Leptospirosis kidney disease: Evolution from acute to chronic kidney disease

Abstract

Leptospirosis is a neglected bacterial disease caused by leptospiral infection that carries a substantial mortality risk in severe cases. Research has shown that acute, chronic, and asymptomatic leptospiral infections are closely linked to acute and chronic kidney disease (CKD) and renal fibrosis. Leptospires affect renal function by infiltrating kidney cells via the renal tubules and interstitium and surviving in the kidney by circumventing the immune system. The most well-known pathogenic molecular mechanism of renal tubular damage caused by leptospiral infection is the direct binding of the bacterial outer membrane protein LipL32 to toll-like receptor-2 expressed in renal tubular epithelial cells (TECs) to induce intracellular inflammatory signaling pathways. These pathways include the production of tumor necrosis factor (TNF)-α and nuclear factor kappa activation, resulting in acute and chronic leptospirosis-related kidney injury. Few studies have investigated the relationship between acute and chronic renal diseases and leptospirosis and further evidence is necessary. In this review, we intend to discuss the roles of acute kidney injury (AKI) to/on CKD in leptospirosis. This study reviews the molecular pathways underlying the pathogenesis of leptospirosis kidney disease, which will assist in concentrating on potential future research directions.

Leptospirosis is a neglected reemerging zoonotic infection and waterborne disease caused by pathogenic Leptospira spp., that is endemic mostly in humid tropical and subtropical regions [1,2]. Because of its rising incidence, it has global public health implications [1,2]. According to estimates, it affects 1.03 million humans and causes 58,900 deaths each year [3,4]. Leptospirosis outbreaks are often associated with flooding. For example, in 2021, a leptospirosis outbreak was reported in New York City after flooding. The clinical manifestations of leptospirosis are variable, ranging from asymptomatic to multiple organ dysfunction, such as renal failure, jaundice, pulmonary hemorrhage, and meningitis [5,6]. One of the clinical symptoms associated with severe leptospirosis is acute kidney failure with an incidence ranging from 10 to 60% of total cases, and its mortality is around 22% [7,8]. Furthermore, asymptomatic and chronic kidney infections caused by Leptospira spp. have been reported in several investigations and may play an important role in disease maintenance and transmission of leptospirosis [9,10]. In this narrative review, we discuss the current research on the link between acute kidney injury (AKI) and chronic kidney disease (CKD) in leptospirosis.

Leptospirosis kidney disease

The kidney and the proximal tubule provide favorable conditions for Leptospira survival and colonization during acute and chronic leptospiral infections. Leptospira can trigger an immune response that results in tubulointerstitial nephritis characterized by the infiltration of mononuclear inflammatory cells [11,12]. Cytokine levels increase during leptospirosis infection [13,14]; interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), and IL-10 were found to be highly expressed in infected kidneys of a mouse model of leptospirosis kidney disease. Expression levels of IL-1β and TNF-α were significantly higher in kidneys at day 28 post-infection compared with mice after leptospiral infection on day 7. Despite the lack of significant increase in the expression of IL-6 and IL-10 in the kidneys at day 28 post-infection compared to day 7, the expression levels of these cytokines remained elevated, indicating a sustained immune response to leptospiral infection [Table 1]. This was also accompanied by high expression of the renal kidney injury molecule (KIM)-1, which was detected on day 7 and 28 after leptospiral infection [15]. The severity of leptospirosis is influenced by uncontrolled cytokine production and renal KIM-1 levels, which are related to the extent of kidney damage [16,17]. In leptospirosis, immunological homeostasis is assumed to be maintained by the anti-inflammatory cytokine IL-10, and excessive IL-10 production may play an important role in modulating the renal immune microenvironment caused by leptospiral infection [13,17]. Following leptospirosis infection, imbalances in cytokine production affect the course of the disease and may be related to leptospirosis severity [17]. Leptospiral infection in the kidney causes renal inflammation and kidney damage, and if the kidney does not heal as a result of the kidney damage and persistent infection, there is a chance that renal fibrosis could occur [18]. The transforming growth factor (TGF)-1/SMAD and Wnt/-catenin pathways are associated with leptospirosis-related kidney fibrosis, as previously demonstrated by in vitro cell and in vivo animal infection experiments [19,20].

Table 1.

Differential inflammatory cytokine expression in kidneys of mice during leptospiral infection. Using the Real-Time qPCR technique, the gene expression of the cytokines IL-1, IL-6, TNF, and IL-10 was quantified in the kidneys of infected mice after infection at 7 and 28 days in comparison to non-infected mice at the time of inoculation [15].

Time (Days post-infection)	Gene expression in kidneys of infected mice (Fold; (Differences between minimum to maximum values)) ∗TBP was used as an internal control
	IL-1β	IL-6	TNF-α	IL-10	HAVCR1 (KIM-1)
7	4.57; (1.69–12.34)	35.58; (5.82–217.65)	7.29; (−1.27–67.16)	48.05; (20.65–111.81)	113.75; (34.71–372.81)
28	7.12; (3.39–14.96)	21.54; (9.15–50.72)	15.48; (1.06–226.36)	36.79; (14.57–92.89)	4.99; (2.28–10.89)

Leptospirosis AKI

Leptospirosis is generally associated with AKI and characterized by acute interstitial nephritis and acute tubular necrosis [21]. The distinctive clinical features of the clinical presentation of AKI in leptospirosis are non-oliguric and hypokalemic, which can be observed in 41–45% of patients with leptospirosis-associated AKI [7,22,23]. On the other hand, disseminated intravascular coagulation has also been reported in patients with severe complications of leptospirosis, and septic AKI is frequently accompanied by oliguria and anuria possibly due to acute tubular necrosis [24]. Factors such as the direct nephrotoxic action of the Leptospira, toxin-induced immune responses, and indirect effects through dehydration and hypoxia are involved in the pathogenesis of AKI in patients with leptospirosis [21,25]. The acute phase of leptospiral infection lasts an average of one week; five to 14 days later, symptoms begin to develop, and an immunological phase follows [26]. Severe leptospirosis can lead to a cytokine storm with elevated levels of TNF-α, IL-6, and IL-10 in their blood [27]. In a 2021 Sri Lankan study, monocyte chemoattractant protein (MCP)-1 and kidney injury molecule (KIM)-1 levels were increased in the blood and urine of patients with leptospirosis-associated AKI, suggesting that KIM-1 appears to be more specific than MCP-1 [28]. TNF-, IL-6, IL-10, MCP-1, and KIM-1 are highly expressed in a mouse model of leptospiral infection during the acute phase. Notable data also show that renal lipocalin 2 (LCN2, also known as neutrophil gelatinase-associated lipocalin [NGAL]) and IL-34 expression levels are increased [15]. Previous studies revealed a correlation between urinary NGAL levels and leptospirosis-associated AKI [29,30]. Additionally, CKD is associated with increased kidney, urine, and serum LCN2 levels [31,32]. Results from earlier research have shown that NGAL, which is released in response to kidney damage, may play a role in the pathogenesis of leptospirosis and may be a factor in the development of CKD. In pathological circumstances, renal tubule epithelial cells produce IL-34, which enhances macrophage-mediated tissue injury and aids the development of AKI and CKD [33,34]. Most patients with AKI caused by leptospirosis have restored renal function according to long-term renal examination, although 9% of patients have impaired renal function, consistent with an early stage of CKD [35]. Additionally, inflammatory infiltration in the interstitium and renal tubules was examined after the patients recovered from antibiotic therapy, with the bulk of the cells being M1 (classically activated) macrophages [11]. The renal function of patients with leptospirosis-associated AKI usually recovers with clinical improvement; however, there may still be residual stimuli, such as chronic inflammation or infection in the kidneys, which could later cause CKD.

Leptospirosis CKD

Several observational studies have reported an association between leptospirosis and CKD; this relationship has recently received increased attention [[36], [37], [38], [39]]. Renal colonization by leptospires results in persistent infection in asymptomatic animals, which is the source of infection in humans. In international investigations, humans have been identified as chronic Leptospira carriers [37,40]. Chronic and asymptomatic kidney infections with prolonged exposure to Leptospira may carry the risk of developing CKD in humans [10,37]. Long-term exposure to Leptospira is linked to kidney lesions characterized by chronic tubulointerstitial nephritis and fibrosis, which are characterized by extracellular matrix accumulation, tubular atrophy, and prolonged inflammation. These lesions may significantly contribute to the development of CKD [11,35]. We previously demonstrated the impact of pathogenic Leptospira on extracellular matrix formation and accumulation via the TGF-1/SMAD pathway, indicating probable mechanisms by which leptospiral infection results in renal fibrosis [20]. To understand the pathogenic mechanisms of leptospirosis and their association with kidney fibrosis, renal transcriptomes from a mouse model of chronic leptospirosis were analyzed [15]. The results showed that toll-like receptor signaling, complement activation, T-helper 1 type immune response, and T cell-mediated responses are strongly associated with progressive tubulointerstitial damage caused by pathogenic leptospiral infection [15]. The pathogenic mechanism of renal fibrosis caused by leptospiral infection remains unclear.

Leptospirosis kidney disease: AKI-to-CKD

Recent findings based on a retrospective cohort study revealed that leptospirosis accompanied by AKI has a higher probability of leading to CKD over the long term, and that AKI severity determines the incidence of CKD [41]. Clinical evidence has demonstrated that the progression of AKI to CKD in leptospirosis kidney disease is associated with the severity of AKI, suggesting that the loss of nephrons and subsequent maladaptive compensation of residual nephrons caused by severe AKI are involved in the progression of leptospirosis kidney disease from AKI to CKD. Here, we discuss the possible biomolecular mechanisms associated with the progression of AKI to CKD in leptospirosis kidney disease. AKI is a factor that influences the onset and progression of CKD [42]. Renal tubule cell death and damage are pathological signs of AKI. The balance between adaptive and maladaptive repair processes after AKI determines the responses during the repair and chronic phases, leading to the structural and functional recovery of the injured kidney [42,43]. AKI can be followed by either adaptive repair processes leading to recovery or maladaptive repair processes which result in progression to CKD, depending on the distinct renal microenvironment. Maladaptive renal repair after AKI has been implicated in CKD progression because it can lead to inflammation, which promotes immune cell infiltration, followed by interstitial fibrosis [42]. Several experimental animal models have been used to investigate the pathophysiology of the progression of AKI to CKD [44]. These biochemical pathways include cell-cycle arrest in the DNA damage response, aberrant epigenetic modifications, prolonged mitochondrial dysfunction leading to oxidative stress, defective phagocyte (fibroblast and macrophage) differentiation and migration, and dysfunctional immune responses [42,[45], [46], [47], [48]].

The renal tubules and tubulointerstitium are the main components of the kidney that respond to injuries; hence, tubular epithelial cells (TECs) play important roles in driving the progression of AKI to CKD. KIM-1 is a biomarker of renal proximal tubule injury [49]. Studies have demonstrated that the extended tubular epithelial cell expression of KIM-1 is associated with a profibrotic phenotype in injured kidney [50]. Thus, KIM-1 may play a role in maladaptive repair and renal fibrosis, providing a link between kidney injury and fibrosis. The renal transcriptomes of mice infected with pathogenic Leptospira spp. showed increased levels of HAVCR1 (the gene encoding KIM-1) transcripts on day 7 post-infection, whereas prolonged expression of HAVCR1 transcripts was observed in the renal transcriptome of mice by day 28 of chronic infection [15]. Additionally, it has been reported that damaged TECs activate the STAT3 transcription factor, a well-known mediator of tubulointerstitial fibrosis, which has been implicated in CKD progression [51]. Following pathogenic leptospiral infection, elevated expression of STAT3-expressing transcriptome signatures was observed in the renal transcriptomes of mice 7 days after acute infection and 28 days after chronic infection [15].

Previous studies demonstrated that cell-cycle arrest in TECs can have a substantial impact on maladaptive repair and renal fibrosis [42,45,52]. The induction of cell-cycle arrest and senescence of proximal tubules at the G2/M phase of the cell-cycle disturbs tubular repair after AKI and promotes the subsequent development of fibrosis, which is associated with an increase in the production and release of pro-inflammatory, profibrotic, and growth factors that contribute to chronic inflammation and CKD progression after AKI [46,48,53,54]. It is reported that injured TECs arrested at G2 phase of the cell-cycle can activate JNK signaling by a cyclin-dependent kinase (CDK) inhibitor p21-dependent pathway to produce profibrotic factors such as transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) [48,55]. During the acute stage of kidney injury, the CDK inhibitor p21 protects DNA-damaged cells to prevent entry into the cell-cycle, whereas the induction of p21 in the chronic stage or under sustained kidney damage causes cell-cycle arrest in the G2/M phase and the production of profibrotic factors for kidney fibrosis progression [55,56]. In the renal transcriptomes of leptospiral-infected mice, the expression of Cdkn1a (p21) mRNA was upregulated at 7 days after acute infection and 28 days after chronic infection. In particular, the Cdkn2b (p15) transcript (encoding inhibitors of CDK4/6) was upregulated in the renal transcriptome of mice after leptospiral infection on day 7; however, on day 28 post-infection, there was no differential expression in the pathogen infection groups [15]. According to a previous report, blocking CDK4/6, a crucial modulator of cell-cycle checkpoint progression from the G1 to S phase, can protect against CKD by ameliorating tubular injury and reducing tubulointerstitial fibrosis in murine models of CKD [57]. We suggest that treating CKD caused by leptospiral infection with a CDK4/6 inhibitor that reduces CDK4/6 activity may be a novel therapeutic approach.

Using experimental data from mice and humans, Baek et al. reported that an IL-34-dependent pathway and macrophage-mediated mechanisms can promote persistent ischemia-induced AKI that progresses to CKD, indicating that IL-34 plays a crucial role as a mediator of AKI and is involved in the progression to CKD [33,58,59]. IL-34 is a cytokine secreted by injured TECs that regulates pro-inflammatory responses in post-AKI conditions that can lead to CKD and promote the destruction of TECs, cell proliferation, and infiltration of macrophages in the kidney [34]. Using the renal transcriptomes of leptospiral-infected mice, Chou et al. demonstrated an increased expression of IL-34-expressing transcriptome signatures in the kidneys on day 7 after acute infection and day 28 following chronic infection [15]. Another possible pathogenic mechanism is chronic tubulointerstitial inflammation caused by acute leptospirosis following recovery from AKI. This mechanism may be related to the carrier status of leptospires in the kidneys because a few studies have reported that the bacteria remain latent in the kidney for a long time [37]. A published study demonstrating the role of toll-like receptor (TLR) 2-mediated induction of human-defensin 2 expression provided insight into the mechanisms of inflammation-mediated kidney tissue damage caused by leptospiral infection [60]. To confirm that leptospires remain in the human kidney to induce persistent chronic infection and influence the immunological milieu of the kidney, it would be necessary to obtain additional evidence, despite the fact that evidence has been demonstrated in animal studies [19]. The injured tubular epithelium triggers a complex local response through the formation of a profibrotic and inflammatory microenvironment of renal cells, with the production of profibrotic factors and cytokines through a variety of mechanisms driving the progression of AKI to CKD. These mechanisms involve various interactions among fibroblasts, immune cells, endothelial cells, and injured tubules. Knowledge of these well-known mechanisms underlying AKI to CKD progression can help our understanding of the progression of AKI to CKD in leptospirosis kidney disease.

Leptospirosis kidney disease: AKI-on-CKD

Clinical investigations have demonstrated that AKI occurs most frequently in patients with pre-existing CKD and is defined as a rapid loss of renal function in the acute deterioration of CKD, also known as acute-on-CKD [61]. Acute-on-CKD is associated with a higher risk of mortality, indicating that CKD has a significant impact on AKI [62]. The understanding of AKI in CKD is limited; however, renal function is known to be more severe in patients with AKI and CKD patients. A meta-analysis of cohort studies by James et al. revealed that CKD increased the risk of AKI in patients with diabetes or hypertension [63].

Patients with CKD are predisposed to or more sensitive to AKI, especially when exposed to nephrotoxic insults. In contrast, only 1.5% of CKD patients with CKD without acute on chronic renal failure developed end-stage renal disease, while those who had acute on chronic renal failure had a 30% higher risk of death or end-stage renal disease [64]. AKI on CKD is typically associated with a high mortality risk [65]. Owing to the influence of already impaired kidneys on future injury, limited adaptive repair is unable to restore renal function, whereas maladaptive repair increases the risk of fibrosis when AKI is superimposed on pre-existing CKD [65]. In patients with CKD and AKI, CKD impairs renal function and slows renal function recovery. Few studies have investigated the effects of CKD on AKI. The mechanism underlying the poor prognosis of AKI in patients with CKD warrants further in-depth research.

Repeated occurrence of AKI in patients with CKD leads to the development of renal interstitial fibrosis that is associated with a progressive loss of renal function over time, which is also a feature of CKD. At present, there is some discussion on the potential mechanisms underlying susceptibility and irreversibility to AKI in patients [[65], [66], [67]]. Pathological changes associated with CKD, such as mitochondrial dysfunction, oxidative stress, aberrant autophagy, chronic inflammation, and vascular dysfunction, may contribute to patients with CKD being susceptible to AKI and have lower rates of recovery. The activation of TGF-β, p53, hypoxia-inducible factor, and critical developmental pathways, as well as by drastic changes of cell signaling in injured renal TECs during the initiation and progression of CKD, may increase the susceptibility of CKD kidneys to AKI [65]. Chronically elevated TGF-β, which causes fibrogenic foci and increases fibrogenesis in CKD, may have an additional synergistic detrimental effect on patients with AKI on CKD [68]. Activation of p53, which regulates the expression of profibrotic genes such as TGF-β, may be associated with CKD, indicating that p53 is involved in renal fibrosis [65,69]. In CKD, Notch is activated in renal TECs, and its sustained expression promotes tubulointerstitial fibrosis and inflammation [65,70]. Recent evidence indicates that the Hedgehog transcriptional activator Gli1, a marker for mesenchymal stem cells, may play an important role in kidney fibrosis progression and that Gli + cells are a major source of myofibroblasts after kidney injury [65,71,72]. CKD is also associated with the reactivation of several kidney development signaling pathways, including the canonical-catenin pathway, to promote renal fibrosis [65,73]. The tubular hypoxia response is a common finding in the pathophysiology of AKI and CKD. Renal hypoxia is a significant pathogenic factor that is accompanied by hypoxia-inducible factor signaling to cause renal fibrosis by regulating extracellular matrix turnover, cooperating with TGF-β1 and promoting epithelial to mesenchymal transition [74].

Leptospirosis is a potential risk factor for CKD [36,37,40]. The occurrence of CKD progression in leptospirosis may possibly be associated with asymptomatic leptospiral colonization of the kidney [15,18,37]. Chou et al. performed renal transcriptomic analysis of an experimental chronic leptospira-infected murine model with subsequent nephrotoxic injury to understand the molecular pathogenesis in the progression of leptospirosis kidney disease from AKI on CKD [19]. Transcript levels of fibronectin and collagen type IV-a1 (Col4a1)-encoding genes were upregulated in injured kidneys and correlated with higher levels of protein expression, implying kidney fibrosis in chronic leptospiral infection in mice with secondary nephrotoxic AKI.

Research evidence shows that secondary nephrotoxic injury occurs in chronic Letospira-infected mice and is strongly associated with fibrosis-related pathways, including integrin-linked kinase (ILK), integrin and ephrin receptor signaling, and immune/inflammation-related pathways [19]. Fibrosis progression can be initiated and aggravated in chronic subclinical leptospiral infections, followed by secondary nephrotoxic injury. Further evidence suggests that the Hedgehog signaling pathway was implicated in kidney injury and fibrosis caused by a chronic leptospiral infection mouse model combined with a subsequent nephrotoxic insult, as shown by the upregulation of the Gli1 gene, a component of the Hedgehog signaling pathway [71,75].

Conclusion

This review provides a comprehensive overview of the pathological roles and molecular mechanisms of AKI-to-CKD and AKI-on-CKD in leptospirosis kidney disease [Fig. 1]. We also provide potential therapeutic targets for leptospirosis kidney disease in Table 2. TGF-β is an important pathogenic factor in AKI, CKD, AKI-to-CKD and AKI-on-CKD, indicating that it serves as a regulator of renal fibrosis and inflammation by controlling the initiation and regulation of leptospirosis kidney disease [76,77]. TNF-α plays a major role in renal inflammation and fibrosis, inducing the release of MCP-1, IL-1β, and TGF-β1 in renal disease [78]. IL-34 induces the expression of chemokines and pro-inflammatory factors, which has the effect of amplifying inflammatory and immunological responses [79]. IL-34 produced by injured TECs plays a role in the differentiation of monocytes into IL-10^high IL-12^low macrophages to promote macrophage-mediated tubular epithelial cell destruction during AKI, which aggravates subsequent CKD [33,79]. Macrophages are the major anti-leptospira phagocytes that invade the kidneys during leptospirosis [80] and IL-34 may exert immunoregulatory and pathogenic effects on the renal microenvironment during leptospirosis. Additionally, IL-10 was found to be highly expressed in injured kidneys during the AKI-to-CKD and AKI-on-CKD phases of leptospirosis. Therefore, further investigation of the pathogenic significance of IL-10 is necessary. IL-10 has two distinct functions during Staphylococcus aureus systemic and localized infections. During systemic infection, IL-10 protects the host, whereas during localized infection, IL-10 promotes bacterial persistence [81]. A systematic review of studies evaluating the use of high-dose corticosteroids in patients with severe leptospirosis revealed that there is insufficient evidence to suggest that high-dose corticosteroids are effective in severe leptospirosis, and a well-designed randomized clinical trial is required [82]. Similarly, it remains undetermined whether immunosuppressive therapy would be beneficial or detrimental for leptospira chronic infection.

Fig. 1.

Schematic illustration highlighting the AKI-to-CKD and AKI-on-CKD phases of Leptospirosis Kidney Disease. Leptospiral infection causes renal injury that results in the release of cytokines and chemokines from the damaged renal tissue. These reactions occur simultaneously with the activation or infiltration of inflammatory cells into the kidney and the prolonged activation of profibrotic cells, which results in chronic inflammation and excessive extracellular matrix deposition. The release of cytokines and chemokines from the injured renal tissue, caused by leptospiral infection, damages the kidneys. These processes lead to the activation and infiltration of inflammatory cells into the kidney, chronic inflammation and persistent activation of profibrotic cells, which results in an excessive extracellular matrix deposition. This diagram does not represent a continuum of development between the AKI-to-CKD and AKI-on-CKD phases. Figure was created with biorender.com (accessed on 12 Nov 2022).

Table 2.

Potential therapeutic targets for leptospirosis kidney disease.

Target	In other types of kidney disease, as known	Reference
AKI to CKD
KIM-1	Extracellular vesicle platform in acutely injured mouse kidney	[84]
IFN-γ	Renal fibrosis	[85]
TGF-β	TGF-β inhibitors in CKD progression and alleviating kidney fibrosis; Fibrotic kidney diseases	[86,87]
TNF-α	Kidney fibrosis and inflammation in a murine model of AAN; Inflammation in a diabetic nephropathy animal model; AKI-to-CKD transition	[[88], [89], [90]]
IL-1β	CKD	[91,92]
MCP-1	Progressive renal injury in diabetic nephropathy	[93]
IL-6	AKI, CKD	[94,95]
IL-10	Extracellular vesicle–encapsulated IL-10 against ischemic AKI	[99]
IL-34	TEC damage caused by cisplatin nephrotoxicity	[97]
IL-18	CKD	[98]
AKI on CKD
KIM-1	Extracellular vesicle platform in acutely injured mouse kidney	[84]
TGF-β	TGF-β inhibitors in CKD progression and alleviating kidney fibrosis; Fibrotic kidney diseases	[86,87]
IL-1β	CKD	[91,92]
MCP-1	Progressive renal injury in diabetic nephropathy	[93]
CCL-5	Renal interstitial fibrosis	[99]
IL-10	Extracellular vesicle–encapsulated IL-10 against ischemic AKI	[96]

Abbreviations: AAN, aristolochic acid-induced nephropathy; TECs, tubular epithelial cells; AKI, acute kidney injury; CKD, chronic kidney disease; KIM-1, kidney injury molecule-1; IFN, interferon; TGF, transforming growth factor; TNF, tumor necrosis factor; IL, interleukin; MCP, monocyte chemoattractant protein; CCL, C–C motif chemokine.

Leptospiral infection causes renal injury that results in the release of cytokines and chemokines from the damaged renal tissue. These reactions occur simultaneously with the activation and infiltration of inflammatory cells into the kidney and the prolonged activation of profibrotic cells, resulting in chronic inflammation and excessive extracellular matrix deposition. Interstitial fibrosis, persistent fibrogenic factor production, and a delayed inflammatory response are characterized by maladaptive repair [44,45,52,83]. Further research is needed on the pathogenic role of maladaptive repair mechanisms associated with the AKI-to-CKD and AKI-on-CKD stages of leptospirosis kidney disease.

Conflicts of interest

The authors have no conflicts of interest to report.