Going Micro in Leptospirosis Kidney Disease Ⅲ
May 10, 2024
7. Prognosis and Mortality
The severe form of leptospirosis accounts for 10% of all reported cases [12]. Without early recognition and diagnosis, the severe form usually presents with rapid multiple-organ dysfunction, including acute renal failure, acute hepatic failure, and acute encephalopathy. In most studies, the mortality is over 10–15% in patients with Weil's disease and more than 50% in cases of pulmonary hemorrhage [99]. Notably, death is uncommon in patients without AKI. There are some studies that have revealed the risk factors of mortality related to age, mental status at the time of diagnosis, abnormal repolarization characteristics on electrocardiography, and thrombocytopenia [100–102]. According to a previous study [103], thrombocytopenia is closely correlated with the occurrence of AKI and is described in all anicteric cases with AKI. Thrombocytopenia with AKI also appears independently of disseminated intravascular coagulation and may be concurrent with severe endotoxemia [104]. Thus, thrombocytopenia may be a sign of an acute form of leptospirosis kidney disease. The conclusion regarding leptospirosis-related CKD is still controversial. AKI may predispose the patient to develop CKD and end-stage renal disease, but a recently published systematic review argued that no definite correlation exists between leptospirosis and CKD [49].
HOW LONG DOES IT TAKE FOR CISTANCHE TO WORK KIDNEY DISEASE PATIENTS?
Many studies have explored the role of biomarkers in predicting the development of AKI, although so far there is no consensus on the recommendation of using biomarkers in terms of routine clinical practice [105]. One of the most vigorous biomarkers for AKI is neutrophil gelatinase-associated lipocalin (NGAL). Several previous studies have used NGAL as an early marker of AKI and as an outcome predictor [106,107]. Srisawat et al. [107] examined the role of NGAL as an early marker and outcome predictor of leptospirosis-associated AKI in multi-center research involving 113 leptospirosis cases across Thailand. It's worth noting that AKI developed in 41 of the 113 patients (37 percent). Patients with developing AKI had considerably greater urine and plasma NGAL levels than those without. The area under the receiver operating characteristic (ROC) curve for urine and plasma NGAL levels associated with AKI was 0.91 and 0.92, respectively. In this particular situation, however, neither of them appeared to have a potential role as a predictor of renal recovery. Perhaps, inhomogeneous samples (acute vs. convalescent samples) could trouble the outcomes. Activating transcription factor 3 (ATF3), a transcriptional factor involved in either the anti-apoptosis or anti-inflammation process during systemic infection may be an interesting molecule in terms of leptospirosis with AKI [108]. In the sepsis-AKI setting, urinary ATF3 increased at the same days of increased serum creatinine which demonstrated the benefit of urinary AFT3 over urinary NGAL in predicting AKI [109]. Urinary ATF3 did not increase before serum creatinine, urinary ATF3 but not urinary NGAL would be a good additive biomarker for supporting the onset of AKI in conditions with only a subtle increase of serum creatinine, including leptospirosis-related AKI.
8. Treatments
8.1. Specific Treatments for Leptospirosis
The treatment of leptospirosis-related kidney disease usually depends on the clinical symptoms, particularly in the early phase of infection. Therefore, early recognition and diagnosis of leptospirosis kidney disease are the principal factors driving favorable outcomes. In severe leptospirosis cases, the recommended intravenous antibiotics must be promptly prescribed at the time of diagnosis; these include 0.5–1 g ampicillin every 6 h, 1 g ceftriaxone every 12 h, or 1 g cefotaxime every 6 h. Notably, a study from Thailand showed that administration of 1.5 million units of intravenous sodium penicillin G every 6 h is equally effective to ceftriaxone in patients with severe leptospirosis [110]. Once-daily dosing has the added benefit of intramuscular administration in an outpatient setting as an alternative to intravenous administration. However, adult outpatients with an early-onset of infection should receive either 100 mg of doxycycline twice a day or 500 mg of azithromycin daily. Antibiotic treatment is effective within 7–10 days of injection, but the injection of 5 million units/day of benzylpenicillin should be prescribed for only 5 days. Patients who are hypersensitive or allergic to the penicillin group may be given 250 mg erythromycin four times a day for 5 days or 100 mg doxycycline twice daily for 10 days. Tetracycline is contraindicated in children, pregnant women, and renal insufficiency patients [111].
8.2. Sepsis and Organ Failure in Leptospirosis
Sepsis in leptospirosis, with or without shock, can occur as an unusual presentation, primarily in urban areas [29]. Similar to general sepsis management, the treatment of sepsis in leptospirosis is based on the rapid administration of the correct antibiotic and the best supportive care [112]. As such, fluid administration is the cornerstone of sepsis resuscitation. In patients with fluid responder (less than 40% of septic patients), the stroke volume increases by 10–15% after a fluid challenge (250–500 mL), following the Frank-Starling principle (as the preload increases, the stroke volume increases until the optimal preload is achieved) [113]. With the optimal preload, the further fluid administration does not increase the stroke volume but increases arterial pressure, venous pressure, pulmonary hydrostatic pressure, and natriuretic peptide (a fluid shifting inducer from the intravascular portion into the interstitial space). Increased venous pressure (and renal subcapsular pressure) decreases the glomerular filtration rate (GFR) of the kidney. According to the Acute Dialysis Quality Initiative (ADQI), fluid therapy in sepsis is divided into rescue (high-volume resuscitation), optimization, stabilization, and de-escalation [114] depending on the individual patient. In the de-escalation phase, a reduction in total fluid administration, diuretics, and/or renal replacement therapy (RRT) might be necessary. For the fluid composition, normal saline (or 0.9% NaCl; a non-physiologic solution) might cause hyperchloremic metabolic acidosis that results in decreased renal blood flow [115]. Synthetic hydroxyethyl starch is potentially nephrotoxic [115]. Although normal saline is currently the main fluid replacement used in sepsis-AKI due to its availability with a reasonable price worldwide, a limited volume of normal saline with partial use of other fluid preparations might be beneficial.
Although acidosis is common in patients with sepsis, bicarbonate treatment is not recommended unless the blood pH is lower than 7.15 because sodium bicarbonate infusion leads to hypernatremia, hypervolemia, intracellular shifting of calcium-induced hypocalcemia, intracellular acidosis, and impaired oxygen delivery [116]. In contrast, the strategies for tissue perfusion improvement (proper respiratory support, and adjusted normal saline volume with other balance solutions) should be considered. Tris-hydroxymethyl aminomethane (THAM), a weak base with intracellular diffusion that is excreted through the kidneys, is mentioned to reduce intracellular acidosis but causes hyperkalemia, hypoglycemia, pseudo hyponatremia, and an increased osmole gap, especially in patients with pre-existing renal dysfunction [117]. Because the reduced vascular tone is a major cause of hypotension and renal injury in sepsis, norepinephrine restores the normal capillary velocity, filtration pressure, and mean arterial pressure, and increases renal medullary circulation without renal blood flow alteration, leading to improved renal function, using as the first-line drug for septic shock.
For the rapid reversal of AKI (due to direct toxins, hypotension, and hypovolemia of leptospirosis), topics of renal replacement therapy (RRT); indications, timing, modality, and delivered dose should be applied. Accordingly, the common RRT indications, "A-E-I-O-U"; Acidosis, Electrolyte disturbance, Intoxication, fluid Overload, and Uremia should be used as severe metabolic acidosis, fluid overload, and uremia are the top three RRT indications in leptospirosis. For the RRT modality, daily dialysis may provide superior outcomes to alternate-day dialysis in severe leptospirosis (Weil's syndrome) [118] and extracorporeal blood purification (absorption therapy with polymyxin B or other cytokine absorbents) might be beneficial [119], especially for the hemodynamic improvement [120], but are still inconclusive. Therefore, the proper biomarkers for several aspects (i.e., stress, injury, functional loss, and recovery) for a proper selection of treatment methods are urgently needed. Among them, the base excess (BE) that is lower than −5 might be associated with the success of renal support discontinuation from our experiences (unpublished data). On the other hand, in leptospirosis-related acute liver failure, extracorporeal support systems do not demonstrate any survival advantage in clinical studies and renal support is not recommended in AKI-superimposed chronic liver injury [121]. Nevertheless, renal support may be considered only in patients with reversible causes [122].
9. Conclusions
leptospirosis-related AKI; for example, direct Leptospira nephrotoxicity, hyperbilirubinemia, rhabdomyolysis, and sepsis. These factors result in high mortality and morbidity rates. Accordingly, a high suspicion of leptospirosis followed by timely treatment, especially with an appropriate antibiotic along with the best supportive care, could improve complications in severe disease cases.
References
1. Tulsiani, S.M.; Lau, C.L.; Graham, G.C.; Van Den Hurk, A.F.; Jansen, C.C.; Smythe, L.D.; McKay, D.B.; Craig, S.B. Emerging tropical diseases in Australia. Part 1. Leptospirosis. Ann. Trop. Med. Parasitol. 2010, 104, 543–556. [CrossRef] [PubMed]
2. Hinjoy, S.; Kongyu, S.; Doung-Ngern, P.; Doungchawee, G.; Colombe, S.D.; Tsukayama, R.; Suwancharoen, D. Environmental and behavioral risk factors for severe leptospirosis in Thailand. Trop. Med. Infect. Dis. 2019, 4, 79. [CrossRef] [PubMed]
3. Lau, C.L.; Townell, N.; Stephenson, E.; van den Berg, D.; Craig, S.B. Leptospirosis: An important zoonosis acquired through work, play and travel. Aust. J. Gen. Pract. 2018, 47, 105–110. [CrossRef] [PubMed]
4. Carter, M.E.; Cordes, D.O. Leptospirosis and other infections of Battus rattus and Rattus norvegicus. N. Z. Vet. J. 1980, 28, 45–50. [CrossRef] [PubMed]
5. Yang, C.W.; Hung, C.C.; Wu, M.S.; Tian, Y.C.; Chang, C.T.; Pan, M.J.; Vandewalle, A. Toll-like receptor 2 mediates early inflammation by leptospiral outer membrane proteins in proximal tubule cells. Kidney Int. 2006, 69, 815–822. [CrossRef] [PubMed]
6. Budihal, S.V.; Perwez, K. Leptospirosis diagnosis: Competancy of various laboratory tests. J. Clin. Diagn. Res. 2014, 8, 199–202. [CrossRef]
7. Costa, F.; Hagan, J.E.; Calcagno, J.; Kane, M.; Torgerson, P.; Martinez-Silveira, M.S.; Stein, C.; Abela-Ridder, B.; Ko, A.I. Global morbidity and mortality of leptospirosis: A Systematic Review. PLoS Negl. Trop. Dis. 2015, 9, e0003898. [CrossRef]
8. Hinjoy, S. Epidemiology of Leptospirosis from Thai National Disease Surveillance System, 2003–2012. Outbreak, Surveillance, and Investigation Reports (OSIR). Available online: http://www.osirjournal.net/index.php/osir/article/view/38 (accessed on 1 November 2021).
9. Torgerson, P.R.; Hagan, J.E.; Costa, F.; Calcagno, J.; Kane, M.; Martinez-Silveira, M.S.; Goris, M.G.; Stein, C.; Ko, A.I.; Abela-Ridder, B. Global burden of leptospirosis: Estimated in terms of disability-adjusted life years. PLoS Negl. Trop. Dis. 2015, 9, e0004122. [CrossRef]
10. Lozano, R.; Naghavi, M.; Foreman, K.; Lim, S.; Shibuya, K.; Aboyans, V.; Abraham, J.; Adair, T.; Aggarwal, R.; Ahn, S.Y.; et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012, 380, 2095–2128. [CrossRef]
11. Yang, C.W.; Pan, M.J.; Wu, M.S.; Chen, Y.M.; Tsen, Y.T.; Lin, C.L.; Wu, C.H.; Huang, C.C. Leptospirosis: An ignored cause of acute renal failure in Taiwan. Am. J. Kidney Dis. 1997, 30, 840–845. [CrossRef]
12. Yang, H.Y.; Yen, T.H.; Lin, C.Y.; Chen, Y.C.; Pan, M.J.; Lee, C.H.; Yu, C.C.; Wu, M.S.; Wu, S.S.; Weng, C.H.; et al. Early identification of leptospirosis as an ignored cause of multiple organ dysfunction syndrome. Shock 2012, 38, 24–29. [CrossRef] [PubMed]
13. Sitprija, V. Renal dysfunction in leptospirosis: A view from the tropics. Nat. Clin. Pract. Nephrol. 2006, 2, 658–659. [CrossRef] [PubMed]
14. Teles, F.; de Mendonça Uchôa, J.V.; Mirelli Barreto Mendonça, D.; Falcão Pedrosa Costa, A. Acute kidney injury in leptospirosis: The Kidney Disease Improving Global Outcomes (KDIGO) criteria and mortality. Clin. Nephrol. 2016, 86, 303–309. [CrossRef] [PubMed]
