Objective: To investigate the common risk factors involved in the pathogenesis of renal stones and diabetes mellitus in adults.
Method: The case-control study was carried out at the urology outpatient department and diabetic clinic of the Liaquat University of Medical and Health Sciences, Hyderabad, Pakistan, from January 2019 to January 2020, and comprised renal stone patients in group A, diabetes mellitus patients in group B and healthy controls in group C. Height and weight were determined for all subjects, followed by calculation of body mass index. Serum samples were analysed for creatinine, uric acid, total antioxidants, iron, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, lactate dehydrogenase, xanthine oxidase, C-reactive protein, and nuclear factor kappa-light-chain-enhancer of activated B cells. Intra-group comparisons were done. Data was analysed using SPSS 22.
Results: Of the 400 subjects, 100(25%) each were in groups A and B, and 200(50%) were in group C. Overall, there were 236(59%) males and 164(41%) females. The age range of the sample was 20-40 years. Obesity was more prevalent in group B 26(26%) as against 4(4%) in group A and 20(10%) in group C. Compared to group C, superoxide dismutase (p=0.0128) and C-reactive protein (p=0.032) levels were higher in group B, while the levels were lower for uric acid (p=0.0067), iron (p=0.0147) and xanthine oxidase (p=0.0360). Compared to group C, serum superoxide dismutase (p=0.0001), malondialdehyde (p=0.0011) and nuclear factor kappa-light-chain-enhancer of activated B cells (p=0.0040) levels were significantly higher in group A, while the levels were lower for xanthine oxidase (p=0.0002) and total antioxidants (p=0.0018). Group A had significantly raised level of malondialdehyde (p=0.0034) and decreased level of total antioxidants (p=0.0232) compared to group B.
Conclusion: Oxidative stress is a common risk factor involved in the pathogenesis of both renal stones and diabetes mellitus. Oxidative stress accompanying low-grade inflammation seems to cause diabetes mellitus, while excessive oxidative stress owing to raised levels of superoxide dismutase and malondialdehyde, and low levels of total antioxidants might lead to renal stone disease.
Renal stones (RS) and diabetes mellitus (DM) are the two main health concerns in many countries of the world. Both diseases are chronic health problems, causing suffering and financial burden for patients, families and nations. The global RS frequency in males aged 70 years ranges from approximately 4% in Britain to 1-5% in Asia, to 13% in North America and to 20% in Saudi Arabia.1-3 The peak age for RS presentation in Pakistan is 20-29 years.4 With an increase in the level of affluence, the overall RS prevalence has increased in both developed and developing countries. According to data available for the United States, 37% increase in RS cases in both genders was noted between 1976-80 and 1988-94.5 Moreover, nephrolithiasis is a recurrent disease with 14%, 35% and 52% chance of recurrence after 1, 5 and 10 years of the first episode, respectively.6 As such, RS is a serious health concern.7
Diabetes mellitus (DM) is a global chronic health issue caused when the pancreas fails to form sufficient insulin or when the insulin formed by the pancreas cannot be efficiently used to keep the normal blood glucose level.8 This ultimately leads to hyperglycaemia, which is an important DM feature.8
Chronic uncontrolled DM over time can lead to various complications, such as retinopathy, peripheral vascular disease, neuropathy and nephropathy.9
As per the International Diabetic Federation (IDF) report of 2017, 451 million people were suffering from DM worldwide, and by year 2045, this figure is estimated to touch 693 million.10 Until recently, DM was seen only in young and elderly people, but it is now frequently reported in children as well.11
In recent years, it has been noted that the prevalence of both RS and DM has increased in many countries. The cases of RS, obesity and DM have nearly doubled during the last 18 years.1,12 The reason for this simultaneous upsurge in the incidence of RS and DM remains obscure.
Oxidative stress (OS), caused when reactive oxygen species are produced in amounts greater than the antioxidant capacity to maintain the balance, has been suggested by many investigators as a cause for the formation of kidney stones13 and the development of DM.14
Since the association between RS and DM is not completely known, there are reports that suggest that these associations between the two do exist and might be bidirectional.15
Elucidation of the underlying links between RS and DM is essential for the development of new therapeutic options.16
The current study was planned to investigate causal link between the genesis of RS and the pathogenesis of DM.
Patients and Methods
The case-control study was carried out at the urology outpatient department and diabetic clinic of the Liaquat University of Medical and Health Sciences (LUMHS), Hyderabad, Pakistan, from January 2019 to January 2020. After approval from the Bioethical Committee of the University of Sindh, Jamshoro, Pakistan, the sample size calculated by using the formula n=Z2Pq/e2 was raised using random sampling technique, and, after taking informed consent, the subjects were divided into RS patients in group A, DM patients in group B and healthy controls in group C.
Patients included regardless of gender in groups A and B had serum creatinine <1.2mg/dl with either RS or DM. RS patients were enrolled from the urology outpatient department (OPD) prior to any intervention procedure, while DM patients were enrolled from the LUMHS diabetic clinic. Group C had healthy controls matched for age, gender and socioeconomic status having no personal or family history of RS or DM, and normal random blood sugar (RBS) level which was checked with a glucometer. Those excluded from all the groups were individuals on any dietary supplements, smokers and alcoholics as well as those with related disorders, such as hypercalcaemia, hyperoxaluria, gout, urinary tract infections and inflammatory diseases.
Body mass index (BMI) was calculated for every subject by dividing their weight in kg with square of height in cm.
The concentration of creatinine, uric acid, lactate dehydrogenase (LDH), C-reactive protein (CRP) and total iron in serum were measured using commercial kits purchased from Roche on Cobas 4000 c311 (CAT No 04826876001 Serial No 16E6-19) analyser.
Serum glutathione peroxidase (GPX), malondialdehyde (MDA), catalase, superoxide dismutase (SOD), xanthine oxidase (XO) and total antioxidants were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits purchased from Korean Biotech Company on Elisa Reader (DIA source, Belgium).
Data was analysed using SPSS 22. Results were presented as mean±standard deviation and frequencies and percentages. Student’s independent samples t-test was applied to assess any significant differences in the mean values of the parameters measured between groups A and C, between groups B and C, and between groups A and B. P<0.05 was considered statistically significant.
Of the 400 subjects, 100(25%) each were in groups A and B, and 200(50%) were in group C. Overall, there were 236(59%) males and 164(41%) females. The age range of the sample was 20-40 years. Obesity was more prevalent in group B 26(26%) as against 4(4%) in group A and 20(10%) in group C.
Compared to group C, SOD (p=0.0128) and CRP (p=0.032) levels were higher in group B, while the levels were lower for uric acid (p=0.0067), iron (p=0.0147) and XO (p=0.0360) (Table 1).
Compared to group C, serum SOD (p=0.0001), MDA (p=0.0011) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) (p=0.0040) levels were significantly higher in group A, while the levels were lower for XO (p=0.0002) and total antioxidants (p=0.0018)
Group A had significantly raised level of MDA (p=0.0034) and decreased level of total antioxidants (p=0.0232) compared to group B (Table 3).
The findings showed that serum parameters SOD, MDA, CRP, NF-KB, uric acid and total antioxidants were significantly (p<0.05) different among controls, DM patients and RS patients. In DM patients, as against the controls, uric acid, iron and XO levels were significantly lower and those of CRP and SOD were significantly higher. The level of NF-KB was also higher in DM patients. This suggests that OS in the presence of low-grade inflammation leads to DM development.17 Increased amount of superoxide activates various cell signalling pathways, ultimately resulting in high serum levels of CRP and NF-KB in DM patients.17
RS patients, compared to the controls, had significantly decreased XO and total antioxidant levels while increased levels of SOD, MDA and NF-KB. Uric acid and GPX levels were also found to be decreased in RS patients compared to the controls. The high serum SOD, MDA and low total antioxidant levels in RS patients suggest that OS is the main culprit involved in the causation of RS.
Likewise, comparison of serum parameters between DM and RS patients revealed that total antioxidants were significantly lower and MDA levels were higher in RS patients than in DM patients. This indicates that RS patients, as against DM patients, are at increased risk of mounting OS.
The results suggest that OS in the presence of low-grade inflammation may cause DM, while excessive OS, manifested by high levels of superoxide anion radical and low levels of total antioxidants, may lead to RS genesis. Since OS is commonly involved in the causation of both DM and RS disease, stress developed by one disease may promote the other.18 This might explain why RS patients are more prone to develop DM, while DM patients, as against the non-diabetics, are at an increased risk of developing RS.18,19
Literature review shows an association of obesity and DM with RS disease. Diet and lifestyle factors may be the common contributing factors for obesity, DM and RS disease.20
Lieske et al.12 in a population-based case-control study found that DM, obesity and hypertension (HTN) were associated with nephrolithiasis.
Literature suggests19 RS can cause HTN, myocardial infarction (MI), chronic renal disease and DM. Similarly, DM and HTN can lead to RS genesis. OS owing to any reason could be the main culprit involved in the pathogenesis of many renal and cardiovascular diseases.19
It is now well established that DM not only causes renal injury and inflammation, but also brings about variations in the urinary milieu which promotes precipitation of various stone-forming salts.10 In this connection, a link between DM and uric acid/calcium oxalate stone formation is strong since DM patients mostly develop dehydration, the main reason of renal stone formation, and have significantly higher excretion of oxalate,9 defective renal ammonia production, low urinary output of hydrogen (pH) and citrate.21-23 This might be the reason for higher rate of recurrence of renal stones in DM patients than in non- diabetics.
OS coupled with low-grade inflammation may cause DM, while excessive OS, manifested by increased amount of superoxide and decreased total antioxidants, may lead to RS development in adults. Since OS is commonly involved in the causation of both RS and DM in adults, OS developed by one disease may promote the other in certain circumstances.
Acknowledgment: We are grateful to the Higher Education Commission (HEC) of Pakistan for financial support.
Conflict of interest: One of the authors was member of the committee which signed the ethics review statement.
Source of Funding: The Higher Education Commission (HEC) of Pakistan.
1. Scales CD, Tasian GE, Schwaderer AL, Goldfarb DS, Star RA, Kirkali Z. Urinary stone disease: Advancing knowledge, patient care, and population health. Clin J Am Soc Nephrol 2016; 11: 1305-12.
2. Romero V, Akpinar H, Assimos DG. Kidney Stones: A global picture of prevalence, incidence, and associated risk factors. Rev Urol 2010; 12: e86-96.
3. Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol 2010; 25: 49-59.
4. Samo MJ, Khand TU, Memon JM, Khand FD, Ansari AF. The epidemiology and chemical composition of uri¬nary stones: A Study at the Liaquat Medical College Hos¬pital, Jamshoro. Specialist, Pak J Med Sci 1995; 12: 61-7.
5. Scales CD Jr, Smith AC, Hanley JM, Saigal CS. Urologic Diseases in America Project: Prevalence of kidney stones in the United States. Eur Urol 2012; 62: 160-5.
6. Uribarri J, Oh MS, Carroll, HJ. The first kidney stone. Ann Intern Med 1989; 111: 1006-9.
7. Kirkali Z, Rasooly R, Star RA, Rodgers GP. Urinary Stone Disease: Progress, Status, and Needs. Urology 2015; 86: 651-3.
8. World Health Organization (WHO) Global Report on Diabetes 2016; WHO: Geneva, Switzerland: 2016.
9. Ahmed KA, Muniandy S, Ismail IS. Type 2 diabetes and vascular complications: a pathophysiologic view. Biomed Res 2010; 21: 147-55.
10. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138: 271-81.
11. Nanditha A, Ma RC, Ramachandran A, Snehalatha C, Chan JC, Chia KS, et al. Review Diabetes in Asia and the Pacific: Implications for the Global Epidemic. Diabetes Care 2016; 39: 472-85.
12. Lieske JC, de la Vega LS, Gettman MT, Slezak JM, Bergstralh EJ, Melton LJ 3rd, et al. Diabetes mellitus and the risk of urinary tract stones: a population based case-control study. Am J Kidney Dis 2006; 48: 897-904.
13. Chaiyarit S, Thongboonkerd V. Mitochondrial dysfunction and kidney stone disease. Front Physiol 2020; 11: 566506.
14. Oguntibeju OO. Type 2 diabetes mellitus, oxidative stress and inflammation: Examining the links. Int J Physiol Pathophysiol Pharmacol 2019; 11: 45-63.
15. Nerli R, Jali M, Guntaka AK, Patni P, Patil S, Hiremath MB. Type 2 diabetes mellitus and renal stones. Adv Biomed Res 2015; 4: 180.
16. Sakhaee K, Maalouf NM, Sinnot B. Kidney stones: pathogenesis, diagnosis, and management. J Clin Endocrinol Metab 2012; 97: 1847-60.
17. Hasna A, Meiyappan K, Periyasam SG, Kalyaperumal M, Bobby Z, Subramaniam AVV. Is urolithiasis associated with increased levels of high sensitivity C-reactive protein and Interleukin-6 in diabetic patients? J Clin Diagn Res 2015; 9: BC01-3.
18. Khan SR. Is oxidative stress a link between nephrolithiasis and obesity, hypertension, diabetes, chronic kidney disease, metabolic syndrome? Urol Res 2012; 40: 95-112.
19. Khan SR. Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: evidence from clinical and experimental investigations. J Urol 2013; 189: 803-11.
20. Taylor EN, Stampfer MJ, Curhan GC. Diabetes mellitus and the risk of nephrolithiasis Kidney Int 2005; 68: 1230-35.
21. Eisner BH, Porten SP, Bechis SK, Stoller ML. Diabetic kidney ston formers excrete more oxalate and have lower urinary pH than Nondiabetics J Urol 2010; 183: 2244-8.
22. Hartman C, Friedlander JI, Moreira DM, Elsamra SE, Smith AD, Okek Z. Differences in 24-h urine composition between nephrolithiasi patients with and without diabetes mellitus” BJU Int 2015; 115: 619 24.
23. Daudon M, Traxer O, Conort P, Lacour B, Jungers P. Type 2 diabete increases the risk for uric acid stones. J Am Soc Nephrol 2006; 17 2026-33.