|Year : 2014 | Volume
| Issue : 1 | Page : 17-23
Urine Albumin/creatinine ratio: A reliable marker of renal injury in sickle cell nephropathy
Ibrahiem S Abdul-Rahman
Department of Internal Medicine, King Fahd Hospital of the University, University of Dammam, Al-Khobar, Kingdom of Saudi Arabia
|Date of Web Publication||7-Mar-2014|
Ibrahiem S Abdul-Rahman
Department of Internal Medicine, King Fahd Hospital of the University, P.O. Box 40032, Al Khobar 31952, Kingdom of Saudi Arabia
Objective: Albumin/creatinine ratio is a sensitive marker of glomerular damage in patients with diabetes mellitus, hypertension and post-infection glomerulonephritis. Whether or not the albumin/creatinine ratio has the same value in sickle cell anemia (SCA) patients is not yet explored. This study was conducted to determine the prevalence of glomerular damage in SCA and the clinical correlation between albumin/creatinine ratio and renal insufficiency in this group of patients.
Materials and Methods: Seventy-nine adult patients with SCA (hemoglobin SS subtype) were included in this study. Albumin excretion rates (expressed as albumin/creatinine ratio) and renal function (creatinine clearance) were determined and clinical and hematologic evaluations were conducted.
Results: Increased albumin/creatinine ratio (micro- and macroalbuminuria) occurred in 57% of the patients. The development of graded albuminuria was time dependent; therefore, at the end of the study, 26.6% of the patients had macroalbuminuria. There were no differences in hemoglobin levels between patients with normoalbuminuria and those with micro- or macroalbuminuria. By multivariate analysis, albuminuria correlated with age and creatinine clearance (Cr Cl) but not with blood pressure (BP) or hemoglobin levels.
Conclusion: Albumin/creatinine ratio is a sensitive marker of glomerular damage in SCA patients, and it correlated well with Cr Cl; therefore, patients with abnormal albumin/creatinine ratio should be monitored closely for progression of renal disease. The development of micro- and macroalbuminuria is related to age but not to the degree of anemia, suggesting that sickle cell glomerulopathy is not solely related to hemodynamic adaptations to chronic anemia.
ملخص البحث :
تهدف هذه الدراسة لتحديد مدى انتشار تلف الكلية لدى مرضى الأنيميا المنجلية وارتباطها السريري بين نسبة الألبومين/الكرياتينين والفشل الكلوي لدى هؤلاء المرضى. احتوت هذه الدراسة على 97 مريض منجلي وأظهرت أن هناك زيادة في معدل الألبومين/الكرياتينين لدى %75 من المرضى، مرتبطة بالفترة الزمنية للمرض.
ويخلص هذا البحث إلى أن معدل الألبومين/الكرياتينين يعتبر مؤشر حساس لمدى إصابة الكلى عند هؤلاء المرضى. وتعتمد هذه الإصابة على عمر المريض أكثر من معدل فقر الدم.
Keywords: Albumin/creatinine ratio, Cr Cl, ESRD, hemoglobin, renal insufficiency, SCA
|How to cite this article:|
Abdul-Rahman IS. Urine Albumin/creatinine ratio: A reliable marker of renal injury in sickle cell nephropathy. Saudi J Med Med Sci 2014;2:17-23
|How to cite this URL:|
Abdul-Rahman IS. Urine Albumin/creatinine ratio: A reliable marker of renal injury in sickle cell nephropathy. Saudi J Med Med Sci [serial online] 2014 [cited 2017 Apr 24];2:17-23. Available from: http://www.sjmms.net/text.asp?2014/2/1/17/128403
| Introduction|| |
The possibility that albuminuria may accelerate kidney disease progression to end-stage renal disease (ESRD) has received support from the results of increasing numbers of experimental and clinical studies.  Researches in nephrology in recent times have yielded substantial information on the mechanisms by which persisting dysfunction of an individual component cell in the glomerulus is generated and signaled to other glomerular cells and to the tubule. , Spreading of disease is central to processes by which nephropathies of different types progress to ESRD. Independent of the underlying causes, chronic proteinuric glomerulopathies have in common a sustained or permanent loss of selectivity of the glomerular barrier to protein filtration.  Glomerular disease in SCA is a progressive lesion beginning at the glomerular capillary wall, the site of abnormal filtration of plasma proteins. Injury is transmitted to the interstitium, favoring the self-destruction of nephrons and eventually of the kidney.  Baseline albuminuria was an independent predictor of renal outcome in patients with diabetes, non-diabetes as well as sickle cell nephropathies. ,, Clinical trials consistently showed renoprotective effects of proteinuric reduction and led to the recognition that the antiproteinuric treatment is instrumental to maximize renoprotection. ,,, Findings that the decline of the glomerular filtration rate (GFR) correlated negatively with albuminuria reduction and positively with residual albuminuria provided further evidence for a pathogenic role of proteinuria.  It was documented that whenever proteinuria is decreased by treatments, progression to ESRD is reduced.  More recently, detecting microalbuminuria was found to be an important screening tool to identify people who are at a high risk for cardiovascular events and the progression of kidney disease and need more intensive therapy compared with subjects with normal albumin excretion rates.  According to the American Diabetes Association, the gold standard for measuring urine albumin excretion is a 24-h urine collection.  However, a more convenient method to detect microalbuminuria is the albumin (μg) creatinine (mg) ratio measured in a random urine specimen.  Currently, the National Kidney Foundation recommends the use of spot urine albumin/creatinine ratio obtained under standardized conditions, i.e. first voided, morning and midstream specimen to detect albuminuria. The albumin/creatinine ratio proved to be a more convenient test for patients with diabetes mellitus and for those with cardiovascular events and to avoid errors of improper collection methods and variations in 24-h protein excretion.  There are, however, few reports that touched the validity of albumin/creatinine ratio and its renal prognostic effect in patients with SCA. This study was conducted to explore this poorly defined field in this group of patients.
| Materials and Methods|| |
In a cross-sectional study, screening for microalbuminuria was performed in all SCA patients admitted to a university hospital, then followed-up during the study period from April 2009 till April 2012. The study was conducted according to the Helsinki Declaration and signed informed consents were obtained from all patients. The total number of patients was 87; two patients with SC disease, four patients with sickle thalassemia and two patients with fasting blood sugar >140 mg/dL at two separate visits were excluded from the study. In addition, patients who exercised 48 h or less before obtaining the samples, patients with HBsAg, hepatitis C-antibody, HIV and those with acute renal failure or ESRD were not included in the study. The remaining 79 patients were all non-diabetic SS disease patients. Urine samples from them were screened for albumin/creatinine ratio every 3 months during the study period. Patients were asked to submit early morning mid-stream spot urine samples at the beginning of the study and at each clinic visit thereafter. Patients with abnormal results on routine screening were asked to return for repeat testing. Urine specimens were not collected at sick visits. All testing was performed on spot samples obtained by the clean catch technique.
Urine microalbumin was measured by radioimmunoassay. Urine samples testing greater than 20 mg/L on the Micral strips were sent to the laboratory for quantitation of the amount of microalbumin present relative to the amount of creatinine. Urine microalbumin was measured by radioimmunoassay using the DPC Coat A Count kit (Diagnostic Products Corp., Los Angeles, CA, USA). Urine creatinine was determined by the alkaline picrate method. Urine microalbumin/creatinine (albumin/creatinine) ratios were calculated and classified as either normal (albumin/creatinine ratio less than 30 μg/mg) or microalbuminuria (albumin/creatinine ratio greater than 30 μg/mg). Patients with albumin/creatinine ratio greater than 300 μg/mg at two or more visits were considered to have persistent proteinuria.  Hgb levels were measured from venous samples obtained at the same clinic visit as the urine microalbumin screen. Creatinine clearance was estimated using the Cockcroft-Gault equation. 
All statistical analyses, including frequencies, t test, multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI), were completed with SPSS for Windows version 20 (IBM, SPSS). Categorical variables were compared by the Wald χ2 test and mean values of continuous variables were compared between groups by the unpaired t-test. Logistic regression was used to calculate the ORs for microalbuminuria after controlling for multiple covariates simultaneously. The following covariates were included in the logistic model: Age, gender, systolic blood pressure, body mass index (BMI), hemoglobin, creatinine clearance and current smoking. All statistical significance was assessed using a level of 0.05, and only those variables that remained statistically significant at the 0.05 level remained in the final multivariate model.
| Results|| |
The study group included 79 patients with Hgb SS, ranging in age from 15 to 36 years, with a mean age of 24.3 ± 4.86 years (median = 24 years). Sixty one (77.2%) of the subjects were male. Length of follow-up varied from 13 months to 36 months (mean = 22 ± 9.4 months). The mean number of urine samples collected per patient was 5.3 ± 2.64, with the number of samples ranging between five and 12 per patient. [Figure 1] shows the relation between age and prevalence of albuminuria. The mean age of patients with an albumin/creatinine ratio >300 μg/mg was 32.7 years in contrast to a mean age of 25.3 years for patients with an albumin/creatinine ratio >30 μg/mg (P < 0.01) and 18.1 for patients with an albumin/creatinine ratio <30 μg/mg (P < 0.001). As shown in [Table 1], 49 (62%) patients and 34 (43%) patients had an albumin/creatinine ratio <30 μg/mg (P < 0.05), 18 (22.8%) patients and 24 (30.4%) patients had an albumin/creatinine ratio >30 μg/mg (P < 0.05) and 12 (15.2%) patients and 21 (26.6%) patients had an albumin/creatinine ratio >300 μg/mg (P < 0.01) at the beginning and at the end of the study period, respectively. The mean Hgb concentration was 8.8 +/-1.4 gm/dL in patients with an albumin/creatinine ratio <30 μg/mg, 8.6 +/-1.4 gm/dL in patients with an albumin/creatinine ratio >30 μg/mg and 8.5 +/-1.3 gm/dL in patients with an albumin/creatinine ratio >300 μg/mg (P > 0.05). The albumin/creatinine ratio was 21.6 +/-7.4 μg/mg, 211 +/-67.3 μg/mg and 668 +/-82.5 μg/mg in the three groups. The mean serum creatinine was 0.8 +/-0.2 mg/dL, 1.3 +/-0.2 (P > 0.05) and 2.4 +/-1.4 mg/dL in the three groups respectively, (P < 0.05 and P < 0.01). The mean creatinine clearance was 96.8 +/-12.6 mL/m in patients with normal albumin excretion <30 μg/mg, 78.7 +/-12.2 mL/m in patients with microalbuminuria (P < 0.05) and 48.6 +/-10.1 mL/m in patients with persistent proteinuria (P < 0.01 and P < 0.001, respectively). To determine the clinical or biochemical markers associated with the development of albuminuria (albumin/creatinine ratio > 30 μg/mg) and renal insufficiency (Cr Cl < 80 mL/m), a multiple linear regression analysis was performed using albuminuria or Cr Cl as the dependent variables. When albuminuria was considered; only Cr Cl (P < 0.001) and, to a lesser degree, age (P < 0.01) were associated with increased albuminuria. When Cr Cl was analyzed as a dependent variable, both albuminuria and age were associated with reduced Cr Cl (P < 0.001) [Table 2]. Multivariate logistic regression analysis on the outcome of albuminuria showed that age (OR = 1.22, 95% CI = 1.20-1.49) (P < 0.01) and Cr Cl (OR = 0.36, 95% CI = 1.16-1.50) (P < 0.001), but not male sex, BMI, Hgb level or systolic blood pressure (P > 0.05), correlated with the outcome of albuminuria [Table 3]. Initial testing showed normal microalbumin excretion in 49 (62%) patients, and data collected longitudinally demonstrated an increase in the prevalence of microalbuminuria from 22.8% to 30.4% ( P < 0.001) and an increase in the prevalence of macroalbuminuria (proteinuria) from 15.2% to 26.6% (P < 0.001) at the beginning and at the end of the study, respectively [Figure 2]. Chronic renal insufficiency CRI was present in 14 (17.7%) patients, and showed a high degree of association with macroalbuminuria (persistent proteinuria) and increased age.
|Figure 2: (a and b) Albumin/creatinine ratio at the beginning and at the end of the study|
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|Table 2: Linear regression analysis: Albuminuria and creatinine clearance|
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|Table 3: Univariate and multivariate analysis on the outcome of albuminuria|
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| Discussion|| |
Patients with SCA may develop proteinuria and renal failure that progresses into terminal ESRD. Previous studies of renal involvement in SCA have focused on patients with nephrotic-range proteinuria, an uncommon presentation in SCA. In our study, we found that glomerular involvement as indicated by micro- and macroalbuminuria is common in sickle cell hemoglobinopathies; microalbuminuria was seen in 30.4% and macroalbuminuria in 26.6% of our SCA patients. In a recent study,  increased albumin excretion occurred in approximately 70% of adults with hemoglobin SS disease and in approximately 40% of adults with other sickling disorders. The renal involvement responsible is a glomerulopathy whose initial marker is albuminuria. In our study, we demonstrated an increased prevalence of albuminuria with age [Figure 1]. This relationship was as well seen in previous studies by Alverez et al.  and Mc Kie et al.,  who demonstrated an increase in the prevalence albuminuria with age, ranging between 21.3% and 28% in older patients with SCA, of which 10.5% of the cases progress to proteinuria within a 20-month follow-up period. This indicates that sickle cell glomerulopathy occurs in a majority of older patients with SS disease, and its prevalence is much higher than previously reported on the basis of a positive urinary dipstick for protein.  Our study also demonstrated a strong relationship between albuminuria and renal function, expressed as Cr Cl, when both albuminuria and Cr Cl were taken as the dependent variant (p 0.0074 and 0.0079, respectively) [Table 2]. In most cases (up to 72%), albuminuria continues to progress into renal failure according to previous retrospective studies.  In a recent prospective study involving 300 adults aged 20-70 years,  the prevalence of albuminuria was 68% (26% proteinuria) in homozygous individuals as opposed to 32% (10% proteinuria) in heterozygous ones. In this same study, 21% of the patients had renal failure as calculated using the Cockroft-Gault formula. However, determining serum creatinine or even the GFR using this value, which is a parameter used for staging chronic kidney disease under the current classification system,  would not be useful in SCA until advanced stages of the disease (GFR < 30-40 mL/min/1.73 m 2 )  as tubular secretion of creatinine is maintained even with an abnormal GFR. When albuminuria appears in SCA patients, the glomerular ultrafiltration coefficient is significantly reduced compared with that of SCA patients without albuminuria, even in those with preserved GFR, meaning that albuminuria is a very sensitive marker for the glomerular damage caused in SCA, unlike in other nephropathies such as type-2 diabetes.  For this reason, some authors  have recommended measuring blood levels of cystatin C as a better approximation of GFR than those based on serum creatinine levels, although more studies are needed to confirm this. Our data demonstrated a relationship between increasing age and microalbuminuria that is better expressed as albumin/creatinine ratio. Therefore, the point prevalence of microalbuminuria in sickle populations will be influenced in part by the mean age of the patients at the time of any survey. Although proteinuria can reach nephrotic levels, it increases gradually with age. In a large longitudinal study of 725 patients, Powars et al. noted the median age for onset of "sickle renal failure" to be 23.1 years. In this prospective study, albuminuria was noted to be a strong predictor of subsequent renal failure. Wigfall et al.  demonstrated that macroalbuminuria is present in a significant number of children with SS disease. These investigators analyzed their registry data on 442 patients and found that macroalbuminuria was present in 12% of the older adolescents but in no children less than 7 years of age. Other investigators have suggested that microalbuminuria precedes proteinuria and serves as an early marker for glomerular injury in sickle cell anemia. ,,,,, Therefore, it is tempting to speculate from our study, and the available literature, that sickle cell glomerulopathy could evolve in four clinical stages: (1) A normoalbuminuric stage of variable duration, followed by a stage of (2) microalbuminuria; this could lead to (3) macroalbuminuria but with preserved GFR and to (4) macroalbuminuria and progressive renal insufficiency. However, evidence of progression from micro-to macroalbuminuria is lacking, and such classification remains a hypothesis. Screening for albuminuria has been proposed as an important first step toward identifying children with early sickle cell nephropathy. ,,,, Once identified, it is not known whether interventions to reduce albuminuria will prevent progression of sickle cell nephropathy. However, amelioration of micro- and macroalbuminuria has been proven to be beneficial in diabetic nephropathy and other glomerulopathies.  Hydroxyurea and angiotensin converting enzyme inhibitors (ACEI) are two therapies that show promise for the prevention or treatment of albuminuria in SCA. ,,,,, Thus far, little data exists on the effectiveness of these agents in preventing or retarding the progression of sickle cell nephropathy. ,,, The pathogenesis of glomerular damage in SCA is not well understood. Children with SCA have renal hemodynamic alterations (renal hyperperfusion and glomerular hyperfiltration) that probably result from renal vasodilatation associated with chronic anemia. In some patients, these changes are followed by the development of glomerular proteinuria and progressive renal insufficiency. Histologically, patients with SCA may develop glomerular hypertrophy and focal segmental glomerulosclerosis, features that are suggestive of hemodynamically mediated injury.  The cause(s) of the hemodynamic injury to the glomerulus in SCA is unclear. Anemia per se could cause glomerular damage by increasing blood flow. In support of this, the prevalence of albuminuria in SS disease (with lower hemoglobin than in other sickling disorders) is higher than that in other sickling hemoglobinopathies. In our study, however, the severity of anemia did not correlate positively with albumin/creatinine, a finding that is supported by a recent publication by Guash et al.,  who reported no difference in hemoglobin levels among groups of SCA with different levels of albuminuria.
The American Diabetes Association approves the 24-h urine collection as the gold standard for measuring urine albumin excretion.  Our study, however, demonstrated a more convenient method for detection of microalbuminuria, i.e. the albumin (μg)/creatinine (mg) ratio measured in a random urine specimen. The American Diabetic Association and the National Kidney Foundation define microalbuminuria as an albumin/creatinine ratio between 30 μg/mg and 300 μg/mg in both men and women ,,,,,,,,,,,,,,,,,,,,, and, currently, the National Kidney Foundation recommends the use of spot urine albumin/creatinine ratio obtained under standardized conditions (first voided, morning, mid-stream specimen) to detect microalbuminuria. The albumin/creatinine ratio in SCA patients is a more convenient test for patients and may be less prone to errors due to improper collection methods and variations in 24-h protein excretion compared with a random urine specimen.  However, more prospective studies are needed to determine the causal relationship of these findings as well as the potential benefits of treatment for the development of albuminuria.
The current study has, however, some drawbacks: First, the sample size is small compared with the number of patients in other studies related to microalbuminuria (in diabetes mellitus, for example). Second, the study depends, for estimation of the renal functions, on the Cr Cl; more recently, estimation of cystatin C may be a more appropriate measure. Third, there is no estimation of the renal blood flow and fourth, that kidney biopsies were not performed to document the type and extent of the glomerular lesions. However, this study has the strength of being the first of its kind to demonstrate the progression of renal disease in SCA using albumin/creatinine ratio as a sensitive marker. The study also extended for approximately 3 years, which allowed for a stronger conclusion concerning the relation between the progression of albuminuria and the renal outcome. In addition, it throws lights on the value of prompt and early control of albuminuria in SCA patients to prevent progression and to improve the outcome of renal disease in this group of patients.
| Conclusion|| |
It is concluded that glomerular damage in adults with SCA is very common and that a majority of patients with SS disease are at risk for the development of progressive renal failure. Albumin/creatinine ratio is a sensitive marker of glomerular damage in SCA patients, and it correlates well with Cr Cl; therefore, patients with abnormal albumin/creatinine ratio should be monitored closely for progression of renal disease. The development of micro- and macroalbuminuria is related to age but not to the degree of anemia, suggesting that sickle cell glomerulopathy is not solely related to hemodynamic adaptations or to chronic anemia.
| Acknowledgment|| |
The author would like to thank the staff of the hematology and radioimmunoassay laboratory for their help during the preparation of this work.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]