prediction of poor outcomes in an emergency department setting1313. Nickolas TL, O’Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med. 2008;148(11):810-9., and identification of patients at risk for kidney disease progression post-hospitalization1414. Puthumana J, Thiessen-Philbrook H, Xu L, Coca SG, Garg AX, Himmelfarb J, et al. Biomarkers of inflammation and repair in kidney disease progression. J Clin Invest. 2021;131(3)..

In the context of human leptospirosis, several kidney injury biomarkers have been studied for their potential use as tools for the early detection of kidney injury and to monitor patients after acute disease to identify those who might develop CKD99. Duarte DB, Lacerda MCSR, Ribeiro YJP, Ribeiro MZD, Frederico M de A, Oliveira MJC. Kidney biomarkers in tropical infections: an update. Pathog Glob Health. 2020;114(6):302-8.,1212. Meneses GC, da Silva GB, Tôrres PPBF, de Castro VQ, Lopes RL, Martins AMC, et al. Novel kidney injury biomarkers in tropical infections: a review of the literature. Rev Inst Med Trop São Paulo. 2020;62.,1515. Srisawat N, Praditpornsilpa K, Patarakul K, Techapornrung M, Daraswang T, Sukmark T, et al. Neutrophil Gelatinase Associated Lipocalin (NGAL) in Leptospirosis Acute Kidney Injury: A Multicenter Study in Thailand. PLoS ONE. 2015;10(12).. Early detection improves the prognosis of CKD by allowing the early implementation of proper interventions1616. Gaitonde DY, Cook DL, Rivera IM. Chronic Kidney Disease: Detection and Evaluation. Am Fam Physician. 2017;96(12):776-83.. This review aimed to gather available information on the measurement of kidney injury biomarkers in leptospirosis, underlining the performance of each biomarker in AKI and CKD.

METHODS

The MEDLINE and LILACS databases were searched in September 2021 using the following search parameters: “((kidney) OR (renal) OR (chronic kidney disease) OR (acute kidney injury)) AND ((biomarker) OR (marker)) AND ((Leptospira) OR (leptospirosis))”. The search did not have a year restriction for publication date. Summaries of the resulting articles were reviewed to apply the inclusion and exclusion criteria, as shown in Figure 1. The inclusion criteria were as follows: the article could be in any language, reporting original data on blood or urine biomarkers associated with kidney injury, and be from humans or animals with leptospirosis determined by positive laboratory tests. Studies with a wide description of biomarker profiles but did not evaluate specific biomarker performance were excluded, as well as studies that only evaluated classic kidney function biomarkers, such as SCr, BUN, or urine albumin. Data extracted from the selected articles included biomarkers measured, year of publication, country, sample size, human or animal study, biospecimen used, diagnosis of leptospirosis, and type of study design used to recruit participants. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for scoping reviews were adapted to report the results of the search.

FIGURE 1:
Flow diagram of study literature search and selection.

RESULTS

The initial search yielded 60 articles, including 59 from MEDLINE and 33 from LILACS, with 32 shared results. All studies were published between 1982 and 2021, with a median publication year of 2015. Fifty-eight studies were conducted in English, one in Danish, and one in Spanish. After applying the inclusion and exclusion criteria (Figure 1), there were 11 articles available for data extraction (Table 1). All the studies were written in English and published between 2014 and 2021. Fifteen biomarkers were evaluated in the selected studies. Four biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), and monocyte chemoattractant protein-1 (MCP-1)) had been evaluated in more than one study. The studies included cross-sectional, cohort, and comparative designs; two studies were conducted in dogs, and the overall sample size was 135 (Table 1).

TABLE 1:
Studies on kidney injury biomarkers associated to Leptospira.

Neutrophil Gelatinase-Associated Lipocalin (NGAL)

NGAL was included in six studies, two of which used NGAL as a reference point for the performance of other biomarkers. NGAL, also known as lipocalin 2, is a protein belonging to the lipocalin family and is present in neutrophil granules and epithelial cells from different organs, including the kidney1717. Borregaard N, Cowland JB. Granules of the Human Neutrophilic Polymorphonuclear Leukocyte. Blood. 1997;89(10):3503-21.,1818. Cowland JB, Borregaard N. Molecular Characterization and Pattern of Tissue Expression of the Gene for Neutrophil Gelatinase-Associated Lipocalin from Humans. Genomics. 1997;45(1):17-23.. Srisawat et al. carried out a multicenter cohort study in Thailand and found that both serum and urinary levels of NGAL were strongly linked with AKI in leptospirosis patients1515. Srisawat N, Praditpornsilpa K, Patarakul K, Techapornrung M, Daraswang T, Sukmark T, et al. Neutrophil Gelatinase Associated Lipocalin (NGAL) in Leptospirosis Acute Kidney Injury: A Multicenter Study in Thailand. PLoS ONE. 2015;10(12).. A cross-sectional study in dogs by Zamagni et al. found no differences in NGAL levels in leptospirosis-induced AKI when compared to other AKI causes1919. Zamagni S, Troìa R, Zaccheroni F, Monari E, Grisetti C, Perissinotto L, et al. Comparison of clinicopathological patterns of renal tubular damage in dogs with acute kidney injury caused by leptospirosis and other aetiologies. Vet J Lond Engl 1997. 2020;266.. Based on a cross-sectional serological study of 489 participants combined with a nested cohort of 282, Riefkohl et al. reported that NGAL levels were significantly elevated among Leptospira seropositive workers relative to seronegative workers, but the effect was reduced after further adjustment by job category2020. Riefkohl A, Ramírez-Rubio O, Laws RL, McClean MD, Weiner DE, Kaufman JS, et al. Leptospira seropositivity as a risk factor for Mesoamerican Nephropathy. Int J Occup Environ Health. 2017;23(1):1-10.. Similar findings were reported by Yang et al. in a cohort study of 88 participants in which there was no association between NGAL and Leptospira microagglutination (MAT) levels2121. Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, et al. Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence. PLoS Negl Trop Dis . 2015;9(10).. Other studies have included NGAL as a reference point to test other biomarkers of leptospirosis-associated AKI. A cohort study by Libório et al. compared biomarker levels among 46 leptospirosis cases and 31 healthy controls and found a correlation between NGAL and SCr levels. In this study, NGAL was used as an acute injury marker to study the performance of syndecam-1 and intercellular adhesion molecule 1 (ICAM-1)2222. Libório AB, Braz MBM, Seguro AC, Meneses GC, Neves FM de O, Pedrosa DC, et al. Endothelial Glycocalyx Damage Is Associated with Leptospirosis Acute Kidney Injury. Am J Trop Med Hyg. 2015;92(3):611-16.. Chagan-Yasutan et al. carried out a similar retrospective study with 143 participants in which NGAL was used as a reference point to evaluate the performance of defensin α1. In this study, NGAL levels were significantly different between leptospirosis cases and control groups2323. Chagan-Yasutan H, Chen Y, Lacuesta TL, Leano PSA, Iwasaki H, Hanan F, et al. Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients. Int J Mol Sci. 2016;17(10)..

Urinary N-acetyl-β-D-glucosaminidase (NAG)

NAG was the second most studied kidney injury biomarker and was included in three studies. Similar to NGAL, NAG was used as a reference point to test other biomarkers2020. Riefkohl A, Ramírez-Rubio O, Laws RL, McClean MD, Weiner DE, Kaufman JS, et al. Leptospira seropositivity as a risk factor for Mesoamerican Nephropathy. Int J Occup Environ Health. 2017;23(1):1-10.,2323. Chagan-Yasutan H, Chen Y, Lacuesta TL, Leano PSA, Iwasaki H, Hanan F, et al. Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients. Int J Mol Sci. 2016;17(10).,2424. Chagan-Yasutan H, Hanan F, Niki T, Bai G, Ashino Y, Egawa S, et al. Plasma Osteopontin Levels is Associated with Biochemical Markers of Kidney Injury in Patients with Leptospirosis. Diagn Basel Switz. 2020;10(7).. NAG is a high-molecular-weight lysosomal enzyme present in various organs, with a high concentration in the proximal renal tubule2525. Kavukçu S, Soylu A, Türkmen M. The clinical value of urinary N-acetyl-beta-D-glucosaminidase levels in childhood age group. Acta Med Okayama. 2002;56(1):7-11.. Chagan-Yasutan et al. published a retrospective study in which urinary NAG was used as a kidney injury biomarker in emergency department patients with leptospirosis in Thailand in 2016, and a second retrospective study was published in 2020. In both studies, NAG was strongly associated with AKI and had specificity for leptospirosis2323. Chagan-Yasutan H, Chen Y, Lacuesta TL, Leano PSA, Iwasaki H, Hanan F, et al. Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients. Int J Mol Sci. 2016;17(10).,2424. Chagan-Yasutan H, Hanan F, Niki T, Bai G, Ashino Y, Egawa S, et al. Plasma Osteopontin Levels is Associated with Biochemical Markers of Kidney Injury in Patients with Leptospirosis. Diagn Basel Switz. 2020;10(7).. In a study by Riefkohl et al., urinary NAG levels were higher in Leptospira seropositive participants than in seronegative participants; however, this was not statistically significant after further model adjustment2020. Riefkohl A, Ramírez-Rubio O, Laws RL, McClean MD, Weiner DE, Kaufman JS, et al. Leptospira seropositivity as a risk factor for Mesoamerican Nephropathy. Int J Occup Environ Health. 2017;23(1):1-10..

Kidney injury molecule 1 (KIM-1)

KIM-1, also known as cell immunoglobulin mucin domain 1 (TIM-1), is a type 1 transmembrane protein that increases rapidly during proximal tubule injury and has been linked to the pathogenesis of renal fibrosis2626. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62(1):237-44.,2727. Liu M, Ning X, Li R, Yang Z, Yang X, Sun S, et al. Signalling pathways involved in hypoxia-induced renal fibrosis. J Cell Mol Med. 2017;21(7):1248-59.. This biomarker has been reported in three studies. Yang et al. evaluated its performance in a cohort study with a two-year follow-up in which leptospirosis MAT antibody titers >1:400 were associated with deterioration in renal function. Patients with high MAT titers also had higher urine KIM-1 and creatinine levels2121. Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, et al. Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence. PLoS Negl Trop Dis . 2015;9(10).. A cross-sectional study by Nisansala et al. found elevated urine KIM-1 levels in patients with leptospirosis related AKI2828. Nisansala T, Weerasekera M, Ranasinghe N, Marasinghe C, Gamage C, Fernando N, et al. Importance of KIM-1 and MCP-1 in Determining the Leptospirosis-Associated AKI: A Sri Lankan Study. BioMed Res Int. 2021;2021:1752904.. Another cross-sectional study on naturally infected dogs by Dias et al. showed an association between high levels of urine KIM-1 and AKI as well as evidence that KIM-1 is an early marker of kidney injury2929. Dias CS, Paz LN, Solcà MS, Portela RWD, Bittencourt MV, Pinna MH. Kidney Injury Molecule-1 in the detection of early kidney injury in dogs with leptospirosis. Comp Immunol Microbiol Infect Dis. 2021;76:101637..

Monocyte chemoattractant protein-1 (MCP-1)

MCP-1 is a protein from the chemokine family that plays a role in the migration and filtration of monocytes3030. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte Chemoattractant Protein-1 (MCP-1): An Overview. J Interferon Cytokine Res. 2009;29(6):313-26.. It is a mediator in acute ischemic and toxic kidney injury as well as a marker of kidney fibrosis3131. Munshi R, Johnson A, Siew ED, Ikizler TA, Ware LB, Wurfel MM, et al. MCP-1 gene activation marks acute kidney injury. J Am Soc Nephrol. 2011;22(1):165-75.,3232. Mansour SG, Puthumana J, Coca SG, Gentry M, Parikh CR. Biomarkers for the detection of renal fibrosis and prediction of renal outcomes: a systematic review. BMC Nephrol. 2017;18.. Yang et al. assessed its capacity as a biomarker in a cohort study and found no link between MCP-1 levels and decreased kidney function2121. Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, et al. Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence. PLoS Negl Trop Dis . 2015;9(10).. In contrast, a cross-sectional study by Nisansala et al. found a link between elevated MCP-1 levels and leptospirosis-related AKI2828. Nisansala T, Weerasekera M, Ranasinghe N, Marasinghe C, Gamage C, Fernando N, et al. Importance of KIM-1 and MCP-1 in Determining the Leptospirosis-Associated AKI: A Sri Lankan Study. BioMed Res Int. 2021;2021:1752904..

Interleukin-18 (IL-18)

Interleukin-18 (IL-18) is a member of the interleukin-1 family and has regulatory effects on innate and acquired immunity3333. Wawrocki S, Druszczynska M, Kowalewicz-Kulbat M, Rudnicka W. Interleukin 18 (IL-18) as a target for immune intervention. Acta Biochim Pol. 2016;63(1):59-63.. This biomarker was reported in a single study. In the combined cross-sectional and cohort study by Riefkohl et al., investigators reported higher IL-18 levels in Leptospira seropositive participants than in seronegative participants; however, this was not statistically significant2020. Riefkohl A, Ramírez-Rubio O, Laws RL, McClean MD, Weiner DE, Kaufman JS, et al. Leptospira seropositivity as a risk factor for Mesoamerican Nephropathy. Int J Occup Environ Health. 2017;23(1):1-10..

Syndecan-1

Syndecan-1 is a major cell surface heparan sulfate proteoglycan in epithelial cells that acts as an adhesion target for bacteria in many infections, and is an endothelial damage biomarker3434. Aquino RS, Teng YHF, Park PW. Glycobiology of syndecan-1 in bacterial infections. Biochem Soc Trans. 2018;46(2):371-7.. A cross-sectional study by Libório et al. with 77 participants showed that blood levels of syndecan-1 were higher in leptospirosis patients with AKI than in patients without AKI2222. Libório AB, Braz MBM, Seguro AC, Meneses GC, Neves FM de O, Pedrosa DC, et al. Endothelial Glycocalyx Damage Is Associated with Leptospirosis Acute Kidney Injury. Am J Trop Med Hyg. 2015;92(3):611-16..

Defensin α1

Defensin α1 is an antimicrobial peptide that was effective against Leptospira in an in vitro model3535. Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L, et al. The human antimicrobial and chemotactic peptides LL-37 and α-defensins are expressed by specific lymphocyte and monocyte populations. Blood. 2000;96(9):3086-93.,3636. Wu Q, Xu L, Wang X, Li S, Wang B. [Investigation of microbicidal activity of neutrophil defensins against leptospires]. Hua Xi Yi Ke Xue Xue Bao J West China Univ Med Sci Huaxi Yike Daxue Xuebao. 1992;23(2):126-9.. High levels of defensin α1 have been reported in inflammation leading to diabetic nephropathy3737. Saraheimo M, Forsblom C, Pettersson-Fernholm K, Flyvbjerg A, Groop PH, Frystyk J, et al. Increased levels of alpha-defensin (-1, -2 and -3) in type 1 diabetic patients with nephropathy. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc. 2008;23(3):914-8.. Chagan-Yasutan et al. measured defensin α1 in a case-control study that evaluated AKI in 112 patients with leptospirosis, and observed higher levels of defensin α1 in AKI patients than in leptospirosis patients without AKI2323. Chagan-Yasutan H, Chen Y, Lacuesta TL, Leano PSA, Iwasaki H, Hanan F, et al. Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients. Int J Mol Sci. 2016;17(10)..

Antioxidant reduced glutathione (GSH)

GSH is an important antioxidant and low-molecular-weight peptide3838. Forman HJ, Zhang H, Rinna A. Glutathione: Overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. 2009;30(1-2):1-12.. The kidney is highly dependent on GSH for its antioxidant properties3939. Lash LH. Role of glutathione transport processes in kidney function. Toxicol Appl Pharmacol. 2005;204(3):329-42.. A cohort case study conducted by Araújo et al. evaluated 12 patients with laboratory-confirmed leptospirosis in an emergency department and assessed oxidative stress markers and complications. In this study, GSH depletion was positively correlated with higher SCr levels; however, no significant difference was observed between leptospirosis patients with and without AKI4040. Araújo AM, Reis EAG, Athanazio DA, Ribeiro GS, Hagan JE, Araujo GC, et al. Oxidative Stress Markers Correlate with Renal Dysfunction and Thrombocytopenia in Severe Leptospirosis. Am J Trop Med Hyg . 2014;90(4):719-23..

Reactive oxygen species (ROS)

ROS are a group of free oxygen radicals produced during different metabolic processes that are highly reactive and potentially harmful4141. Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, et al. ROS and ROS-Mediated Cellular Signaling. Oxid Med Cell Longev. 2016;2016:4350965.. Increased ROS levels have also been linked to CKD4242. Daenen K, Andries A, Mekahli D, Van Schepdael A, Jouret F, Bammens B. Oxidative stress in chronic kidney disease. Pediatr Nephrol Berl Ger. 2019;34(6):975-91.. Araújo et al. included ROS in a cohort study that evaluated GSH and found that ROS levels were positively correlated with serum potassium levels. There was no significant difference between leptospirosis patients with and without AKI4040. Araújo AM, Reis EAG, Athanazio DA, Ribeiro GS, Hagan JE, Araujo GC, et al. Oxidative Stress Markers Correlate with Renal Dysfunction and Thrombocytopenia in Severe Leptospirosis. Am J Trop Med Hyg . 2014;90(4):719-23..

Angiopoietin-2 (Angpt-2) Asymmetric Dimethylamines (ADMA), and Symmetric dimethylarginines (SDMA)

Angpt-2, ADMA, and SDMA are markers of endothelial inflammation4343. Scholz A, Plate KH, Reiss Y. Angiopoietin-2: a multifaceted cytokine that functions in both angiogenesis and inflammation. Ann N Y Acad Sci. 2015;1347:45-51.. Angpt-2 is an important angiogenic factor that has been linked to adverse kidney outcomes in cirrhotic patients4444. Wu Q, Xu WD, Huang AF. Role of angiopoietin-2 in inflammatory autoimmune diseases: A comprehensive review. Int Immunopharmacol. 2020;80:106223.,4545. Allegretti AS, Vela Parada X, Ortiz GA, Long J, Krinsky S, Zhao S, et al. Serum Angiopoietin-2 Predicts Mortality and Kidney Outcomes in Decompensated Cirrhosis. Hepatol Baltim Md. 2019;69(2):729-41.. Dimethylarginines are guanidine metabolic residues with uremic toxicity4646. Tain YL, Hsu CN. Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA). Toxins. 2017;9(3).. Lukasz et al. conducted a retrospective cohort study using samples from patients diagnosed with leptospirosis and found higher levels of Angpt-2, ADMA, and SDMA in patients with evidence of AKI than in patients without AKI4747. Lukasz A, Hoffmeister B, Graf B, Wölk B, Noeckler K, Bode-Böger SM, et al. Association of angiopoietin-2 and dimethylarginines with complicated course in patients with leptospirosis. PloS One. 2014;9(1):e87490..

Osteopontin (OPN)

OPN is a highly phosphorylated glycophosphoprotein that has multiple important functions4848. Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem. 2018;59:17-24.. Kidneys have tubulogenic properties and other beneficial effects. Increased levels of OPN have been described in urolithiasis and kidney disease4949. Kaleta B. The role of osteopontin in kidney diseases. Inflamm Res Off J Eur Histamine Res Soc Al. 2019;68(2):93-102.. Chagan-Yasutan et al. reported higher levels of serum and urine OPN in patients with altered urinary dipstick parameters in a retrospective study of 112 febrile patients with confirmed acute leptospirosis2424. Chagan-Yasutan H, Hanan F, Niki T, Bai G, Ashino Y, Egawa S, et al. Plasma Osteopontin Levels is Associated with Biochemical Markers of Kidney Injury in Patients with Leptospirosis. Diagn Basel Switz. 2020;10(7)..

Galectine-9 (Gal-9)

Gal-9 is a lectin from the galectin family with immunomodulatory and anti-inflammatory effects that act through the suppression of TH1 and TH17 lymphocytes5050. Niki T, Fujita K, Rosen H, Hirashima M, Masaki T, Hattori T, et al. Plasma Galectin-9 Concentrations in Normal and Diseased Condition. Cell Physiol Biochem. Karger Publishers; 2018;50(5):1856-68.. In patients with type II diabetes, its levels have been linked to kidney function and the presence of CKD5151. Kurose Y, Wada J, Kanzaki M, Teshigawara S, Nakatsuka A, Murakami K, et al. Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease. BMC Nephrol . 2013;14:23.. In a retrospective study of 112 patients with leptospirosis, Chagan-Yasutan et al. found an association between Gal-9 and severe leptospirosis; however, the levels were not linked to kidney damage during leptospirosis2424. Chagan-Yasutan H, Hanan F, Niki T, Bai G, Ashino Y, Egawa S, et al. Plasma Osteopontin Levels is Associated with Biochemical Markers of Kidney Injury in Patients with Leptospirosis. Diagn Basel Switz. 2020;10(7)..

DISCUSSION

Leptospirosis-related CKD has been linked to renal fibrosis, secondary to persistent or recurrent kidney colonization by pathogenic species, or because of unresolved AKI5252. Wu MY, Wu MS. Pathophysiology of Leptospirosis Kidney Disease. Leptospirosis Kidney . 2019;7:10-9.,5353. Ganoza CA, Matthias MA, Saito M, Cespedes M, Gotuzzo E, Vinetz JM. Asymptomatic Renal Colonization of Humans in the Peruvian Amazon by Leptospira. PLoS Negl Trop Dis . 2010;4(2).. Colonization causes tubulointerstitial nephritis, followed by interstitial persistence of Leptospira, which causes tubulointerstitial fibrosis and, if not treated, kidney failure5454. Tian YC. Leptospirosis and Kidney Fibrosis. Leptospirosis Kidney . Karger Publishers; 2019;7:57-64.. Studies of biomarkers related to kidney damage have centered on the development of AKI during leptospirosis, with promising results suggesting their possible use as biomarkers for the early detection of kidney alterations. Because the pathogenesis of leptospiral CKD is related to renal fibrosis, biomarkers linked to this process could become potential study targets44. Yang HY, Chang CH, Yang CW. Leptospirosis and Chronic Kidney Disease. Leptospirosis Kidney. 2019;7:27-36.. Alteration of kidney damage biomarkers precedes that of SCr and could be used to detect kidney injury before progression to CKD5555. Pianta TJ, Succar L, Davidson T, Buckley NA, Endre ZH. Monitoring treatment of acute kidney injury with damage biomarkers. Toxicol Lett. 2017;268:63-70.,5656. Hosohata K. Biomarkers for Chronic Kidney Disease Associated with High Salt Intake. Int J Mol Sci . 2017;18(10):2080.. However, as opposed to leptospirosis and AKI, there are fewer studies on kidney damage biomarkers for CKD that can be used to monitor patients.

With only 60 articles, the search results revealed a generally limited knowledge base on the use of these biomarkers for leptospirosis, despite no language or year restrictions. Of these, only 11 studies met the criteria for evaluating the performance of novel biomarkers associated with kidney injury during leptospirosis. Five were cross-sectional studies with no possibility of evaluating longitudinal changes in kidney function after confirmed leptospirosis infection. Studies tended to have a small sample size, which limited the ability to identify statistically significant differences or to evaluate potentially important patient and pathogen-level factors.

The limited evidence does support kidney injury biomarkers as a promising tool in the management of leptospirosis, potentially applicable in the diagnosis, prognosis, and follow-up of patients. NGAL and NAG were the two most studied biomarkers and provide supportive evidence as biomarkers of kidney injury. They have also been used in leptospirosis studies as a reference point to evaluate other biomarkers of AKI2222. Libório AB, Braz MBM, Seguro AC, Meneses GC, Neves FM de O, Pedrosa DC, et al. Endothelial Glycocalyx Damage Is Associated with Leptospirosis Acute Kidney Injury. Am J Trop Med Hyg. 2015;92(3):611-16.

23. Chagan-Yasutan H, Chen Y, Lacuesta TL, Leano PSA, Iwasaki H, Hanan F, et al. Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients. Int J Mol Sci. 2016;17(10).
-2424. Chagan-Yasutan H, Hanan F, Niki T, Bai G, Ashino Y, Egawa S, et al. Plasma Osteopontin Levels is Associated with Biochemical Markers of Kidney Injury in Patients with Leptospirosis. Diagn Basel Switz. 2020;10(7).. KIM-1 is a biomarker that has shown increased levels in leptospirosis patients with evidence of CKD, suspected persistence of Leptospira, and reduced kidney function2020. Riefkohl A, Ramírez-Rubio O, Laws RL, McClean MD, Weiner DE, Kaufman JS, et al. Leptospira seropositivity as a risk factor for Mesoamerican Nephropathy. Int J Occup Environ Health. 2017;23(1):1-10.. NAG and IL-18 have shown evidence of potential use in Leptospira-related CKD2121. Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, et al. Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence. PLoS Negl Trop Dis . 2015;9(10).. Syndecan-1, defensin α1, GSH, Angpt-2, ADMA, and SDMA have evidence suggesting they might be useful biomarkers in leptospirosis-related AKI2222. Libório AB, Braz MBM, Seguro AC, Meneses GC, Neves FM de O, Pedrosa DC, et al. Endothelial Glycocalyx Damage Is Associated with Leptospirosis Acute Kidney Injury. Am J Trop Med Hyg. 2015;92(3):611-16.,2323. Chagan-Yasutan H, Chen Y, Lacuesta TL, Leano PSA, Iwasaki H, Hanan F, et al. Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients. Int J Mol Sci. 2016;17(10).,4040. Araújo AM, Reis EAG, Athanazio DA, Ribeiro GS, Hagan JE, Araujo GC, et al. Oxidative Stress Markers Correlate with Renal Dysfunction and Thrombocytopenia in Severe Leptospirosis. Am J Trop Med Hyg . 2014;90(4):719-23.,4747. Lukasz A, Hoffmeister B, Graf B, Wölk B, Noeckler K, Bode-Böger SM, et al. Association of angiopoietin-2 and dimethylarginines with complicated course in patients with leptospirosis. PloS One. 2014;9(1):e87490..

Further evaluation of biomarkers is needed to identify their role in prognosis following leptospirosis-associated AKI, and to help prioritize patients in highly endemic regions5757. Lin CY. Leptospirosis-Associated Acute Kidney Injury. Leptospirosis Kidney . 2019;7:20-6.. For example, a biomarker such as KIM-1, found to have a potentially significant capability of predicting CKD in a non-leptospirosis study2121. Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, et al. Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence. PLoS Negl Trop Dis . 2015;9(10).,5858. Zhou LT, Lv LL, Pan MM, Cao YH, Liu H, Feng Y, et al. Are Urinary Tubular Injury Markers Useful in Chronic Kidney Disease? A Systematic Review and Meta Analysis. PLoS ONE . 2016;11(12):e0167334., could be used to monitor the development of CKD in patients with leptospirosis. More evidence may help integrate scientific knowledge of kidney injury biomarkers into patient care applications and everyday clinical practice. More attention needs to be paid to the link between leptospirosis and CKD, particularly in highly endemic regions where persistent and recurrent infections have been described5353. Ganoza CA, Matthias MA, Saito M, Cespedes M, Gotuzzo E, Vinetz JM. Asymptomatic Renal Colonization of Humans in the Peruvian Amazon by Leptospira. PLoS Negl Trop Dis . 2010;4(2)., including research on host-pathogen interactions that predispose patients to chronic damage.

The kidney disease model may also vary about which species of Leptospira are involved, as not all pathogenic species have the same virulence. For example, Leptospira interrogans is associated with aggressive episodes of leptospirosis with a higher degree of kidney impairment5959. Silva ÉF, Santos CS, Athanazio DA, Seyffert N, Seixas FK, Cerqueira GM, et al. Characterization of virulence of leptospira isolates in a hamster model. Vaccine. 2008;26(31):3892-6.. In contrast, Leptospira santarosai favors less aggressive leptospirosis, which tends to persist in the kidney6060. Agudelo-Flórez P, Durango H, Aranzazu D, Rodas JD, Travi B. [Genotyping and evaluation of infection dynamics in a Colombian isolate of Leptospira santarosai in hamster as an experimental model]. Biomed Rev Inst Nac Salud. 2014;34(3):460-72.. These represent two different clinical models showing a biological gradient capable of developing CKD. One would follow severe infections with higher kidney impairment, and the other would develop over a longer time because of recurrent kidney insults associated with mild or asymptomatic leptospirosis6161. Heung M, Chawla LS. Predicting progression to chronic kidney disease after recovery from acute kidney injury. Curr Opin Nephrol Hypertens. 2012;21(6):628-34.. These species or strain differences in pathogenesis should be considered in future studies to evaluate biomarkers.

A 2017 review by Mansour et al. on renal fibrosis biomarkers not related to Leptospira identified that urine transforming growth factor-beta (TGF-β), blood and urine matrix metalloproteinase-2 (MMP-2), and MCP-1 were associated with adverse renal outcomes based on a longitudinal follow-up of patients3232. Mansour SG, Puthumana J, Coca SG, Gentry M, Parikh CR. Biomarkers for the detection of renal fibrosis and prediction of renal outcomes: a systematic review. BMC Nephrol. 2017;18.. No studies evaluating the role of TGF-β and MMP-2 in leptospirosis were identified in this review. Considering their potential association with renal fibrosis in CKD, future research should consider their use in leptospirosis-associated CKD. Urine MCP-1 has been evaluated in leptospiral-related kidney damage by Yang et al. with mixed results2121. Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, et al. Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence. PLoS Negl Trop Dis . 2015;9(10).. This finding could also be attributed to the two-year follow-up period and small sample size, with fibrosis not having time to manifest itself.

Kidney damage biomarkers could be a potential tool for the early detection of kidney impairment, with evidence from other disease models showing promise as a tool for identifying patients who may develop AKI6262. Zwiers AJM, de Wildt SN, van Rosmalen J, de Rijke YB, Buijs EAB, Tibboel D, et al. Urinary neutrophil gelatinase-associated lipocalin identifies critically ill young children with acute kidney injury following intensive care admission: a prospective cohort study. Crit Care Lond Engl. 2015;19:181. and CKD6363. Obert LA, Elmore SA, Ennulat D, Frazier KS. A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies. Toxicol Pathol. 2021;49(5):996-1023.; however, evidence is currently limited to assessing the clinical applications of these biomarkers in leptospirosis. The small number of studies included in this review shows that more research is needed to improve our understanding of injury-related biomarkers and their use in leptospirosis. That they can be measured in urine increases their potential use in rural and low-complexity primary healthcare settings with high leptospirosis endemicity.

ACKNOWLEDGMENTS

Authors thank Dr. Mark Rosenberg from the University of Minnesota Medical School for reviewing the last version of this manuscript.

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  • Financial Support: This review was done as part of a project funded by the Dirección de Investigación e Innovación of Universidad CES, Code INV.032022.002.

Publication Dates

  • Publication in this collection
    23 Jan 2023
  • Date of issue
    2023

History

  • Received
    14 Aug 2022
  • Accepted
    01 Dec 2022
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