"Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has."

Margaret Mead
Original article
peer-reviewed

Prevalence and Risk Factors for Microalbuminuria in Children with Sickle Cell Disease at King Abdulaziz University Hospital: A Retrospective Cross-sectional Study



Abstract

Objectives: Previous studies have not addressed microalbuminuria in pediatric patients with sickle cell disease (SCD) in Jeddah, Saudi Arabia. This study aimed to determine the prevalence of microalbuminuria and to identify associated risk factors in children with SCD at King Abdulaziz University Hospital.

Results: Overall, 42.5% of the patients enrolled were Saudi Arabian and 51% were male. The mean age was 12.4 years, and the highest percentage (40%) was in the age group of 15-18 years. The prevalence of microalbuminuria was 9.6%, and hematuria was present in 8% of cases. The percentage of patients with hematuria was significantly higher in the microalbuminuria group (22.6%) than in the nonmicroalbuminuria group (6.5%; P = 0.007). The percentage of patients with acute chest syndrome was also higher in the microalbuminuria group (26%) than in the nonmicroalbuminuria group (8%; P = 0.005). The percentage of patients with gallbladder stones was higher in the microalbuminuria group (13%) than in the nonmicroalbuminuria group (2.4%; P = 0.014). However, the mean number of blood transfusions was higher in the nonmicroalbuminuria group than in the microalbuminuria group (P = 0.002). Sickle cell nephropathy manifests as microalbuminuria, begins at an early age, occurs in all types of SCD, and is associated with disease severity.

Introduction

Sickle cell disease (SCD) is one of the most important autosomal recessive diseases. In the Kingdom of Saudi Arabia (KSA), the prevalence of the sickle cell trait ranges from 2% to 27%, and as many as 2.6% of affected individuals develop SCD. SCD is characterized by vaso-occlusive events, hemolytic crises, and organ damage [1].

Renal impairment is a chronic complication of SCD and a major factor associated with mortality [2]. This association with mortality is stronger than that observed with an episode of acute stroke, a febrile episode with positive blood culture, acute chest syndrome, or severe acute anemia [3].

In SCD, microalbuminuria is one of the most common clinical manifestations of sickle cell nephropathy (SCN) [4-5], which appears to be associated with a more rapid deterioration in renal function [6]. The reported incidence of microalbuminuria in children with SCD ranges from 18.4% to 46% [7-9]. The identification of microalbuminuria in a patient with SCD is a predictor of end-organ disease, including renal damage [10-11]. Children with SCD experience hyperfiltration and hyperperfusion, which are associated with renal damage [12-13]. Therefore, the early detection of microalbuminuria may represent an important early sign of renal disease [14].

A prolonged period of microalbuminuria precedes persistent proteinuria, which is followed by renal failure in SCD patients [15]. Therefore, the identification of risk factors for microalbuminuria may allow earlier intervention to prevent renal complications [7]. The KSA faces a high burden of SCD, with a prevalence rate of 2.6% in newborns in a population of >24 million, and children with SCD are prone to developing microalbuminuria and chronic renal failure with advancing age. Nevertheless, previous research in the KSA has not addressed this problem. Therefore, this study aimed to determine the prevalence of microalbuminuria in children with SCD and to identify the risk factors associated with microalbuminuria in children with SCD at King Abdulaziz University Hospital (KAUH).

Materials & Methods

The study was approved by the institutional review board of the KAUH (reference number: 186-19). This cross-sectional prevalence study retrospectively reviewed medical records of children aged 2-18 years who were diagnosed with SCD and visited the KAUH Pediatric Sickle Cell Clinic.

The following data were obtained from recent outpatient follow-up visits: sex, age, nationality, weight, height, ABO blood group type, sickle cell genotype, blood transfusion (BT) status, and number of transfusions. Additionally, the frequencies of vaso-occlusive events and SCD complications were collected.

From the urinalysis results, microalbuminuria was defined as a protein level of >1+. Hematuria was defined as a RBC count >5.

Statistical analysis

Descriptive statistics was used to assess the study participants’ demographic characteristics. Means ± standard deviations (SDs) and median values were used to describe continuous variables. Frequencies with proportions are used to report categorical variables. Numerical variables were compared between groups using the independent t-test, whereas categorical variables were compared using the chi-square and Fisher’s exact tests. Statistical significance was set at a P value <0.05. All statistical analyses were performed using IBM SPSS statistics, version 23 (IBM, Armonk, NY, USA).

Results

The prevalence of microalbuminuria and its associated factors were assessed in 322 pediatric patients with SCD. The patients' characteristics are presented in Table 1.

Variable n Percentage
Nationality
Non-Saudi Arabian 185 57.5
Saudi Arabian 137 42.5
Gender
Female 157 48.8
Male 165 51.2
Age group
2 to 5 years 30 9.3
6 to 10 years 87 27.0
11 to 14 years 77 23.9
15 to 18 years 128 39.8
Sickle cell genotype
Hemoglobin SB 0 (Beta-zero) thalassemia 4 1.2
Hemoglobin SB+ (beta) thalassemia 41 12.7
Hemoglobin SS disease (sickle cell disease) 233 72.4
Sickle cell trait (hemoglobin S disease) 44 13.7
Microalbuminuria
No 291 90.4
Yes 31 9.6
Hematuria
No 296 91.9
Yes 26 8.1
Blood type
A RhD negative (A-) 3 0.9
A RhD positive (A+) 84 26.1
AB RhD positive (AB+) 15 4.7
B RhD negative (B-) 3 0.9
B RhD positive (B+) 32 9.9
O RhD negative (O-) 9 2.8
O RhD positive (O+) 176 54.7
Blood transfusions
No 143 44.4
Yes 179 55.6
Frequency of:
Pneumonia 30 9.3
Priapism 3 0.9
Avascular necrosis 3 0.9
Acute chest syndrome 31 9.6
Aplasia 2 0.6
Stroke 14 4.3
Acute coronary syndrome 10 3.1
Dactylitis 3 0.9
Spleen sequestration 24 7.5
Gallbladder stones 11 3.4
Osteomyelitis 23 7.1
  Mean SD Median
Age (years) 12.43 4.64 13.00
Number of blood transfusions 8.67 26.71 1.00

The characteristics of the nonmicroalbuminuria (291 patients) and microalbuminuria group (31 patients) and comparisons of different variables between the groups are shown in Table 2. The prevalence of hematuria differed significantly between the groups, and was higher in the microalbuminuria group than in the nonmicroalbuminuria group (P = 0.007). However, a significant difference was observed in the distribution of blood groups (P = 0.022). The percentage of acute chest syndrome was significantly higher in the microalbuminuria group than in the nonmicroalbuminuria group (P = 0.005). The percentage of gallbladder stones was significantly higher in the microalbuminuria group than in the nonmicroalbuminuria group (P = 0.014). The mean number of BTs was higher in the nonmicroalbuminuria group than in the microalbuminuria group (P = 0.002). No other variables differed significantly between the groups.

    Without microalbuminuria (n=291) With microalbuminuria (n=31) P-value
n % n %
Nationality
Non-Saudi Arabian 167 57.4 18 58.1 0.942
Saudi Arabian 124 42.6 13 41.9
Sex
Female 144 49.5 13 41.9 0.424
Male 147 50.5 18 58.1
Age group
2 to 5 years 27 9.3 3 9.7 0.432
6 to 10 years 82 28.2 5 16.1
11 to 14 years 70 24.1 7 22.6
15 to 18 years 112 38.5 16 51.6
Sickle cell genotype
Hemoglobin SB 0 (beta-zero) thalassemia 4 1.4 0 0.0 0.928
Hemoglobin SB+ (beta) thalassemia 37 12.7 4 12.9
Hemoglobin SS disease (sickle cell disease) 210 72.2 23 74.2
Sickle cell trait (Hemoglobin S disease) 40 13.7 4 12.9
Hematuria
No 272 93.5 24 77.4 0.007*
Yes 19 6.5 7 22.6
Blood type
A RhD negative (A-) 2 0.7 1 3.2 0.022*
A RhD positive (A+) 75 25.8 9 29.0
AB RhD positive (AB+) 10 3.4 5 16.1
B RhD negative (B-) 3 1.0 0 0.0
B RhD positive (B+) 31 10.7 1 3.2
O RhD negative (O-) 9 3.1 0 0.0
O RhD positive (O+) 161 55.3 15 48.4
Blood transfusions
No 131 45.0 12 38.7 0.502
Yes 160 55.0 19 61.3
 Frequency of:
Pneumonia 28 9.6 2 6.5 0.752
Priapism 3 1.0 0 0.0 1
Avascular necrosis 3 1.0 0 0.0 1
Acute chest syndrome 23 7.9 8 25.8 0.005*
Aplasia 2 0.7 0 0.0 1
Stroke 14 4.8 0 0.0 0.377
Acute coronary syndrome 10 3.4 0 0.0 0.607
Dactylitis 3 1.0 0 0.0 1
Spleen sequestration 22 7.6 2 6.5 1
Gallbladder stones 7 2.4 4 12.9 0.014*
Osteomyelitis 20 6.9 3 9.7 0.474
  Without microalbuminuria With microalbuminuria P-value
Mean SD Median Mean SD Median
Age 12.29 4.62 12.00 13.74 4.68 15.00 0.098
Number of transfusions 9.26 27.97 1.00 3.13 5.60 1.00 0.002*

Discussion

Secondary renal failure affects 5%-20% of adult patients with SCD, and the progression of renal disorder begins in childhood [16]. Microalbuminuria is one of the earliest manifestations of SCN. Hence, many studies have aimed to determine the prevalence of microalbuminuria among SCD patients as an indicator of the severity of the condition [17-18]. In this study, we determined the prevalence of microalbuminuria of 9.6% among pediatric patients with a mean age of 12.4 years. This condition emerged at a very young age (2 years) and increased continuously to the highest percentage among young adults (15-18 years), who exhibited a prevalence of 51.6%. The mean age and average prevalence of microalbuminuria among older patients in our study were consistent with the prevalence rates of 46% as reported by Dharnidharka et al. [17] and of 39%-43% in adults with SCD as reported by McBurney et al. [7]. However, the overall prevalence of microalbuminuria among all patients (9.6%) was lower than the average prevalence reported by those previous studies. Alkhunaizi et al. [19] determined that the prevalence of microalbuminuria among adult Saudi Arabian patients (>18 years) was 25%, very similar to our findings in the same age group.

Dharnidharka et al. [17] and McBurney et al. [7] reported that no microalbuminuria was detected in children aged <7 years. Conversely, 9.7% of microalbuminuria patients in our study were aged 2-5 years. Our findings were supported by those of Aloni et al. [20] who confirmed the presence of microalbuminuria in patients aged <7 years. This early deterioration of glomerular function could be explained by the presence of certain factors, including a genetic predisposition, fetal hemoglobin (HbF) level, environmental factors, efficacy of medical care, and lifestyle factors associated with developing countries [21]. However, the small sample size in our study may also reasonably explain these contradictory results. The studies by Dharnidharka et al. [17] and by McBurney et al. [7] enrolled 104 and 151 patients, respectively. Interestingly, when we compared the microalbuminuria and nonmicroalbuminuria groups, we observed no significant difference in terms of age (P = 0.432), suggesting that this was not a defining variable in either group. Nevertheless, age was a defining variable in the progression of microalbuminuria in the affected group.

Previous publications have reported a female predominance of microalbuminuria. Eke et al. reported a microalbuminuria prevalence of 9.7% among female patients and 6.1% among male patients [5], while Okpere et al. [22] reported results consistent with female predominance (45.3% vs. 20.4% of males). We did not observe a significant difference in sex between the microalbuminuria and nonmicroalbuminuria groups in our study, consistent with the findings of McBurney et al. [7] and Dharnidharka et al. [17]. Consequently, additional research evidence is needed to clarify these contrasting results.

Our findings demonstrated that microalbuminuria occurs in association with most hemoglobin genotypes. The highest percentage was observed with the Hb-ss genotype (74.2%) in the microalbuminuria group, similar to the results of a previous study conducted by Wigfall et al. [23]. No microalbuminuria was detected in the HB-Sβ0 (Beta-Zero) thalassemia sub-group. Most previous studies included few patients with Sβ-thalassemia, and only a few studies have published mixed results regarding this patient group. Becton et al. [18] reported that only one patient with Sβ-thalassemia had microalbuminuria.

We further examined the frequencies of several clinical complications that may be associated with microalbuminuria (Table 2). We compared the microalbuminuria and nonmicroalbuminuria groups to identify definitive variables that varied significantly between the groups. Interestingly, we found that most patients in the microalbuminuria group experienced acute chest syndrome, gallbladder stones, osteomyelitis, pneumonia, and spleen sequestration, whereas none reported priapism, avascular necrosis, aplasia, stroke, acute coronary syndrome (ACS), or dactylitis. These findings were consistent with those reported by Dharnidharka et al. [17] and McBurney et al. [7] who observed no significant correlation between microalbuminuria and stroke and those of McBurney et al. [7] and Becton et al. [18] who reported no significant correlation with ACS. Our observation of a significant association between acute chest syndrome and microalbuminuria (P = 0.005) was consistent with the findings reported by Alvarez et al [24]. By contrast, Bodas et al. [25] reported that the glomerular filtration rate was not correlated with episodes of either stroke or acute chest syndrome, suggesting that the etiologies of these complications may differ from the etiologies underlying the development of SCN. However, that study included only 48 patients, and the relatively small sample size likely influenced the significant correlation between the two conditions.

We further identified a significant correlation between microalbuminuria and the development of gallbladder stones (P = 0.014). Our findings were consistent with those of Alexander-Reindorf et al. [26] and Bond et al. [27] who reported significantly higher morbidity and more hospital admissions among SCD patients with gallbladder stones. Additionally, the mean age in our microalbuminuria group was 13.74 years, consistent with the findings of Martins et al. [28] who reported patients of ages 11 and 29 years, with a higher prevalence of cholelithiasis and gallbladder stones respectively.

In our study, the number of BTs was significantly and negatively associated with microalbuminuria, suggesting that BTs are a renoprotective process in the management of SCD. Alvarez et al. [24] reported similar results and suggested that the early initiation of transfusion could protect the kidney and hinder deterioration of the SCN. However, the side effects of transfusion, such as iron overload, must be considered before starting this process. By contrast, Aloni et al. [20] reported that BT is not a significant factor with respect to microalbuminuria.

Becton et al. [18] stated that 36% of SCD patients presented with hematuria. However, the authors reported no significant difference in the frequency of hematuria between the microalbuminuria and nonmicroalbuminuria groups. By contrast, we observed a statistically significant difference in the frequency of hematuria between patients with and without microalbuminuria (P = 0.007). Our results were consistent with the findings of Sesso et al. [29] who reported higher frequencies of hematuria in the Hb-SS and Hb-AS groups. The authors stated that hematuria is caused by the increased sickling of RBCs in the renal medulla, resulting in extravasation and ischemia. We further determined that most patients with SCD had type O RhD+ blood and that this variable varied significantly between the two groups (P = 0.022). This result was consistent with the findings of Alagwu et al. [30] who reported an O blood group frequency of 63% among Hb-ss patients. This finding could be explained by the fact that the O Rh+ blood group is the most prevalent group in humans.

Conclusions

In conclusion, our findings highlight the importance of early investigations (e.g., urinalysis) for the assessment of microalbuminuria and hematuria, as well as the determination of the degree of SCN. The observation that the average number of BTs was significantly higher in the nonmicroalbuminuria group than in the microalbuminuria group could suggest a protective role of transfusion against the development of microalbuminuria. Nevertheless, further investigations are needed to confirm our results. We also reported significantly higher rates of acute chest syndrome and gallbladder stones in patients with microalbuminuria. These factors must be considered, and special care should be provided to affected patients. We recommend routine screening of SCD patients for microalbuminuria and hematuria.


References

  1. Jastaniah W: Epidemiology of sickle cell disease in Saudi Arabia. Ann Saudi Med. 2011, 31:289-293. 10.4103/0256-4947.81540
  2. Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C: Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore). 2005, 84:363-376. 10.1097/01.md.0000189089.45003.52
  3. Platt OS, Brambilla DJ, Rosse WF, et al.: Mortality in sickle cell disease--life expectancy and risk factors for early death. N Engl J Med. 1994, 330:1639-1644.
  4. Embury SH, Hebbel RP, Mohandas N, Steinberg MH: Sickle Cell Disease: Basic Principles and Clinical Practice. Raven Press, New York; 1994.
  5. Eke CB, Okafor HU, Ibe BC: Prevalence and correlates of microalbuminuria in children with sickle cell anaemia: experience in a tertiary health facility in Enugu, Nigeria. Int J Nephrol. 2012, 2012:240173. 10.1155/2012/240173
  6. Pham PT, Pham PC, Wilkinson AH, Lew SQ: Renal abnormalities in sickle cell disease. Kidney Int. 2000, 57:1-8.
  7. McBurney PG, Hanevold CD, Hernandez CM, Waller JL, McKie KM: Risk factors for microalbuminuria in children with sickle cell anemia. J Pediatr Hematol Oncol. 2002, 24:473-477.
  8. King L, MooSang M, Miller M, Reid M: Prevalence and predictors of microalbuminuria in Jamaican children with sickle cell disease. Arch Dis Child. 2011, 96:1135-1139. 10.1136/archdischild-2011-300628
  9. Ochigbo SO, Jacob UJ, Nlemadim AC, Kudirat OO: Comparative efficacy of serum ceatinine and microalbuminuria in detecting early renal injury in asphyxiated babies in Calabar, Nigeria. Int J Child Heal Nutr. 2016, 5:147-151.
  10. Motala AA: Micro-albuminuria in diabetes mellitus--significance and screening. S Afr Med J. 1998, 88:365-366.
  11. Mogensen CE: Microalbuminuria as a predictor of clinical diabetic nephropathy. Kidney Int. 1987, 31:673-689.
  12. Guasch A, Cua M, Mitch WE: Early detection and the course of glomerular injury in patients with sickle cell anemia. Kidney Int. 1996, 49:786-791.
  13. Etteldorf JN, Tuttle AH, Clayton GW: Renal function studies in pediatrics: I. Renal hemodynamics in children with sickle cell anemia. AMA Am J Dis Child. 1952, 83:185-191.
  14. Aoki RY, Saad ST: Microalbuminuria in sickle cell disease. Braz J Med Biol Res. 1990, 23:1103-1106.
  15. Foucan L, Bourhis V, Etienne-Julan M, Salmi RL: A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am J Med. 1998, 104:339-342.
  16. McKie KT, Hanevold CD, Hernandez C, Waller JL, Ortiz L, McKie KM: Prevalence, prevention, and treatment of microalbuminuria and proteinuria in children with sickle cell disease. J Pediatr Hematol Oncol. 2007, 29:140-144.
  17. Dharnidharka VR, Dabbagh S, Atiyeh B, Simpson P, Sarnaik S: Prevalence of microalbuminuria in children with sickle cell disease. Pediatr Nephrol. 1998, 12:475-478.
  18. Becton LJ, Kalpatthi RV, Rackoff E, Disco D, Orak JK, Jackson SM, Shatat IF: Prevalence and clinical correlates of microalbuminuria in children with sickle cell disease. Pediatr Nephrol. 2010, 25:1505-1511.
  19. Alkhunaizi AM, Al-Khatti AA, Alkhunaizi MA: Prevalence of microalbuminuria in adult patients with sickle cell disease in Eastern Saudi Arabia. Int J Nephrol. 2018, 2018:5015764.
  20. Aloni MN, Mabidi JL, Ngiyulu M, et al.: Prevalence and determinants of microalbuminuria in children suffering from sickle cell anemia in steady state. Clin Kidney J. 2017, 10:479-486.
  21. Hay SI, Gupta S, Weatherall DJ, Williams TN: Global burden of sickle cell anaemia in children under five, 2010 - 2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 2013, 10:1001484.
  22. Okpere AN, Anochie IC, Eke FU: Prevalence of microalbuminuria among secondary school children. Afr Health Sci. 2012, 12:140-147.
  23. Wigfall DR, Ware RE, Burchinal MR, Kinney TR, Foreman JW: Prevalence and clinical correlates of glomerulopathy children with sickle cell disease. J Pediatr. 2000, 136:749-753.
  24. Alvarez O, Montane B, Lopez G, Wilkinson J, Miller T: Early blood transfusions protect against microalbuminuria in children with sickle cell disease. Pediatr Blood Cancer. 2006, 47:71-76.
  25. Bodas P, Huang A, Riordan MAO, Sedor JR, Dell KM: The prevalence of hypertension and abnormal kidney function in children with sickle cell disease - a cross sectional review. BMC Nephrol. 2013, 14:237.
  26. Alexander-Reindorf C, Nwaneri RU, Worrell RG, Ogbonna A, Uzoma C: The significance of gallstones in children with sickle cell anemia. J Natl Med Assoc. 1990, 82:645-650.
  27. Bond LR, Hatty SR, Horn MEC, Dick M, Meire HB, Bellingham AJ: Gall stones in sickle cell disease in the United Kingdom. Br Med J (Clin Res Ed). 1987, 295:234-236.
  28. Martins RA, Soares RS, Vito FB, et al.: Cholelithiasis and its complications in sickle cell disease in a university hospital. Rev Bras Hematol Hemoter. 2017, 39:28-31.
  29. Sesso R, Almeida MA, Figueiredo MS, Bordin JO: Renal dysfunction in patients with sickle cell anemia or sickle cell trait. Braz J Med Biol Res. 1998, 31:1257-1262.
  30. Alagwu EA, Akukwu D, Uloneme GC: ABO/Rhesus blood group and correlation with sickle cell disease and type-ii diabetes mellitus in South East and South-South of Nigeria. UK J Pharma Biosci. 2016, 4:78-82.
Original article
peer-reviewed

Prevalence and Risk Factors for Microalbuminuria in Children with Sickle Cell Disease at King Abdulaziz University Hospital: A Retrospective Cross-sectional Study


Author Information

Yahya A. Alzahrani Corresponding Author

Pediatrics, King Abdulaziz University Hospital, Jeddah, SAU

Malak A. Algarni

Pediatrics, Family Medicine, Ibn Sina National College for Medical Studies, Jeddah, SAU

Maryam M. Alnashri

Pediatrics, King Abdulaziz University Hospital, Jeddah, SAU

Hanan M. AlSayyad

Pediatrics, King Abdulaziz University Hospital, Jeddah, SAU

Khadijah M. Aljahdali

Pediatrics, King Abdulaziz University Hospital, Jeddah, SAU

Joud E. Alead

Pediatrics, King Abdulaziz University Hospital, Jeddah, SAU

Yara A. Alhjrsy

Pediatrics, King Abdulaziz University Hospital, Jeddah, SAU

Fatma Alzahrani

Pediatrics, King Abdulaziz University Hospital, Jeddah, SAU

Osama Safdar

Pediatrics, King Abdulaziz University, Jeddah, SAU


Ethics Statement and Conflict of Interest Disclosures

Human subjects: Consent was obtained by all participants in this study. Unit of biomedical ethics at King Abdulaziz university issued approval 186-19. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.


Original article
peer-reviewed

Prevalence and Risk Factors for Microalbuminuria in Children with Sickle Cell Disease at King Abdulaziz University Hospital: A Retrospective Cross-sectional Study


Figures etc.

SIQ
-
RATED BY 1 READER
CONTRIBUTE RATING

Scholary Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. Learn more here.