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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
RENAL DATA FROM ASIA-AFRICA  
Year : 2012  |  Volume : 23  |  Issue : 6  |  Page : 1320-1330
Evaluation of microalbuminuria in relation to asymptomatic bacteruria in Nigerian patients with sickle cell anemia


1 Department of Biochemistry and Nutrition, Nigerian Institute of Medical Research, Yaba, Nigeria
2 IRU PHC, Victoria Island, Nigeria
3 Department of Biochemistry, Lagos State University, PMB 1087, Apapa, Nigeria
4 Maternal and Child Health Complex, General Hospital, Ikorodu, Lagos, Nigeria

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Date of Web Publication17-Nov-2012
 

   Abstract 

Studies have identified microalbuminuria (MA) and asymptomatic bacteruria (ASB) as co-morbid factors in sickle cell anemia (SCA). However, the relationship between these comorbid factors remains unclear and data are lacking for Nigerian patients. This study determined the prevalence of MA and ASB in a cohort of patients with SCA in a steady state, in Lagos, Nigeria. Early morning mid-stream urine samples were collected in sterile bottles from 103 patients comprising 48 males and 55 females with a mean age of 10.4 years. Aerobic culture and colony count of organisms was done using conventional methods. Serum creatinine and hematological indices, including irreversibly sickled cells (ISC), were also assayed. Of the 103 urine samples screened, 23 (22.3%) had albuminuria (ALB), and consisted of nine males and 14 females (P > 0.05); 16.5% of the cases had MA (P <0.05). Age at onset of MA was seven years, and children accounted for 23.5% of all cases with ALB (P >0.05). The prevalence of confirmed ASB was 14.6%, with females accounting for 14 of 19 probable ASB cases (P <0.05). Univariate regression analysis demonstrated a significant (P <0.05) association between age at onset of MA, hemoglobin level, reticulocyte count, ISC and occurrence of ASB, but with only ISC evolving as an independent predictor. Twenty-eight bacterial isolates predominated by Escherichia coli (39.3%; P <0.05), of whom 89.3% were multi-drug resistant, were recovered from the ASB urine samples. In conclusion, both MA and ASB are common in Nigerian SCA patients, with the former occurring from the first decade of life.

How to cite this article:
Iwalokun B A, Iwalokun S O, Hodonu S O, Aina O A, Agomo P U. Evaluation of microalbuminuria in relation to asymptomatic bacteruria in Nigerian patients with sickle cell anemia. Saudi J Kidney Dis Transpl 2012;23:1320-30

How to cite this URL:
Iwalokun B A, Iwalokun S O, Hodonu S O, Aina O A, Agomo P U. Evaluation of microalbuminuria in relation to asymptomatic bacteruria in Nigerian patients with sickle cell anemia. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2014 Sep 1];23:1320-30. Available from: http://www.sjkdt.org/text.asp?2012/23/6/1320/103589

   Introduction Top


Sickle cell anemia (SCA) remains significant as a cause of morbidity and mortality among the Africans, Arabs and people from the Meditteranean. [1],[2] In Africa, Nigeria bears the greatest brunt of the disease, with a prevalence rate of 2%; 150,000 children are affected by SCA per annum, and the carrier rate of sickle cell trait is 25%. [3],[4] SCA is characterized by sickling-induced chronic hemolysis and episodic vaso-occlusive crisis (VOC) that result in intermittent cessation and restoration of blood flow in the vasculature of virtually all the organs of the body. [5] In patients with SCA, the kidney has been established as a potential target for VOC, leading to a decline in kidney function. [6],[7] This has been attributed to anemia and physiological conditions of relative hypoxia, acidosis and hypertonicity of the renal medulla. [8] These factors enable sickling and hyperfiltration of the glomerulus that may lead to glomerular hypertrophy, necrosis and loss of vasa recta, causing impaired urinary concentrating ability, an incomplete tubular acidosis and altered potassium secretion. [9],[10] Microalbuminuria (MA), defined as an abnormal urinary excretion of albumin between 30 and 300 ug/day or urinary albumin concentration between 20 and 200 ug/mg creatinine, [11] is well established as a prominent indicator of incipient renal damage. [12],[13] The prevalence of proteinuria has been estimated to be 20-25%, and decreased renal function has been found in 5- 30% of SCA patients. [14] In the USA, close to 1% of new cases of end-stage renal disease are accounted for by sickling-induced nephropathy in SCD patients. [15] Early detection of MA is therefore crucial for the prevention of severe kidney injury and renal failure in SCA patients.

The classical immune deficit in SCD patients has also made them vulnerable to urinary tract infections (UTI) that are preceded by asymptomatic bacteruria (ASB). [16] ASB is defined as a urinary growth of bacteria with a colony count greater than 10 5 units per milliliter of urine without symptoms of UTI. [17] It has been established as a risk factor of UTI and has been associated with increased incidence of pyelonephritis, cystitis, urethritis, pre-term delivery and low birth weight in pregnant women and diabetics. [16],[17],[18] In the context of sickle cell disease, few studies have provided evidence that identify ASB as a pre-disposing factor to UTI and sickle cell crisis in patients from Africa, Asia and America. [16],[19],[20] Investigators also believe that presence of albumin in urine is expected to enhance bacterial growth and cause bacteruria. [21] By this expectation, MA and ASB may co-exist as subclinical conditions in UTI-vulnerable SCD patients.

A search of the literature indicates that there is paucity of data on MA and asymptomatic bacteruria in Nigerian patients with SCA. [22],[23] The relationship between these sub-clinical conditions and risk factors are also not known. In this study, a cohort of SCD patients in a stable state was screened for MA and ASB. The relationship between these sub-clinical conditions was studied and the impact of hematological indices as risk factors was investigated.


   Materials and Methods Top


Study design and patients

This is a cross-sectional study of patients with SCA who were being followed-up at four medical centers in Lagos State, Nigeria. The study sites included Lagos University Teaching Hospital (LUTH), Lagos State University Teaching Hospital (LASUTH), Maternal and Child Health Health Complex, General Hospital and Ikorodu and Iru Primary Health Centre (Iru PHC). The patients were enrolled in the steady state of the disease between December 2008 and April 2009. Prior to enrollment, the ptients were clinically examined to ascertain their steady state. Patients presenting with crisis or history of crisis and those with clinical symptoms of UTI at presentation or history of UTI during or two weeks prior to clinic visit were excluded from the study. Also excluded from the study were those with protenuria, glucosuria and ketonuria by the dipstick method as well as those with pregnancy and systolic and diastolic pressures equal to or greater than 140 and 90 mmHg, respectively. A patient was classified as being in a steady state if any of the following clinical conditions were absent: painful bone crisis, severe anemia, laboratory diagnosis of bacteremia, acute chest syndrome, aplastic anemia, splenic sequestration and behaviors such as anxiety and hallucination. [24] To participate in the study, a written informed consent was obtained from each patient after the study protocol was approved by the Ethical Committee of the Hospital Management Board, Lagos State, Nigeria. SCD-HbSS was the status of each patient, which was confirmed based on a positive sickling test [25] and cellulose acetate electrophoresis of βs -hemoglobin at pH 8.6 compared with the controls: HbAA, HbAS, HbSS and HbSC. [26] The patients' case files were reviewed for age, sex, number of pain episodes in the last one year and number of blood transfusions received.

Laboratory analysis

Each patient provided two random spot midstream urine samples (MSU-1 and MSU-2) that were collected aseptically into separate sterile bottles and labeled. MSU-1 and MSU-2 were assayed immuno-turbidometrically for urinary albumin concentration (UAC) using Randox Microalbuminuria (RANDOX Laboratories, UK) with intra- and inter-assay coefficients of variation of 2.17-4.78 at 11.6-142.8 mg/L UAC. Each assay was run in duplicates and results obtained were averaged. Normo-albuminuria was defined as UAC <17 mg/L, MA as UAC 17-174 mg/L and macroalbuminuria as UAC >174 mg/L. [11] MSU-1 was cultured by spread plating 2 μL aliquot of sample on MacConkey and 5% sheep blood agar plates. The inoculated plates were subsequently incubated aerobically at 37°C for 24 h. A growth-positive plate was significant if it yielded a count equal to or above 10 5 colony forming units (cfu) per milliliter of urine of not more than two organisms. [16] Positive plates due to more than two organisms were said to be contaminated and thus repeated.

MSU-1 plates yielding >10 5 cfu/mL counts represented cases of probable ASB. Antibiotic susceptibility testing was done for pure isolates from MSU-1 plates with probable ASB using disk diffusion assay with zone of inhibition interpreted according to the National Committee on Clinical Laboratory Standards. [27] The single antibiotic disk used from Oxoid (UK) were ciprofloxacin (Cip), 5 μg; ceftazidime (Caz), 30 μg; cefotaxime (Cef), 30 μg; ceftriaxone (Ctx), 30 μg; gentamicin (Gen), 25 μg; nitrofurantoin (Nit), 200 μg; co-trimoxazole (Cot), 30 μg and ampicillin (Amp), 30 μg. All probable ASB cases were confirmed by analysis of their paired MSU-2 samples. Confirmation was indicated by the presence of ASB due to the same UTI pathogens recovered in the MSU-1 sample with similar antibiogram. [16]

Venous blood samples were collected from the patients into appropriate tubes and used for hematocrit and hemoglobin determination. [25],[26] Aliquots of blood samples (20 μL each) were lysed in the volume ratio 1:20 with Turk's solution (2% glacial acetic acid in water plus gentian violet) and 1% ammonium oxalatae in the ratio 1:100 with Tommasson solution (NaCl, 1 g; Na 2 SO 4 , 8 g; glycerol, 20 mL; distilled water, 160 mL) for the determination of total leukocyte, platelets and erythrocyte counts. [28] The cells were counted using an improved Neubauer Hematocytometer at ×40 magnification. Reticulocyte counts were performed on blood films pre-stained with brilliant cresyl blue supravital stain for 5 min and expressed as a percentage of 200 nucleated and non-nucletaed erythrocytes counted in four to five fields. Irreversible sickle cells (ISC) were also examined microscopically (at ×100 magnification) on another Leishman's stained blood film and expressed as a percentage of total number of erythrocytes counted. [29] Hemoglobin F level in percentage was determined manually using the protocol of Betke as described by Dacie and Lewis. [30] Serum creatinine was assayed using the alkaline picrate method.


   Statistical Analysis Top


Data expressed as mean ± SD and percentages (%) were analyzed using SPSS version 7.5.2 for Windows (SPSS Inc., Chicago, IL, USA). SCA patients with and without albuminuria were compared regarding their hematological and biochemical parameters using Student's t test. Disparity between frequency values (n) was evaluated using the Chi-square (χ2) test. The relationship between MA (based on MSU-albumin level), age and hematological indices was analyzed by univariate regression. Multi-variate regression models were used to determine independent determinants of MA and incidence of ASB in the HBSS patients. Outcomes with probability (P) value <0.05 were considered to be significant.


   Results Top


A total of 103 patients with SCA, consisting of 48 males and 55 females, were studied. They were further stratified into children (6- 12 years), adolescents (13-19 years) and adults (20 years and above) [Figure 1]. Twenty-three patients had albuminuria, yielding a prevalence rate of 22.3%; of them, 17 (16.5%) had MA and six (5.8%) had macroalbuminuria. MA was found in all age groups as follows: children (n = 4, 3.9%), adolescents (n = 6, 5.8%) and adults (n = 7, 6.8%) (P > 0.05), [Table 1], [Figure 2]. The age at onset of albuminuria was seven years (results not shown), but cases of macroalbuminuria were not seen in the children studied.
Figure 1: Age and sex group distribution of the sickle cell anemia patients studied.

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Figure 2: Pattern of albuminuria and bacteruria in relation to age among the sickle cell anemia patients.

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Table 1: Demographic and laboratory analysis of the Nigerian sickle cell anemia patients with and without albuminuria.

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Significant differences (P < 0.05) were observed between patients with albuminuria and those without albuminuria in their mean number of irreversibly sickled cells (ISC 7.4 ± 0.4% vs. 4.4 ± 0.1%), reticulocyte counts (RC, 8.7 ± 0.1% vs. 7.1 ± 0.2%), PCV (24.7 ± 0.3% vs. 26.8 ± 0.5%) and serum creatinine (0.78 ± 0.04 mg/dL vs. 0.51 ± 0.02 mg/dL), with the risk of ASB being 6.1-11.5 times higher in patients with albuminuria relative to those without albuminuria. However, disparity in the levels of measured parameters including fetal hemoglobin (HbF) level and leukocyte count between the two sickle cell groups was found to be non-significant (P >0.05).

Further analysis showed that albuminuria elicited a significant (P < 0.05) positive correlation (r = 0.51-0.65) with age, number of ISC and serum creatinine concentration and negative correlation [r = -0.42-(-0.52)] with hemoglobin (Hb) concentration and the hematocrit (PCV), while association with RC was not significant (r = -0.24; P >0.05) [Table 2]. Of these significantly associated parameters, only ISC was found by multivariate regression model to be an independent predictor of albuminuria in the sickle cell patients [Table 3]. Of the 103 urine samples analyzed, 19 grew bacteria significantly to yield a prevalence rate of 18.4% for probable ASB, of which 15 were confirmed ASB (prevalence rate of 14.6%). A total of 28 isolates belonging to eight genera of gram positive and gram negative bacteria were recovered from these urine samples with ASB. The isolates were predominated by Escherichia coli (11 of 28 isolates, 39.3%; P <0.05). In decreasing order of occurrence, other isolates were Proteus mirabilis (17.9%), Enterobacter cloaceae (10.7%), 7.1% each of the gram positive strains of Staphylococus saprophyticus and Enterococcus sp. as well as gram negative strains of Serratia marcescens and Pseudomonas aeruginosa and 3.6% each of Citrobacter freundii and Klebsiella pneumoniae.
Table 2: Univariate regression analysis of demographic and laboratory variables associated with albuminuria among the sickle cell anemia patients studied.

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Table 3: Multiple regression analysis of demographic and laboratory variables as predictors of albuminuria among the sickle cell anemia patients studied.

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The uropathogens were tested against nine antibiotics and results indicated that they displayed high resistance to ampicillin and cotrimoxazole (89.3-100%), mild to moderate resistance to augmentin, ceftriaxone, cefuroxime and ceftazidime (32.1-57.1) and very low resistance of 7.1% (due to Pseudomonas aeruginosa strains alone) to ciprofloxacin. All the isolates were sensitive to nitrofurantoin [Table 4]. Further analysis differentiated the uropathogens into 11 resistance patterns, with 10.7% and 89.3% of the isolates resistant to one and two or more antibiotics, respectively [Table 5] and [Table 6].
Table 4: Percentage resistance and sensitivity to antibiotics of the pathogens recovered from urine samples with asymptomatic bacteruria.

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Table 5: Antibiotic resistance pattern of pathogens isolated from cases with asymptomatic bacteruria.

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Table 6: Summary of the number of antibiotics to which the uropathogens isolated from asymptomatic bacteruria cases were resistant in the sickle cell anemia patients.

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The presence of ASB in relation to age indicted that age 20 years and above accounted for 15 of the 28 (53.6%) positive cases, while nine (32.1%) isolates were recovered from the 13-19 years age-group. The remaining four cases belonged to the age-group six months to 12 years, and represented cases of probable ASB that were not confirmed due either to new bacterial profile or antibiogram [Table 7].
Table 7: Distribution of pathogens isolated from urine samples with asymptomatic bacteruria in relation to age.

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The occurrence of ASB in relation to gender is shown in [Table 8]. Females accounted for 14 of the 19 (P <0.05) probable and 11 of the 15 (P >0.05) confirmed ASB cases compared with their male counterparts.
Table 8: Comparative analysis of asymptomatic bacteruria by gender among the sickle cell anemia patients.

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   Discussion Top


Nephropathy is a common complication in patients with SCA, which is heralded by the occurrence of MA and, in the absence of early intervention, progresses to end-stage renal disease. [14],[15] The results of this study indicate that both MA and ASB, as sub-clinical conditions in SCA, exist in Nigerian patients and relate significantly with each other and other classical hematological risk factors of crisis in SCA. Our observed prevalence rate of MA of 16.8% is similar to the findings of Becton et al, [31] Alvarez et al [32] and Acknoundou-N'Guessen et al. [33] The workers reported prevalence rates of 15.8%, 15.8% and 17.3% in separate cohorts of SCA patients in the USA, Spain and Cote D'Voire. However, higher prevalence rates of MA of 18.8-26.5% have also been found by other investigators. [34]-[38] Our findings, compared with others, suggest that the occurrence of MA in SCA patients is heterogeneous in frequency and may be influenced by varied prevailing risk factors in the different SCA populations. MA is a marker of less severe pore size and charge selectivity damage of the renal glome-rulus and forewarns a subsequent development of renal failure in SCA patients. [39] In this study, MA was found in all age-groups, with children accounting for 3.9% of the cases. Although this rate is lower than findings from other related pediatric SCA studies, [35],[37] it indicates potential early development of nephropathy in Nigerian SCA children. The possibility that this rate is underestimated because of small sample size (28 of 103 patients) cannot be ruled out. Most of the pediatric studies on MA found in the literature employed sample sizes that were greater than ours, and some were longitudinal studies in addition. [34],[36],[37],[38]

The age at onset of MA found in this study was seven years. This is in consonance with related studies from other parts of the world, with the exception of the study carried out by Marsenic et al, [35] in which the age at onset of MA was four years. The incidence of MA in older SCA age-groups has been well reported [16],[33],[38] and can be explained by the fact that the number of recurrent VOC in the renal glomerulus increases with age, posing greater risk for the development of MA.

The absence of macroalbuminuria in our SCA children implies non-detection of severe pore size selectivity damage in this age-group. [40] This is in contrast to the findings of Acknoundou-N'Guessen et al [33] and Marsenic et al. [35]

In this study, we found that albuminuria correlated positively with age, serum creatinine and percentage of ISC, but negatively with PCV. Our findings thus identify these parameters as risk factors for albuminuria in this environment. Previous studies have consistently showed anemia characterized by lower hematocrit or Hb <10 g/dL as a risk factor of MA in SCA patients. [31],[32],[33],[34],[36] However, discrepancy exists in the recognition of age as a risk factor of MA; some studies found that age correlated with MA, [32],[35],[36],[37],[38] while others did not. [33] The observation of ISC and serum creatinine as correlates of MA further confirms that SCA patients with MA are at a higher risk of sickling-induced renal abnormalities compared with those without MA. The identification of ISC as an independent marker of MA suggests that other risk factors may not individually provoke MA in the absence of a pathologic level of ISC.

It has been estimated that renal failure occurs in 4.2% of SCA patients, [41] with an increase to 18% in patients with MA, [42] with death occurring about four years after its onset, [43] at a reported mean age of 27-40 years. [43],[44] Therefore, early detection of MA in SCA patients is critical for the implementation of measures that would revert it and inhibit its progression to renal failure. This will subsequently improve the quality of life and enhance the longevity of SCA patients.

Furthermore, we also identified ASB as a correlate of albuminuria in our cohort, suggesting that this parameter may play a potential role in the development of MA in Nigerian SCA patients. In previous studies carried out outside Nigeria, there have been concerns that ASB may affect screening for MA and that there is a high possibility of ASB co-existing with MA, which together may accelerate progression of nephropathy in diabetic and hypertensive patients as well as patients with ventricular dysfunction. [16],[45],[46] In this context, identification of pathogens responsible for ASB and an understanding of the antibiotic susceptibility profile of such pathogens is crucial to the implementation of appropriate therapeutic measures and prevention of ASB in SCA patients. In this study, we isolated 28 pathogens from 19 bacteruric samples, with E. coli being the predominant pathogen. Our findings therefore raise the possibility of a potential UTI in our infected SCA patients, as E. coli is a major uropathogen in the general population. [47],[48],[49] In other studies as well, E. coli was recovered as the major pathogen. However, pathogens such as microaerophillic Streptococcus, Bacteroides (mixed) and Streptococcus viridans (mixed) reported by Cummings et al [16] were not found in our bacteruric samples. In contrast, pathogens such as Staphylococcus saprophyticus and Citrobacter freundii detected in this study were not reported by Cummings et al. [16] This disparity may be a reflection of different infectious disease epidemiology in the two populations. However, our results are similar to the etiologic pattern of ASB pathogens reported by Akinloye et al [48] and Okonko et al [49] in separate populations in Nigeria, sug-gesting similar endemic patterns of agents of bacteruria in Nigeria. An exception to this is the different antibiotic susceptibility pattern reported by the investigators. Unlike our isolates, Akinloye reported a high sensitivity of their isolates to ceftazidime and ceftriaxone, while the pathogens recovered in the study by Okonkon et al [49] were sensitive to nalidixic acid. The disparity observed in the antibiogram of these bacteruric agents may be due to the different pattern of antibiotic use and levels of exposure offered by the environment. Although the Nigerian bacteruric cases referenced in this study were hospital based, they involved preg-nant women who accidentally share vulnerability to ASB, like the SCA patients. Nevertheless, like other investigators, we observed a high level of sensitivity of the bacteruric pathogens to nitro-furantoin. Our isolates also exhibited a high level of sensitivity to ciprofloxacin, while sensitivity to cefotaxime was moderate. Therefore, these antibiotics may be of therapeutic importance in the treatment of ASB in SCA patients in this environment. However, their use, especially cefotaxime and ciprofloxacin, should be based on the antibiotic susceptibility outcome as the levels of resistance to these antibiotics are currently on the increase in the general population. [47] Furthermore, the high rate of multi-drug resistant (MDR) ASB observed in this study is now a common phenolmenon in Nigeria and other countries of the world. [16],[47],[48],[49],[50] Therefore, continuous surveillance of MDR in bacteruria and monitoring of drug susceptibility patterns of pathogens are needed for better control and management of ASB in the general population.

Based on the findings in this study, screening of SCA patients from childhood for albuminuria, ASB and hemotological indices beyond PCV is recommended in this environment.

 
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Correspondence Address:
B A Iwalokun
Biochemistry and Nutrition Division, Nigerian Institute of Medical Research, PMB 2013 Yaba, Lagos
Nigeria
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DOI: 10.4103/1319-2442.103589

PMID: 23168877

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