J. Parasitol., 101(2), 2015, pp. 244–247 Ó American Society of Parasitologists 2015
Acute Kidney Injury in Schistosomiasis: A Retrospective Cohort of 60 Patients in Brazil ˆ Daniella Bezerra Duarte*†‡, Lucas Alexandre Vanderlei*, Raianne K´ıvia de Azevedo Bispo*, Maria Eliete Pinheiro*, Geraldo Bezerra da Silva Junior†§, and Elizabeth De Francesco Daherjj, *Department of Internal Medicine, School of Medicine, Federal University of Alagoas, CEP 57072-900, Macei´ o, Alagoas, Brazil; †School of Medicine, Post-Graduation Program in Collective Health, University of Fortaleza, CEP 60811-905, Fortaleza, Ceara´, Brazil; ‡Run Vicente Linhares, 1198, CEP 60135-270, Fortaleza Ceara´, Brazil; §School of Medicine, Post-Graduation Program in Collective Health, Health Sciences Center, University of Fortaleza, CEP-60811-905, Fortaleza, Ceara´, Brazil; jjDepartment of Internal Medicine, School of Medicine, Federal University of Ceara´, CEP 60430-160, Fortaleza, Ceara´, Brazil. Correspondence should be sent to: [email protected]
the best of our knowledge, there are no reports describing acute kidney injury (AKI) in patients with schistosomiasis. Since AKI is not well studied in schistosomiasis and its pathophysiology is not completely understood, this study was conducted to investigate the occurrence of AKI in hospitalized patients with hepatosplenic schistosomiasis and to describe its clinical and laboratory features. The findings of this study are important to parasitology because they will increase knowledge about schistosomiasis-associated AKI, an important and potentially fatal complication that can be found in this disease. This is a retrospective study conducted with 60 consecutive patients with epidemiologic, clinical, and laboratory diagnosis of hepatosplenic schistosomiasis who had been admitted to the Professor Alberto Antunes ´ Brazil, between November 2008 and University Hospital in Maceio, October 2012. The protocol of this study was approved by the Ethics Committee of the institution. Etiologic diagnosis of schistosomiasis was based on a previous detection of schistosome eggs in feces, rectal, or liver biopsy. Epidemiological criterion was based on the patient’s origin area endemic for schistosomiasis. Clinical diagnosis of hepatosplenic schistosomiasis was based on the presence of hepatomegaly and splenomegaly in physical or ultrasonographic examination, periportal fibrosis, increased portal vein diameter, history of gastrointestinal bleeding, presence of esophageal varices at endoscopy, or previous splenectomy. A standardized case investigation form was used to record demographical, epidemiological, clinical, and laboratory data. Patients with previous kidney disease (acute or chronic), nephrolithiasis, and use of nephrotoxic drugs were excluded as well as patients who did not meet diagnostic criteria for schistosomiasis or had, besides schistosomiasis, other liver diseases (hepatitis B and C, alcohol-related, autoimmune, cancer) (Fig. 1). The study protocol was approved by the Ethical Committee of the Institution. The CHILD (Child-Pugh) and MELD (Model for End-Stage Liver Disease) scores, used to assess the severity and prognosis of chronic liver disease of patients, were calculated in all patients (Child and Turcotte, 1964; Pugh et al., 1973; Kamath et al., 2001). AKI was defined according to the RIFLE criteria, a classification system for AKI formed by the acronym Risk of renal dysfunction (R), Injury to the kidney (I), Failure of kidney function (F), Loss of kidney function (L), and End-stage kidney disease (E) (Bellomo et al., 2004). The RIFLE criteria take into account acute changes in serum creatinine and urine output. The diuresis criterion was not used to define AKI. We used only the acute change in serum creatinine. AKI was detected at hospital admission and during hospital stay. Patients who had elevated serum creatinine levels at admission and whose levels remained stable were not classified as AKI. The patients were divided into 2 groups: patients with and without AKI. We compared these 2 groups to investigate differences in clinical manifestations, laboratory features, and factors associated with AKI. Statistical analysis was performed using the software SPSS 16.0 (SPSS, Chicago, Illinois). The chi-square test was performed to compare percentages, and Student’s t-test was used to compare means. To verify the normality of distribution of continuous variables, the Kolmogorov– Smirnov test was used. The Levene test was used to compare variances. In the condition of data normality, the comparison between 2 means was
ABSTRACT:
The aim of this study is to investigate renal involvement in schistosomiasis. This is a retrospective cohort of 60 consecutive patients ´ Brazil. with schistosomiasis admitted to a university hospital in Maceio, The patients were divided into 2 groups: patients with and without acute kidney injury (AKI) according to the RIFLE criteria. We compared the groups for differences in clinical manifestations and laboratory tests. Patients’ mean age was 58 6 16 yr, and 56.7% were female. The average length of hospital stay was 16.4 6 12.1 days. Patients with hypertension and diabetes were 35% and 21.7% respectively. The main clinical symptoms and signs presented were ascites (86.7%), splenomegaly (80%), and hepatomegaly (63.3%). Current or previous history of upper gastrointestinal bleeding was found in 45% of patients, esophageal varices on endoscopy were present in 92%, and periportal fibrosis on ultrasound examination in 81% of patients. AKI incidence was 43.3% during hospital stay. Mean age and length of hospitalization were higher in the AKI group. Diuretic use, such as furosemide and spironolactone, ascites, and AST levels were also associated with AKI. Death occurred in 5 cases (8.5%), 4 of them in the AKI group. The classifications Child-Pugh score (CHILD) and Model for End-Stage Liver Disease (MELD), used to assess the severity and prognosis of chronic liver disease, presented higher scores among patients with AKI (CHILD: 9.5 6 1.5 vs. 8.4 6 1.7, P ¼ 0.02; MELD: 19 6 5.8 vs. 13 6 3.9, P , 0.001). Renal dysfunction is an important feature of schistosomiasis, which is associated with significant morbidity and possible increased mortality. Further studies are necessary to establish the mechanisms through which schistosomiasis can lead to renal dysfunction.
Schistosomiasis is a parasitic disease caused by organisms from the genus Schistosoma, which is endemic in tropical areas (Ross et al., 2002; Chitsulo et al., 2004). It is estimated that more than 200 million people worldwide have schistosomiasis, with an estimated mortality of approximately 100,000 deaths per year (Chitsulo et al., 2004; Maguire, 2010). In Brazil, only Schistosoma mansoni is present. The disease is found in almost the entire national territory, but with a higher prevalence in northeastern states where it is considered endemic. An estimated 8 million people in Brazil are infected (Chitsulo et al., 2004; Resendes et al., 2005; Maguire, ´ 2010; Ministerio da Saude, ´ 2010). In the infection by S. haematobium, a parasitic disease predominant in African countries, urinary tract involvement is common (Brower et al., 2003). Hematuria and dysuria can be observed due to inflammation and ulceration in the bladder mucosa, generally occurring 3 to 4 mo after primary infection. Polyps, hypertrophic nodules, and egg deposition can be observed through cystoscopy. Granulomas, fibrosis, and calcifications in the vesical wall can cause vesico-ureteral reflux and obstructive uropathy, leading to hydronephrosis, chronic bacteriuria, vesical cancer, and, less frequently, renal insufficiency (Maguire, 2010). Schistosoma mansoni infection–associated kidney disease is not frequently described in the literature. Chronic glomerular involvement is the most frequently reported kidney disease (Silva Junior et al., 2013). To DOI: 10.1645/13-361.1 244
SHORT COMMUNICATIONS
FIGURE 1. Patients admitted to hospital during the study period and reasons for exclusion. made by Student’s t-test. In the case of non-normal data, the Mann– Whitney test was applied. P values 0.05 were considered statistically significant. Patients’ mean age was 58 6 16 yr, and 34 (56.7%) were female. The average length of hospital stay was 16.4 6 12.1 days. Patients with hypertension and diabetes were 35% and 21.7%, respectively. The main clinical symptoms and signs presented were ascites (86.7%), splenomegaly (80%), and hepatomegaly (63.3%). Current or previous history of upper
245
gastrointestinal bleeding was found in 45% of patients, and the finding of esophageal varices on endoscopy was present in 92%. Periportal fibrosis on ultrasound examination was found in 81%. The most common reasons for hospitalization were ascites (63.3%), upper gastrointestinal bleeding (21.7%), and infection (6.7%). According to the RIFLE criteria, 26 (43.3%) patients had AKI during their hospital stay, 10 (38.5%) in the class ‘‘Risk,’’ 10 (38.5.5%) in ‘‘Injury,’’ and 6 (23.1%) in ‘‘Failure.’’ The clinical and laboratory features for AKI and non-AKI patients are summarized in Tables I and II. Mean age and length of hospital stay were higher in the AKI group. Hypertension was more frequent among patients with AKI (50% vs. 23.5%, P ¼ 0.05). Use of diuretics, such as furosemide and spironolactone, ascites, and aspartate aminotransferase (AST) levels, were also associated with AKI (Tables I, II). There were no significant differences in the frequencies of clinical symptoms and signs and laboratory tests between the 2 groups, except that AST levels were higher in the AKI group (52 6 23 vs. 36 6 14, P ¼ 0.004). Also there was no difference between the groups regarding the frequency of paracentesis and frequency of patients with weight change .1 kg/day (Tables I, II). Death occurred in 5 cases (8.3%). Two of these had AKI in class ‘‘Injury,’’ 2 was in class ‘‘Failure,’’ and 1 had no AKI. The classifications CHILD and MELD presented higher scores among patients with AKI (CHILD: 9.5 6 1.5 vs. 8.4 6 1.7, P ¼ 0.02; MELD: 19 6 5.8 vs. 13 6 3.9, P , 0.001), as summarized in Table III. The prevalence of renal involvement in schistosomiasis is variable depending on the study population. Considering all the forms of the disease, the incidence of glomerular involvement is estimated in 5–6% and increases to 15% in the hepatosplenic form (Van Velthuysen, 1996; Brito et al., 1999; Rodrigues et al., 2010). Proteinuria is reported in 20% of patients with S. mansoni infection (Martinelli and Rocha, 1996). In our study, proteinuria was present in 34.6% and hematuria in 26.9% of cases and did not correlate with AKI.
TABLE I. Characteristics and clinical manifestation of schistosomiasis patients with and without acute kidney injury (AKI) admitted to a tertiary hospital.
Age, years* Female Time of hospitalization, days* Diabetes mellitus# Arterial hypertension# Systolic blood pressure (mmHg)* Diastolic blood pressure (mmHg)*
Non-AKI
AKI
P value
[34] 54 6 16 18/34 (52.9) [34] 12 6 8 8/34 (23.5) 8/34 (23.5) [28] 113.9 6 10.8 [28] 73.3 6 7.4
[26] 64 6 16 16/26 (61.5) [26] 22 6 14 5/26 (19.2) 13/26 (50.0) [23] 113.4 6 10.9 [23] 70.5 6 5.6
0.02 0.60 0.002 0.76 0.05 0.87 0.13
Signs and symptoms# Ascites Splenomegaly Hepatomegaly Upper GI bleeding Esophageal varices Periportal fibrosis Prior splenectomy
26/34 24/27 23/34 16/34 32/33 24/29 7/34
(76.5) (88.9) (67.6) (47.1) (97.0) (82.8) (20.6)
26/26 16/23 15/26 9/26 23/25 19/24 3/26
(100) (69.6) (57.7) (34.6) (92.0) (79.2) (11.5)
0.008 0.17 0.58 0.43 0.57 0.74 0.56
17/34 20/34 11/34 9/34 17/34 14/34 16/34
(50.0) (58.8) (32.4) (26.5) (50.0) (41.2) (47.1)
24/26 23/26 10/26 10/26 20/26 7/26 13/26
(92.3) (88.5) (38.5) (38.5) (76.9) (26.9) (50.0)
0.001 0.01 0.78 0.40 0.06 0.28 0.82
Treatment (during hospital stay and chronic use)# Furosemide use Spironolactone use Weight change .1 kg/day iECA use Paracentesis b-blocker therapy Antibiotics use Mortality#
1/34 (2,9)
4/26 (15,4)
0.15
* Student’s t and # chi-square test; data are expressed as [number of investigated patients] mean 6 SD and number of positive patients/number of investigated patients (percentage %). P , 0.05 was considered significant.
246
THE JOURNAL OF PARASITOLOGY, VOL. 101, NO. 2, APRIL 2015
TABLE II. Laboratory result comparisons between schistosomiasis patients with and without acute kidney injury (AKI) admitted to a tertiary hospital. Abbreviations: Adm, admission; Max, maximum; Scr, serum creatinine; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Hematuria, %# Proteinuria, % # Leukopenia, %# Thrombocytopenia, %# ScrAdm, mg/dl* ScrMax, mg/dl* UreaAdm, mg/dl* UreaMax, mg/dl* Hemoglobin, g/dl* Hematocrit, %* ALT, UI/L* AST, UI/L* Lactate dehydrogenase, UI/L* Alkaline Phosphatase, UI/L* Total bilirubin, mg/dl* Direct bilirubin, mg/dl* Indirect bilirubin, mg/dl* Albumin, g/dl* Na, mEq/L* K, mEq/L* Calcium, mg/dl* Albumin ascitic fluid, g/dl*
Non-AKI
AKI
P value
6/28 (21.4) 7/28 (25.0) 20/34 (58.8) 24/34 (70.6) [34] 0.7 6 0.3 [34] 0.8 6 0.3 [33] 37 6 19 [33] 45 6 29 [34] 9.7 6 2.6 [34] 29.7 6 7.7 [33] 34 6 33 [33] 36 6 14 [17] 229 6 100 [23] 150 6 134 [33] 1.3 6 1.0 [33] 0.4 6 0.3 [33] 0.8 6 0.8 [32] 2.9 6 0.6 [34] 136 6 4.0 [34] 4.2 6 0.5 [13] 8.3 6 0.7 [15] 0.7 6 0.7
8/24 (33.3) 11/24 (45.8) 9/26 (34.6) 16/26 (61.5) [26] 0,9 6 0.5 [26] 1.6 6 0.6 [26] 52 6 40 [26] 80 6 54 [26] 9.9 6 1.8 [26] 29.7 6 5.2 [25] 39 6 20 [26] 52 6 23 [11] 258 6 106 [23] 157 6 86 [26] 1.8 6 2.4 [26] 0.9 6 1.5 [26] 0.9 6 1.0 [26] 2.7 6 0.5 [26] 135 6 3.9 [26] 4.6 6 0.7 [13] 8.4 6 1.0 [18] 0.7 6 0.4
0.36 0.14 0.07 0.58 0.15 ,0.001 0.09 0.006 0.67 0.98 0.54 0.004 0.48 0.84 0.28 0.10 0.93 0.18 0.09 0.05 0.83 0.99
* Student’s t and # chi-square test; data are expressed as [number of investigated patients] mean 6 SD and number of positive patients/number of investigated patients (percentage %). P , 0.05 was considered significant. We compared patients with and without AKI regarding clinical and laboratory characteristics. Most of the data available in the literature describe AKI in patients with cirrhosis of different etiologies. Studies reporting ARF in patients with hepatic involvement due to schistosomiasis are scarce. Co-infection with either hepatitis B virus or hepatitis C virus and S. mansoni is frequent and is associated with accelerated deterioration of hepatic function (Aquino et al., 2000). In our study we excluded patients with other liver diseases (hepatitis B virus, hepatitis C virus, alcohol-related, autoimmune, cancer), so that kidney injury could be attributable to schistosomiasis itself or its complications. In schistosomiasis, hepatocellular synthetic function is preserved until the very late stages of the disease (Ross et al., 2002; Domingues and Novais, 2004). In our study, patients in AKI group had higher AST levels than non-AKI group. No other markers of liver function, such as ALT, alkaline phosphatase, albumin, bilirubin, and International Normalized Ratio, Prothrombin time (INR), were altered in the group with AKI, and assessment of liver decomposition requires further analysis. AKI prevalence is variable in patients hospitalized for decompensating liver cirrhosis. Hartleb and Gutkowski (2012) found a prevalence of around 20% in this population. Another recent study found AKI prevalence greater than 60%, and the mortality was significantly higher in the group that developed AKI (Belcher et al., 2013). The most common causes of AKI in cirrhosis are pre-renal azotemia, hepatorenal syndrome, TABLE III. Child–Pugh score (CHILD) and Model for End-Stage Liver Disease (MELD) classifications in schistosomiasis patients with and without acute kidney injury (AKI) admitted to a tertiary hospital.
CHILD* MELD*
Non-AKI (n ¼ 30)
AKI (n ¼ 24)
P value
8.45 6 1.76 13.9 6 3.9
9.58 6 1.56 19.1 6 5.8
0.02 ,0.001
* Student’s t test; data are expressed as mean 6 SD. P , 0.05 was considered significant.
` and Schrier, 2009; Hartleb and and acute tubular necrosis (Gines Gutkowski, 2012). In our study, according to the RIFLE criteria acute renal failure was present in 43.3% of patients during hospital stay, therefore similar prevalence to that of liver cirrhosis patients. There were no significant differences in the frequencies of ascites, sodium levels, and b-blocker therapy between AKI and non-AKI patients. The classifications CHILD and MELD presented higher scores among patients with AKI, evidencing that AKI is associated with worse prognosis in this group of patients. Tense ascites causes an increase in intra-abdominal pressure, giving rise to abdominal compartment syndrome, which is a known risk factor for AKI developing in critically ill patients (De Waele et al., 2011). Intraabdominal pressure .20 mmHg, measured in the urinary bladder, leads to severe impairment of renal venous blood flow and secondary disturbances in arterial perfusion of the kidneys (Kashtan et al., 1981). Ascitic patients show increased heart rate and cardiac output and low diastolic arterial pressure, which are accentuated after paracentesis (Peltekian et al., 1997; Salo´ et al., 1997). Mechanisms of paracentesis-induced circulatory dysfunction are not entirely clear, but paracentesis causes further reduction of volemia in the central circulation with simultaneous stimulation of all vasoconstrictive systems, having a deleterious effect on renal function (Hartleb and Gutkowski et al., 2012). In our study, there was an association between ascites and AKI; ascites was present in 100% of patients with AKI, but there was no correlation between AKI and paracentesis. This suggests that renal dysfunction might have occurred mainly due to intra-abdominal hypertension more than induced by paracentesis. There were only 5 deaths, and 4 of them occurred among the group with AKI. AKI seems to be a common complication in hospitalized patients with schistosomiasis and seems to contribute to an increased length of hospitalization of these patients. In summary, renal dysfunction is an important feature of schistosomiasis, which is associated with significant morbidity and possible increased mortality. Further studies are necessary to establish the mechanisms by which schistosomiasis can lead to renal dysfunction.
SHORT COMMUNICATIONS
LITERATURE CITED ´ AQUINO, R. T., P. P. CHIEFFI, S. M. CATUNDA, M. F. ARAUJO , M. C. RIBEIRO, E. F. TADDEO, AND E. G. ROLIM. 2000. Hepatitis B and C v ´ırus markers among patients with hepatosplenic mansonic schistosomiasis. Revista do Instituto de Medicina Tropical de Sao Paulo 42: 313–320. BELCHER, J. M., G. GARCIA-TSAO, A. J. SANYAL, H. BHOGAL, J. K. LIM, N. ANSARI, N. G. COCA, AND C. R. PARIKH. 2013. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 57: 753–762. BELLOMO, R., C. RONCO, J. A. KELLUM, R. L. MEHTA, AND P. PALEVSKY. 2004. Acute renal failure—Definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care 8: R204–R212. BRITO, T., I. NUSSENZVEIG, C. R. W. CARNEIRO, AND A. M. G. SILVA. 1999. Schistosoma mansoni associated glomerulopathy. Revista do Instituto de Medicina Tropical de Sa˜o Paulo 41: 269–272. BROWER, K. C., P. D. NDHLOVU, Y. WAGATSUMA, A. MUNATSI, AND C. J. SHIFF. 2003. Epidemiological assessment of Schistosoma haematobium induced kidney and bladder pathology in rural Zimbabwe. Acta Tropica 85: 339–347. CHILD, C. G., AND J. G. TURCOTTE. 1964. Surgery and portal hypertension. In The liver and portal hypertension, C. G. Child (ed.). Saunders, Philadelphia, Pennsylvania, p. 50–64. CHITSULO, L., P. LOVERDE, AND D. ENGELS. 2004. Schistosomiasis. Nature Reviews Microbiology 2: 12–13. DE WAELE, J. J., I. DE LAET, A. W. KIRKPATRICK, AND E. HOSTE. 2011. Intra-abdominal hypertension and abdominal compartment syndrome. American Journal of Kidney Disease 57: 159–169. DOMINGUES, A. L. C., AND S. NOVAIS. 2004. Esquistossomose Mansonica. ˆ ´ In Condutas em Cl ´ınica Medica, N. A. Filgueira (ed.). Medsi, Rio de Janeiro, Brazil, p. 659–669. ` , P., AND R. W. SCHRIER. 2009. Renal failure in cirrhosis. New GINES England Journal of Medicine 361: 1279–1290. HARTLEB, M., AND K. GUTKOWSKI. 2012. Kidneys in chronic liver diseases. World Journal of Gastroenterology 18: 3035–3049. KAMATH, P. S., R. H. WIESNER, M. MALINCHOC, W. KREMERS, T. M. THERNEAU, C. L. KOSBERG, G. D’AMICO, E. R. DICKSON, AND W. R. KIM. 2001. A model to predict survival in patients with end-stage liver disease. Hepatology 33: 464–470.
247
KASHTAN, J., J. F. GREEN, E. Q. PARSONS, AND J. W. HOLCROFT. 1981. Hemodynamic effect of increased abdominal pressure. Journal of Surgical Research 30: 249–255. MAGUIRE, J. H. 2010. Trematodes (schistosomes and other flukes). In Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, 7th ed., G. L. Mandell, J. E. Bennett, and R. Dolin (eds.). Churchill Livingstone Elsevier, Philadelphia, Pennsylvania, p. 3595– 3605. ¸ ˜ o em Nefrologia MARTINELLI, R., AND H. ROCHA. 1996. Revisa˜o/Atualizaca Cl ´ınica: Envolvimento glomerular na esquistossomose mansonica. ˆ Jornal Brasileiro de Nefrologia 18: 279–282. ´ ´ DA SAUDE (BRAZILIAN MINISTRY OF HEALTH). SECRETARIA DE MINISTERIO ˆ ´ ´ VIGILANCIA EM SAUDE . 2010. Guia de vigilancia ˆ epidemiologica, 7th ´ ed. Ministerio da Saude, ´ Bras ´ılia, 813 p. PELTEKIAN, K. M., F. WONG, P. P. LIU, A. G. LOGAN, M. SHERMAN, AND L. M. BLENDIS. 1997. Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites. American Journal of Gastroenterology 92: 394–399. PUGH, R. N., I. M. MURRAY-LYON, J. L. DAWSON, M. C. PIETRONI, AND R. WILLIAMS. 1973. Transection of the oesophagus for bleeding oesophageal varices. British Journal of Surgery 60: 646–649. RESENDES, A. P. C., S. R. SOUZA, AND C. S. BARBOSA. 2005. Hospitalization and mortality from mansoni schistosomiasis in the State of Pernambuco, Brazil, 1992/2000. Cadernos de Saude ´ Publica ´ 21: 1392–1401. RODRIGUES, V. L., A. OTONI, I. VOIETA, C. M. ANTUNES, AND J. R. LAMBERTUCCI. 2010. Glomerulonephritis in schistosomiasis mansoni: A time to reappraise. Revista da Sociedade Brasileira de Medicina Tropical 43: 638–642. ROSS, A. G. P., P. B. BARTLEY, A. C. SLEIGH, G. R. OLDS, Y. LI, G. M. WILLIAMS, AND D. P. MCMANUS. 2002. Schistosomiasis. New England Journal of Medicine 346: 1212–1220. ` , P. GINES ` , C. PIERA, W. JIMENEZ ´ , M. GUEVARA, G. SALO´ , J., A. GINES FERNA´NDEZ-ESPARRACH, P. SORT, R. BATALLER, V. ARROYO, ET AL. 1997. Effect of therapeutic paracentesis on plasma volume and transvascular escape rate of albumin in patients with cirrhosis. Journal of Hepatology 27: 645–653. SILVA JUNIOR, G. B., D. B. DUARTE, E. J. G. BARROS, AND E. F. DAHER. 2013. Schistosomiasis-associated kidney disease: A review. Asian Pacific Journal of Tropical Disease 3: 79–84. VAN VELTHUYSEN, M. L. F. 1996. Glomerulopathy associated with parasitic infections. Parasitology Today 12: 102–107.
Acute Kidney Injury in Schistosomiasis: A Retrospective Cohort of 60 Patients in Brazil ˆ Daniella Bezerra Duarte*†‡, Lucas Alexandre Vanderlei*, Raianne K´ıvia de Azevedo Bispo*, Maria Eliete Pinheiro*, Geraldo Bezerra da Silva Junior†§, and Elizabeth De Francesco Daherjj, *Department of Internal Medicine, School of Medicine, Federal University of Alagoas, CEP 57072-900, Macei´ o, Alagoas, Brazil; †School of Medicine, Post-Graduation Program in Collective Health, University of Fortaleza, CEP 60811-905, Fortaleza, Ceara´, Brazil; ‡Run Vicente Linhares, 1198, CEP 60135-270, Fortaleza Ceara´, Brazil; §School of Medicine, Post-Graduation Program in Collective Health, Health Sciences Center, University of Fortaleza, CEP-60811-905, Fortaleza, Ceara´, Brazil; jjDepartment of Internal Medicine, School of Medicine, Federal University of Ceara´, CEP 60430-160, Fortaleza, Ceara´, Brazil. Correspondence should be sent to: [email protected]
the best of our knowledge, there are no reports describing acute kidney injury (AKI) in patients with schistosomiasis. Since AKI is not well studied in schistosomiasis and its pathophysiology is not completely understood, this study was conducted to investigate the occurrence of AKI in hospitalized patients with hepatosplenic schistosomiasis and to describe its clinical and laboratory features. The findings of this study are important to parasitology because they will increase knowledge about schistosomiasis-associated AKI, an important and potentially fatal complication that can be found in this disease. This is a retrospective study conducted with 60 consecutive patients with epidemiologic, clinical, and laboratory diagnosis of hepatosplenic schistosomiasis who had been admitted to the Professor Alberto Antunes ´ Brazil, between November 2008 and University Hospital in Maceio, October 2012. The protocol of this study was approved by the Ethics Committee of the institution. Etiologic diagnosis of schistosomiasis was based on a previous detection of schistosome eggs in feces, rectal, or liver biopsy. Epidemiological criterion was based on the patient’s origin area endemic for schistosomiasis. Clinical diagnosis of hepatosplenic schistosomiasis was based on the presence of hepatomegaly and splenomegaly in physical or ultrasonographic examination, periportal fibrosis, increased portal vein diameter, history of gastrointestinal bleeding, presence of esophageal varices at endoscopy, or previous splenectomy. A standardized case investigation form was used to record demographical, epidemiological, clinical, and laboratory data. Patients with previous kidney disease (acute or chronic), nephrolithiasis, and use of nephrotoxic drugs were excluded as well as patients who did not meet diagnostic criteria for schistosomiasis or had, besides schistosomiasis, other liver diseases (hepatitis B and C, alcohol-related, autoimmune, cancer) (Fig. 1). The study protocol was approved by the Ethical Committee of the Institution. The CHILD (Child-Pugh) and MELD (Model for End-Stage Liver Disease) scores, used to assess the severity and prognosis of chronic liver disease of patients, were calculated in all patients (Child and Turcotte, 1964; Pugh et al., 1973; Kamath et al., 2001). AKI was defined according to the RIFLE criteria, a classification system for AKI formed by the acronym Risk of renal dysfunction (R), Injury to the kidney (I), Failure of kidney function (F), Loss of kidney function (L), and End-stage kidney disease (E) (Bellomo et al., 2004). The RIFLE criteria take into account acute changes in serum creatinine and urine output. The diuresis criterion was not used to define AKI. We used only the acute change in serum creatinine. AKI was detected at hospital admission and during hospital stay. Patients who had elevated serum creatinine levels at admission and whose levels remained stable were not classified as AKI. The patients were divided into 2 groups: patients with and without AKI. We compared these 2 groups to investigate differences in clinical manifestations, laboratory features, and factors associated with AKI. Statistical analysis was performed using the software SPSS 16.0 (SPSS, Chicago, Illinois). The chi-square test was performed to compare percentages, and Student’s t-test was used to compare means. To verify the normality of distribution of continuous variables, the Kolmogorov– Smirnov test was used. The Levene test was used to compare variances. In the condition of data normality, the comparison between 2 means was
ABSTRACT:
The aim of this study is to investigate renal involvement in schistosomiasis. This is a retrospective cohort of 60 consecutive patients ´ Brazil. with schistosomiasis admitted to a university hospital in Maceio, The patients were divided into 2 groups: patients with and without acute kidney injury (AKI) according to the RIFLE criteria. We compared the groups for differences in clinical manifestations and laboratory tests. Patients’ mean age was 58 6 16 yr, and 56.7% were female. The average length of hospital stay was 16.4 6 12.1 days. Patients with hypertension and diabetes were 35% and 21.7% respectively. The main clinical symptoms and signs presented were ascites (86.7%), splenomegaly (80%), and hepatomegaly (63.3%). Current or previous history of upper gastrointestinal bleeding was found in 45% of patients, esophageal varices on endoscopy were present in 92%, and periportal fibrosis on ultrasound examination in 81% of patients. AKI incidence was 43.3% during hospital stay. Mean age and length of hospitalization were higher in the AKI group. Diuretic use, such as furosemide and spironolactone, ascites, and AST levels were also associated with AKI. Death occurred in 5 cases (8.5%), 4 of them in the AKI group. The classifications Child-Pugh score (CHILD) and Model for End-Stage Liver Disease (MELD), used to assess the severity and prognosis of chronic liver disease, presented higher scores among patients with AKI (CHILD: 9.5 6 1.5 vs. 8.4 6 1.7, P ¼ 0.02; MELD: 19 6 5.8 vs. 13 6 3.9, P , 0.001). Renal dysfunction is an important feature of schistosomiasis, which is associated with significant morbidity and possible increased mortality. Further studies are necessary to establish the mechanisms through which schistosomiasis can lead to renal dysfunction.
Schistosomiasis is a parasitic disease caused by organisms from the genus Schistosoma, which is endemic in tropical areas (Ross et al., 2002; Chitsulo et al., 2004). It is estimated that more than 200 million people worldwide have schistosomiasis, with an estimated mortality of approximately 100,000 deaths per year (Chitsulo et al., 2004; Maguire, 2010). In Brazil, only Schistosoma mansoni is present. The disease is found in almost the entire national territory, but with a higher prevalence in northeastern states where it is considered endemic. An estimated 8 million people in Brazil are infected (Chitsulo et al., 2004; Resendes et al., 2005; Maguire, ´ 2010; Ministerio da Saude, ´ 2010). In the infection by S. haematobium, a parasitic disease predominant in African countries, urinary tract involvement is common (Brower et al., 2003). Hematuria and dysuria can be observed due to inflammation and ulceration in the bladder mucosa, generally occurring 3 to 4 mo after primary infection. Polyps, hypertrophic nodules, and egg deposition can be observed through cystoscopy. Granulomas, fibrosis, and calcifications in the vesical wall can cause vesico-ureteral reflux and obstructive uropathy, leading to hydronephrosis, chronic bacteriuria, vesical cancer, and, less frequently, renal insufficiency (Maguire, 2010). Schistosoma mansoni infection–associated kidney disease is not frequently described in the literature. Chronic glomerular involvement is the most frequently reported kidney disease (Silva Junior et al., 2013). To DOI: 10.1645/13-361.1 244
SHORT COMMUNICATIONS
FIGURE 1. Patients admitted to hospital during the study period and reasons for exclusion. made by Student’s t-test. In the case of non-normal data, the Mann– Whitney test was applied. P values 0.05 were considered statistically significant. Patients’ mean age was 58 6 16 yr, and 34 (56.7%) were female. The average length of hospital stay was 16.4 6 12.1 days. Patients with hypertension and diabetes were 35% and 21.7%, respectively. The main clinical symptoms and signs presented were ascites (86.7%), splenomegaly (80%), and hepatomegaly (63.3%). Current or previous history of upper
245
gastrointestinal bleeding was found in 45% of patients, and the finding of esophageal varices on endoscopy was present in 92%. Periportal fibrosis on ultrasound examination was found in 81%. The most common reasons for hospitalization were ascites (63.3%), upper gastrointestinal bleeding (21.7%), and infection (6.7%). According to the RIFLE criteria, 26 (43.3%) patients had AKI during their hospital stay, 10 (38.5%) in the class ‘‘Risk,’’ 10 (38.5.5%) in ‘‘Injury,’’ and 6 (23.1%) in ‘‘Failure.’’ The clinical and laboratory features for AKI and non-AKI patients are summarized in Tables I and II. Mean age and length of hospital stay were higher in the AKI group. Hypertension was more frequent among patients with AKI (50% vs. 23.5%, P ¼ 0.05). Use of diuretics, such as furosemide and spironolactone, ascites, and aspartate aminotransferase (AST) levels, were also associated with AKI (Tables I, II). There were no significant differences in the frequencies of clinical symptoms and signs and laboratory tests between the 2 groups, except that AST levels were higher in the AKI group (52 6 23 vs. 36 6 14, P ¼ 0.004). Also there was no difference between the groups regarding the frequency of paracentesis and frequency of patients with weight change .1 kg/day (Tables I, II). Death occurred in 5 cases (8.3%). Two of these had AKI in class ‘‘Injury,’’ 2 was in class ‘‘Failure,’’ and 1 had no AKI. The classifications CHILD and MELD presented higher scores among patients with AKI (CHILD: 9.5 6 1.5 vs. 8.4 6 1.7, P ¼ 0.02; MELD: 19 6 5.8 vs. 13 6 3.9, P , 0.001), as summarized in Table III. The prevalence of renal involvement in schistosomiasis is variable depending on the study population. Considering all the forms of the disease, the incidence of glomerular involvement is estimated in 5–6% and increases to 15% in the hepatosplenic form (Van Velthuysen, 1996; Brito et al., 1999; Rodrigues et al., 2010). Proteinuria is reported in 20% of patients with S. mansoni infection (Martinelli and Rocha, 1996). In our study, proteinuria was present in 34.6% and hematuria in 26.9% of cases and did not correlate with AKI.
TABLE I. Characteristics and clinical manifestation of schistosomiasis patients with and without acute kidney injury (AKI) admitted to a tertiary hospital.
Age, years* Female Time of hospitalization, days* Diabetes mellitus# Arterial hypertension# Systolic blood pressure (mmHg)* Diastolic blood pressure (mmHg)*
Non-AKI
AKI
P value
[34] 54 6 16 18/34 (52.9) [34] 12 6 8 8/34 (23.5) 8/34 (23.5) [28] 113.9 6 10.8 [28] 73.3 6 7.4
[26] 64 6 16 16/26 (61.5) [26] 22 6 14 5/26 (19.2) 13/26 (50.0) [23] 113.4 6 10.9 [23] 70.5 6 5.6
0.02 0.60 0.002 0.76 0.05 0.87 0.13
Signs and symptoms# Ascites Splenomegaly Hepatomegaly Upper GI bleeding Esophageal varices Periportal fibrosis Prior splenectomy
26/34 24/27 23/34 16/34 32/33 24/29 7/34
(76.5) (88.9) (67.6) (47.1) (97.0) (82.8) (20.6)
26/26 16/23 15/26 9/26 23/25 19/24 3/26
(100) (69.6) (57.7) (34.6) (92.0) (79.2) (11.5)
0.008 0.17 0.58 0.43 0.57 0.74 0.56
17/34 20/34 11/34 9/34 17/34 14/34 16/34
(50.0) (58.8) (32.4) (26.5) (50.0) (41.2) (47.1)
24/26 23/26 10/26 10/26 20/26 7/26 13/26
(92.3) (88.5) (38.5) (38.5) (76.9) (26.9) (50.0)
0.001 0.01 0.78 0.40 0.06 0.28 0.82
Treatment (during hospital stay and chronic use)# Furosemide use Spironolactone use Weight change .1 kg/day iECA use Paracentesis b-blocker therapy Antibiotics use Mortality#
1/34 (2,9)
4/26 (15,4)
0.15
* Student’s t and # chi-square test; data are expressed as [number of investigated patients] mean 6 SD and number of positive patients/number of investigated patients (percentage %). P , 0.05 was considered significant.
246
THE JOURNAL OF PARASITOLOGY, VOL. 101, NO. 2, APRIL 2015
TABLE II. Laboratory result comparisons between schistosomiasis patients with and without acute kidney injury (AKI) admitted to a tertiary hospital. Abbreviations: Adm, admission; Max, maximum; Scr, serum creatinine; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Hematuria, %# Proteinuria, % # Leukopenia, %# Thrombocytopenia, %# ScrAdm, mg/dl* ScrMax, mg/dl* UreaAdm, mg/dl* UreaMax, mg/dl* Hemoglobin, g/dl* Hematocrit, %* ALT, UI/L* AST, UI/L* Lactate dehydrogenase, UI/L* Alkaline Phosphatase, UI/L* Total bilirubin, mg/dl* Direct bilirubin, mg/dl* Indirect bilirubin, mg/dl* Albumin, g/dl* Na, mEq/L* K, mEq/L* Calcium, mg/dl* Albumin ascitic fluid, g/dl*
Non-AKI
AKI
P value
6/28 (21.4) 7/28 (25.0) 20/34 (58.8) 24/34 (70.6) [34] 0.7 6 0.3 [34] 0.8 6 0.3 [33] 37 6 19 [33] 45 6 29 [34] 9.7 6 2.6 [34] 29.7 6 7.7 [33] 34 6 33 [33] 36 6 14 [17] 229 6 100 [23] 150 6 134 [33] 1.3 6 1.0 [33] 0.4 6 0.3 [33] 0.8 6 0.8 [32] 2.9 6 0.6 [34] 136 6 4.0 [34] 4.2 6 0.5 [13] 8.3 6 0.7 [15] 0.7 6 0.7
8/24 (33.3) 11/24 (45.8) 9/26 (34.6) 16/26 (61.5) [26] 0,9 6 0.5 [26] 1.6 6 0.6 [26] 52 6 40 [26] 80 6 54 [26] 9.9 6 1.8 [26] 29.7 6 5.2 [25] 39 6 20 [26] 52 6 23 [11] 258 6 106 [23] 157 6 86 [26] 1.8 6 2.4 [26] 0.9 6 1.5 [26] 0.9 6 1.0 [26] 2.7 6 0.5 [26] 135 6 3.9 [26] 4.6 6 0.7 [13] 8.4 6 1.0 [18] 0.7 6 0.4
0.36 0.14 0.07 0.58 0.15 ,0.001 0.09 0.006 0.67 0.98 0.54 0.004 0.48 0.84 0.28 0.10 0.93 0.18 0.09 0.05 0.83 0.99
* Student’s t and # chi-square test; data are expressed as [number of investigated patients] mean 6 SD and number of positive patients/number of investigated patients (percentage %). P , 0.05 was considered significant. We compared patients with and without AKI regarding clinical and laboratory characteristics. Most of the data available in the literature describe AKI in patients with cirrhosis of different etiologies. Studies reporting ARF in patients with hepatic involvement due to schistosomiasis are scarce. Co-infection with either hepatitis B virus or hepatitis C virus and S. mansoni is frequent and is associated with accelerated deterioration of hepatic function (Aquino et al., 2000). In our study we excluded patients with other liver diseases (hepatitis B virus, hepatitis C virus, alcohol-related, autoimmune, cancer), so that kidney injury could be attributable to schistosomiasis itself or its complications. In schistosomiasis, hepatocellular synthetic function is preserved until the very late stages of the disease (Ross et al., 2002; Domingues and Novais, 2004). In our study, patients in AKI group had higher AST levels than non-AKI group. No other markers of liver function, such as ALT, alkaline phosphatase, albumin, bilirubin, and International Normalized Ratio, Prothrombin time (INR), were altered in the group with AKI, and assessment of liver decomposition requires further analysis. AKI prevalence is variable in patients hospitalized for decompensating liver cirrhosis. Hartleb and Gutkowski (2012) found a prevalence of around 20% in this population. Another recent study found AKI prevalence greater than 60%, and the mortality was significantly higher in the group that developed AKI (Belcher et al., 2013). The most common causes of AKI in cirrhosis are pre-renal azotemia, hepatorenal syndrome, TABLE III. Child–Pugh score (CHILD) and Model for End-Stage Liver Disease (MELD) classifications in schistosomiasis patients with and without acute kidney injury (AKI) admitted to a tertiary hospital.
CHILD* MELD*
Non-AKI (n ¼ 30)
AKI (n ¼ 24)
P value
8.45 6 1.76 13.9 6 3.9
9.58 6 1.56 19.1 6 5.8
0.02 ,0.001
* Student’s t test; data are expressed as mean 6 SD. P , 0.05 was considered significant.
` and Schrier, 2009; Hartleb and and acute tubular necrosis (Gines Gutkowski, 2012). In our study, according to the RIFLE criteria acute renal failure was present in 43.3% of patients during hospital stay, therefore similar prevalence to that of liver cirrhosis patients. There were no significant differences in the frequencies of ascites, sodium levels, and b-blocker therapy between AKI and non-AKI patients. The classifications CHILD and MELD presented higher scores among patients with AKI, evidencing that AKI is associated with worse prognosis in this group of patients. Tense ascites causes an increase in intra-abdominal pressure, giving rise to abdominal compartment syndrome, which is a known risk factor for AKI developing in critically ill patients (De Waele et al., 2011). Intraabdominal pressure .20 mmHg, measured in the urinary bladder, leads to severe impairment of renal venous blood flow and secondary disturbances in arterial perfusion of the kidneys (Kashtan et al., 1981). Ascitic patients show increased heart rate and cardiac output and low diastolic arterial pressure, which are accentuated after paracentesis (Peltekian et al., 1997; Salo´ et al., 1997). Mechanisms of paracentesis-induced circulatory dysfunction are not entirely clear, but paracentesis causes further reduction of volemia in the central circulation with simultaneous stimulation of all vasoconstrictive systems, having a deleterious effect on renal function (Hartleb and Gutkowski et al., 2012). In our study, there was an association between ascites and AKI; ascites was present in 100% of patients with AKI, but there was no correlation between AKI and paracentesis. This suggests that renal dysfunction might have occurred mainly due to intra-abdominal hypertension more than induced by paracentesis. There were only 5 deaths, and 4 of them occurred among the group with AKI. AKI seems to be a common complication in hospitalized patients with schistosomiasis and seems to contribute to an increased length of hospitalization of these patients. In summary, renal dysfunction is an important feature of schistosomiasis, which is associated with significant morbidity and possible increased mortality. Further studies are necessary to establish the mechanisms by which schistosomiasis can lead to renal dysfunction.
SHORT COMMUNICATIONS
LITERATURE CITED ´ AQUINO, R. T., P. P. CHIEFFI, S. M. CATUNDA, M. F. ARAUJO , M. C. RIBEIRO, E. F. TADDEO, AND E. G. ROLIM. 2000. Hepatitis B and C v ´ırus markers among patients with hepatosplenic mansonic schistosomiasis. Revista do Instituto de Medicina Tropical de Sao Paulo 42: 313–320. BELCHER, J. M., G. GARCIA-TSAO, A. J. SANYAL, H. BHOGAL, J. K. LIM, N. ANSARI, N. G. COCA, AND C. R. PARIKH. 2013. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 57: 753–762. BELLOMO, R., C. RONCO, J. A. KELLUM, R. L. MEHTA, AND P. PALEVSKY. 2004. Acute renal failure—Definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care 8: R204–R212. BRITO, T., I. NUSSENZVEIG, C. R. W. CARNEIRO, AND A. M. G. SILVA. 1999. Schistosoma mansoni associated glomerulopathy. Revista do Instituto de Medicina Tropical de Sa˜o Paulo 41: 269–272. BROWER, K. C., P. D. NDHLOVU, Y. WAGATSUMA, A. MUNATSI, AND C. J. SHIFF. 2003. Epidemiological assessment of Schistosoma haematobium induced kidney and bladder pathology in rural Zimbabwe. Acta Tropica 85: 339–347. CHILD, C. G., AND J. G. TURCOTTE. 1964. Surgery and portal hypertension. In The liver and portal hypertension, C. G. Child (ed.). Saunders, Philadelphia, Pennsylvania, p. 50–64. CHITSULO, L., P. LOVERDE, AND D. ENGELS. 2004. Schistosomiasis. Nature Reviews Microbiology 2: 12–13. DE WAELE, J. J., I. DE LAET, A. W. KIRKPATRICK, AND E. HOSTE. 2011. Intra-abdominal hypertension and abdominal compartment syndrome. American Journal of Kidney Disease 57: 159–169. DOMINGUES, A. L. C., AND S. NOVAIS. 2004. Esquistossomose Mansonica. ˆ ´ In Condutas em Cl ´ınica Medica, N. A. Filgueira (ed.). Medsi, Rio de Janeiro, Brazil, p. 659–669. ` , P., AND R. W. SCHRIER. 2009. Renal failure in cirrhosis. New GINES England Journal of Medicine 361: 1279–1290. HARTLEB, M., AND K. GUTKOWSKI. 2012. Kidneys in chronic liver diseases. World Journal of Gastroenterology 18: 3035–3049. KAMATH, P. S., R. H. WIESNER, M. MALINCHOC, W. KREMERS, T. M. THERNEAU, C. L. KOSBERG, G. D’AMICO, E. R. DICKSON, AND W. R. KIM. 2001. A model to predict survival in patients with end-stage liver disease. Hepatology 33: 464–470.
247
KASHTAN, J., J. F. GREEN, E. Q. PARSONS, AND J. W. HOLCROFT. 1981. Hemodynamic effect of increased abdominal pressure. Journal of Surgical Research 30: 249–255. MAGUIRE, J. H. 2010. Trematodes (schistosomes and other flukes). In Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, 7th ed., G. L. Mandell, J. E. Bennett, and R. Dolin (eds.). Churchill Livingstone Elsevier, Philadelphia, Pennsylvania, p. 3595– 3605. ¸ ˜ o em Nefrologia MARTINELLI, R., AND H. ROCHA. 1996. Revisa˜o/Atualizaca Cl ´ınica: Envolvimento glomerular na esquistossomose mansonica. ˆ Jornal Brasileiro de Nefrologia 18: 279–282. ´ ´ DA SAUDE (BRAZILIAN MINISTRY OF HEALTH). SECRETARIA DE MINISTERIO ˆ ´ ´ VIGILANCIA EM SAUDE . 2010. Guia de vigilancia ˆ epidemiologica, 7th ´ ed. Ministerio da Saude, ´ Bras ´ılia, 813 p. PELTEKIAN, K. M., F. WONG, P. P. LIU, A. G. LOGAN, M. SHERMAN, AND L. M. BLENDIS. 1997. Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites. American Journal of Gastroenterology 92: 394–399. PUGH, R. N., I. M. MURRAY-LYON, J. L. DAWSON, M. C. PIETRONI, AND R. WILLIAMS. 1973. Transection of the oesophagus for bleeding oesophageal varices. British Journal of Surgery 60: 646–649. RESENDES, A. P. C., S. R. SOUZA, AND C. S. BARBOSA. 2005. Hospitalization and mortality from mansoni schistosomiasis in the State of Pernambuco, Brazil, 1992/2000. Cadernos de Saude ´ Publica ´ 21: 1392–1401. RODRIGUES, V. L., A. OTONI, I. VOIETA, C. M. ANTUNES, AND J. R. LAMBERTUCCI. 2010. Glomerulonephritis in schistosomiasis mansoni: A time to reappraise. Revista da Sociedade Brasileira de Medicina Tropical 43: 638–642. ROSS, A. G. P., P. B. BARTLEY, A. C. SLEIGH, G. R. OLDS, Y. LI, G. M. WILLIAMS, AND D. P. MCMANUS. 2002. Schistosomiasis. New England Journal of Medicine 346: 1212–1220. ` , P. GINES ` , C. PIERA, W. JIMENEZ ´ , M. GUEVARA, G. SALO´ , J., A. GINES FERNA´NDEZ-ESPARRACH, P. SORT, R. BATALLER, V. ARROYO, ET AL. 1997. Effect of therapeutic paracentesis on plasma volume and transvascular escape rate of albumin in patients with cirrhosis. Journal of Hepatology 27: 645–653. SILVA JUNIOR, G. B., D. B. DUARTE, E. J. G. BARROS, AND E. F. DAHER. 2013. Schistosomiasis-associated kidney disease: A review. Asian Pacific Journal of Tropical Disease 3: 79–84. VAN VELTHUYSEN, M. L. F. 1996. Glomerulopathy associated with parasitic infections. Parasitology Today 12: 102–107.
