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Original Research (Original Article) 


Saroj Kunwar et al, 2019;3(8):648–653.

International Journal of Medicine in Developing Countries

Hyperuricemia, anemia, and chronic kidney disease: a conundrum in the shadow

Saroj Kunwar1*, Bimal Chaulagain1, Rajendra K. C.1, Pradeep Pokhrel1, Apeksha Niraula2

Correspondence to: Saroj Kunwar

*Department of Biochemistry, Modern Technical College, Lalitpur, Nepal.

Email: sarojkunwar00 [at] gmail.com

Full list of author information is available at the end of the article.

Received: 30 November 2018 | Accepted: 20 February 2019


ABSTRACT

Background:

Chronic kidney disease (CKD) refers to all five stages of kidney damage, from very mild damage in Stage 1 to complete kidney failure in Stage 5. CKD results in increased morbidity and mortality in high-risk patients. Hyperuricemia and anemia are the two well-studied complications of CKD which progresses along with the severity of the disease. Thus, this study intended to assess hyperuricemia and anemia in patients with different stages of CKD in Nepal population.


Methodology:

Two hundred seventy-seven patients (217 cases and 60 controls) were enrolled in this study. Laboratory analysis was done at Modern Technical College Clinical Laboratory, Nepal. Serum uric acid, creatinine, urea, and hemoglobin concentration were measured using spectrophotometric assay.


Results:

The prevalence of anemia in stages 2, 3, 4, and 5 were found to be 21.80%, 55.50%, 83.70%, and 91.50%, respectively, with an overall prevalence of 62.21% among CKD patients. Hemoglobin level was found significantly lower in CKD subjects than non-CKD controls (p < 0.001). Among the total subjects, 48.3% of CKD cases and 20% of non-CKD controls had anemia. The incidence of hyperuricemia in stages 2, 3, 4, and 5 was found to be 7.8%, 20%, 24.3%, and 35.20%, respectively, with an overall prevalence of 25.1% among CKD patients. Uric acid levels were significantly higher in CKD subjects than non-CKD controls (p < 0.001).


Conclusion:

The present study depicts a high incidence of anemia and hyperuricemia with the progression of CKD in the Nepal population. Hence, the study reports a strong association of anemia and hyperuricemia with CKD.


Keywords:

Anemia, hyperuricemia, chronic kidney disease (CKD), hemoglobin.


Introduction

Chronic kidney disease (CKD) is considered to be a global health problem progressing to end-stage renal disease (ESRD) [1]. The disease has been associated with various complications attributable to impaired renal function and predisposing to the development of cardiovascular diseases (CVD) [1]. The two common complications of CKD are anemia and hyperuricemia, both of which are associated with increased risk of CVD, increased morbidity and mortality in high-risk group patients [2]. Anemia in CKD is multi-factorial with one of the major cause being the loss of peritubular fibroblast within the renal cortex that synthesizes erythropoietin [3]. In addition to erythropoietin deficiency, different other factors including iron deficiency decreased the half-life of red blood cells, inflammation could also lead to anemia in CKD [4]. Epidemiological studies have demonstrated that uric acid is an independent risk factor for the declining glomerular filtration rate and development of CKD in the general population [5]. Various drugs like cyclosporine have been studied to raise the uric acid, and it is also found that the renal disease induced by cyclosporine could be worsened by increased levels of uric acid and hemoglobin. Identification of anemia and hyperuricemia in CKD at an early period could help in retardation of ESRD and could consequently reduce morbidity and mortality rates due to CVD [6,7]. There is a high incidence of mortality (58%) due to CVD in CKD patients as compared with the general population [8,9]. To the best of our knowledge, this is the first ever study assessing the status of hyperuricemia and anemia in different stages of CKD in Nepal population.


Subjects and Methods

This is a hospital-based cross-sectional study conducted from September 2015 to March 2016 in Modern Technical College, Nepal after obtaining the ethical approval from Institutional Ethical Review Board (IRB) of Modern Technical College. A total of 277 patients were enrolled after receiving written informed consent. Patients were recruited from the outpatient Department of Internal Medicine (OPD), and Nephrology Unit of Sumeru Hospital, Lalitpur, Nepal. The physician on duty assessed the patient’s history and performed the general physical examination. Among the total subjects, 217 participants had CKD and 60 were non-CKD healthy controls. All patients were aged between 16 and 60 years. Demographic characteristics including age, sex, and occupation were recorded. It was made sure that all the study participants in both the group were strictly not under iron therapy or cyclosporine for at least 6 months prior to the time of the enrollment. Participants younger than 16 years and more than 60 years, H/O hemolytic disorders, known cases of anemia and hyperuricemia caused by diseases other than CKD, pregnancy, liver disease, thyroid disorder, and patient under medication for anemia and hyperuricemia were excluded from the study. A 5 ml of venous blood was drawn from the study subjects for hematological and biochemical tests, respectively. Laboratory standard operating procedure was followed for all the laboratory analysis. Internal quality control sera, both normal and pathological were also run for each lot of the test samples in order to validate the results. Serum creatinine concentration was measured by the modified Jaffe’s method. Serum uric acid level was measured by uricase method and hemoglobin, packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were measured using standard laboratory techniques. Hyperuricemia was defined as the serum uric acid level greater than 7 mg/dl in men and greater than 6 mg/dl in women. Furthermore, anemia was defined as the hemoglobin level less than 13.0 g/dl for men and less than 12.0 g/dl for women as per the World Health Organization guidelines. CKD was defined as either (a) the presence of microalbuminuria (>3.4 mg/mmol of albumin creatinine ratio) as a marker of kidney damage or (b) reduced excretory function with an estimated glomerular filtration rate (eGFR) <60 ml/minute/1.73 m² as a marker of kidney dysfunction or both for more than 3 months. Furthermore, CKD was defined and classified into five stages of CKD as per the National Kidney Foundation guidelines. The formula of the modified diet renal disease equation was used to calculate eGFR. Data were entered in Microsoft Excel 2007 and then converted to IBM Statistical Package for the Social Sciences and analyzed in version 20. Descriptive statistics were used to analyze demographic parameters. Descriptive statistics were interpreted in the form of mean with standard deviation (SD), median with interquartile range. Independent t-test, chi-square test, and one way analysis of variance (ANOVA) was used for inferential statistics. Data were first checked for normal distribution using the Kolmogorov–Smirnov test. For normally distributed data, mean with SD, Pearson co-relation, independent’s test were applied. ANOVA test was applied for different stages of CKD. A p-value less than 0.05 at 95% confidence interval was considered statistically significant.

Table 1. Pattern of anemia and hyperuricemia in male and female study subjects.

Male population Female population Total study population
CKD Control CKD Control CKD Control
Total number 138 37 79 23 217 60
Anemia 88 (63.8%) 7 (18.9%) 47 (59.5%) 5 (21.7%) 135 (62.2%) 12 (20%)
Hyperuricemia 32 (23.2%) 3 (8.1%) 22 (27.8%) 3 (13.0%) 54 (24.8%) 6 (10%)

Results

The present study found the mean age of the female having CKD and non-CKD to be 47 ± 13 years and 31 ± 11 years, receptively, and mean age for the male with CKD and non-CKD were 49 ± 12 years and 39 ± 16 years, respectively (Table 1). The comparison of the various biochemical parameters in the study population has been illustrated in Table 1. Graphical representation of the gender and total prevalence of anemia and hyperuricemia in different stages of CKD and overall CKD population has been represented in Figures 1 and 2, respectively. The present study found that male and female subjects are equally affected by CKD in the study population. Among the total CKD subjects, 62.2% of the patients were found to be anemic and 24.8% had hyperuricemia as illustrated in Table 2. The comparison of mean between the two study groups demonstrated a significant difference between all the parameters except age. Mean serum urea, creatinine, and uric acid were significantly higher and low levels of hemoglobin and eGFR were observed in CKD group. CKD was differentiated into five stages based on the eGFR. The mean difference in biochemical parameters between the two groups showed a statistically significant difference as depicted in Table 3. Mean uric acid levels showed an increasing trend from stage 1 CKD (4.76 ± 1.54 mg/dl) to stage 5 CKD (6.08 ± 2.42 mg/dl). Mean hemoglobin levels were significantly decreased from stage 2 CKD (13.59 ± 2.06 g/dl) to stage 5 CKD (9.65 ± 2.29 g/dl).

Figure 1. Bar diagram showing gender-wise total prevalence of anemia in different stages of CKD and in total CKD population.

Figure 2. Bar diagram showing gender wise total prevalence of hyperuricemia in different stages of CKD and in total CKD population.


Discussion

The present study involved assessment of different hematological and biochemical markers: hemoglobin, PCV, MCV, MCH, MCHC, serum uric acid, and urea to determine whether CKD is associated with anemia/hyperuricemia or not. The findings demonstrated that the mean hemoglobin level was significantly lower in the group comprising CKD patients compared with the control group. Serum uric acid level and urea level were significantly higher in the CKD group as compared with the non-CKD healthy control group. This study highlights an increased prevalence of anemia and hyperuricemia in non-dialysis CKD patients with the mean hemoglobin concentration of 11.5 ± 2.29 and 9.65 ± 2.29 g/dl for stage 4 CKD and stage 5 CKD, respectively. The uric acid concentration was 5.61 ± 1.70 and 6.08 ± 2.42 mg/dl for stage 4 and stage 5 CKD, respectively. This was in agreement with similar studies done by Afsar et al. [10] and Suiga et al. [11] which reported 75% and 73.1% of the patients with anemia in stage 4 and stage 5 CKD patients, respectively. In this study, a total of 33.1% of patients had an advanced stage of CKD, i.e., stage 5 CKD. The present study found 21.80% of stage 2 CKD, 55.50% of stage 3 CKD, 83.70% of stage 4 CKD, 91.50% of stage 5 CKD, and 62.21% of all stage CKD to be developing anemia. Furthermore, 7.80% of stage 2 CKD, 20% of stage 3 CKD, 24.30% of stage 4 CKD, and 35.20% of stage 5 CKD, and 22.10% of all stage CKD had hyperuricemia. McClellan et al. [12] conducted a study using a larger sample size (5,222 patients) with a cut-off point of 12 g/dl hemoglobin concentration to define anemia and found the overall incidence of anemia in CKD subjects to be 47.75% [7] which was lower than what is reported in the present study. The development of anemia in CKD was advocated by different factors such as absolute and/or relative hormone deficiency, inflammation, and oxidative stress. High degree of anemia was found to be related to the environmental factors including parasitic infestation: hookworm infestation, malnutrition, deficiencies of iron, folic acid, and vitamin B12. Iron profile, vitamin B12, and folic acid were not assessed in the present study which could be considered as one of the limitations of this study. The present study reports the high prevalence and strong association of anemia in CKD subjects. Few other factors including platelets dysfunction could also cause an increased risk for gastrointestinal bleeding, shorting half-life of RBC, and hemolysis due to uremic toxins accumulation resulting in anemia. The extent of anemia increases progressively with the decline of eGFR [9]. Furthermore, a significant decrease in hemoglobin level, PCV, MCV, MCH, and MCHC with the stages of CKD accounts for anemia. Similarly, the gradual increase in uric acid concentration with the progression of CKD stages indicates a strong association of uric acid concentration with CKD. A renewed interest in regard to the relationship between uric acid and nephropathy has been considered to be a deceased topic in the past epochs [13]. Studies from various research studies have suggested high serum uric acid as a risk factor for CKD. But, the therapies directed to lower uric acid on renal outcomes are indistinct. Larger studies are essential to determine the efficacy and safety of uric acid lowering therapies [14]. Hyperuricemia in CKD has been attributed to reduced fractional excretion with an increased proximal tubular reabsorption due to mild volume depletion as a result of relative aldosterone deficiency [15]. The hyperuricemia caused due to renal insufficiency results in increased fractional excretion of uric acid [16]. The present study depicts an increased concentration of serum uric acid in CKD compared to non-CKD patients. Among the patients with CKD, stage 5 CKD subjects had higher uric acid concentration compared to stage 2 CKD subjects with a statistically significant difference between the two groups. This was in accordance with the studies reported by Zivna et al. [15], Wu et al. [17], and Ito et al. [18]. Since the present study found anemia and hyperuricemia was exceedingly increased during the progression of CKD from stage 2 to stage 5, future studies are recommended on treatment plans directed toward treating anemia and lowering the serum uric acid level which could definitely delay the progression of CKD and consequent decrease in GFR to a large extent.

Table 2. Comparison of different variables between the study groups.

Study characteristics Female Male Total
CKD Non-CKD p-value CKD Non-CKD p-value CKD Non-CKD p-value
Mean age (years) 47 ± 13 31 ± 11 0.355 49 ± 12 39 ± 16 0.228 48 ± 12 36 ± 15 0.094
Urea (mg/dl) 81 ± 60 60 ± 27 <0.001 87 ± 65 28 ± 13 <0.001 85 ± 64 27 ± 11 <0.001
Creatinine (mg/dl) 3.4 ± 3.1 0.7 ± 0.07 <0.001 3.7 ± 3.4 0.8 ± 0.1 <0.001 3.6 ± 3.3 0.7 ± 0.1 <0.001
Uric acid (mg/dl) 5 ± 2.2 4.9 ± 1.4 <0.001 5.8 ± 1.8 4.9 ± 1.6 <0.001 5.5 ± 1.9 4.9 ± 1.5 <0.001
Hbconc 11.3 ± 2.4 13.5 ± 2.4 <0.001 11.9 ± 2.8 14.6 ± 1.8 <0.001 11.7 ± 2.7 14.1 ± 2.1 <0.001
PCV 32.9 ± 6.7 37.4 ± 9.6 <0.001 34.7 ± 7.9 41.7 ± 5.4 <0.001 34 ± 7.5 40 ± 7.5 <0.001
MCV (fl) 86.3 ± 5.9 85.8 ± 5.8 <0.001 85.8 ± 11.1 84.6 ± 11.3 <0.001 86 ± 9.5 85 ± 9.6 0.062
MCH (pg) 29.4 ± 2.7 29.8 ± 2.6 <0.001 29.8 ± 2.9 29.9 ± 3.3 <0.001 29.6 ± 2.8 29.9 ± 3 <0.001
MCHC (%) 34 ± 1.5 34.6 ± 1.4 <0.001 34.2 ± 1.4 34.5 ± 1.6 <0.001 34.1 ± 1.5 34.6 ± 1.5 <0.001
eGFR (ml/minute) 37.9 ± 30.4 106.5 ± 13.6 <0.001 38.4 ± 27.3 127.5 ± 30.1 <0.001 38.1 ± 28.4 119.5 ± 27 <0.001

Table 3. Comparison of hemoglobin level, RBC indices, and uric acid in different stages of CKD.

Parameters CKD V CKD IV CKD III CKD II p-value
Uric acid (mg/dl) 6.08 ± 2.42 5.61 ± 1.70 5.45 ± 1.67 4.76 ± 1.54 <0.001
Hemoglobin (g/dl) 9.65 ± 2.29 11.50 ± 2.29 12.27 ± 2.02 13.59 ± 2.06 <0.001
PCV (%) 28.43 ± 6.58 34.0 ± 6.30 35.67 ± 6.17 39.16 ± 5.55 <0.001
MCV (fl) 86.31 ± 6.49 85.86 ± 7.47 84.80 ± 16.71 86.60 ± 6.0 0.062
MCH (pg) 29.30 ± 2.62 29.09 ± 3.07 30.22 ± 2.96 29.90 ± 2.7 <0.001
MCHC (%) 33.92 ± 1.51 33.75 ± 1.44 34.23 ± 1.47 34.58 ± 1.35 <0.001

Conclusion

A high prevalence of anemia and hyperuricemia was found in all stages of CKD. Also, it was found that the incidence of anemia and hyperuricemia increased with the progression of CKD, reporting a strong association between hyperuricemia and anemia with CKD. Moreover, the present study recommends treatment plans directed toward maintaining the hemoglobin levels and decreasing the uric acid concentration that would help in delaying the progression of CKD and consequent decrease in eGFR to a large extent.


Acknowledgment

We kindly acknowledge Modern Technical College and Sumeru Kidney Hospital for the support in the study.


List of Abbreviations

CKD Chronic kidney disease
CVD Cardiovascular disease
eGFR Estimated glomerular filtration rate
MCH Mean corpuscular hemoglobin
MCV Mean corpuscular volume
MCHC Mean corpuscular hemoglobin concentration
PCV Packed cell volume

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this article.


Funding

None.


Consent for publication

Informed consent was obtained from all the participants.


Ethical approval

This study has been approved by the Institutional ethical review Board, Modern Technical College, No. 11/15/16; dated 7/7/2015.


Author details

Saroj Kunwar1, Bimal Chaulagain1, Rajendra K. C.1, Pradeep Pokhrel1, Apeksha Niraula2

  1. Department of Biochemistry, Modern Technical College, Lalitpur, Nepal
  2. Department of Biochemistry, B.P. Koirala Institute of Health Sciences, Dharan, Nepal

References

  1. Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Amer Soc Nephrol. 2005;16(2):489–95. https://doi.org/10.1681/ASN.2004030203
  2. McCullough PA, Lepor NE. The deadly triangle of anemia, renal insufficiency, and cardiovascular disease: implications for prognosis and treatment. Rev Cardiovasc Med. 2005;6(1):1. https://doi.org/10.1016/j.carrev.2005.06.002
  3. Delaney MP, Price CP, Lamb EJ. Kidney disease. In Teitz textbook of clinical chemistry and molecular diagnostics. 5th ed. Philadelphia, PA: Elsevier Publishers; 2013. pp. 669–707.
  4. Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleveland Clin J Med. 2006;73(3):289. https://doi.org/10.3949/ccjm.73.3.289
  5. Kang D, Nakagawa T, Watanabe S, Kanellis J, Johnson RJ. Hypertension and the kidney: new roles for uric acid in the pathogenesis of hypertension and renal disease. Nephrology. 2003;8:A4.
  6. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Amer J Kid Dis. 2006;47(5 Suppl 3):S11.
  7. Plantinga LC, Tuot DS, Powe NR. Awareness of chronic kidney disease among patients and providers. Adv Chronic Kid Dis. 2010;17(3):225–36. https://doi.org/10.1053/j.ackd.2010.03.002
  8. Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG, et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension. 1989;13(5_supplement):I80.
  9. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Amer Soc Nephrol. 1998;9(12 Suppl):S16–23.
  10. Afshar R, Sanavi S, Salimi J, Ahmadzadeh M. Haematological profile of chronic kidney disease (CKD) patients in Iran in predialysis stages and after initiation of haemodialysis. Saudi J Kidney Transpl. 2010;21:368–71.
  11. Suega K, Bakta M, Dharmayudha TG, Lukman JS, Suwitra K. Profile of anemia in chronic renal failure patients: comparison between predialyzed and dialyzed patients at the Division of Nephrology, Department of Internal Medicine, Sanglah Hospital, Denpasar, Bali, Indonesia. Acta Med Indones. 2005;37:190–4.
  12. McClellan W, Aronoff SL, Bolton WK, Hood S, Lorber DL, Tang KL, et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin. 2004;20:1501–10.
  13. Beck LH. Requiem for gouty nephropathy. Kidney Int. 1986;30:280–7.
  14. Eleftheriadis T, Golphinopoulos S, Pissas G, Stefanidis I. Asymptomatic hyperuricemia and chronic kidney disease: narrative review of a treatment controversial. J Adv Res. 2017;8(5):555–60. https://doi.org/10.1016/j.jare.2017.05.001
  15. Zivna M, Hulkovs H, Matignon M, Hodanova K, Vyletal P, Kalbacova M, et al. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Amer J Human Genet. 2009;85(2):204–13. https://doi.org/10.1016/j.ajhg.2009.07.010
  16. Danovitch GM. Uric acid transport in renal failure a review. Nephron. 1972;9(5):291–9. https://doi.org/10.1159/000180160
  17. Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Hung MJ, et al. Re-evaluating the predictive roles of metabolic complications and clinical outcome according to eGFR levels—a four-years prospective cohort study in Taiwan. BMC Nephrol. 2013;14(1):92. https://doi.org/10.1186/1471-2369-14-92
  18. Ito H, Antoku S, Furusho M, Shinozaki M, Abe M, Mifune M, et al. The prevalence of the risk factors for atherosclerosis among type 2 diabetic patients is greater in the progressive stages of chronic kidney disease. Nephron Extra. 2013;3(1):66–72. https://doi.org/10.1159/000353592


How to Cite this Article
Pubmed Style

Kunwar S, Chaulagain B, KC R, Pokhrel P, Niraula A. Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow. IJMDC. 2019; 3(8): 648-653. doi:10.24911/IJMDC.51-1542790103


Web Style

Kunwar S, Chaulagain B, KC R, Pokhrel P, Niraula A. Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow. http://www.ijmdc.com/?mno=18223 [Access: September 23, 2019]. doi:10.24911/IJMDC.51-1542790103


AMA (American Medical Association) Style

Kunwar S, Chaulagain B, KC R, Pokhrel P, Niraula A. Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow. IJMDC. 2019; 3(8): 648-653. doi:10.24911/IJMDC.51-1542790103



Vancouver/ICMJE Style

Kunwar S, Chaulagain B, KC R, Pokhrel P, Niraula A. Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow. IJMDC. (2019), [cited September 23, 2019]; 3(8): 648-653. doi:10.24911/IJMDC.51-1542790103



Harvard Style

Kunwar, S., Chaulagain, . B., KC, . R., Pokhrel, . P. & Niraula, . A. (2019) Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow. IJMDC, 3 (8), 648-653. doi:10.24911/IJMDC.51-1542790103



Turabian Style

Kunwar, Saroj, Bimal Chaulagain, Rajendra KC, Pradeep Pokhrel, and Apeksha Niraula. 2019. Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow. International Journal of Medicine in Developing Countries, 3 (8), 648-653. doi:10.24911/IJMDC.51-1542790103



Chicago Style

Kunwar, Saroj, Bimal Chaulagain, Rajendra KC, Pradeep Pokhrel, and Apeksha Niraula. "Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow." International Journal of Medicine in Developing Countries 3 (2019), 648-653. doi:10.24911/IJMDC.51-1542790103



MLA (The Modern Language Association) Style

Kunwar, Saroj, Bimal Chaulagain, Rajendra KC, Pradeep Pokhrel, and Apeksha Niraula. "Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow." International Journal of Medicine in Developing Countries 3.8 (2019), 648-653. Print. doi:10.24911/IJMDC.51-1542790103



APA (American Psychological Association) Style

Kunwar, S., Chaulagain, . B., KC, . R., Pokhrel, . P. & Niraula, . A. (2019) Hyperuricemia, anemia and chronic kidney disease: a conundrum in the shadow. International Journal of Medicine in Developing Countries, 3 (8), 648-653. doi:10.24911/IJMDC.51-1542790103