Background: Over the last 3 decades, over 700 million individuals worldwide have been diagnosed with chronic kidney disease (CKD). In a 2017 survey in southern Brazil, 11.4% of those surveyed had CKD. Early identification and effective therapy in Brazil may reduce CKD’s impact. This panel discusses the early diagnosis and treatment of CKD and the barriers and actions needed to improve the management of CKD in Brazil. A panel of Brazilian nephrologists was provided with relevant questions to address before a multiday conference. During this meeting, each narrative was discussed and edited through several rounds until agreement on the relevant topics and recommendations was achieved. Summary: Panelists highlighted hurdles to early diagnosis and treatment of CKD. These include, but are not limited to, a lack of public and patient education, updated recommendations, multidisciplinary CKD treatment, and a national CKD database. People-centered, physician-centered, and healthcare institution-centered actions can be taken to improve outcomes. Patient empowerment is needed via multiple channels of CKD education and access to health-monitoring wearables and apps. Primary care clinicians and nonspecialists must be trained to screen and manage CKD-causing illnesses, including diabetes and hypertension. The healthcare system may implement a national health data gathering system, more screening tests, automated test result reporting, and telehealth. Key Messages: Increasing access to early diagnosis can provide a path to improving care for patients with CKD. Concerted efforts from all stakeholders are needed to overcome the barriers.

Chronic kidney disease (CKD) is a silent disease characterized by the slow and progressive loss of kidney function for months or years and is irreversible [1]. Worldwide, CKD affects 10–12% of the general population [2, 3]. Over the past 3 decades, the incidence of CKD has increased by almost 30%, reaching nearly 700 million cases [4]. Hypertension, diabetes, and obesity are all recognized as important risk factors for CKD, and the ongoing epidemics of these diseases might explain the rising CKD prevalence [5, 6], which might be underestimated [7, 8].

As CKD progresses, the complications from the loss of renal function increase, as well as the risk of death from all causes and cardiovascular events [9]. The close relationship between CKD and cardiovascular disease (CVD) is well known and is evidenced by the fact that measures that attenuate traditional CVD risk factors, such as good blood pressure (BP) control, adequacy of glycemic control, and lifestyle changes, translate into simultaneous attenuation of both CVD burden and the progression of renal disease [10, 11].

Data on CKD prevalence in Brazil are scarce, with methodology limitations and, consequently, with variable results. Based on the estimated glomerular filtration rate (eGFR) alone, the 2014–2015 laboratory data from the National Health Survey (n = 7,457 individuals aged 18 years and older) in Brazil, the prevalence rate for eGFR <60 mL/min/1.73 m2 was 6.7% and for eGFR <30 mL/min/1.73 m2 was 0.3%. The rate differed significantly for female (8.2%) to male patients (5.0%) and was higher for individuals over 60 years (21.4%) [12].

A prospective multicenter study using Kidney Disease Improving Global Outcomes (KDIGO) criteria to define CKD (2008–2010) involved six Brazilian states and more than 14,500 participants (age: 35–74 years). This study showed an overall prevalence of CKD in the country of 8.9%, being higher in individuals of lower socioeconomic status (SES), as well as in people of African descent (PAD) and Native Brazilians [13]. In 2017, Piccolli et al. [14] also used KDIGO criteria. They revealed a CKD prevalence of 11.4% in a random population of 5,216 participants in southern Brazil, which matches the prevalence in other countries [15]. PAD had a 4-fold higher risk for CKD than white people, with a more rapid kidney function decline, even though both groups had a similar CKD prevalence in the earlier stages [16‒21]. It remains to be seen if this reported prevalence is similar in northern Brazil, where the SES is lower, there are fewer white people, and there is a higher preponderance of PAD.

This high prevalence of CKD in PAD has been ascribed to SES and healthcare access. Still, data indicate the association between genetic variants and nephropathy in PAD [17, 18, 20, 22]. PAD have two genetic variants of the gene responsible for apolipoprotein L1 (gene APOL1) [18]. These APOL1 gene variants are responsible for most cases of global focal glomerulosclerosis, HIV-associated nephropathy, hypertensive nephrosclerosis, and lupus nephritis in this population. Thus, the PAD population has genetic risk factors besides SES and access factors.

According to the 2020 Brazilian Dialysis Census, the estimated number of patients in a dialysis program in Brazil was 144,779 [23]. This is an extrapolated estimate from the 30% of dialysis centers that responded to the survey.

Studies show that early detection and intervention are essential to prevent the disease from reaching later stages when dialysis is needed, reducing morbidity and mortality [24]. It is important to note that income and geography play an important role in prognosis. Patients in low- and middle-income countries who survive CKD during progression often die within months once they reach end-stage disease due to a lack of access to disease identification and management tools [25‒27]. Unfortunately, we have no reliable data on the process that leads to an early diagnosis of CKD in Brazil. Because the majority of these patients are seen in the advanced stages of the disease, we predict that the process of identifying and following up of patients with CKD in Brazil needs to be reconsidered.

The epidemic prevalence of CKD surpasses the availability of nephrology specialists and requires primary care physicians (PCPs) to care for most of these patients. The PCP is responsible for managing patients with CKD stages 1–3, yet may be unaware of the current guidelines for screening and managing patients with CKD.

Given the broad benefits of slowing the progression of CKD, clear and objective recommendations on early diagnosis and effective treatments should be widely disseminated, thus reducing the burden of CKD. In this paper, this panel discusses the early diagnosis and treatment of CKD and the barriers and actions needed to improve the management of CKD in Brazil.

The Americas Health Foundation (AHF) identified five experts in CKD from Brazil. They were convened for a 3-day virtual meeting on May 25–27, 2022, to develop recommendations for overcoming barriers to early diagnosis and management of CKD in Brazil. To identify the panel, AHF conducted a literature review using PubMed, MEDLINE, and Embase to identify scientists and clinicians from Brazil who have published in the field of CKD since 2016. Augmenting this search, AHF contacted opinion leaders from Brazil’s medical field to corroborate that the list of individuals adequately represented the necessary fields of study. All the experts who attended the meeting are named authors of this manuscript. An AHF staff member moderated the discussion and is an author of the manuscript. The panelists retain complete control over the content of the paper.

The following search terms were used: “chronic kidney disease,” “early detection,” “quality of life,” and “screening” in combination with “Brazil,” from January 01, 2016, until October 11, 2021. The articles identified were in English, Portuguese, and Spanish. Particular attention was paid to identifying literature and research from Latin America.

AHF developed specific questions to address barriers to early diagnosis and management of CKD in Brazil and assigned one to each panel member. A written response to each question was drafted by individual panel members based on the literature review and personal expertise. The entire panel reviewed and edited each narrative during the 3-day conference through numerous rounds of discussion until a total agreement was reached. For issues with disagreement among the panel, additional dialogues took place until all panel members agreed to the content included in this paper. The recommendations developed were based on the evidence gathered, expert opinion, and personal experience and were approved by the entire panel. After the conference, the final manuscript was distributed by email to the panel for review and approval.

Diagnostic Journey

According to KDIGO Guidelines, CKD is diagnosed after a duration of over 3 months, with one or more of the following characteristics: eGFR below 60 mL/min/1.73 m2, albuminuria above 30 mg/g of creatinine, definitive structural or functional renal changes, or a kidney transplant [28]. Estimating equations such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) replaced the need for direct measurement in clinical practice [29, 30]. It is not advisable to evaluate renal function solely based on the value of isolated serum creatinine, which is influenced by the patient’s muscle mass or to calculate creatinine clearance based on 24-h urine collection because of the risk of urine collection errors. Recently, a new equation for estimating glomerular filtration rate (GFR), CKD-EPI-2021, based on serum creatinine, age, and sex, has been adopted [30]. The previous CKD-EPI equation contained the patient’s race [29]. Including race in the equation for estimating GFR was a problem in Brazil, as many Brazilian people are of mixed race, and defining race is not always an easy task. Furthermore, the diagnosis of CKD and therapeutic measures were delayed in PAD individuals compared to non-PAD individuals because they had a higher eGFR value using the old equation.

Laboratories now routinely use eGFR based on creatinine with the potential addition of cystatin C (cysC). Unlike creatinine, cysC concentration is not affected by gender, muscle mass, race, or protein intake. Since it is more accurate in estimating earlier stages of CKD, guidelines recommend using the CKD-EPIcys equation in the earlier stages of CKD, if available. Adding the value of cysC to the equation makes the eGFR more accurate, especially in patients with altered metabolism or creatinine production [31].

Regarding albuminuria, the most precise measurements come from a first-morning urine sample, although random samples are acceptable. Albuminuria can also be measured in a 24-h urine sample and expressed in mg/24 h. Values equal to or greater than 30 mg/24 h indicate CKD [28]. The urine albumin-to-creatinine ratio is preferable to the protein-to-creatinine ratio since the former seems to be more standardized and more accurate for lower proteinuria values [28, 32]. CKD is classified based on GFR into five stages and additional three stages according to albuminuria, as shown in Figure 1 [28].

Fig. 1.

Classification of GFR and albuminuria. The highlighted area corresponds to the CKD spectrum. The red arrow indicates the risk of progression to end stage renal disease.

Fig. 1.

Classification of GFR and albuminuria. The highlighted area corresponds to the CKD spectrum. The red arrow indicates the risk of progression to end stage renal disease.

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Importance of Early Diagnosis

Spending on renal replacement therapy (RRT) represents about 5% of the budget that the Sistema Único de Saúde (SUS, the Brazilian National Health System) spends on medium and high-complexity cases [33]. Therefore, actions to delay the progression of CKD are essential to reduce the economic burden.

The progression of CKD is associated with the appearance of many systemic complications (Fig. 1) resulting from the loss of renal function, which can be progressively disabling. In addition, CKD progression is associated with increased cardiovascular and all-cause mortality [34].

The epidemic prevalence of CKD exceeds the availability of nephrologists in Brazil and requires PCPs to care for most of these patients. This epidemic scenario is associated with a significant cardiorenal burden, as most cases of CKD are attributed to diabetes and/or hypertension, which are recognized risk factors for CVD and mortality [5, 15, 35].

Identifying CKD requires recognizing individual risks and appropriate laboratory testing (serum creatinine and/or urinary protein) [28] since symptoms do not usually manifest in early stages and are often underrecognized by patients and physicians. Notably, up to 44% of patients may remain undiagnosed in the early stages [36]. Delay in diagnosis denies these patients’ access to treatment at an early stage, leaving CKD to progress to a more advanced stage. In fact, the adoption of simple measures such as treatment with renin-angiotensin-aldosterone system inhibitors in the early stages of the disease can confer a significant attenuation in the cardiorenal outcome in this population besides leading to the preservation of health-related quality of life and lower healthcare costs [10, 11].

Management of CKD

Given the complexity of symptoms affecting the patient with CKD, as shown in Figure 2, a systematic and thorough approach is needed to reduce the progression rate and minimize the associated clinical complications. Measures to delay the loss of renal function should be instituted as soon as risk factors are identified. BP control is essential to achieve this goal, especially with the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), as these renin-angiotensin-aldosterone system inhibitor antihypertensive drugs are effective in slowing the progression of CKD, especially in patients with proteinuria [37‒39]. Combining ACEI and ARB drugs is not recommended [40]. In Brazil, ACEIs and ARBs are available for all patients at no charge.

Fig. 2.

Complications that can arise from CKD.

Fig. 2.

Complications that can arise from CKD.

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There is evidence that keeping the sodium bicarbonate concentration above 22 mmol/L contributes to slowing the progression of CKD [41]. Regarding protein intake, 0.55–0.60 g/kg or 0.6–0.8 g/kg of body weight per day is recommended for patients in stages CKD 3–5 who are metabolically stable, without and with diabetes, respectively [42].

Glycemic control is another critical measure to prevent CKD and delay its progression. Keeping hemoglobin A1c below 7% is imperative to slow the progression of CKD [43]. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new class of antidiabetic drugs, have shown particular benefit in delaying the progression of CKD in patients with and without diabetes [44, 45].

Among other mechanisms, reducing intraglomerular pressure, with a consequent reduction of proteinuria, is the primary pathophysiological mechanism to explain renal protection with ACEIs, ARBs, and SGLT2 inhibitors. While ACEIs and ARBs dilate the glomerular efferent arteriole, the action of the SGLT2 inhibitor constricts the glomerular afferent arteriole. Another class of antidiabetic drugs, the glucagon-like peptide-1 receptor agonists, has also shown a proteinuria reduction [46, 47]. Finerenone, a new nonsteroidal, selective, synthetic mineralocorticoid receptor antagonist, has also slowed CKD progression and decreased proteinuria in patients with diabetic kidney disease [48].

As the loss of renal function progresses, complications arise and must be addressed individually (Fig. 2). Anemia is treated with iron and erythropoietin replacement. Hyperparathyroidism is managed with vitamin D replacement and phosphate binder. Calcitriol is indicated when, despite normalization of 25OH-cholecalciferol levels, parathyroid hormone levels remain high. Hyperkalemia is treated with diet, potassium chelators, and sometimes suspension or reduction of ACEIs or ARBs [28].

Patients with CKD are more susceptible to the development of acute kidney injury. Therefore, anti-inflammatory drugs, iodinated contrast agents, and excess diuretic and hypotensive agents should be avoided. It is also important to treat other comorbidities, such as dyslipidemia and hypothyroidism.

Finally, from stage 4 CKD onward, patients need to be prepared for RRT, i.e., hemodialysis, peritoneal dialysis, or kidney transplantation. To be fully ready for the start of RRT, these patients must be continuously monitored by a nephrologist [28].

As mentioned above and as shown in Figure 3, CKD has several risk factors, its diagnosis is straightforward, and treatment ranges from patient self-healthcare to medication. Early diagnosis followed by early management will improve patient outcomes while reducing costs. The patient’s complete journey, from risk to diagnosis and treatment, is represented in Figure 4.

Fig. 3.

Risk factors, diagnostics, and management of CKD.

Fig. 3.

Risk factors, diagnostics, and management of CKD.

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Fig. 4.

CKD management.

Guidelines

CKD management worldwide is based on the KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease [28] and some updates for diabetes (2020) [49], and for the management of BP (2021) [50].

Guidelines in Brazil

The Brazilian Ministry of Health (MoH) guideline in 2014 covered all important aspects of early diagnosis and management of CKD [51] (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000538068). Even so, most patients with CKD are seen only in the advanced stages of the disease. Several problems explain this gap, which are addressed in other sections of this manuscript.

The PCP is responsible for managing patients with CKD stages 1–3. This physician may not be aware of the current guidelines for screening and managing patients with CKD (Fig. 5).

Fig. 5.

Screening tool to guide CKD diagnosis.

Fig. 5.

Screening tool to guide CKD diagnosis.

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Nevertheless, some initiatives were implemented. In 2006, MoH guidelines for the early diagnosis of CKD focused on risk groups, such as patients with diabetes, hypertension, and those with a family history of CKD [52]. This document was a milestone in the policy addressing CKD recognition as it defined each team member’s role and included reference and counter-reference criteria. In 2014, the MoH published a comprehensive and detailed guideline for the care of patients with CKD [51]. This document clarified the importance of primary care in the early recognition of CKD and the physician’s role in primary care.

In 2011, the Brazilian federal government developed the Strategic Actions Plan for Combating Chronic Noncommunicable Diseases (NCDs). This regulation proposed goals focused on the prevention of NCD, emphasizing the reduction of premature mortality in chronic conditions such as CKD by 2% per year through strategic actions in the prevention of obesity, hypertension, and diabetes [53]. Finally, in 2014, following the recommendations proposed by the KDIGO group, the MoH launched the Clinical Guidelines for the Care of Patients with CKD in the SUS with emphasis on the use of CKD-EPI and Modification of Diet in Renal Disease equations, as well as the description of clinical management according to the CKD stages and the availability of flowcharts for the assessment of CKD [54].

In recent years, the Brazilian legislature has made advances in managing patients with CKD. However, these improvements have not been incorporated into daily practice. In a survey of 87 physicians in São Paulo, only 42.5% responded affirmatively about having had any training in the care of patients with CKD. The combined use of eGFR from serum creatinine and urinalysis (urine spot sample analysis) was employed by 56% of physicians to diagnose CKD, and 64.6% reported classifying the CKD stages [55]. In summary, the study showed the need for physicians to update their knowledge and procedures to provide a comprehensive and efficient approach to treating CKD patients in primary care.

The SUS clinical guidelines for the care of patients with CKD, developed in 2014, follow international guidelines [54]. However, they need to be revised and updated, considering new advances in the care of these patients.

Coverage for Currently Available Treatments

In Brazil, government funding for most aspects of CKD treatment occurs through SUS. Seven out of ten Brazilians, or more than 150 million people, depend exclusively on SUS for treatment. Data from the National Health Survey for 2019, released by the Instituto Brasileiro de Geografia e Estatística (IBGE/Brazilian Institute of Geography and Statistics), showed that 59.7 million people, corresponding to 28.5% of the country’s population, have private healthcare, whether medical or dental. Within some areas of the country, personal healthcare coverage disparities are an issue. São Paulo and the federal district have 38.4% and 37.4% of residents with private health plans, respectively, which are much higher than the national average. Meanwhile, the states of Maranhão (5.0%), Roraima (7.4%), Acre (8.3%), and Amapá (8.7%) have the lowest coverage proportions [56].

The SUS provides charge-free ACEIs, ARBs, statins, sulfonylurea, metformin, and insulins. In addition, it offers high-cost drugs such as calcitriol, sevelamer, and erythropoietin. The MoH approved dapagliflozin, an SGLT2 inhibitor for treating type 2 diabetes mellitus in patients 65 years or older who have developed CVD and do not achieve adequate control with optimized metformin and sulfonylurea treatment (PORTARIA No. 16, of April 29, 2020). Regarding the SGLT2 inhibitors, the SUS makes it available only to patients with type 2 diabetes, aged 65 or older, who did not achieve adequate glycemic control with treatment with metformin and sulfonylurea [57].

In Brazil, one of the most urgent challenges is to overcome the fragmentation and fragility of the SUS in the clinical follow-up of individuals by improving the quality of primary care and promoting healthy living [58]. The low level of patient awareness of CKD, including general knowledge of CKD and its risk factors, is aggravated by recent national projects for privatizing and commodifying healthcare [59]. This delay in recognizing early-stage CKD leads to a greater focus on high-complexity care, such as RRT and/or kidney transplantation. Consequently, awareness of CKD remains unacceptably low, despite recent attempts to increase knowledge by disseminating clinical practice guidelines and recommendations for patients with CKD and its risk factors to providers. Promoting global health awareness of the disease by emphasizing the primary prevention of cardiovascular events and the progression of kidney disease through the primary healthcare system is still a challenge.

Barriers

Low health literacy is associated with lower medical and therapeutic adherence, faster progression of CKD, and more cardiovascular complications [60]. In the Programme for International Student Assessment (PISA) 2018, students in Brazil scored lower than the global average in reading, mathematics, and science, and 43% scored below the minimum level of proficiency in all three subjects [61]. Patients with inadequate literacy may have difficulty assimilating the information that CKD patients ideally receive and read, including lifestyle/therapeutic instructions.

PCPs are the most essential players in the early diagnosis of CKD, but they are often not trained to screen for and manage CKD. This lack of training is the main obstacle to the early diagnosis of CKD in Brazil. Patients generally progress to later stage disease and then are treated in tertiary hospitals. Consequently, late referrals lead to increased morbidity and costs [62].

Before the MoH published the guidelines in 2006, health policy and steps for early diagnosis were unclear. However, it is challenging for the primary care service to monitor patients with high quality due to the lack of professionals, low health literacy of the population leading to a lack of self-care, and lack of laboratories capable of performing the exams, among other reasons. In addition, the healthcare team often does not have ongoing medical education on CKD recognition and the need to follow recommended guidelines. Since no updates to the Clinical Guidelines for the Care of Patients with Chronic Kidney Disease in the SUS51 have been made since 2014, despite important advances in the field, the continuing education of the teams in primary care and the reassessment of this document are mandatory.

However, it should be noted that this document promoted the incorporation of measures to estimate the GFR, such as the Modification of Diet in Renal Disease and CKD-EPI, and presented flowcharts that demonstrated the recommended interval between consultations, which tests to order, and when to refer to a specialist. Still, there is a need for timely updates and a system to disseminate the updated guidelines to physicians. Thus, there are still barriers to be overcome concerning the lack of early diagnosis and management of CKD in Brazil.

Recommendations

It is essential to have a big picture of the reality of CKD in Brazil to better outline prevention and early treatment strategies seeking to modify the progressive and harmful course of CKD. Several actions should be taken to promote better kidney health in Brazil. They can be described as people-centered, physician-centered, and healthcare institution-centered actions.

People-Centered Actions

  • Promote ongoing education on healthy lifestyle habits and kidney health, raising awareness of the risk factors and protective factors associated with CKD; highlight the importance of avoiding exposure to tobacco and maintaining a healthy weight.

  • Encourage people to know about their kidney function. For that, national campaigns with slogans such as “Do you know what your creatinine is?” (“Você sabe qual a sua creatina?”), “Do you know how well your kidneys are working?” (“Você sabe quão bem seus rins estão funcionando?”), “Don’t forget to ask your doctor about your kidney function” (“Não esqueça de perguntar ao seu médico como está a sua função renal”) could be periodically released on social media platforms.

  • Empower patients to self-manage CKD, including keeping BP under control, eating foods with less salt and the optimal amount of protein, and controlling blood sugar.

  • Patients can use technology to monitor their health, such as at-home BP and glucose monitors, cell phone apps, and wearables.

  • Leaflets, videos, and other educational materials can work as coadjutant strategies to empower patients to better manage CKD.

  • Use multiple outreach channels – digital, written, community support, and celebrate the World Kidney Day initiative.

  • Stress the need for strict control of diabetes and hypertension to prevent or delay the progression of CKD.

Physician-Centered Actions (Healthcare Professionals)

  • Educate and certify PCPs on the importance of early detection of CKD [28].

  • Encourage physicians and healthcare providers through societies and CME programs to adopt evidence-based interventions to delay the progression of CKD [28, 45, 63].

  • PCPs and nonspecialists should be able to identify patients at moderate to high risk (hypertension, diabetes, CVD) of developing CKD and screen them properly.

  • PCPs should be encouraged to incorporate the early detection of CKD into CVD risk assessment and diabetes check routines.

  • PCPs and nonspecialists should have broad access to qualified and updated CME programs on managing diabetes, hypertension, CVD, obesity, dyslipidemia, and CKD.

Healthcare Institutions-Centered Actions (Governmental Actions and Private)

  • A national collaborative effort of all stakeholders is required for a straightforward action plan to reduce the growing burden of CKD and its complications in Brazil.

  • Ongoing education in line with the updated guidelines for preventing, diagnosing, and treating CKD and its risk factors should be offered to healthcare providers by healthcare agencies.

  • A national health data collection system should be available at all points of care to support continuous improvements in the prevention, detection, and management of kidney disease.

  • Increase access to screening tests for CKD (serum creatinine and urine albumin-to-creatinine ratio) in primary healthcare centers.

  • Automated reporting of patients’ eGFR by clinical analysis laboratories should be widely adopted [64, 65].

  • Increase the use of telemedicine to provide access to specialist services (nephrologists) and advice to PCPs (telementoring) where needed.

  • The SUS incorporating drugs proven to reduce the progression of CKD [66, 67] is essential to increase adequate and inclusive treatment of CKD in Brazil.

  • Establish public-private relationships to promote improved access to emerging therapeutics.

  • Healthcare agencies should promote a multidisciplinary approach, including dieticians, physical therapists, psychologists, and social workers.

  • Strengthen CKD surveillance via a national database to capture SUS and privately insured patients.

CKD has been recognized as an epidemic public health concern worldwide. Along with other associated NCDs, such as diabetes, hypertension, and obesity, CKD care must be taken to overcome the barriers that prevent the effective prevention and control of these diseases.

These actions range from educational and awareness measures for the general population on the importance of maintaining healthy lifestyles and controlling risk factors such as diabetes, hypertension, and obesity, to implementing certified CME programs in primary healthcare attention. Governmental and nongovernmental agencies must provide resources for laboratory tests and new drugs that are effective in slowing the progression of CKD. A national collaborative effort of all stakeholders is required for a straightforward action plan to reduce the growing burden of CKD and its complications in Brazil.

We would like to acknowledge the assistance of Dawn M. Bielawski, Ph.D. (The Editing & Writing Alchemist, LLC, https://theeditingandwritingalchemist.com/), with editing this manuscript, and Kelly Schrank, MA, ELS (Bookworm Editing Services LLC, https://headbookworm.com/), with the formatting of this manuscript.

The authors have no conflicts of interest to declare.

This work was supported by AHF through an unrestricted grant from AstraZeneca.

A.C.B., R.M.E., H.A., M.C.B., and M.C.R.: writing – original draft, investigation, formal analysis, and validation. A.M.J.: writing – review and editing, visualization, conceptualization, methodology, and project administration.

Additional Information

Andrea Carla Bauer and Rosilene M. Elias contributed equally to this work.

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