Prognostic Factors in Hemodialysis Patients : Experience of a Havana Hospital

INTRODUCTION Knowledge of prognostic factors in end-stage renal disease patients has improved dialysis management and methods for reducing morbidity and mortality, underlining the importance of identifi cation, prevention and control of these factors. OBJECTIVE Identify factors affecting prognosis (survival or death) in hemodialysis patients at the Medical-Surgical Research Center in Havana over a ten-year period. METHODS Descriptive, prospective study of 81 end-stage renal disease patients who received hemodialysis at the Medical-Surgical Research Center from 1995 to 2004. Prognostic factors were identifi ed at initiation of and during dialysis treatment, using chi square, t test, McNemar test, Kaplan Meier analysis, log-rank test and Cox regression model, with signifi cance threshold set at p <0.05. RESULTS Hypertension and diabetes were the leading causes of endstage renal disease. Six patients were referred late. Mean survival was 4.4 years; with survival of 86.6%, 54.7% and 26.6% at one, three and fi ve years respectively. Factors predictive of decreased survival that were most frequent at initiation of hemodialysis were hypertension and chronic anemia (both present in 95.9% of cases); malnutrition, hypoalbuminemia, cardiovascular disease and chronic liver disease increased during treatment while hypertension decreased. In multivariate analysis, prognostic factors that signifi cantly predicted decreased survival were hypertension, inadequate vascular access and diabetes. Patients aged ≥60 years and those with malnutrition, hypoalbuminemia, anemia, cardiovascular disease or liver disease had lower survival fi gures at the end of the study period. Leading causes of death were infections (45.2%) and cardiovascular disease (41.9%); the latter was present in 93.5% of deaths, independent of underlying cause of death. CONCLUSIONS Survival of hemodialysis patients diminished at fi ve years. Some negative predictive factors are present at initiation of hemodialysis, such as diabetes, hypertension and chronic anemia; others increased later, including malnutrition, hypoalbuminemia, cardiovascular disease and liver disease.


INTRODUCTION
In recent decades, chronic kidney disease (CKD) has become a serious global health problem, its epidemiological picture revealing substantial and even alarming increases in both incidence and prevalence.The number of patients with end-stage renal disease (ESRD) continues to grow rapidly, [1] requiring major investment of resources in medical care.Despite better management of dialysis patients, morbidity and mortality continue to rise.Thus, identifi cation, prevention and control of CKD risk factors before, at initiation of, and during dialysis are important for patient outcomes, population health and health systems.[2][3][4] The increasing prevalence of CKD refl ects the increasing prevalence of its leading causes, such as diabetes and hypertension, as well as with worldwide trends in aging.Thus, early in CKD progression, control of underlying causes is key, but in later stages, renal replacement therapies become necessary.
Cuba has a CKD prevention program that covers the whole population through family physicians and community nephrologists (integrated with secondary and tertiary care for dialysis and kidney transplant patients), which contributes to decreasing late diagnosis of this disease, a problem everywhere.Early diagnosis aids comprehensive patient care prior to dialysis and kidney transplantation and improves patient survival.[2,5,6] Although specifi cs are not completely known for all factors predictive of hemodialysis patient survival, the infl uence of many of them on patient progress is known.Some, such as diabetes, are causes of ESRD; others include advanced age, late diagnosis and referral to nephrologist, malnutrition, and vascular access problems.It is important to identify these factors in order to develop comprehensive risk reduction strategies to facilitate channeling health resources and activities to their prevention and treatment.[7] The objective of this study was to identify prognostic factors in ESRD patients on hemodialysis.

METHODS
A descriptive, longitudinal, study was done of 81 ESRD patients receiving periodic hemodialysis at the Medical-Surgical Research Center (CIMEQ, the Spanish acronym) in Havana from January 1995 through December 2004.Each admission to hemodialysis was considered one case, for a replacement therapy population of 96, since 15 patients returned to hemodialysis after transplant failure and were considered new cases for purposes of this analysis.
Included were end stage, or stage 5, CKD patients (dialysis-dependent ESRD patients) aged ≥15 years who had been in a hemodialysis program for at least three months.Excluded were patients on temporary hemodialysis or who had been receiving treatment for less than three months, those for whom hemodialysis was permanently discontinued, and patients whose treatment began with peritoneal dialysis or who were transferred to peritoneal dialysis.Patient data were recorded from initiation of hemodialysis until the end of the study, transfer to renal transplant therapy or death.Ethics This was a noninterventional descriptive study based on analysis of hemodialysis patient records, without treatment modifi cation.Patient identifi cation information was kept confi dential.The project was approved by CIMEQ's ethics committee and scientifi c advisory council.

RESULTS
Mean patient age was 40.9 ± 12.9 years; there were no age differences by sex.Most subjects were men (60/81, 74.1%).
Only Factors present in patients at initiation of and during dialysis treatment are listed in Table 1.Considerable uncontrolled hypertension and anemia were observed at treatment initiation.There were substantial increases in chronic liver disease, malnutrition, hypoalbuminemia and cardiovascular diseases over the course of treatment, while there was a signifi cant decrease in uncontrolled hypertension.
Mean hemodialysis patient survival at the end of the study period was 4.4 years, (95% CI: 2.2-5.3 years).At one year, survival was 88.6%, falling to 54.7% at three years and 26.6% at fi ve years (Figure 1).

Original Research
Underlying causes of death in hemodialysis patients were infections in 45.2% (14/31) and cardiovascular diseases in 41.9% (13/31).In the latter group, acute myocardial infarction predominated (38.5%, 5/13).Other causes accounted for 12.9% of deaths (cirrhosis of the liver, cancer and head trauma).Regardless of underlying cause of death, 93.5% of those who died had cardiovascular disease (Table 3).

DISCUSSION
The majority of hemodialysis patients in this study were men, congruent with studies in Europe.[13] It has been suggested that men with glomerular disease may have worse prognosis, but there is no conclusive evidence that sex is a determining factor in CKD progression.[13,14] Hypertension, diabetes and glomerular diseases were the leading causes of CKD in these hemodialysis patients, similar to reports from other studies.[14,15] Hypertension is a cause, consequence and aggravating factor of CKD, and is highly prevalent in hemodialysis patients.Hypertension is often determined to be the cause of CKD by exclusion of other causes; defi ning hypertension as causal without histological confi rmation of nephroangiosclerosis may lead to overestimation.This might constitute bias and be a study limitation, resulting from decisions common in medical practice to dispense with renal biopsy in these patients, since biopsy benefi ts may not outweigh risks.[16] Diabetic nephropathy is, along with hypertension, a major cause of CKD, consistent with our fi ndings.An alarming global increase has been reported in incidence of diabetic nephropathy in type 2 diabetes, progressively displacing glomerular diseases among the main CKD etiologies.[16] The late nephrology referral rate seen in our patients is a satisfactory fi nding when compared with reports ranging from 25% to 50%.[17] One of the advantages of early diagnosis is to ensure adequate vascular access, indispensable for successful dialysis.This is consistent with our fi nding that the majority in this series had adequate vascular access.
In this series, 4.2% of cases were malnourished at dialysis initiation, a percentage that increased perceptibly during hemodialysis.Malnutrition can coincide with development of CKD due to the infl uence of underlying causes, and has been reported in 40% to 50% of patients at dialysis initiation, [18] proportions much higher than in our sample, for reasons that deserve further investigation.The causes of malnutrition are many: among them, appetite suppressants, certain socioeconomic and cultural conditions, comorbidity and depression.Hormonal imbalances associated with CKD-peripheral insulin resistance, secondary hyperparathyroidism and low levels of growth hormone-are conducive to malnutrition.[19] It is important to clarify that BMI was used to evaluate nutritional status, as has been done by others, [20] without analyzing other aspects, such as anthropomorphic variables, biochemical imbalances, body composition and diet.Thus, this could result in underreporting of malnutrition in patients before and during dialysis, a study limitation to bear in mind for future research.
In addition to the abovementioned factors, others can lead to impaired nutrition in dialysis patients, including dialysis technique, nutrient loss during dialysis (water-soluble vitamins, amino acids and peptides) and the nausea and vomiting that frequently accompany hemodialysis.Furthermore, blood contact with the dialysis membrane triggers an infl ammatory response that stimulates protein catabolism; response intensity depends on membrane composition, and is more pronounced with cellulose membranes.[21] We found no statistically signifi cant effect of serum albumin values on survival, possibly a result of small sample size.Serum albumin is a biochemical marker that can decrease modestly with the reduced protein and calorie intake associated with uremic syndrome, without signifi cant comorbidity or elevated proinfl ammatory cytokines; this imbalance is known as type 1 malnutrition.In other cases, hypoalbuminemia can be substantial and be associated with elevated resting energy expenditure, increased oxidative stress and protein metabolism, and there can also be considerable

Original Research
comorbidity and elevated concentrations of proinfl ammatory cytokines; this state is known as type 2 malnutrition.[22] Uncontrolled hypertension decreased dramatically over the course of dialysis treatment, although it continued to be a problem, as reported for other series.[22] This implies that in addition to volume overload, other mechanisms must infl uence pathogenesis of hypertension.The possible mechanisms implicated are related to increase in peripheral vascular resistance.It is known that worldwide some 80% to 90% of patients enter dialysis with hypertension, which does not seem to be controlled with the dialysis treatment they normally receive.In some patients, blood pressure can rise during a hemodialysis session as a paradoxical side effect of ultrafi ltration, due to the renin-angiotensin-aldosterone system reaction to excessive volume loss.[23] Anemia showed few changes over the course of treatment, maintaining a prevalence of 93.8%.This may be because our patients did not receive erythropoietin systematically until the end of the study; anemia is common in ESRD patients who are not receiving erythropoietin, and our levels may have remained high because the drug was not available until the end of the study period.In dialysis patients, anemia can considerably affect various organs and systems, primarily the cardiovascular and endocrine systems and cognitive function.[24] It has been shown that for each g/dL increase in hemoglobin, relative risk of death decreases by 5% and of hospitalization by 4%.[25,26] Despite this, we found no signifi cant effect of anemia, and the proportion of anemic patients did not change appreciably over the study.
Inadequate vascular access for hemodialysis in this series was a prognostic factor that infl uenced survival.These results concur with reports from other authors, in which the greatest risk of mortality is related to more frequent infections in patients with suboptimal vascular access.[27] The high prevalence of CVD in ESRD patients is well established, and it is the leading cause of morbidity and mortality in hemodialysis.It is reported that only 16% of patients enter hemodialysis with a normal echocardiogram, 65% have left ventricular hypertrophy, 41% have ischemic heart disease and 40% have heart failure.
[28] Our study found that there was a substantial increase in CVD during dialysis therapy.
Besides the well-known traditional contributors to CVD pathogenesis, dialysis patients have additional ones, including anemia, a hyperdynamic state induced by the arteriovenous fi stula, secondary hyperparathyroidism, hyperphosphatemia and malnutrition.These factors do not entirely explain increased CVD in this population; and in recent years there has been reference to new, nontraditional factors that must be involved, such as oxidative stress and systemic infl ammatory response.[29] The considerable CVD increase we observed during dialysis may be related to underreporting before dialysis initiation.Additionally, absence of symptoms revealing this disease may have impeded heart disease diagnosis in the predialysis stage.Early diagnosis of CKD could enable earlier detection of CVD.
The observed negative effect of CVD on survival grew more marked over time and was most dramatic at fi ve years, when there were no longer any survivors without CVD.Death from a cardiovascular cause is more frequent among dialysis patients and even more so in those who are diabetic and elderly.[30] Analysis of patient survival with diabetes as the prognostic factor showed signifi cant differences.When diabetics begin renal replacement therapy, they present greater comorbidity, greater frequency of heart failure, peripheral vascular disease and chronic liver disease.Vascular causes of death, primarily cardiovascular causes, are also the most frequent among diabetic patients on maintenance dialysis.[31][32][33] A high prevalence liver disease was observed among patients in our study, even in the context of the high rates in the dialysis population globally.[16] Our results may refl ect greater use of blood transfusions prior to the time when erythropoietin became available.Notably, only 25% of our patients received erythropoietin in 2000, increasing progressively to 100% coverage reached by the study's end.Measures to prevent transmission of hepatitis C virus continue to be vitally important.
In renal replacement therapy, patient survival is undoubtedly the most important question.Dialysis technique has been shown to infl uence survival; [34] also important is the correct prescription and adjustment of dialysis, ensuring sessions are long enough to meet patient needs.[23] Other infl uential factors associated with the need for or conditions of dialysis include dialysis center experience, adherence to therapy, and comorbidities such as CVD and diabetes.[34] It has been noted that the most common causes of death are, in general, more closely related to these associated factors than to the technique itself.In fact, comorbiditiesprincipally CVD and diabetes-prior to hemodialysis initiation are a key determinant of prognosis and patient survival.[34,35] These aspects were not addressed in the present study and should be explored in future research.
Our fi ndings that infections and CVD are the primary underlying causes of death are similar to those of other reports, in which causes of vascular origin were found in up to 50% of cases, with infections in second place (the latter the most frequent cause in patients aged 20-44 years).[36,37] Potentially fatal infections are 50 times more frequent in these patients than in the general population.[38]

CONCLUSIONS
The probable negative effect of prognostic factors, particularly CVD and infections, on morbidity and survival of ESRD patients in dialysis makes prevention, identifi cation and control of these conditions critically important for optimal patient survival.

in Hemodialysis Patients: Experience of a Havana Hospital
• Causes of ESRD (hypertension; diabetes; chronic glomerular diseases; polycystic kidneys; urological disorders, such as Prognostic Factors variables and t test for quantitative variable means.The McNemar test was used to compare presence of prognostic factors at initiation of and during dialysis treatment, signifi cance level set at p <0.05.The Kaplan Meier method was used for survival analysis.A log-rank test was used to compare different levels of a single variable.A Cox regression model was fi tted to assess risk of death for a given prognostic factor (presence or worsening during the study).

Table 1 : Prognostic factors in ESRD patients at initiation and during a hemodialysis, 1995-2004 (n = 96)
a At any point during survival on dialysis b Not susceptible to change during dialysis c Not applicable prior to dialysis ESRD: end-stage renal disease

Table 2 : Hemodialysis patient survival by prognostic factor, 1995-2004
a by fi ve years, all surviving patients had developed cardiovascular disease