Abstract
Uruguay is a developing country with a privileged established program for renal replacement therapy (RRT) for all patients with end stage renal disease (ESRD) since 1981. In December 2004, the RRT prevalence reached 916 patients per million population. The ESRD incidence has not changed significantly in the last eight years, differing with what is observed in other countries. In contrast, the ESRD incidence secondary to diabetic nephropathy has shown a permanent increase. The prevention of chronic kidney disease (CKD) began in 1989 with the Program of Prevention and Treatment of Glomerulonephritis (PPTG), being extended in 2002 to all CKD and canalized through the National Program of Renal Healthcare (NPRH) since 2004. The registry of glomerulonephritis has been demonstrated in recent years: patients are referral to nephrologists earlier, there is an increase of the frequency of patients with “clinical remission,” and thus there is a decrease of the frequency of ESRD in the first three months after referral. The NPRH has been developed in a progressive way with the involvement of government authorities and the active participation of the nephrologists. A global prevention program, integrating the prevention of CKD, cardiovascular diseases, hypertension, and diabetes was developed. The first steps of the program have had important achievements: a rational reorientation of nephrologic care in the first level of attention, patient access to renoprotective medications without cost; a registration system of patients, the creation of a formal multidisciplinary team, and the instauration of a continuous medical education program.
DEMOGRAPHIC DATA
Uruguay has an area of 176.215 km2, divided into 19 administrative regions (departments), and 3,241,003 inhabitants, 13.7% of whom are older than 65 years, per the 2004 census.Citation[1] The ethnic distribution in the national survey conducted in 1996 was 93.2% white, 5.9% black (or mixed black-white), 0.4% indigenous (or mixed native-white), and 0.4% yellow (or mixed yellow-white race).Citation[2]
In 2001, the gross domestic product (GDP) per capita was US $8,400, and the human development index 0.834. Relative expenditure in health was 10.9% of the GDP. The life expectancy at birth is 75 years for the total population, and the infant mortality rate is 14 per 1000 live births. The percentage of the population with access to potable water and adequate sanitation was 98% and 94%, respectively. The adult literacy rate (age 15 and above) was 97.6%.Citation[3]
During the second half of the 20th century, the conditions of health of the Uruguayan population have improved as a consequence of a change in the conditions of life and the implementation of public health policies of great impact, mainly oriented to the prevention of transmissible diseases. Uruguay has also displayed a process of demographic transition similar to the one of developed countries with an increase in the life expectancy at birth. This fact together with the best control of the transmissible diseases has derived in an epidemiologic transition with greater weight to non-transmissible diseases. Hypertension, diabetes, cardiovascular diseases (CVD), and chronic kidney diseases (CKD) are, among others, the leading chronic diseases. The epidemiologic transition also determines a shift in morbidity to the older population, an increase in severely disabled people, and a negative impact on the economies of developing countries. The fast increase of non-transmissible diseases represents one of the more important sanitary challenges for the present century and jeopardizes the health of million people.
END STAGE RENAL DISEASE AND RENAL REPLACEMENT THERAPY
Renal Replacement Therapy (RRT) in Uruguay began to expand rapidly after the creation of the National Found of Resources (NFR) in 1980. The NFR supports treatment by dialysis and renal transplantation for all patients with end-stage renal disease (ESRD). In 1981, the Dialysis Registry and the Renal Transplant Registry were developed and have since accumulated data from the entire population from the start of RRT program in the country.Citation[4],Citation[5] Up until December 31, 2004, data from 7757 patients in the Dialysis Registry and from 809 patients in the Renal Transplant Registry have been collected. According to these registries, there has been a steady increase in all modalities of treatment, reaching by December 2004 a prevalence of 916 patients per million population (pmp). The incidence of dialysis patients had a progressive growth from 32 pmp in 1981 to 152 pmp in 2004 (see ). This incidence is similar to that reported in the majority of developed countries,Citation[6] but, unlike most other developing countries, it had not changed significantly in the last eight years.Citation[7],Citation[8] The number of renal transplants per year reached 32 pmp in 2004, 89% from deceased donors. From 1999–2004, the gross mortality rate in dialysis patients varied from 12.3 to 15.9 deaths per 100 patients. The most frequent cause of death were CVD, 34.4%; infectious diseases, 18.8%; cancer, 9.7%; and withdrawal from treatment, 11.6%. In the same period, the nine-year survival in patients with a deceased donor transplant was 88% for patients and 53% for grafts.
Figure 1 Incidence and prevalence rate in dialysis treatment. Data from the Uruguayan Dialysis Registry.
POPULATIONS AT RISK
The two most important populations at risk for CKD are those with arterial hypertension or diabetes mellitus. The incidence of ESRD secondary to vascular nephropathy, associated with hypertension, was 31.1 pmp from 2001 to 2002. The incidence of diabetic nephropathy in the same period was 26.7 pmp.
The prevalence of hypertension (systolic blood pressure [SBP] ≥140 mmHg, diastolic blood pressure [DBP] ≥90 mmHg) in Uruguay ranges between 33% and 39%.Citation[9–12] In 1986, a home survey with a random sample of the population of Montevideo (1396 individuals) had found a prevalence of 20.0% with a cutoff level of 160 mmHg for SBP and 95 mmHg for DBP.Citation[9] In a second analysis, considering the current definition of hypertension (BP ≥140/90), the prevalence was 38.5%. In a multivariate analysis, this epidemiological study had found that the variables significantly associated with hypertension, ordered by their importance, were age, obesity, familiar hypertension, nephropathy, diabetes, anxious personality, and sedentarium.Citation[9] In another study published in 1999, from a random sample of 2070 subjects within a prepaid healthcare institution, the prevalence of hypertension (BP ≥140/90) was 33.2%.Citation[12]
The prevalence of diabetes in the general population was 8% in a recent survey in people between 20 and 79 years after a fasting serum glucose test, 6.4% who were aware of the diabetic status and 1.6% who were unaware. The percentage of patients with abnormal fasting serum glucose (between 100 and 125 mg/dL) was 8.2%.Citation[13]
At this time, there is no study on the prevalence of CKD and its causes in Uruguay, but some data can be inferred from the ESRD registry.Citation[14],Citation[15] The most frequent causes of ESRD have been vascular nephropathy, diabetic nephropathy, glomerulonephritis, and obstructive nephropathy (see ). The incidence of vascular nephropathy increased from 6.6 pmp in 1985 to 34.2 pmp in 2000 but had not changed in 2002. The incidence of primary glomerulonephritis and obstructive nephropathy had not changed since 2000. The incidence of diabetic nephropathy, as observed in the rest of the world, had a continuous increase, reaching an incidence of 26.7 pmp in 2002 (see ). The incidence of obstructive nephropathy (13.1 pmp in 2002) is a matter of concern in Uruguay, as it was three times higher than that reported in the USRDS 1997–2001.Citation[6],Citation[16]
Table 1 ESRD incident rates by time periods by diagnoses, per million population (pmp). From the Uruguayan Dialysis Registry
Figure 2 Annual incidence of ESRD secondary to diabetic nephropathy by time periods (95% confidence interval). Data from the Uruguayan Dialysis Registry.
The incidence of ESRD patients more than 64 years old increased from 251 pmp in 1991 to 480 pmp in 2001, whereas the incidence of ESRD patients younger than 65 over the same period was 78 pmp and 73 pmp, respectively. In patients older than 64, the major causes of ESRD during 1999–2001 were vascular nephropathy (190 pmp), diabetic nephropathy (75.5 pmp), and obstructive nephropathy (64.9 pmp).
With the aim of determining the actual prevalence of risk factors for CVD and renal disease in Uruguay, a national survey will be performed in the second half of 2006. It will be held by the Public Health Ministry (PHM) and the Public School of Medicine, with participation of the Uruguayan Societies of Nephrology, Cardiology, Diabetes, Hypertension, and Obesity.
RISK FACTORS FOR PROGRESSION
Several studies have analyzed the risk factors for progression of renal disease and clearly state the importance of optimal blood pressure control, proteinuria reduction, strict glucose control in diabetics, and serum lipid levels reduction.Citation[17],Citation[18] Other studies have shown that reduced glomerular filtration rate (GFR) is associated with a higher prevalence of CVD, establishing CKD patients as a high-risk population for CVD.Citation[18–21] The Uruguayan Registry of Glomerulonephritis (URG) has shown the importance of several risk factors in the progression of CKD (see ). After adjusting for confounding factors, older age, higher level of initial serum creatinine, and higher average level (in the follow-up) of proteinuria increased the ESRD risk. The ESRD risk also increased significantly when the average values (in the follow-up) of SBP were greater than 140 mmHg. The higher ESRD risk with higher initial serum creatinine emphasized the importance of the early referral to nephrologists. Patients referred at stage 3, 4, or 5 (with estimated GFR) had a significant higher risk than those referred in stage 1 or 2 (see ).
Table 2 Relative risk of ESRD, adjusted for confounding factors. From the Uruguayan Registry of Glomerulonephritis
An inadequate quality of care is another risk factor for progression of CKD. The URG showed that from 2000–2004, the percentages of patients with proteinuria <1.0 g/day and with SBP ≤120 mmHg were only 34.5 and 43.4%, respectively (see ). Only 41.8% of patients were taking ACE inhibitors or angiotensin receptor blockers, although the registry showed that this treatment diminished significantly the risk of ESRD (see ).
Table 3 Indicators to evaluate the Prevention Program. Data from the Uruguayan Registry of Glomerulonephritis
The Registry of Dialysis has shown that 11% of the patients enter into dialysis without an etiological diagnosis—these are the patients who had a late referral to nephrologists. The analysis of the conditions of medical care before the initiation of dialysis treatment has shown inadequate quality of care. From 2000–2003, 63.4% of patients initiated dialysis treatment in an uncoordinated way and required emergency dialysis; 63.0% had an hematocrit level <30%; and 76.5% of patients did not have vascular access made ≥60 days before the start of hemodialysis.
PREVENTION STRATEGIES FOR CHRONIC KIDNEY DISEASE
The prevention of CKD started in Uruguay with the Program of Prevention and Treatment of the Glomerulonephritis (PPTG). This program was implemented in 1989 by the School of Medicine of the National University and the Uruguayan Society of Nephrology (SUN) and was made official by the PHM in 2000. In 2002, all kidney diseases were included, and the Program of Prevention of Kidney Diseases was planned. Finally, in 2004, the National Program of Renal Healthcare (NPRH) was implemented according to the declaration of the Montevideo Workshop (PHM Authorities, SUN, School of Medicine of the National University, Subcommittee of Renal Health of the Latin American Society of Nephrology and Hypertension [SLANH], NFR, and nephrologists); currently, the prevention actions are canalized through this program.
The NPRH was planned by the SUN, according the new renal health concept proposed by the SLANHCitation[22] and under the logical framework matrix, in agreement with the PHM and the NFR authorities. The goals of the program are to improve the renal healthcare of the total population and to make sustainable and tenable the prevention of kidney diseases and the integral assistance of patients with kidney disease. The specific objectives are:
To promote the education of renal health and healthy lifestyles in the general population.
To integrate renal health care into the first level of attention.
To promote the early diagnosis of CKD in high-risk population.
To optimize patients´ care in all stages of CKD.
For the program to be considered successful, the active and organized participation of nephrologists was considered mandatory, as well as the involvement of government authorities and the general public.Citation[23] The SUN created the Committee for Renal Healthcare, integrated by nephrologists of the public and private health institutions. In agreement with the criterion adopted by the International Society of Nephrology (ISN) in the KHDC Program (Detection and Management of Chronic Kidney Disease, Hypertension, Diabetes and Cardiovascular Disease in Developing Countries),Citation[24] the PHM constituted a committee with the representative members of the Societies of Cardiology, Nephrology, Diabetes, Arterial Hypertension, Arteriosclerosis, and Obesity to develop a global prevention program. This multidisciplinary committee of non-transmissible diseases has developed coordinated guidelines toward prevention for the physicians of primary attention and is organizing a national survey of risk factors according to the WHO stepwise approach to the surveillance of non-communicable diseases (STEPS).Citation[25]
The planned activities for achieving the objectives were as follows:
Information campaigns directed to the general population through different media (radio, television, etc.) promoting health care and information about healthy habits and risk factors for renal and cardiovascular disease. This information has also been dispersed in different health centers of primary prevention through posters, brochures, and conferences.
The NPRH has promoted the reorientation of renal care toward the first level of attendance, integrating nephrologists to the primary care team in a reference and counter-reference system. The tasks of the nephrologists in the first level of attention were defined, establishing the importance of the education of the general physician in renal health, because a successful program depends strongly on the active participation of the primary care physicians. The nephrologists must also interact with cardiologists and specialist in diabetes mellitus to articulate the execution of an integrated program. The recommendations of referral to the nephrologists were as follows: to send all patients with evidence of kidney disease (persistent urinary abnormalities and/or impaired renal function) to the specialist to make or confirm the diagnosis, to evaluate the risk factors for progression and co-morbid conditions, and to establish a therapeutic and follow-up plan. The next consultations will depend on the CKD stage. The management of patients should be shared between the general physician and the nephrologists, with an increasing visit schedule through stage 1, 2 or 3 of the CKD. At stage 4, the nephrologists should take over the general management of the patient.
In order to rationalize and reduce the variability of the medical care, the consistent application of evidence-based medicine has been used to improve the care and follow-up of patients with kidney diseases. Clinical guidelines of handling the CKD have been elaborated based on the guidelines of the U.S. National Kidney Foundation.Citation[17] Protocols for glomerulonephritis treatment have been established. These guidelines and protocols have been published in the program's Web page (http://www.nefroprevencion.org.uy) and have been discussed in workshops and conferences.
The authorities of the PHM, NFR, and SUN decided to develop the NPRH in steps, beginning with a pilot program in the Public Health Assistance of the west side of Montevideo, which has 144,120 affiliated individuals more than 20 years old. The pilot program began in October 2004. A nephrologist was assigned to act in the first attention level. The reference of patients to the CKD clinic was made by the general physicians and by a social worker from the clinical laboratory when an abnormal result in urine examination or serum creatinine level was observed. The administration of renoprotective drugs (ACE inhibitors, angiotensin receptor blockers, statins, and diuretics) was assured. A registry of patients with CKD was created, as was a computerized system of alarms that warns when the patient fails to attend to subsequent appointments. The goals are to encourage patient lifestyle changes (e.g., the cessation of smoking; increased exercise; a reduction in the intake of salt, protein, and calories; weight loss, if appropriate) and to use a multidrug approach to lower BP (<120/80 mmHg), proteinuria (<300 mg/day), LDL cholesterol (<100 mg/dL), LDL+VLDL (<130 mg/dL), and HbA1c (<7.0% in diabetics). This multidrug approach also encourages the use of aspirin or another antiplatelet.Citation[26],Citation[27]
A pre-dialysis clinic with a multidisciplinary team (nephrologists, nurses, dietitians, social workers, psychologists, and vascular surgeons) was created for the reference of patients in stage 4 at the third level hospital. The purposes of the clinic are to inform the patient and the family about the different methods of renal replacement; to offer nutritional, social, and psychological support; to coordinate the accomplishment of the vascular access; and to determine timely dialysis.
In December 2004, a nephrologist was assigned to interact in primary attention with the east side of Montevideo (about 130,688 people), thus ensuring that all of the public health assistance of the Department of Montevideo was covered by the program. In August 2005, the NPRH was extended to the San José Department, integrating the whole population 20 years and older into the department (public and private health assistance, 69,964 people). In the San José Department, the programs of CKD, CVD, and diabetes have been integrated with the participation of cardiologists, clinical diabetologists, and the community. In October 2005, the NPRH had begun in the Florida Department (public and private health assistance, 45,937 people).
OUTCOME ANALYSIS
Recently, the data obtained from the Uruguayan Registry of Glomerulonephritis have shown that patient referral to nephrologists had resulted in less impairment of renal function and better control of blood pressure (see ).Citation[28] The number of patients referred at stage 1 of CKD has risen from 16.8% in 1989 to 32.4% in 2004, with a concurrent diminishing in the frequency of patients referred at stage 5. The percentage of patients at stage 1 of CKD referred with a SBP of less than 120 mmHg had risen from 11.1% (1989) to 24.2% (2003), and the percentage with SBP ≥160 mmHg diminished from 16.0% (1989) to 5.3% (2004).
The outcome analysis showed that the frequency of patients in “clinical remission” increased from 13.7% (1989) to 22.1% (2004) (see ). The analysis of the ESRD frequency is considered separately for the first three months, as patients had been referred to nephrologists after the third month. These indicators, however, provide different information: the ESRD frequency in the first three months is related to the time of referral and the treatment response in patients with rapidly progressive clinical presentation, while the evolution after the third month depends on the progression of the CKD. The ESRD frequency in the first three months diminished from 18.1% (1994) to 7.6% (2004). The low risk of ESRD was statistically significant even after the adjustment for age, sex, initial serum creatinine, and etiological diagnosis (see ). The ESRD rate per 100 patients after the third month showed no significant changes in the three analyzed periods. The future analysis of these indicators in the national registry will allow for an outcome evaluation of all the etiologies of CKD.
Figure 3 Relative risk of end stage renal disease in the first three months of Registry. Data adjusted for age, gender, diagnosis, and initial serum creatinine. Data from the Uruguayan Registry of Glomerulonephritis.
The pilot program of Renal Healthcare of Montevideo initiated the CKD Registry in October 2004. The registry includes patients with at least one of the following conditions:
serum creatinine greater than 1.5 mg/dL
GFR lower than 60 mL/min/1.73m2
persistent proteinuria >300 mg/day
diabetic patients with microalbuminuria >30 mg/day
renal abnormalities in the images test.
In the first ten months, 303 patients have been enrolled with a mean age of 64.7±14 (see ).Citation[29] The most frequent diagnoses have been hypertension, diabetic nephropathy, obstructive nephropathy, and chronic glomerulonephritis. The most frequent risk factors were hypertension, dyslipidemias, diabetes mellitus, and obesity. In all, 65.3% of the patients were referred at stage 3 of CKD and only 2.8% at stage 1. The control of 116 patients at the third month showed a significant decline of the mean value of total cholesterol and of low-density lipoprotein cholesterol. The percentages of patients treated with statins have risen from 12% to 40%, and the ones treated with ACE inhibitors or AT1 receptor blockers from 63% to 82% (see ).
Table 4 Patient characteristics at the first consultation., from the Registry of Chronic Kidney Disease. Pilot Program of Renal Healthcare of Montevideo
Table 5 Analysis of three months follow-up data, from the Registry of Chronic Kidney Disease. Pilot Program of Renal Healthcare of Montevideo
CONCLUSION
Uruguay is a developing country with a privileged established program for regular RRT for all patients with ESRD since 1981. Recently, an intensive effort was made through prevention strategies to diminish the global burden of CKD. The benefice of the early referral and the renoprotection is now evident in the outcome analysis of the URG. The recent NPRH is also working successfully. The first steps of the program have had important achievements: a rational reorientation of nephrologic care in the first level of attention, patient access to renoprotective medications without cost, a registration system of patients, the creation of a formal multidisciplinary team, and the instauration of a continuous medical education program.
Hopefully, this NPRH approach will have an important impact on the health of the total population and will offer a real possibility toward diminishing the morbidity and the mortality of renal disease in Uruguay.
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