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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2017  |  Volume : 28  |  Issue : 3  |  Page : 524-531
Assessment of renal function in Indian patients with sickle cell disease


1 Research Division, Sickle Cell Institute Chhattisgarh, Raipur, Chhattisgarh, India
2 Department of Biochemistry, Pt. Jawahar Lal Nehru Medical College, Raipur, Chhattisgarh, India
3 Department of Botany, Government Nagarjuna Postgraduate College of Science, Raipur, Chhattisgarh, India
4 Research Division, Sickle Cell Institute Chhattisgarh; Department of Biochemistry, Pt. Jawahar Lal Nehru Medical College, Raipur, Chhattisgarh, India

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Date of Web Publication18-May-2017
 

   Abstract 

Sickle cell disease (SCD) and its variants are genetic disorders resulting from the presence of a mutated form of hemoglobin. Renal disease is one of the most frequent complications, and kidney damage starts very early and progresses throughout life causing severe complications. The present study is aimed to analyze creatinine-based estimated glomerular filtration rate (eGFR) in 616 SCD patients (507 HbSS and 109 HbSB+), receiving medical care at outpatient wing of Sickle Cell Institute, Chhattisgarh. Glomerular filtration rate (GFR) estimated using the Modification of Diet in Renal Disease (MDRD), Cockcroft-Gault, chronic kidney disease epidemiology collaboration (CKD-EPI) (<17 years analyzed with Schwartz), and SCD specific Jamaica Sickle Cell Cohort Study (JSCCS)-GFR equations were compared. Further, eGFR calculated using the CKD-EPI and Schwartz equations was used to define various stages of kidney function and compared with clinical and hematological variables. The mean age of patients was 15.8 years. Comparison of eGFR using various formulas revealed that MDRD and JSCCS formulas overestimated the GFR. Among SCD patients, prevalence of glomerular hyperfiltration (GHF) is high followed by renal insufficiency (RI) and renal failure (RF). However, no differences were found in hematological profiling among different functional stages of kidney. Age and body surface area are significantly more in SCD individuals with normal kidney function and GHF. Participants with RF showed a higher level of blood urea and fetal hemoglobin. In summary, this is the first study to analyze different functional stages of kidney among SCD patients of India. Our study revealed that the GHF and RI are the important indicators of kidney damage.

How to cite this article:
Lakkakula BV, Verma HK, Choubey M, Patra S, Khodiar PK, Patra PK. Assessment of renal function in Indian patients with sickle cell disease. Saudi J Kidney Dis Transpl 2017;28:524-31

How to cite this URL:
Lakkakula BV, Verma HK, Choubey M, Patra S, Khodiar PK, Patra PK. Assessment of renal function in Indian patients with sickle cell disease. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Nov 14];28:524-31. Available from: http://www.sjkdt.org/text.asp?2017/28/3/524/206440

   Introduction Top


Sickle cell disease (SCD) is a serious public health malady, and by any measure, India has a serious problem on its hands. Although reliable epidemiological data are not available, with a population of 1.25 billion individuals, India is estimated to be home to over 50% of the global SCD patient population.[1] Although the exact reason is not known, the HbS gene is mainly concentrated in scheduled tribal, scheduled caste, and other backward caste populations of Madhya Pradesh, Orissa, Chhattisgarh, Jharkhand, Gujarat, Andhra Pradesh, and Kerala states where carrier frequencies range between 5% and 40% or more. Previous studies demonstrated that the SCD is milder in Indians because they often have Arab-Indian HBB gene cluster haplotype that is associated with high fetal hemoglobin (HbF) levels.[2] Common complications include acute painful episodes, stroke, dactylitis, leg ulceration, pulmonary hypertension, acute chest syndrome, priapism,[3],[4] and early mortality.[4] Better and more aggressive treatments for SCD have prolonged life above the age of 50 years, whereas before the 1960s, only 50% of SCD patients survived to age 20 years.[5],[6] Most of the gain in life expectancy in recent decades has been due to early treatment with antibiotics, better pain management, and especially the use of hydroxyurea.[7]

Blockages of the small blood vessels cause acute painful episodes and cause tissue infarctions in SCD patients. Repeated episodes occur unpredictably and may result in organ damage. The kidneys are sensitive to the effects of red blood cell (RBC) sickling. High osmolality in the renal medulla increases cell propensity to sickling and lead to medullary ischemia and papillary necrosis.[8] Due to recurrent episodes of hematuria and tubular abnormalities such as a concentrating defect, impaired potassium excretion, and an acidification de- feet, kidneys are particularly susceptible to damage in SCD patients. As the SCD patient age increases, the effects of acute and chronic tissue injury may ultimately result in kidney failure. Renal failure accounts for 10%–15% of deaths in SCD patients.[9] The renal manifestations of SCD represent an anatomical and functional continuum. Radiographic studies revealed the prevalence of renal infarcts and papillary necrosis in 30%–40% in SCD cases.[10] The other renal manifestations are hematuria, proteinuria, tubular disturbances, and chronic kidney disease (CKD).[11] As the age increases, 70% of SCD patients may develop microalbu- minuria and 26% of patients develop CKD.[12]

In India, the sickle cell screening program is yet to cover the affected regions of the country. Hence, SCD patients visiting hospitals have organs that are already damaged or abnormal due to longer diagnostic delay. The present study is aimed to determine the prevalence of CKD among SCD patients visiting outpatient department (OPD) and to assess variations in the clinical and biochemical variables across CKD groups.


   Materials and Methods Top


A hospital-based cross-sectional study was conducted at OPD of our institute which is a dedicated center for treating SCD patients of this region. The present study included confirmed HbSS and HbSB+ patients. The case history of SCD was verified from the record of patients. Patients with sickle pain crisis, suspected urinary tract infections, and gross hema- turia or any other acute illness were excluded from the study. This study was approved by the Institutional Ethics Committee, and the ethical principles of the Declaration of Helsinki were followed. Written informed consent was obtained from all the adult participants. Parents or legal guardians provided written consent on behalf of minors. Anthropometric measurements were taken without heavy outdoor clothing. Stature was measured to the nearest millimeter using an anthropometric rod. Weight was measured on a prestandardized body weighing machine. Body mass index (BMI) was calculated using the formula, weight (kg) divided by height (meter square). Based on the WHO proposed cutoff points of BMI, adults were classified as underweight (BMI <18.5), healthy weight (BMI 18.5–24.9), overweight (BMI 25–29.9), and obese (BMI > 30). In children and teen (2–19 years), BMI for age according to the Centers for Disease Control and Prevention growth charts were used to define underweight (<5th percentile), healthy weight (5th–84th percentile), overweight (85th–95th per- centiles), and obese (>95th percentile).[13] The body surface area (BSA) was calculated using Dubois and Dubois formula.[14]

Following an overnight (12 h) fast, blood samples were collected to perform biochemical and hematological assays. HbF levels in all these patients were assessed on BIORAD variant using beta-thalassemia short program. Serum creatinine and blood urea (B. Urea) were analyzed using standard assay methods on ILab 650 automatic analyzer. Hematolo- gical assays were performed on fresh anti- coagulated blood using an automated analyzer (Mindray BC 3000 Plus, Shenzhen, China). Comparison of glomerular filtration rate (GFR) estimated by plasma clearance method (Gates method) with modification of diet in renal disease (MDRD) prediction equation showed higher interindividual variability.[15] In steady- state SCD patients, GFR measured using iohexol plasma clearance (gold standard) showed lowest bias and the greatest precision with the GFR predicted using CKD epidemiology collaboration (CKD-EPI) equation.[16] In the present study, estimated GFR (eGFR) was assessed separately in adults and children (<17 years), respectively, using CKD-EPI equation[17] and Schwartz equation.[16],[18] The CKD stage in all the SCD patients was determined according to the National Kidney Foundation recommendations[19] and patients were divided into Stage 1 (normal; eGFR >90 mL/ min/1.73 m2), Stage 2 (mild kidney damage eGFR= 60–89 mL/min/1.73 m2), Stage 3 (moderate kidney damage: eGFR = 30–59 mL/ min/1.73 m2), Stage 4 (severe kidney damage: eGFR = 15–29 mL/min/1.73 m2), and Stage 5 (kidney failure eGFR = <15 mL/min/1.73 m2). Further, patients with eGFR >140 mL/min/ 1.73 m2 is denoted as glomerular hyperfil- tration (GHF), eGFR <89 to 60 mL/min/1.73 m2 as renal insufficiency (RI), and eGFR <59 mL/min/1.73 m2 as renal failure (RF).[19]

Quantitative clinical data were compared between study subgroups using Mann-Whitney U-test and were presented as mean (mean rank). Kruskal-Wallis test was used to assess whether the quantitative traits differed among the study subgroups. All statistical analyses were performed with Statistical Package for the Social Sciences (SPSS statistical software version 16.0 (SPSS Inc., Chicago, IL, USA) for Windows. P <0.05 (two-tailed) was considered statistically significant.


   Results Top


Six hundred and sixteen patients were studied, of which 343 males (55.7%) and 273 females (44.3%). Their mean age was 15.8 years, and their ages ranged from 2 to 61 years. Sex-wise distribution of these SCD patients in different age groups is shown in [Figure 1]. Among SCD patients, 109 were HbSB+ genotype (17.7%). Characteristics of the study participants by Hb variant are presented in [Table 1]. The age of participants with HbSB+ genotype and the HbSS genotype were not significantly different from each other when the two groups were compared by age group (P = 0.883). BMI in HbSS is 15.83 ± 2.82 and in HbSB+ is 16.22 ± 2.97 and individuals with lean body weight were higher in both HbSB+ genotype (48.6 %) and HbSS (59.2%). BSA and B. Urea are not statistically different between HbSS and HbSB+. Low levels of serum creatinine were found in patients with HbSB+ (0.65 ± 0.24 mg/dL) and HbSS (0.60 ± 0.19 mg/dL) genotypes. However, higher mean eGFR was noted in participants with HbSB+ genotype (111.72 ± 27.01 mL/ min/1.73 m2) than in those with HbSS genotype (104.47 ± 32.47 mL/min/1.73 m2; P = 0.030). The distribution of CKD stages in both male and female is depicted in [Figure 2]. The prevalence of GHF ranging from 9.5% in HbSS to 11.9% in HbSB+, but the prevalence of RI in HbSS (16%) is slightly higher than HbSB+ (10.1%). Further, renal failure is more in HbSS (6.7%) than the HbSB+ (0.9%). HbSB+ genotype group had a higher RBC count (3.86 ± 2.41 χ 1012 /L; P = 0.001), but platelets (325.27 ± 176.7 χ 109 /L; P = 0.006) and HbF (21.02±7.2%) were higher in patients with HbSS genotype [Table 2].
Table 1: Baseline characteristics of study participants by hemoglobin variant.

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Table 2: Distribution of various hematological variables according to kidney function.

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Figure 1: Percentage of men and women in different age groups.

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Figure 2: Distribution of different chronic kidney disease stages in both male and female.

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GFR was estimated using the CKD-EPI equation, MDRD Study equation, Cockcroft-Gault (CG) equation and Jamaica Sickle Cell Cohort Study SCD-specific (JSCCS) equations[20] were depicted in [Figure 3]a. The eGFR estimated using MDRD and JSCCS were higher than the CKD-EPI and CG formulas [Figure 3]a. Age- wise distribution of eGFR based on different formulas is depicted in [Figure 3]b. Based on CKD-EPI and Schwartz equation in adults and children, respectively, 35 (5.68%) patients have renal failure (eGFR <59). Among those with kidney damage, 34 (97.14%) comprises HbSS genotype and 25 (71.4%) having age <12 years [Figure 3]b. Participants with normal kidney function (NKF) and different stages of kidney damage had almost similar hematological profile [Table 2]. Individuals with renal failure showed a higher HBF levels (24.5 ± 5.7%) compared to other stages (GHF and RI) to those with NKF (20.3 ± 7.7%; P = 0.016). [Figure 4]a shows a dot plot of the SCD patient’s age, B. Urea in relation to their kidney status and [Figure 4]b shows a dot plot of the relationship between BAS, HbF, and kidney status. Age and BSA are significantly more in SCD individuals with NKF and GHF compared to RI and RF groups. In contrast to this, significantly higher level of B. Urea was found in RI and RF groups compared to the GHF and NKF groups [Table 2].
Figure 3: Scatter chart showing the correlation of creatinine (a) and age (b) with the glomerular filtration rate calculated by different formulas.

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Figure 4: (a) Distribution of patients' age and blood urea in those with different kidney stages. (b) Boxplot of body surface area, fetal hemoglobin, and different kidney stages in sickle cell disease patients.

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   Discussion Top


Estimation of eGFR based on CKD-EPI revealed that the kidney damage (eGFR <59) among SCD patients is 5.68%. Comparison of eGFR estimated using MDRD, JSCCS, CKD- EPI, and CG formulas denoted that the MDRD and JSCCS formulas overestimated the GFR compared to the CKD-EPI and CG formulas. RI remained as a major functional stage followed by GHF and renal failure (RF). However, no differences were found in hema- tological profile among different functional stages of kidney. Age and BSA are significantly more in SCD individuals with NKF and GHF. Patients with RF showed a higher level of B. Urea and fetal hemoglobin.

Several lines of evidences demonstrated that SCD can cause both renal functional disturbances and anatomical alterations due to pathophysiologic changes of the kidneys. Initial studies of renal function in sickle cell anemia reported lower mean serum creatinine levels in 77.2% of SCD patients and high prevalence and severity of proteinuria and chronic RI with increasing age.[21] Further, proximal tubule defects generally impair urinary concentration of bicarbonate, while more distal tubule defects may undermine potassium excretion, expedite hyperkalemia.[22] Furthermore, with increasing age in SCD patients, glome- rular hypertrophy with reduplication of the basement membrane and mesangial proliferation was observed.[23] High renal blood flow and glomerular hyperfiltration are also notable early glomerular changes in SCD.[24],[25]

About one-fourth of patients with SCD have proteinuria, and enalapril was shown to decrease the degree of proteinuria of these patients, suggesting that glomerular capillary hypertension may be a pathogenic factor in sickle cell nephropathy.[22] In SS disease, albuminuria correlated with age and serum creatinine but not with blood pressure or hemoglobin levels suggesting that sickle cell glomerulopathy is not solely related to vaso-occlusive effects or hemodynamic adaptations to chronic anemia.[12] Although the appropriate cutoff values for defining abnormal albuminuria is not known for SCD, mildly elevated albumin-to-creatinine ratio (ACR) signifies renal and glomerular epithelial dysfunction, precursor to CKD.[26] Important hematological indices including Hb, RBC count, platelet count, leukocyte count, and hematocrit did not show any relationship with kidney damage defined by eGFR. These findings were supported by earlier studies, in which important clinical and laboratory indices 12 27 28 do not correlate with renal impairment. In contrast to this, leukocyturia was associated with urinary abnormalities in SCD patients.[22] Analysis of renal function in an inadequate resource setting from the Democratic Republic of Congo, revealed that the hyperfiltration, low creatinine, low urea, and high uric acid are more common in SCD children than the controls.[29] In our study, GHF was present in 9.9% of SCD patients. Africans from Republic of Congo and African Americans from USA, reported GHF of 308% and 76%, respectively, in SCD patients.[29],[30] RI (eGFR 89–60 mL/ min/1.73 m2) was present in 27.1% of SCD children of our study is higher than that reported in SCD patients (12.3%) from the Democratic Republic of Congo.[29]

Our study had both strengths and limitations. The strengths are, our study is planned with good number of samples selected from homogenous population of central India and all the participants were from single center. Our study participants comprise all age groups. We have adopted five different equations to calculate eGFR. In spite of these advantages, the present study also has a number of limitations. The results of this study are limited by the cross- sectional design. We did not measure the albumin, which prevented us to calculate the prevalence of microalbuminuria and ACR. Subsequently, this information could be useful in assessing the risk factors to CKD advancement in SCD. Thus, it is recommended that a longitudinal study to characterize the progress- sion of CKD for early therapeutic intervention to control the morbidity and mortality associated with SCD. In summary, this is the first study to analyze different functional stages of kidney among SCD patients of central India. Our Study revealed that the RI and glomerular hyperfiltration are important indicators of kidney damage. Further, our study highlights no differences in hematological profile of different functional stages of kidney.


   Acknowledgement Top


This study was supported by an intramural grant from the Sickle Cell Institute Chhattisgarh, State Government of Chhattisgarh, India.

Conflict of interest: None declared.

 
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Correspondence Address:
Pradeep Kumar Patra
Department of Biochemistry, Pt. Jawahar Lal Nehru Medical College, Raipur - 492 991, Chhattisgarh
India
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DOI: 10.4103/1319-2442.206440

PMID: 28540888

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