The Evaluation Incidence and Risk Factors of Mortality among Patients with End Stage Renal Disease in Southeast Turkey

Abstract

Aim. End stage renal disease (ESRD) presents with higher morbidity and mortality with respect to the general population. In recent study, the causes of mortality and associated risk factors in ESRD have been evaluated. Materials and Methods. In this study, 1538 patients diagnosed with ESRD in 10-year period were evaluated retrospectively. The patients were divided as dead (group 1) and alive (group 2). The patients' demographic features, causes of death, comorbidity at hospitalization, hematological and biochemical analyses, creatinine clearance at the beginning of hospitalization, daily urine volume, blood gas results, CRP value as inflammatory marker, ejection fraction, interventricular septum diameter, left ventricle posterior wall end-diastolic diameter, and left atrium diameter determined with echocardiography were recorded. Results. Mortality ratio of ESRD patients in a 10-year period was 14.1%. While the general mean age of all patients was 54.7 ± 16.6 and male/female ratio was 781/757, these ratios were 66.3 ± 21.8 and 114/103 in Group 1 and 52.8 ± 21.7 and 667/654 in Group 2. One or more comorbid pathologies were present in 82.9% of Group 1. The most common cause of mortality was cardiovascular diseases (CVD), and the most common cause of comorbidity was infections. Older age, anemia, absence of residual renal function, hypoalbuminemia, inflammation, impaired Ca and P metabolism, and left ventricular hypertrophy were significantly higher in Group 1 than in Group 2. Conclusion. CVD are the most important preventable causes of morbidity and mortality in all stages of chronic kidney disease. Taking precaution against CVD and the associated complications will provide a positive contribution in reducing morbidity and mortality among ESRD patients.

Keywords:

• end-stage renal disease
• all-causes mortality and morbidity

INTRODUCTION

Chronic kidney disease (CKD) is one of the major causes of morbidity and mortality in adult population. This situation is more dramatic in end stage renal disease (ESRD) and especially in cases with diabetic background. In the United States, diabetic nephropathy constitutes 35% of the etiology in ESRD, and a patient on chronic hemodialysis program has approximately a 20% five-year survival rate.[1] Survival of ESRD patients undergoing dialysis is worse than general population mainly because of serious cardiovascular diseases (CVD).[2–4] In spite of the contemporary point reached in the renal replacement therapy, the most important causes of death in the world are ESRD and related complications. For now, the mortality rate due to ESRD is even higher than many kinds of cancer, such as colon and prostate cancers.[3] Increased mortality ratio in CKD is present both before and during renal replacement therapy.[5] The most important cause of mortality in CKD patients is CVD. In dialysis patients, together with traditional risk factors CVD, current risk factors such as albuminuria and inflammation are important in this process.[6],[7] In addition, maintaining residual renal functions in ESRD is a good prognostic parameter.[8] Apart from cardiovascular events, sepsis, and infections, cerebrovascular events and gastrointestinal disorders are the other pathologies playing a role in morbidity and mortality among ESRD patients.[9–13]

In this study, we aimed to determine causes of mortality due to complications of ESRD and the associated risk factors over a 10-year period.

MATERIALS AND METHODS

Patients hospitalized in Dicle University Faculty of Medicine Nephrology Clinic between January 1996 and December 2005 with a diagnosis of ESRD were evaluated retrospectively. Southeastern Turkey is a developing region that shows a progression through to the modern civilization by adoption of west culture. The records of 1538 patients hospitalized within this period were investigated. The patients were divided into two groups as dead (Group 1) and alive (Group 2). Age, sex, causes of death, comorbidity at hospitalization, levels of urea, creatinine, glucose, Na, K, P, Ca, total protein, albumin, ALT, AST, total bilirubin, direct bilirubin, ALP, LDH, total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, uric acid, values of hemoglobin and hematocrit, counts of leukocyte and platelets, iron level and total iron binding capacity, transferrin saturation index, levels of ferritin, folic acid, vitamin B-12, and intact parathyroid hormone (iPTH) were enrolled. As inflammatory marker, levels of CRP at hospitalization were recorded, and Ca × P product was calculated.

Biochemical analyses were done by using routine biochemical procedures on Aeroset / C8000 autoanalyzer (Abbott Diagnostics, Illinois, USA). Complete blood counts were measured on Cell-dyn 3700 (Abbott Diagnostics, USA). Bicarbonate (HCO₃), pH, pO2, and pCO2 levels were assessed in heparinized arterial blood on radiometer blood gas analyzer ABL-735 (Belgium). CRP levels were established by electro chemiluminescence method on Roche Elecsys 2010 immunoassay analyzer, and intact parathormone (iPTH) was detected with two-site chemiluminescent enzyme-labeled immunometric method on IMMULITE 2000.

To evaluate renal functions at the beginning of hospitalization, creatinine clearance (CrCl) was calculated using the standard formula:

and in oligoanuria patients, the Cockcroft-Gauld Formula was used:

(for women, the estimated CrCl is multiplied by 0.85), and daily urine amount was recorded.

In evaluating cardiac functions, systolic and diastolic blood pressures measured with manual sphygmomanometer, ejection fraction, interventricular septum diameter, left ventricle posterior wall end-diastolic diameter, and left atrium diameter determined with echocardiography were detected using Hewlett-Packard Sonos 4500® Echocardiography System (Duluth, Georgia, USA).

Statistical analysis was done with Chisquare test, Pearson's correlation test, and Cox regression analysis on SPSS-11 PC program. The data were demonstrated as mean ± SD, and p < 0.05 was considered as statistically significant.

RESULTS

In all, 217 cases (14.1%) were in group 1 and 1321 (85.1%) were in group 2. Diabetes mellitus predominates in the etiologic distribution of ESRD in general and in both groups. Etiologic distribution of ESRD was shown in Table 1. One or more comorbid pathology was present 82.9% of Group 1, and 37 cases had no comorbidity. The most common comorbidity in all groups was infection (23.9%). Comorbidities and causes of death of cases at hospitalization were shown in Tables 2 and 3, respectively. Mean age of the patients was found to be 54.7 ± 16.6 years (i.e., mean age of male and female patients were 56.6 ± 15.3 years and 52.6 ± 18.1 years, respectively), and while male/female ratio was 781/757 among all patients, of the 217 patients in group 1, 114 (52.6%) were male and 103 (47.4%) were female, and mean mortality ratio was 14.1% among ESRD patients over the 10-year period. When considering five-year periods, this ratio was 19.5% for first five years (1996–2000) and 9.8% in the last five years (2001–2005). Distribution of causes of mortality was shown according to years in Figure 1, mortality ratio according to five-year periods was demonstrated in Figure 2, and the distribution of admissions and death was shown in Figure 3. Demographic, hematological, and biochemical features of patients' and CRP values as inflammatory parameter and echocardiographic findings and the distribution of these data according to groups were summarized in Tables 4 and 5.

Figure 1. Distributions of the causes of the mortality between 1996 and 2005. Abbreviations: CVS = cardiovascular causes, CVA = cerebrovascular accidents.

Figure 2. Mortality ratio according to five-year period and in total.

Figure 3. Number of total patients and exitus according to years.

Table 1 Etiological causes of ESRD according to groups and overall

Etiology	Groups
	Group I		Group II		Overall
	n	Ratio (%)	n	Ratio (%)	n	Ratio (%)
DM	40	18.44	312	23.62	352	22.89
HT	32	14.75	202	15.29	234	15.21
CGN	37	17.06	184	13.93	221	14.37
CTIN	12	5.54	119	9.01	131	8.52
CRD	11	5.07	108	8.17	119	7.74
Amiloidosis	11	5.07	86	6.51	97	6.31
VUR	5	2.30	26	1.97	31	2.01
UD	10	4.60	15	1.13	25	1.62
Alport syndrome	3	1.38	22	1.67	25	1.62
Malignancy	3	1.38	12	0.90	15	0.98
Urate nephropaty	3	1.38	9	0.68	12	0.78
MM kidneys	4	1.84	4	0.30	8	0.52
Unknown	46	21.19	222	16.81	268	17.43
Total	217	100.00	1321	100.00	1538	100.00

Abbreviations: DM = diabetes mellitus, CGN = chronic glomerulonephritis, HT = hypertension, CTIN = chronic tubulointerstisiel nephritis, CRD = cystic renal disease, VUR = vesicoureteral reflux, MM = multiple myeloma, UD = urologic disease (benign prostatic hyperplasia, stones, bladder tumor, etc.).

Table 2 Comorbid conditions at admission time

Comorbidity	Number of patients (n)	Ratio (%)
Infections	52	28.9
Pneumonia	31	17.2
Sepsis	21	11.7
Cardiovascular diseases	46	25.5
Ischemic heart disease	31	17.2
Heart failure	15	8.3
Gastrointestinal disorders	41	22.8
Cirosis/acites/ peritonitis	26	14.4
Bleeding	13	7.2
Pancreatitis	2	1.1
Neuroligical events	26	14.4
Stroke	21	11.7
Intracranial hemorrhagie	5	2.7
Pulmonary disorders	15	8.3
COPD	5	2.7
PTE	4	2.2
ARDS	4	2.2
Tuberculosis	2	1.1
Total	180	100

Abbreviations: COPD = chronic obstructive pulmonary disease, PTE = pulmonary thromboemboly, ARDS = acute respiratory distress syndrome.

Table 3 Causes of mortality

Cause	Patients (n)	Ratio (%)
Cardiovascular disorders	99	45.63
Cerebrovascular events	42	19.35
Infections	40	18.43
Respiratory disorders	11	5.07
Gastrointestinal disorders	9	4.15
Malignancy (prostate, lung, gastric lymphomas)	4	1.84
Others (More than one cause)	12	5.53
Total	217	100.00

Table 4 General profiles of all patients

Parameters	Overall
Age (years)	54.7 ± 16.6
Gender (M/F)	781/757
Blood pressure (systolic/diastolic; mmHg)	124.7 ± 31.8/72.8 ± 17.7
Hematocrit (%)	26.1 ± 5.7
Urea (mg/dL)	207.7 ± 71.9
Creatinin (mg/dL)	8.2 ± 4.5
CrCl (mL/min)	6.0 ± 5.4
Urine volume (mL/24h)	709.9 ± 664.1
Glucose (mg/dL)	131.5 ± 61.6
Albumin (g/dL)	3.2 ± 0.7
Total cholesterol (mg/dL)	146.8 ± 61.3
Triglyceride (mg/dL)	163.9 ± 110.3
HCO3 (mEq/L)	16.4 ± 5.1
C-RP (mg/dL)	15.4 ± 7.5
iPTH (pg/mL)	350.0 ± 189.9
Ca × P (mg^2/dL^2)	45.0 ± 15.7
LVEF (%)	55.8 ± 9.0
IVSD (mm)	18.0 ± 0.1
LVPWDd (mm)	11.6 ± 1.0
LAD (mm)	39.9 ± 5.0

Table 5 Demographic, hematological, biochemical, and echocardiographical properties of cases according to groups

Parameters	Group I (n = 217)	Group II (n = 1321)	p
Age (years)	66.3 ± 21.8	52.8 ± 21.7	0.045
Gender (M/F)	114/103	667/654	0.002
Blood pressure (systolic/diastolic; mmHg)	145.7 ± 33.5/83.6 ± 15.9	121.2 ± 31.5/71.0 ± 17.9	0.004
Hematocrit (%)	22.5 ± 6.3	26.7 ± 5.6	0.049
Urea (mg/dL)	227.3 ± 66.8	204.5 ± 72.7	0.432
Creatinin (mg/dL)	11.7 ± 5.9	7.6 ± 4.3	0.039
CrCl (mL/min)	5.1 ± 4.5	6.6 ± 5.5	0.147
Urine volume (mL/24h)	355.8 ± 260.5	768.0 ± 730.4	0.001
Glucose (mg/dL)	129.8 ± 44.9	131.7 ± 64.3	0.651
Albumin (g/dL)	2.7 ± 0.5	3.3 ± 0.7	0.047
Total cholesterol (mg/dL)	135.9 ± 78.3	148.6 ± 58.5	0.071
Triglyceride (mg/dL)	161.0 ± 90.5	164.4 ± 113.5	0.373
HCO3 (mEq/L)	14.8 ± 5.5	16.6 ± 5.0	0.169
C-RP (mg/dL)	37.6 ± 14.5	11.7 ± 6.3	0.042
iPTH (pg/mL)	355.8 ± 125.6	349.0 ± 200.4	0.078
Ca × P (mg^2/dL^2)	59.9 ± 21.7	42.5 ± 14.7	0.048
LVEF (%)	49.8 ± 11.3	56.7 ± 8.6	0.054
IVSD (mm)	2.15 ± 1.3	1.74 ± 0.9	0.037
LVPWDd (mm)	1.79 ± 0.26	1.06 ± 0.74	0.031
LAD (mm)	4.23 ± 0.41	3.95 ± 0.28	0.035

Older age, existence of hypertension, anemia, high creatinine levels, lower residual renal function, hypoalbuminemia, high Ca × P and/or high iPTH levels (presence of secondary hyperparathyroidism), high CRP levels, and left ventricular hypertrophy were significantly more common in group 1 than in group 2, and these parameters were evaluated as mortality-associated risk factors. In Cox regression analysis a statistically significant association was found between comorbid conditions and death (chi-square: 0.937, p < 0.001).

DISCUSSION

According to the records of Turkish Society of Nephrology (TSN), although life expectancy and quality are getting better in HD patients, there is still a high rate of morbidity and mortality.[14] Whatever the etiologic cause, the prognosis of ESRD patients results in higher mortality than normal population, and ESRD is one of the most prevalent causes of death after CVD and malignancies.[1–5] In recent times, ESRD patients have importance as a leading cause of morbidity and mortality in respect of CVD when considering both traditional risk factors, such as age, sex, diabetes, and smoking habit, and non-traditional risk factors currently investigated, such as albuminuria and inflammation.[2],[4],[15] Because CVD account for 50% of mortality among chronic hemodialysis patients, the question of whether to develop a new concept establishing the connection between the treatment of renal failure and CVD arises.[4–6] This concept is possibly inflammation, which can be determined with CRP level and is an independent risk factor associated with high mortality developed by cardiovascular and other reasons.[7–12],[16–22]

The fact that inflammation is found to be increased in occasions during the process of the disease such as anemia, malnutrition, dialysis-related events, infections, and sepsis emphasizes its importance in ESRD patients. Inflammation has a multifactorial basis in ESRD.[17–24] While there are more sensitive markers for inflammation like IL-6,[24] in practice, CRP is used as a prototype of marker for inflammation.[7] CRP as an acute phase reactant in ESRD may increase in conditions related to dialysis (graft, fistula and catheter infections, membrane or dialysate reactions, endotoxin exposure, back filtration, etc.) or independent of dialysis (infections, malnutrition).[7],[25],[26] Inflammatory reaction in ESRD also may develop due to anemia,[23] secondary hyperparathyroidism,[27] hypoalbuminemia,[19],[26],[27] and acidosis.[28] In recent study, in accord with the literature, statistically significant differences was found between CRP levels of groups 1 and 2 (p = 0.042). In addition, parameters associated with inflammation such as anemia, Ca × P product, high iPTH levels, and hypoalbuminemia were similarly significantly different between two groups.

In ESRD population, unlike the general population, non-traditional risk factors such as inflammation, albuminuria, electrolytes imbalance, hyperhomocysteinemia, high BNP, and endogenous inhibition of nitric oxide synthetase emerged as predictors of LVH and LV dysfunction, and risk factors special to the uremic condition, such as asymmetric dimetil arginine deposition or low serum albumin levels, help to explain mortality due to CVD in this disease population.[26] In our cases, CVD were determined as the most frequent cause of mortality (45.63%) and the second cause of comorbidity (21.2%). Echocardiographic parameters showing left ventricular hypertrophy were statistically more significant in group 1 than in group 2.

In our patients, anemia was determined as an independent factor having an effect on survival of patients and also inducing CVD and inflammation. Mean Htc levels were 22.5 ± 6.3 in group 1 and 26.7 ± 5.6 in group 2. Statistically significance was present between two groups (p = 0.049). Although the CREATE study[29] suggested that early correction of anemia or elevating target hemoglobin levels did not provide additional benefit, anemia, which is an independent risk factor for morbidity and mortality in ESRD, also activates inflammatory reactions and leads to both LVH and ventricle dysfunction. Thus, anemia does not only impair the quality of life but also threatens the survival of dialysis patients.[23]

High CRP and hypoalbuminemia in ESRD are associated with increased risk of mortality. In several studies—even in stage 3 and 4, which are predialytic stages of renal failure—it has been found that the coexistence of inflammation and hypoalbuminemia is an independent risk factor not only for CVD, but for all causes of mortality.[19] In our cases, notably being more prominent in the group presenting with mortality, hypoalbuminemia was present, and there was statistically significance between two groups (p = 0.047). Hypoalbuminemia is known to lay the groundwork for more dramatic syndromes like MIA (malnutrition-inflammation-atherosclerosis) syndrome or MIC (malnutrition-inflammation-cachexia) syndrome.[30]

An important part of these patients die from infections (e.g., pulmonary, catheter).[10] In particular, staphylococcal infections preserve their importance as a major pathogen that threatens the life in this population of patients.[31] In our study, while changing among years, infections were the most common cause of comorbidity (23.9%) and the third most common cause of mortality (18.4%).

Mortality due to cerebrovascular accidents (CVA) has been reported in different rates in several studies.[9],[13],[14] Approximately 10% of patients receiving renal replacement therapy are lost because of stroke.[2] The predisposition of CVD and diabetes has been reported as a very important factor in the development of this complication.[16],[32] In our cases, stroke and other neurological complications were the second most frequent mortal pathology (19.35%) and determined as comorbid disease in 12.0%.

Gastrointestinal disorders are frequently encountered in ESRD; however, they rarely are of vital importance. Gastrointestinal disorders that present the highest ratio of morbidity and mortality are upper and lower gastrointestinal system bleeding, high hepatitis virus prevalence (particularly in developing countries, such as ours), and consequent problems such as chronic hepatitis or cirrhosis and acute pancreatitis. By comaparison, mortality due to these problems is 1–5% in developed countries.[11] Lung diseases, especially pulmonary thromboembolia cause about 1–3% of mortality in ESRD.[12] Data of our country and our study are similar to these results.

According to Turkish Society of Nephrology records, 10% of ESRD patients die annually, and the causes of mortality are CVD (42.1.7%), infections (10.6%), neoplasms (9.3%), CVA (8.7%), hepatic failure (1.6%), pulmonary thromboembolia (1.2%), and multiple causes (26.3%).[14] According to NKF data, every year, 10% of patients die owing to complications of ESRD. Cardiovascular events are the most frequent ones (50%).[33]

In our study, 133 patients died in the first five-year period, while 84 patients died on account of many causes in the second five-year period. Mortality ratio in general was 14.1%, whereas it was 19.5% for the first five years and declined to 9.8% for the last second five years. This decrease in the last five years could be the result of patients' early reference to a nephrologist, early starting renal replacement therapy, sufficient and efficient dialysis therapy, early discovery and treatment of complications and risk factors, and current technical developments in dialysis therapy in recent years. Even though a marked improvement has been achieved in the mortality ratio, no change has been found in causes of mortality and order of frequencies of these causes. The most common cause of mortality was CVD (45.63%); various comorbid disorders were determined in 82.9% of all patients. At least one cardiovascular comorbidity was determined in 21.2% of our cases. In Cox regression analysis, there was association between comorbidity and deaths.

ESRD patients having residual renal function have a low prevalence of mortality and morbidity and also complications.[34] Our data, in accord with the literature, showed low mortality in patients having higher residual renal function.

The presence of a history of prior cardiovascular disease and/or diabetes, hypertension, impaired Ca-P metabolism, anemia, high CRP levels with hypoalbuminemia, left ventricle hypertrophy, and dysfunction determined at admission was statistically significant in patients with mortality due to CVD. Statistical significance was determined when comparing these data to patients died from other causes.

In conclusion, CVD and cardiovascular complications are the most important preventable causes of morbidity and mortality in all stages of CKD. Taking precautions against CVD and the associated complications will provide a positive contribution in reducing morbidity and mortality of ESRD patients.