Risk Factors of End Stage Renal Disease in Peshawar, Pakistan: Odds Ratio Analysis

AIM: The basic aim of this study was to discover the association of End Stage Renal Disease (ESRD) with various risk factors. End Stage Renal Failure is the last stage of the chronic renal failure in which kidneys become completely fail to function. MATERIALS AND METHODS: The data were collected from the patients of renal diseases from three major hospitals in Peshawar, Pakistan. Odds ratio analysis was performed to examine the relationship of ESRD (a binary response variable) with various risk factors: Gender, Diabetic, Hypertension, Glomerulonephritis, Obstructive Nephropathy, Polycystic kidney disease, Myeloma, SLE Nephritis, Heredity, Hepatitis, Excess use of Drugs, heart problem and Anemia. RESULTS: Using odds ratio analysis, the authors found that the ESRD in diabetic patients was 11.04 times more than non-diabetic patients and the ESRD were 7.29 times less in non-hypertensive patients as compared to hypertensive patients. Similarly, glomerulonephritis patients had 3.115 times more risk of having ESRD than non-glomerulonephritis. Other risk factors may also, to some extent, were causes of ESRD but turned out insignificant due to stochastic sample. CONCLUSION: The authors concluded that there is a strong association between ESRD and three risk factors, namely diabetes, hypertension and glomerulonephritis.


Introduction
Statistical methods are applied frequently in medical research, which deals with issues that are of great concern for the general public. It is now a wellknown fact that no research could be carried out without having sufficient knowledge of Statistics. Particularly, medical research requires a good understanding of statistical methods.
End Stage Renal Disease (ESRD) is the last stage of the chronic renal failure in which kidneys fail to function completely. At this stage, the kidney stops its functions to remove the impurities and control electrolytes. The symptoms of ESRD comprise less urine output, swelling of legs, face, nausea and vomiting [1].
ESRD is one of the major health problems throughout the world. Several investigations have been carried out to study various risk factors of the ESRD. The United States Renal Data System (USRDS) established in 1989. This system is the largest and most comprehensive national Chronic Kidney Disease (CKD) and ESRD surveillance system [2]. The death rate due to ESRD in western countries especially in the USA is higher, but in Asian countries like Pakistan, India, Bangladesh; there are also a significant number of deaths due to ESRD [3].
It has been established that both low estimated Glomerular Filtration Rate (eGFR) and high albuminuria were independently associated with http://www.mjms.mk/ http://www.id-press.eu/mjms/ mortality and ESRD regardless of age across a wide range of populations [4]. A retrospective crosssectional study was conducted to investigate the prevalence and associated comorbidities of Stage 3 (GFR 30-59 ml/min/1.73 m^2) and Stages 4 and 5 (GFR <30 mL/min/1.73 m^2) CKD among Chinese nursing home older adults. The researchers concluded that stages 3 to 5 CKD are widespread in Chinese nursing home older adults [5]. Regardless of higher risks of mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and Albumin-to-Creatinine Ratio (ACR) are much the same irrespective of the presence or absence of diabetes, highlighting the significance of kidney disease as a predictor of clinical outcomes [6].
It has been recognized that males and females face increased risk of all-cause mortality, cardiovascular mortality, and ESRD with lower estimated GFR and higher albuminuria [7]. It has been shown that declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD development [8]. A kidney failure definition, including treated and untreated disease identifies more cases than linkage to the United States Renal Data System registry alone, particularly among older adults [9]. It has been found that CKD is increasingly common in older adults. Competing risks of death influence the risk of development to ESRD [10].
By using survival analysis through the Cox proportional hazard model, the researchers found that the elevated C -reactive protein (CRP) was a robust predictor of mortality in ESRD patients. In a study of 663 ESRD patients (374 males and 289 females), the researchers also found that CRP was a strong predictor. CRP had positive correlation (= 0.369; pvalue equal to 0.001) in addition, the coefficient of correlation for females (= 0.519; p-value < 0.0001) and male correlation (= 0.372; p-value < 0.0001) [11].
A univariate Cox regression analysis was carried out and the researchers found that the chlamydia pneumonia infection was related to the cardiovascular risk of ESRD patients. In a cohort of 227 ESRD patients, the Hazard Ratio of mortality was 1.08 with 95% confidence interval (0.678 to 1.722); pvalue = 0.737. The researchers concluded that the chlamydia pneumonia infection is a major risk factor in patients with ESRD [12].
In a prospective cohort study of 143802 patients in China, having an age of 40 years or above, the researchers found that the Body Mass Index (BMI) is strongly associated with ESRD. The multivariateadjusted risks for ESRD are 1.389 with 95% confidence interval (1.021 to 1.909) for BMI < 18.52 kg/m, 1.213 with 95% confidence interval (0.919 to 1.598) for BMI (25.01 to 29.93 kg/m) and 2.142 with confidence interval 95% (1.392 to 3.289) for BMI ≥ 30.01 kg/m with J-shaped association [13]. A cohort study was carried out in survival analysis and the researchers concluded that the independent risk factors of ESRD are sex, race, anemia and heredity [14].
In this study, odds ratio analysis was used to examine the relationship of ESRD with various risk factors.

Materials and Methods
To determine the effects of various risk factors on ESRD, this study was carried out based on the data obtained from three major hospitals in Peshawar: (i) Hayatabad Medical Complex, (ii) Lady Reading Hospital and (iii) Khyber Teaching Hospital. The association of various risk factors with the occurrence of ESRD was determined through the statistical technique of odds ratio analysis. A total of 407 patients was examined for the presence or absence of ESRD. The statistical analyses were performed with SPSS software package.
Odds and the odds ratio: The probability of interested events divided by the probability of noninterested events are called the Odds, i.e. Odd = P/1-P, where P is the probability of interested events. If the observed dichotomous data contain 'X' number of interested events in 'n' outcomes, then the odds ratio of interest can be calculated as: 'X' denotes the number of occurrences of interested events and 'n-X' indicates the number of noninterested events.
In order to compare two binary data sets, the ratio of odds of interest in one set to the odds of the other data set, is a relative measure of odds of interest. The odds ratio is denoted by  , and mathematically, it is defined as: If the probability of interest in two data sets is equal, then the odds ratio (Ψ) = 1 and if odd ratio (Ψ) < 1, then the odds of interest will be less in the first data set than in the second one. On the other hand, if the odds ratio (Ψ) > 1, then the odds of an interest will be greater in the first data set [15].

Statistical inference based on odds ratio:
To estimate the odds ratio, the binary data are needed to arrange in (2x2) contingency table given as:  This estimated odds ratio ( ) is usually termed as "cross-product ratio", as it is obtained by multiplying the two pairs of diagonal values in the (2 x 2) contingency table [16].

Contingency
To test such an association, the hypothesis is considered as: that the two variables (ESRD and Risk factors) are independent, that is, risk factors do not affect ESRD.
The test-statistic is: has an approximate standard normal distribution. An approximate 100 (1-α) % confidence interval for ) ln( is constructed as: The confidence interval given by equation (I) on inversion will give us the confidence interval for ψ as: If the interval contains unity, it indicates independence; otherwise an association between risk factor and ESRD is significant.

Results
Several researchers have investigated the association of ESRD and its various risk factors. A meta-analysis study was conducted. The interpretation of this study was that CKD should be regarded as at least an equally relevant risk factor for mortality. These researchers further interpreted that ESRD in individuals without hypertension should be regarded as it is in those with hypertension [17]. It has been revealed that diabetes, higher systolic blood pressure, lower estimated glomerular filtration rate and black race were risk factors for developing treated chronic kidney failure irrespective of albuminuria status, although the absolute risk of kidney failure in participants without albuminuria was very low. These researcher also showed that their findings support testing for kidney disease in high-risk populations, which often have otherwise unrecognized kidney disease [18].
To investigate the relationship of ESRD with various risk factors, we used odds ratio analysis.

ESRD versus gender
Contingency  The odds of ESRD show that the males are 1.4 times more exposed to ESRD than the females and the Log of the odds ratio is 0.336 (with a standard error = 0.208). The confidence interval for the odds ratio is (0.931, 2.104) at the 5% level of significance. The interval contains unity; it indicates independence (no association between Gender and ESRD). Also, pvalue is greater than 0.05, the result is insignificant. It is concluded that there is no association between Gender and ESRD.

ESRD versus diabetic
Contingency table of ESRD versus diabetic is given in Table 2. The calculated values are: Odd Ratio = 11.04, Chi-square = 141.883, p-value < 0.001 and the confidence interval is (6.913, 17.63). The odds of ESRD show that the diabetic patients are 11.04 times more exposed to ESRD than the non-diabetic patients and the Log of odds ratio is 2.402 (with a standard error = 0.239). The confidence interval for the odds ratio is (6.913, 17.63) at the 5% level of significance. The interval does not contain unity; it indicates that there is an association between Diabetic and ESRD. Also, observed p-value is less than 0.05, the result is significant. It is concluded that there is a strong association between diabetes and ESRD.

ESRD versus hypertension
Contingency table of ESRD versus hypertension is given in Table 3. The calculated values are: Odd Ratio = 7.287, Chi-square = 77.56, pvalue < 0.001 and the confidence interval is (4.571, 11.616). The odds of ESRD show that the hypertensive patients are 7.287 times more exposed to ESRD than the non-hypertensive patients and the Log of odds ratio is 1.986 (with a standard error = 0.238). The confidence interval for the odds ratio is (4.571, 11.616) at the 5% level of significance. The interval does not contain unity; it indicates there is an association between hypertension and ESRD. Also, observed p-value is less than 0.05, the result is significant. It is concluded that there is a strong association between hypertension and ESRD.

ESRD versus glomerulonephritis
Contingency  The odds of ESRD show that the glomerulonephritis patients are 3.115 times more exposed to ESRD than the non-glomerulonephritis patients and the Log of odds ratio is 1.136 (with a standard error = 0.211). The confidence interval for the odds ratio is (2.059, 4.712) at the 5% level of significance. The interval does not contain unity; it indicates there is association between glomerulonephritis and ESRD. Also, observed p-value is less than 0.05, the result is significant. It is concluded that there is a strong association between glomerulonephritis and ESRD. Contingency  table  of  ESRD  versus  obstructive nephropathy is given in Table 5. The calculated values are: Odd Ratio = 1.2, Chi-square = 0.542, p-value = 0.462 and the confidence interval is (0.738, 1.952). The odds of ESRD show that the obstructive nephropathy patients are 1.2 times more exposed to ESRD than the non-obstructive nephropathy patients and the Log of odds ratio is 0.182 (with standard error = 0.248). The confidence interval for the odds ratio is (0.738, 1.952) at the 5% level of significance. The interval contains unity; it indicates independence. Also, observed p-value is greater than 0.05, the result is insignificant. It is concluded that there is no association between obstructive nephropathy and ESRD.

ESRD versus polycystic kidney disease
Contingency table of ESRD versus Polycystic kidney is given in Table 6. The calculated values are: Odd Ratio = 1.67, Chi-square = 0.186, p-value = 0.403 and Confidence Interval is (0.553, 2.527). The odds of ESRD show that the patients, who had Polycystic kidney disease, are 1.67 times more exposed to ESRD than the patients who do not have Polycystic kidney disease and the Log of odds ratio is 0.167 (with standard error = 0.288). The confidence interval for the odds ratio is (0.553, 2.527) at the 5% level of significance. The interval contains unity; it indicates independence. Also, observed pvalue is greater than 0.05, the result is insignificant. It is concluded that there is no association between polycystic kidneydisease and ESRD.

ESRD versus myeloma
Contingency table of ESRD versus myeloma is given in Table 7. The calculated values are: Odd Ratio = 1.081, Chi-square = 0.20, p-value = 1.000 and Confidence Interval is (0.368, 3.174). The odds of ESRD show that the myeloma patients are 1.081 times more exposed to ESRD than the non-myeloma patients and the Log of odds ratio is 0.078 (with a standard error = 0.302). The confidence interval for the odds ratio is (0.368, 3.174) at the 5% level of significance. The interval contains unity; it indicates independence. Also, observed p-value is greater than 0.05, the result is insignificant. It is concluded that there is no association between myeloma and ESRD.

ESRD versus SLE nephritis
Contingency  The odds of ESRD show that the SLE nephritis patients are 1.123 times more exposed to ESRD than the non-SLE nephritis patients and the Log of odds ratio is 0.116 (with standard error = 0.551). The confidence interval for the odds ratio is (0.41, 3.077) at the 5% level of significance. The interval contains unity; it indicates independence. Also, observed pvalue is greater than 0.05, the result is insignificant. It is concluded that there is no association between SLE nephritis and ESRD.

ESRD versus heredity
Contingency table of ESRD versus heredity is given in Table 9. The calculated values are: Odd Ratio = 1.757, Chi-square = 1.818, p-value = 0.202 and Confidence Interval is (0.767, 4.024). The odds of ESRD show that the patients, who have a family history of ESRD, are 1.757 times more exposed to ESRD than the patients who do not have a family history of ESRD and the Log of odds ratio is 0.564 (with standard error = 0.423). The confidence interval for the odds ratio is (0.767, 4.024) at the 5% level of significance. The interval contains unity; it indicates independence. Also, p-value is greater than 0.05, the result is insignificant. It is concluded that there is no association between heredity and ESRD.

ESRD versus hepatitis
Contingency table of ESRD versus hepatitis is given in Table 10. The calculated values are: Odd Ratio = 1.792, Chi-square = 4.495, p-value = 0.063 and Confidence Interval is (0.747, 2.277). The odds of ESRD show that the hepatitis patients are 1.792 times more exposed to ESRD than the non-hepatitis patients and the Log of odds ratio is 0.253 (with a standard error = 0.277). The confidence interval for the odds ratio is (0.747, 2.277) at the 5 % level of significance. The interval contains unity; it indicates independence. Also, observed p-value is greater than 0.05, the result is insignificant. It is concluded that there is no association between hepatitis and ESRD.

ESRD versus drug usage
Contingency table of ESRD versus drug usage is given in Table 11. The calculated values are: Odd Ratio = 1.157, Chi-square = 0.091, p-value = 0.809 and Confidence Interval is (0.100, 2.994). The odds of ESRD show that the patients, who used a lot of drugs, are 1.157 times more exposed to ESRD than the patients who do not use a lot of drugs and the Log of odds ratio is 0.146 (with standard error = 0.485). The confidence interval for the odds ratio is (0.100, 2.994) at the 5% level of significance. The interval contains unity; it indicates independence. Also, observed p-value is greater than 0.05, the result is insignificant. It is concluded that there is no association between drug usage and ESRD.

ESRD versus heart problem
Contingency table of ESRD versus heart problem is given in  The odds of ESRD show that the patients who have heart problem are 1.231 times more exposed to ESRD than the patients who do not have heart problems and the Log of the odds ratio is 0.208 (with standard error = 0.422). The confidence interval for the odds ratio is (0.543, 2.285) at the 5% level of significance. The interval contains unity; it indicates independence. Also, observed p-value is greater than 0.05, the result is insignificant. It is concluded that there is no association between heart problem and ESRD.

ESRD versus anemia
Contingency table of ESRD versus anemia is given in Table 13. The calculated values are: Odd Ratio = 1.083, Chi-square = 0.088, p-value = 0.788 and Confidence Interval is (0.676, 4.024).
The odds of ESRD show that the anemia, patients are 1.083 times more exposed to ESRD than the non-anemia patients and the Log of odds ratio is 0.080 (with a standard error = 0.269). The confidence interval for the odds ratio is (0.767, 4.024) at the 5 % level of significance. The interval contains unity; it indicates independence. Also, observed p-value is greater than 0.05, the result is insignificant. It is concluded that there is no association between anemia and ESRD.

Discussion
The major aim of this study was to determine the most important risk factors of ESRD in Peshawar. A total of 407 patients was examined in the three major hospitals of Peshawar and the phenomena of ESRD was studied in relation to different risk factors like diabetic, hypertension, glomerulonephritis, obstructive nephropathy, polycystic kidney diseases, myeloma, SLE nephritis, heredity, hepatitis, excess use of drugs, heart problem and anemia.  Using odds ratio analysis, it was found that the ESRD in diabetic patients were 11.04 times more than non-diabetic patients and the ESRD in hypertensive patients were 7.29 times more than nonhypertensive patients. Similarly, glomerulonephritis patients have 3.115 times more chances to have ESRD than non-glomerulonephritis. This analysis shows that there was a strong association between ESRD and the three risk factors diabetes, hypertension and glomerulonephritis. The odds of ESRD for heredity were 1.76 times more than nonheredity patients. The odds of ESRD for non-hepatitis patients were 1.792 times less than hepatitis patients.
Based on odds ratio analysis, using data from 407 patients from three major hospitals of Peshawar, the researchers concluded that the main causes of ESRD were the three risk factors i.e. diabetes, hypertension and glomerulonephritis. Other risk factors, i.e. obstructive nephropathy, heredity and hepatitis may also, to some extent, causes of ESRD but in this study, it turned out to be insignificant due to stochastic sample.
The researchers concluded that the main finding of this study is that there is a strong association between ESRD and the three risk factors namely diabetic, hypertension & glomerulonephritis.