Global costs attributed to chronic kidney disease: a systematic review

1. Postgraduate Program in Collective Health, Health Sciences Center, University of Fortaleza. Fortaleza (CE), Brasil 2. Department of Epidemiology and Prevention of Renal Disease, Brazilian Society of Nephrology. São Paulo (SP), Brasil 3. Nephrology Service, General Hospital of Fortaleza. Fortaleza (CE), Brasil 4. Postgraduate Program in Constitutional Law, Center for Legal Sciences, University of Fortaleza. Fortaleza (CE), Brasil


INTRODUCTION
Chronic kidney disease (CKD) is fast growing in Brazil and worldwide, and is associated with high financial expenditures for patients and healthcare systems.Scaling up its economic repercussions and proposing strategies to minimize the costs involved in its treatment has been configured as a challenge for the scientific community.
Defined as the presence of kidney damage or decreased kidney function for three months or more, with repercussions on the general state of the pa-tient 1 , CKD has as its main causes systemic arterial hypertension (SAH) (35%) and diabetes mellitus (DM) (30%) 2 , both chronic non-communicable diseases (CNCDs) with a high impact on morbidity and mortality and with high prevalence worldwide.In addition, CKD has a strong relationship with aging 3 and, based on the Brazilian population, according to projections, by 2050, the estimated number of elderly will be 66 million, while children and adolescents will be 31.8million, reversing the scenario of 2010, when values for these age groups were 19.6 and 49.9 million, respectively. 4n general, aging is related to the risk of multi-morbidity, that is, the individual is affected by more than one chronic illness at the same time, which generates greater use of healthcare services and a considerable increase in treatment costs, considering that these are proportional to the number of associated diseases 5 .Population aging, if analysed in isolation, already presents numerous challenges for all sectors of society and imposes the need to rethink the dimension of the supply of services needed to meet the demands of this population group in the long term 4 .
In the more advanced stages of CKD, characterized by a severe decline in the glomerular filtration rate (GFR), the patient must initiate one of the modalities of renal replacement therapy (RRT), whose current options are haemodialysis (HD), peritoneal dialysis (PD) and kidney transplant.Such therapeutic options demand numerous expenses for the healthcare system because, in addition to having a high cost, its users are susceptible to prolonged hospitalizations, continuous treatment and the use of high cost medications.It is known that dialysis and kidney transplant consume disproportionate amounts of healthcare budgets, since about 5% of budgets are consumed by less than 1% of the population 1 .
Studies of financial growth suggest that the greatest macroeconomic burden of CKD and other chronic diseases falls on low-and middle-income countries, where high prevalence and high treatment costs create a proportional burden on gross domestic product (GDP) 6 .It is known that the provision of RRT by countries has a directly proportional relation with their GDP, suggesting that poverty is an important disadvantage with respect to the access of individuals to the modalities of CKD treatment 7 .In addition, in the personal sphere, expenditures attributed to healthcare commonly affect the family financial structure, with considerable property loss, in a context of insufficient resources.
Faced with global financial instability, the uncertainties surrounding healthcare financing in developing and underdeveloped countries, the certainty of increasing life expectancy and the consequent increase in chronic health conditions, this review proposes to discuss financial costs attributed to CKD and its repercussions on healthcare systems in developing countries, such as Brazil.

MATERIALS AND METHODS
This is a systematic review carried out in the PubMed/Medline database, using the terms "costs" and "chronic kidney disease", in January 2017.The search was expanded to other bases, such as Scielo and Google Scholar, with the purpose of identifying local studies related to this matter, published in journals not indexed in PubMed.Only articles published since 2012 have been included, considering the period of the last five years as recent.Studies focused on the costs of CKD and its treatment modalities were prioritized.The studies focused on the cost-effectiveness of drug regimens and therapeutic behaviours were excluded.The detailed selection process of the articles is described in Figure 1.

RESULTS
In total, the search resulted in 392 articles (PubMed and other sources), of which 291 were excluded because they avoided the main theme of this review.Of the remaining 101, 19 articles were excluded because they were reviews, comments and study protocols, and 45 because they deal with costs of procedures, therapeutic behaviours and cost-effectiveness of specific drug regimens.The study included 37 articles focused on the overall costs related to CKD (Table 1).Research has warned that CKD is one of the most costly diseases in healthcare (38), and that its economic burden is already considerably high in the early stages, and can be equal to or greater than the costs attributed to cancer or cerebrovascular accident in adults 8 .With the progression of the disease and the need to initiate dialysis, there is a significant increase in direct costs related to health maintenance 15 .
When comparing the financial expenditures related to the modalities of RRT, patients who are not on dialysis and kidney transplant patients are considered less costly to healthcare systems than those on dialysis 9 .Among dialysis, hemodiafiltration, a form of HD, is considered as a cost-effective therapeutic option 22 .In contrast to HD, PD stood out as a lower cost option 10, 19 .In Spain, HD is five times more expensive than the treatment of the more advanced stages of CKD and three times more expensive than transplantat 33 .Continuous ambulatory peritoneal dialysis was mentioned as the most efficient use of institutional and family resources 31 .
In Sweden, in relation to the healthcare costs of the general population, patients on HD, PD and kidney transplant present a 45, 29 and 11 times higher cost, respectively 14 .In Australia, CKD patients represent an 85% higher healthcare cost and require 50% more government subsidies than the general population 23 .
In Brazil, HD and kidney transplant stand out because of the high costs, which may be related to the high prevalence of the two modalities in the coun-try12.In India, costs associated with transplant are considered catastrophic and are responsible for a serious financial crisis 42 .
The socioeconomic profile of chronic kidney disease patients was highlighted in several articles as a relevant factor in the outcomes.Higher mortality was found among those with low income, unemployed 11 , males and the elderly 12 .In addition, evidence shows that the prevalence of CKD increases considerably in the elderly 34 .
A study carried out in England showed that the main causes of death in chronic kidney patients were not related to kidney problems but to heart disease, and that despite this, CKD added to hospital costs high values in the last 12 months of life 14 .In India, hospital costs of CKD patients were found to be substantially higher than those without CKD 32 .
In diabetic patients, progression of CKD makes treatment more costly 37 and the direct costs of hospital admissions of patients with kidney complications are considerably higher than those without this complication 32 .In addition, CKD is responsible for the increase in expenses borne by DM patients, which strengthens the finding that it is the most expensive complication 24 .Other clinical conditions that, when associated with CKD, further increase their financial burden are autosomal polycystic kidney disease 26, 27 and secondary hyperparathyroidism 43 .The financial repercussions of CKD treatment also have a strong impact on the economic structure of families 18,40 .A study points out that, for parents with chronic kidney disease children, the main culprits are the impossibility of maintaining employment and high expenses related to treatment 28 .Other research also highlights school drop-out as one of the consequences of treating the disease 42 .
With a view to reducing CKD financial expenditures, studies suggest that clinical follow-up before and after initiation of dialysis and management of comorbidities are potential sources of savings in CKD care 9 .In specific cases, home death is associated with reduced hospital costs 14 and that some clinical criteria may guide the diagnosis of CKD and reduce its costs 16 .
Figure 2 summarizes the annual costs of treating CKD in different modalities in different countries.Despite the characteristics of the analyses of the articles of this review, such as the variability of the factors included in the total expenditure and year of the study, when presented graphically, the costs of the CKD treatment show a significant difference between the different modalities of treatment, with haemodialysis having the highest cost.

DISCUSSION
Chronic kidney disease (CKD) has been gaining major repercussion due to its increasing incidence and prevalence worldwide, becoming a serious public health problem.The treatment of CKD is costly and, therefore, it is necessary to discuss possible cost reduction solutions, especially in Brasil, where political and economic crises are repeatedly faced.Although the methods and analyses are diverse, the results of the studies incorporated in this review are unanimous in alerting about the strong financial and social impact of CKD that affects the public and private healthcare systems, patients with the disease, family members and society as a whole.It is noted that the costs of CKD, compared to data from several countries, are higher in the long term for renal replacement therapies, especially in the haemodialysis modality.Transplant, despite being a high-cost surgi-cal procedure, has become more cost-effective over the years, not to mention improving patient survival and quality of life.
Although the economic repercussions of CKD in developing countries are even more serious in the face of the economic difficulties faced in various sectors, it is observed that these are not different in developed countries.A study carried out in Italy concluded that annual costs for patients undergoing CKD treatment before dialysis were set at EUR 11,123 (approximately USD 13,668) versus EUR 53,764 (approximately USD 66,067) for dialysis patients, proving that prevention, early diagnosis and the consequent delay in starting dialysis could considerably reduce healthcare sector expenditures 15 also in countries with a more stable economy.
In the United States, considering the population served by Medicare, aged 65 or over, the total costs for parties A (Hospital Insurance, or HI) and B (Supplementary Medical Insurance, or SMI) increased by 11.5% to USD 227.100 million between 2008 and 2012, while such costs rose 53.6% to USD 44.6 billion among patients with CKD.The costs for patients with CKD and DM increased 70.2% between 2008 and 2012, while similar costs for patients without CKD, DM or congestive heart disease increased by only 4.1% 45 .
In India, the average monthly cost of HD in the city of Mumbai, for example, was INR 6,142.33 (approximately USD 92), while the per capita income in the country was INR 5,130 (approximately USD 77) , according to data from 2011-2012, that is, the majority of patients were not able to pay for the treatment of CKD, since there are no state HD programs in the country 18 , and this cost in India is significantly lower than in others countries analysed in our study, even lower than in Brasil.However, there is insufficient data to explain the reasons for this lower cost.It is estimated that in 2010 there were 2.6 million people on dialysis and 93% lived in countries with middle-high or high incomes, but the estimated number of people around the world who needed RRT was 4.9 to 9 million, indicating that approximately 2.3 million people died due to lack of access to adequate CKD care 6 .
In Brasil, most of the specialized services (secondary and tertiary care) that have the treatment modalities of CKD are linked to the Brazilian Healthcare System (SUS), representing one of the biggest bottlenecks in the system, which currently faces serious management and transfer of resources prob-lems.According to an article of the Folha de S.Paulo newspaper, on March 29, 2014, for every BRL 100 (approximately USD 30) invested in healthcare, BRL 54 (approximately USD 15) come from the families and corporate investment, and only BRL 46 (approximately USD 13) come from the public sector.According to experts, among the countries that adopt the universal healthcare system, Brasil is the only one where government healthcare spending is lower than private investment.It should be remembered that Brasil is the country with the largest public and universal healthcare system, and therefore should invest a much larger amount of public capital in the healthcare sector.In the United Kingdom, public sector spending accounts for 83% of the total; in Canada, 70.4% and in Argentina, 61% 46 .
Regarding the Human Development Index (HDI), in the comparison between different countries, there is a proportional association with the transplant rate 47 .In 2014, Norway ranked first in the global HDI ranking (0.944) and performed 53.5 kidney transplants per million population (pmp), while in the same period, Brasil ranked 75 th in the HDI (0.755) and performed 29.6 transplants pmp 48, 49 .It is emphasized that the goal for the country is to reach 50 kidney transplants pmp by 2018 49 .
Based on the evidence that kidney transplant is the mode of treatment for CKD with better clinical and quality of life outcomes, these data show that, although developed countries feel the financial repercussions of the CKD, their citizens are in a privileged position, in terms of access to the best therapeutic options.The HDI ratio and number of transplants also reveals the intrinsic association between CKD and financial support, because although the magnitude of the disease is transcultural, clinical outcomes are irremediably dependent on adequate funding.
Using Brasil as a reference, it was observed that in an analysis of the years 2008 and 2013 (last report available), about BRL 61.8 and BRL 189 million (approximately USD 17 and 55 million) were spent, respectively, in kidney transplants, that is, in the five-year period, the increase in expenditures was 300% 50 .However, in the same period, kidney transplants increased only 67.6% 49 .This disparity may be related to the improvement of surgical techniques, the incorporation of new less invasive technologies; to the use of new, more potent and more reliable immunosuppressive drugs, both in induction and maintenance therapy after transplant, and in the treatment of rejections; to the growth of transplant teams in number and staff; and greater longevity of patients and grafts, which generate a greater prevalence of outpatient visits in post-transplant follow-up.However, if this trend of rising charges continues, funding for the healthcare system will be seriously compromised in the future.
Given the high costs and complexity of treatments, the trend is for greater visibility to healthcare at the secondary and tertiary levels, but the results of this review point to the urgency of investing in primary care as a viable alternative for containment of expenses related to CKD.
Therapeutic interventions in the early stages of CKD are proven effective in slowing its progression.Considering that CKD, in general, is based on diseases such as hypertension and DM, continuous follow-up of patients and their families, screening new cases in the population, increasing the chances of early diagnosis, and implementing treatment for preserving kidney function are actions that need to be firmly incorporated into healthcare service practices, with emphasis on those offering basic care.
Increasing numbers of CKD and the high material and immaterial values involved in treatment modalities in a context of scarce resources have alerted to the need to develop tools and implement policies to control disease progression, aiming to reduce need for dialysis, transplant and complications.

CONCLUSIONS
It can be seen that the economic impact of CKD is global.It reaches all countries, regardless of the level of development and the model of healthcare.The studies analysed warn of the importance of primary and secondary prevention of CKD as a healthcare economy strategy.The association between population aging and the expansion of NCDs requires countries to reformulate care strategies and target their healthcare systems.The magnitude of the situation can be verified through the high incidence rates and prevalence of CKD, which is a complication of chronic diseases such as hypertension and DM.Massively investing in prevention and measures to slow the progression of CKD to the final stages, and hence avoid the need for dialysis and transplant, can represent a huge, not yet calculated, economy for patients and healthcare systems worldwide.

FIGURE 1 :
FIGURE 1: SELECTION PROCESS OF ARTICLES ON THE COSTS OF CHRONIC KIDNEY DISEASE FOUND IN THE SYSTEMATIC REVIEW AND INCLUSION/EXCLUSION CRITERIA.

FIGURE 2 :
FIGURE 2: ANNUAL COSTS (IN US DOLLARS) OF THE TREATMENT OF CHRONIC KIDNEY DISEASE (CKD) IN ITS DIFFERENT MODALITIES.

TABLE 1 :
STUDY ON THE OVERALL COSTS RELATED TO CKD Roggeri(15)Italy Retrospective cohort Costs of CKD treatment CKD is associated with a high economic burden and the beginning of dialysis with an increase in direct costs with health care.Mendu (!6) United States Retrospective cohort Rational clinical criteria for the diagnosis of CKD.Some clinical criteria can guide the diagnosis of CKD and reduce its costs.Silva (17) Brazil Cost analysis/Literature review Costs of CKD treatment Kidney transplant stood out as the best alternative from a financial and clinical point of view, under the perspective of the Unified Health System (SUS).