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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 5  |  Page : 903-908
Proteinuria in adult Saudi patients with sickle cell disease is not associated with identifiable risk factors

Department of Medicine, Division of Hematology/Oncology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

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Date of Web Publication31-Aug-2010


Renal involvement in patients with sickle cell disease (SCD) is associated with signi­ficant morbidity and mortality. Proteinuria is common in patients with SCD and is a risk factor for future development of renal failure. We sought to identify risk factors, if any, associated with pro­teinuria in adult Saudi patients with SCD. We studied 67 patients with SCD followed-up at the King Khalid University Hospital, Riyadh, Saudi Arabia. All patients underwent 24-hour urine collection to measure creatinine clearance and to quantify proteinuria. In addition, blood was examined for evaluation of hematological and biochemical parameters. Clinical information was gathered from review of the patients' charts. A urine protein level of more than 0.150 grams/24 hours was consi­dered abnormal. Urine protein was correlated with various clinical and laboratory parameters. Thirty­one males and 36 females were evaluated. The mean age of the cohort was 23.8 (± 7.2) years. Twenty-seven patients (40.3%) had proteinuria of more than 0.150 grams/24 hours. The study group had a mean hemoglobin level of 8.5 (± 2.8) g/dL and mean fetal hemoglobin (HbF) level of 14.4% (± 7.3%). Majority of the patients (61) had hemoglobin SS genotype and six patients had S-β0 thala­ssemia. None of the parameters evaluated correlated with proteinuria although there was a border­line association with older age and higher systolic blood pressure (P = 0.073 and 0.061 respec­tively). Hydroxyurea use for more than a year was not beneficial. In conclusion, our study suggests that proteinuria in adult Saudi patients is not associated with any clear identifiable risk factors.

How to cite this article:
Aleem A. Proteinuria in adult Saudi patients with sickle cell disease is not associated with identifiable risk factors. Saudi J Kidney Dis Transpl 2010;21:903-8

How to cite this URL:
Aleem A. Proteinuria in adult Saudi patients with sickle cell disease is not associated with identifiable risk factors. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2022 May 22];21:903-8. Available from: https://www.sjkdt.org/text.asp?2010/21/5/903/68889

   Introduction Top

Sickle Cell Disease (SCD) is one of the most common genetic disorders worldwide as well as in Saudi Arabia. Sickle cell anemia is caused by a single base pair DNA mutation encoding the β-globin molecule, resulting in substitution of valine for glutamic acid at the sixth position of β-globin chain. SCD is characterized by chronic hemolysis with frequent vaso-occlusive crises. Various complications of SCD result from ab­normal shape (sickling) and deformability of red blood cells causing obstruction in the mic­rovasculature of different organs and premature destruction of red cells. Subsequent acute and chronic tissue ischemia leads to progressive or­gan damage. The kidney is particularly suscep­tible to sickling of red cells and hypoxic damage because of the hypertonic and acidic environ­ment of renal medulla. [1] Studies in pediatric pa­tients reveal that renal damage starts during child­hood years and continues throughout life. [2] Pro­longed glomerular hyperfiltration in SCD during childhood and early adult years leads to glome­rular injury resulting in glomerular sclerosis, proteinuria and progressive renal failure. [1],[3],[4]

Proteinuria is an early manifestation of sickle cell related renal disease and considered to be a risk factor for developing renal impairment in future. [5],[6],[7] We have previously shown that some of the serious complications of SCD like pul­monary hypertension (PHT) and proteinuria are common in Saudi patients originating from the South and South-Western provinces, but their clinical significance and prognostic value is not known. [8],[9] We conducted this study to identify any risk factors associated with proteinuria in adolescent and adult Saudi patients with SCD from the South and South-Western province in an attempt to study the patho-physiology of this potentially serious complication of SCD.

   Patients and Methods Top

Patients with SCD followed-up at adult hema­tology outpatient clinic, King Khalid University Hospital, Riyadh, were studied. These patients were originally recruited in a prospective study to identify renal abnormalities in SCD. Eligi­bility criteria included age 14 years or older and documented homozygous or compound hetero­zygous SCD. Patients were evaluated in steady state with no acute illness during two weeks prior to the assessment. All patients gave in­formed consent. Patients with sickle cell trait were excluded.

Twenty-four hour urine samples were collec­ted to measure creatinine clearance and to quan­tify proteinuria. Details of the methods of urine sample collection for proteinuria have been des­cribed previously. [9] Briefly, twenty-four hour urine sample collection was carried out from 8 am to 8 am next day according to the standard proto­col. Samples were analyzed for quantitative pro­teinuria and creatinine clearance. Protein excre­tion of more than 0.150 grams per 24-hours was considered abnormal. Clinical information was obtained from the patients' charts. All patients had blood extraction for measurement of hema­tological and biochemical parameters. Blood sam­ples were extracted within four weeks of urine sample collection. In some cases, blood sam­ples analyzed were taken more than four weeks apart from urine samples but an attempt was made to analyze samples collected only during steady state of the patients.

The following parameters were evaluated for correlation with proteinuria: age, gender, systo­lic and diastolic blood pressure, hydroxyurea use for more than one year, total hemoglobin (Hb), hematocrit, white blood cell (WBC) count, platelet count, mean corpuscular volume (MCV), reticulocyte count, blood urea nitrogen (BUN), serum creatinine, level of sickle (HbS) and fetal (HbF) Hb, total bilirubin, alanine aminotrans­ferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, serum albumin, lactate de­hydrogenase (LDH) and serum ferritin. Patients were divided into two groups for analysis; those with 24-hour urine protein level above 0.150 gram (proteinuria group) and the second group with protein level of less than 0.150 gram per 24-hours.

   Statistical Analysis Top

Statistical analysis for comparison of measure­ments was made using relevant tests with Sta­tistical Package for Social Sciences (SPSS, ver­sion 13.0) software. Subjects' data and different parameters are given as mean ± SD. A P value of < 0.05 was considered significant.

   Results Top

A total of 69 patients with SCD were eva­luated. Two patients with nephrotic range pro­teinuria and renal impairment were excluded from analysis. The study population consisted of 36 females (53.7%) and 31 males (46.3%) with a mean age of 23.8 (± 7.2) years. The study group had a mean Hb level of 8.5 (± 2.8) g/dL and a mean fetal Hb (HbF) level of 14.4% (± 7.3%). Majority of the patients (n = 61) had Hb SS genotype and six patients had S-β0 thala­ssemia. Twenty-seven patients (40.3%) had pro­teinuria of more than 0.150 grams/24-hours. The mean age of the proteinuria group was 25.7 (± 8.6) years while that of non-proteinuria group was 22.2 (± 6.6) years. There were equal num­ber of males (51%) and females (49%) in the proteinuria group.

The demographic, clinical and laboratory data of patients are summarized in [Table 1]. None of the parameters analyzed correlated with protei­nuria. There was a borderline association of pro­teinuria with older age (P = 0.073) and a higher systolic blood pressure (P = 0.061), which did not reach statistical significance.
Table 1 :The demographic, clinical and laboratory data of the study patients.

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Fifteen of the 27 patients (55.5%) with protei­nuria and 21 out of 40 patients (52.5%) without proteinuria were taking hydroxyurea (HU) for more than one year at the time of assessment. There was no significant difference between different parameters in the two groups taking hydroxyurea, indicating no benefit of this com­pound (P = 0.23). When the patients with pro­teinuria were analyzed separately, there was no difference in the degree of proteinuria in pa­tients taking hydroxyurea in comparison to those not taking it (data not shown).

Comparison of different parameters between the patient groups with and without proteinuria and the relevant P-values are shown in [Table 2].
Table 2 :Comparison of different parameters between the patient groups with and without proteinuria.

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   Discussion Top

The kidney is a frequent site of involvement in patients with SCD and renal impairment is a cause of significant morbidity and mortality in these patients. [10],[11] Proteinuria is one of the most common and early manifestations of sickle cell related renal disease and patients with protei­nuria are at increased risk of developing renal failure in future. [5],[6],[7] As proteinuria in the early stages of nephropathy is associated with future deterioration of renal function, it is important to detect this early as intervention at this stage may prevent or delay the renal damage. In addi­tion, identification of any risk factors associated with proteinuria may also help in developing preventive strategies by attempting to modify some of these risk factors.

Previously, different factors commonly repor­ted to be associated with proteinuria/microalbu­minuria in adults and children with SCD were older age and severe anemia. [12],[13],[14],[15] Faulkner et al reported severe anemia to be associated with glomerular injury and proteinuria in a small study of seven adult patients with SCD. [15] Ano­ther study in pediatric patients with SCD found that proteinuria was significantly associated with lower Hb concentration, higher mean cor­puscular volume, and higher leukocyte count. [12] Recently Ataga et al studied risk factors for albuminuria in 73 adult patients and showed that microalbumin/creatinine ratio was signifi­cantly associated with PHT and a history of leg ulcers, and observed significant correlation bet­ween microalbumin/creatinine ratio and age, systolic blood pressure, LDH, and Hb level. [17]

Other investigators did not find any correlation between lower Hb and proteinuria. In a large study of gromerular involvement in adult pa­tients with sickle hemoglobinopathies, older age was found to be a risk factor for microalbu­minuria/proteinuria, but there was no associa­tion with Hb level. [16] In an earlier study, Akoi and Saad did not observe any correlation bet­ween the urinary albumin excretion and multi­ple clinical and laboratory factors studied inclu­ding age, Hb level and leg ulcers. [18]

We did not find any correlation between pro­teinuria and any of the clinical and laboratory parameters studied. There was a borderline as­sociation of proteinuria with older age and hig­her systolic blood pressure which did not reach statistical significance. Our findings resemble those of Aoki and Saad from Brazil, who also could not identify any risk factors associated with proteinuria. [18] It is possible that the SCD in this group of Brazilian patients resembles the di­sease in our patients from south-western Saudi Arabia.

These conflicting results from different studies can possibly be explained on the basis of dif­ferences in patient characteristics and SCD be­havior in different parts of the world. This is evidenced by the observation that variable asso­ciations have been found even in patients of similar origin, studied at different centers. [12],[13],[14],[15],[16],[17] This highlights the issue that there may be a complex interaction of genetic and environmen­tal factors in individuals and patient populations with SCD. Some of the factors which may po­ssibly be responsible for these differences in different studies are different age-groups of the patient populations, modifying effects of diffe­rent levels of fetal Hb, presence of alpha gene deletions, βS -gene-cluster haplotypes, and other genetic and environmental factors not yet iden­tified. [19],[20],[21],[22] In one of these studies, it was shown that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans. [19]

Majority of the patients at our center originate from the South-Western province of Saudi Ara­bia. They have a moderately severe disease and, certain complications of SCD like priapism and stroke are less common and leg ulcers are rare in these patients. [20],[22],[23],[24],[25],[26] It is interesting to note that none of our patients had leg ulcers, a fin­ding which has been reported to be associated with a more severe form of clinical disease and increased likelihood of end-organ damage such as renal failure and pulmonary hypertension. [10],[27]

Measures which may prevent or reduce protei­nuria/microalbuminuria after its development, include regular blood transfusions and angio­tensin converting enzyme (ACE) inhibitor the­rapy. [28],[29],[30],[31] Blood transfusions, for this purpose, cannot be recommended routinely because of the strong commitment required and the asso­ciated complications. Hydroxyurea has been re­ported to reduce proteinuria/microalbuminuria in children with SCD in conjunction with other measures in small studies, but does not appear to be very effective on its own. [32],[33] We did not observe any benefit of hydroxyurea therapy for more than a year, in reducing proteinuria. ACE inhibitor therapy has an established role in preventing and reversing diabetic nephropathy and renal damage. [34] ACE inhibitor therapy also appears to be an effective measure to reduce microalbuminuria/proteinuria in SCD, [28],[29],[30],[31] but long-term studies are needed to prove their effectiveness in preventing or reversing renal damage.

In summary, proteinuria in adolescent and adult Saudi patients from South and South-Western Saudi Arabia is not associated with any clear identifiable risk factors. As microalbuminuria/ proteinuria usually start to develop during the second decade of life, all patients with SCD should be screened from early second decade and those found to be positive, should be con­sidered for ACE inhibitor therapy.

   References Top

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12.Wigfall DR, Ware RE, Burchinal MR, Kinney TR. Prevalence and clinical correlates of glome­rulopathy in children with sickle cell disease. J Pediatr 2000;136(6):749-53.  Back to cited text no. 12      
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16.Guasch A, Navarrete J, Nass K, Zayas CF. Glome-rular involvement in adults with sickle cell he­moglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol 2006;17(8):2228-35.  Back to cited text no. 16      
17.Ataga KI, Brittain JE, Jones SK, et al. Clinical and laboratory correlates of albuminuria in sickle cell disease. Blood 2008;112(11): 250-2.  Back to cited text no. 17      
18.Aoki RY, Saad ST. Microalbuminuria in sickle cell disease. Braz J Med Biol Res 1990;23 (11):1103-6.  Back to cited text no. 18      
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20.El-Hazmi MA, Bahakim HM, Warsy AS. DNA polymorphism in beta gene cluster in Saudi Arabia: relation to severity of sickle cell anemia. Acta Haematol 1992;88:61-6.  Back to cited text no. 20  [PUBMED]    
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22.el-Hazmi MA, al-Swailem AR, Bahakim HM, al-Faleh FZ, Warsy AS. Effect of alpha thala­ssaemia, G-6-PD deficiency and Hb F on the nature of sickle cell anaemia in south-western Saudi Arabia. Trop Geogr Med 1990;42(3):241­-7.  Back to cited text no. 22      
23.Perrine RP, Pembrey ME, John P, Perrine S, Shoup F. Natural history of sickle cell anemia in Saudi Arabs. A study of 270 subjects. Ann Intern Med 1978;88:1-6.  Back to cited text no. 23  [PUBMED]    
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26.El-Hazmi MA. Heterogeneity and variation of clinical and haematological expression of haemoglobin S in Saudi Arabs. Acta Haematol 1992;88:67-71.  Back to cited text no. 26  [PUBMED]    
27.Kato GJ, McGowan V, Machado RF, et al. Lactate dehydrogenase as a biomarker of hemo­lysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 2006;107:2279-85.  Back to cited text no. 27  [PUBMED]  [FULLTEXT]  
28.Alvarez O, Montane B, Lopez G, Wilkinson J, Miller T. Early blood transfusions protect against micro-albuminuria in children with sickle cell disease. Pediatr Blood Cancer 2006;47(1):71-6.  Back to cited text no. 28      
29.Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC. Prevalence and patho­logic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med 1992;326(14):910-5.  Back to cited text no. 29      
30.Aoki RY, Saad ST. Enalapril reduces the albu­minuria of patients with sickle cell disease. Am J Med 1995;98(5):432-5.  Back to cited text no. 30      
31.Foucan L, Bourhis V, Bangou J, Merault L, Etienne-Julan M, Salmi RL. A randomized trial of captopril for microalbuminuria in normo­tensive adults with sickle cell anemia. Am J Med 1998;104(4):339-42.  Back to cited text no. 31      
32.Fitzhugh CD, Wigfall DR, Ware RE. Enalapril and hydroxyurea therapy for children with sickle nephropathy. Pediatr Blood Cancer 2005; 45(7):982-5.  Back to cited text no. 32      
33.Alvarez O, Lopez-Mitnik G, Zilleruelo G. Short-term follow-up of patients with sickle cell disease and albuminuria. Pediatr Blood Cancer 2008;50(6):1236-9.  Back to cited text no. 33      
34.Kshirsagar AV, Joy MS, Hogan SL, Falk RJ, Colindres RE. Effect of ACE inhibitors in dia­betic and nondiabetic chronic renal disease: a systematic overview of randomized placebo­controlled trials. Am J Kidney Dis 2000;35 (4):695-707.  Back to cited text no. 34      

Correspondence Address:
Aamer Aleem
Associate Professor, Consultant Hematologist Department of Medicine (38) King Khalid University Hospital, P.O. Box 7805, 11472, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

PMID: 20814129

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