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Feature: CHRONIC KIDNEY DISEASE

Managing diabetes and hypertension in chronic kidney disease

Mead, Daniel DNP, APRN-FPA, AGNP-C, CNN-NP, CHSE; Dinh, Nhan MSN, CNP, AGACNP-BC; Wentworth, Danielle MSN, FNP-BC; Thomas, Sofia DNP, MSN, MHA, APRN, CNN-NP, FNP-C, CPH, FNKF; Suthar, Meera MSN, FNP-C, CNN-NP

Author Information
doi: 10.1097/01.NPR.0000794508.22673.f2
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Chronic kidney disease (CKD) is the most common chronic condition affecting more than 37 million Americans or 1 in 7 adults.1 Diabetes mellitus and hypertension (HTN) are the most common causes of CKD and better management of these conditions should decrease progression to kidney failure as well as cardiovascular disease (CVD) and/or stroke. As the bulk of CKD management is done by primary care, it is important for NPs to know and implement new guidelines to improve the health and wellbeing of their patients.

Kidney Disease: Improving Global Outcomes (KDIGO) is an international group of the world's experts in kidney disease. For the last two decades, nurse practitioners (NPs) have looked to KDIGO for guidelines to diagnose and manage kidney disease. Recently, these guidelines have been modernized to include specific updates on comorbidities in CKD.2 In October 2020, KDIGO published updated guidelines on the management of diabetes in CKD.3 These guidelines discuss comprehensive care for diabetes, glycemic monitoring and targets, and lifestyle and antihyperglycemic interventions along with approaches to self-management and optimal models of care.3

KDIGO followed this up with guidelines on the management of HTN in CKD, the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in CKD.4 This guideline discusses BP measurement and targets as well as lifestyle modification therapies and reviews antihypertensive therapies in patients with CKD. It also includes special sections regarding kidney transplant recipients and pediatric patients.

As in many areas of medicine, race—especially the inclusion of race in estimated glomerular filtration rate (eGFR) calculators in kidney disease—is a topic for debate. A joint task force was created by the American Society of Nephrology (ASN) and the National Kidney Foundation (NKF), which reviewed if race modifiers should or should not be included in eGFR calculators.5 Leaders of the NKF and ASN agreed that current race-based equations should be replaced, and they further stated the need for a well-researched and accurate replacement standardized in every lab in the US.6

In 2021, based on the strength of data from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, the FDA approved dapagliflozin to reduce decline in GFR, as well as incidence of kidney failure, hospitalization for heart failure, and CVD in adults with CKD who are at risk for disease progression.7,8 This new indication is for patients with CKD both with and without diabetes to improve kidney outcomes and reduce death from both renal and cardiovascular causes.

Because of the importance of the primary care NP in CKD management, we highlight details on each of these topics that will help slow progression of CKD.

Diabetes management in CKD

In October 2020, KDIGO released the Clinical Practice Guideline for Diabetes Management in CKD, the organization's first guideline for clinically managing patients with these two complex chronic diseases.3 The KDIGO Work Group consisted of a diverse, international, multidisciplinary team including two patients who provided unique perspectives.

In order to allow for tailored patient care, the clinician guidance is divided into:

  • Recommendations
    • Higher grade evidence
    • Systematic review was completed
  • Practice Points
    • Weaker grade evidence
    • Clinical guidance

Topics covered include: care of patients with CKD and type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), management after kidney transplant, and management of patients receiving dialysis. The visual components, including algorithms for medication selection, dosing, recommendations, and practice points, are particularly useful.3

Although the title would suggest diabetic medication management for patients with CKD, the guideline opens with a discussion of recommendations concerning renin-angiotensin-aldosterone system (RAAS) inhibition. Since these agents can help delay CKD progression, the guidelines recommend that patients with diabetes, HTN, and albuminuria (urine albumin-to-creatinine ratio greater than 30 mg/g) be treated with a RAAS inhibitor such as an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB). Once initiated, RAAS inhibiting medications should be titrated up to the maximum recommended dose tolerated.3

KDIGO highlights a comprehensive approach to managing patients with CKD and diabetes. Initially and throughout care, all patients should be counseled to stay physically active, follow a healthy diet, maintain BP within parameters, control dyslipidemia, and cease use of tobacco-containing products. With specific regard to glycemic management, the Work Group recommends utilizing hemoglobin A1c (HbA1c) to monitor overall therapeutic adequacy and encourages practitioners to individualize patient HbA1c goals. The HbA1c is not as accurate for patients with advanced CKD or those on dialysis due to their chronic anemia. Providers should consider this and perhaps utilize continuous glucose monitoring (CGM) or self-monitoring of blood glucose, since the results do not appear to be affected the same way as the HbA1c.3

Continuing with lifestyle management strategies, KDIGO recommends patients with CKD eat 0.8 g/kg/day of dietary protein, with weak evidence for the recommendation. Patients on dialysis have augmented dietary protein intake need between 1.0 and 1.2 g/kg/day due to the hypercatabolic state of these patients. KDIGO reminds us to take into consideration cultural preferences, food availability, cost, and skill level when discussing dietary recommendations with patients. A low sodium diet (less than 2 g of sodium daily) is important for all patients with CKD as is a moderate-intensity physical activity goal of 150 minutes/week, adjusted to an individual's tolerability.3

The guideline includes the most current published data for management of patients with CKD and diabetes regarding specific antihyperglycemic agents. KDIGO highlights and recommends initial therapy with sodium–glucose cotransporter-2 inhibitors (SGLT2i) in conjunction with metformin for patients with an eGFR greater than or equal to 30 mL/min/1.73 m2. Recent multiple randomized controlled trials have demonstrated that SGLT2i use confers both cardioprotective and renoprotective benefits on patients with CKD and T2DM. Evidence for kidney, and/or mortality benefits is lacking with metformin. However, because of the affordability, efficacy, availability, safety, cardiovascular protection, and association with weight loss, metformin is maintained as an initial therapeutic option.3 Unfortunately, metformin remains contraindicated for patients with an eGFR less than 30 mL/min/1.73 m2. SGLT2i use is covered later in this article.

When a patient does not meet individualized HbA1c goals for age and comorbidities on metformin and an SGLT2i, the guidelines recommend adding a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) as the next step. Like the SGLT2i trials, GLP-1 RAs have kidney and cardiovascular benefits for patients with CKD and T2DM. While some GLP-1 RAs can be utilized in patients with advanced CKD or those on dialysis, there is insufficient evidence regarding whether the cardiovascular and kidney benefits extend to this patient subgroup.3

The importance of overall CKD and diabetes goals is understood by NPs but patient buy-in is important. Using a structured diabetes self-management educational program may help patients reach their glycemic targets. Diabetic self-management education can help with weight loss and improve psychosocial outcomes. Education should be tailored to the patient and can be delivered live or via telemedicine, in either a group setting or through individualized one-on-one counseling. KDIGO recognizes the complexity of patients with CKD and diabetes and recommends an integrated, multi-disciplinary approach to caring for these patients. In order to provide this type of care, practitioners need continued and future support from policymakers and larger healthcare systems.3

Hypertension management in CKD

While diabetes is the more common cause of end stage kidney disease (ESKD), it is followed closely by HTN.9 HTN prevalence ranges from 60 to 90% depending on the stage of CKD and primary cause.10 The presence of HTN in CKD may further accelerate kidney injury and progression to ESKD. The KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease, published in 2021, covers proper BP measurement, optimal BP targets, lifestyle interventions, and antihypertensive therapies for patients with CKD as well as kidney transplant recipients and pediatric patients.4

Prior to deciding on the need for treatment, it is important to accurately measure the BP.11 Consistency in both home and office/clinic measurements is vital.

  • Sit for 3-5 minutes in a chair with back support
  • Feet flat on the floor
  • Correct size and position of cuff
  • Arm in comfortable position

In patients with HTN and CKD who are not receiving dialysis, KDIGO suggests lifestyle intervention to lower BP consisting of:

  • A sodium intake less than 2 g per day. Of note, dietary sodium restriction is usually not appropriate for patients with sodium-wasting nephropathy.
  • KDIGO highlights precautions regarding the Dietary Approaches to Stop Hypertension (DASH) diet due to issues with hyperkalemia in patients with CKD
  • Moderate-intensity physical activity for 150+ minutes per week or to a level compatible with the patient's cardiovascular and physical tolerance is advised. The type and intensity of physical activity or exercise should be personalized based on patient's condition

The greatest change in the 2021 KDIGO guidelines is the systolic BP (SBP) goal. In patients with CKD with or without diabetes, the target SBP is less than 120 mm Hg. A standardized office BP measurement is required prior to implementing such a strict goal. Patients with very limited life expectancy or symptomatic postural hypotension may require less intensive BP-lowering therapy.4

CKD is classified on the basis of risk, with many cardiac guidelines noting that the diagnosis of CKD moves the patient to high risk for CVD. Regardless of the patient's diabetes status, starting RAAS inhibitors (ACEis or ARBs) is recommended in patients with CKD, HTN, and albuminuria, and may be appropriate in patients with HTN and CKD without albuminuria. Major points of this guideline are as follows:

  • Titrate RAAS inhibitor therapy to the highest approved dose, as tolerated
  • KDIGO suggests monitoring for changes in BP, kidney function, and potassium levels within 2 to 4 weeks of medication initiation or titration
  • If hyperkalemia associated with use of RAAS inhibitor occurs, utilization of dietary changes and/or a potassium binder to lower serum potassium is recommended
  • Continue RAAS inhibitor therapy unless there is a rise of greater than 30% in serum creatinine within 4 weeks following either initiation of treatment or an increase in dose
  • Reducing the dose or discontinuing RAAS inhibitor therapy should be considered when iatrogenic effects occur despite medical treatment
  • Mineralocorticoid receptor antagonists are effective for management of refractory HTN but may cause hyperkalemia and/or a reversible decline in kidney function, especially in those with low eGFR
  • Avoiding any combination of ACEi, ARB, and direct renin inhibitor (DRI) therapy in patients with CKD is recommended

While the SBP goal in CKD is less than 120 mm Hg, the goal in adult kidney transplant recipients is less than 130 mm Hg systolic and less than 80 mm Hg diastolic. The need to profuse the donated kidney takes priority over lowering of BP required. A dihydropyridine calcium channel blocker (CCB) or an ARB are recommended as first-line antihypertensive agents in this population.4

In children with CKD and HTN, 24-hour mean arterial pressure (MAP) via ambulatory BP monitoring (ABPM) should be lowered to less than or equal to the 50th percentile for age, sex, and height. Annual ABPM with quarterly standardized auscultatory office BP measurement is suggested. It is reasonable to obtain manual auscultatory office BP measurement in a protocol-driven standardized setting targeting achieved SBP less than the 90th percentile for age, sex, and height of normal children when ABPM is not available. Despite carrying the risk of hyperkalemia and adverse fetal risks for pregnant women, RAAS inhibitor therapy should be used as first-line therapy due to its renoprotective benefits. It should be stopped as soon as pregnancy is known.4

KDIGO aims to provide clinicians practical resources on HTN management in CKD. The use of standardized measurement of BP with an SBP target of less than 120 mm Hg and utilization of RAAS inhibitor therapy are strongly emphasized for most CKD subpopulations. Lastly, nephrology referral should be made in those with increased risk for ESKD and/or refractory HTN.4

Race modifiers in eGFR measurement

At a time of great societal controversy regarding race and its potential for propagating inequities and health disparities, the NKF and ASN appointed a joint task force to assess the inclusion of race in eGFR equations within the US.5 Internationally, opinion leans toward removing the use of race in eGFR equations as well as throughout general medicine.12 In Spring 2021, the NKF-ASN task force issued an interim result rather than a final report.6 In studying the issue, they found that the question was much more convoluted and difficult than they expected and the task force wished to give the question further time and research before a decision could be rendered. However, leaders from the ASN and the NKF have unequivocally stated that race will be removed from the eGFR calculators, prompting the issue of building a replacement to the present eGFR calculator.13

The interim report primarily focuses on presenting evidence on the complexity of the exploration of race and kidney disease. As noted in the interim report, many stakeholders use eGFR calculations. These include the FDA (medication dosing via eGFR), the National Institutes of Health (NIH) for trials presently underway (adverse events reported via eGFR), and labs across the world. If changes are made to the eGFR calculations, all these entities would need to revamp their reporting. The task force submitted its final report in August 2021 for review.14 We anxiously await publication of the full recommendations on how to remove race from eGFR equations while maintaining scientific accuracy with an eye toward the potential ramifications of such a move.6

To understand the impact of this undertaking, considerations for use of race-based eGFR equations must first be appreciated. In determining eGFR, it had been thought that Black patients had more muscle mass (which produces creatinine) leading to an ‘adjustment’ in the creatinine-based eGFR as compared to non-Black patients. Race was assigned by researchers who developed the eGFR calculators. Race-based eGFR equations have been customary in clinical practice decision-making, underpinning medication selection, contrast-based diagnostic and prognostic exam utilization, and surgical complication risk estimates as well as national CKD population surveillance and regulatory practices.6 Continued use of race-based equations have rippling implications on general kidney disease diagnosis, safety and effectiveness of pharmacotherapy, management and mitigation of kidney disease risk factors, and the timeliness of nephrology referral, kidney donation, and kidney transplantation.15

While we await publication of the final report, the interim report provides an appreciation for the complexity of the issue. The initial GFR calculator, the Cockcroft-Gault (CG) equation, was developed from a hospitalized White male population.16 The Modification of Diet in Renal Disease (MDRD) equation, and its subsequent derivations and refinements including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, which added a non-race-based filtration marker, cystatin C, replaced CG.17,18 At the time of publishing, the task force's final report is not yet publicly available.14 However, even with the final task force report, this is just the beginning of discussion on race, ethnicity, and their intersections with kidney health.

SGLT2i, CKD, and new horizons

For more than 2 decades, ACEis and ARBs represented the main pharmacologic tools to prevent progression of CKD along with optimizing diet, hypertension, and diabetes mellitus. Now, a new player has emerged: dapagliflozin, an SGLT2i. Dapagliflozin is now FDA approved to treat CKD in patients with and without diabetes mellitus.7 Previously, SGLT2is have been used for treatment in diabetes. Trials to evaluate cardiac endpoints showed that SGLT2i also slowed eGFR decline in patients with CKD and T2DM.19,20 The next question was if these medications also benefitted patients with CKD without T2DM. The DAPA-CKD randomized placebo-controlled trial tested the hypothesis that dapagliflozin might benefit patients with CKD without T2DM.8

This novel trial of over 4,000 participants had a placebo arm and a dapagliflozin arm. Participant initial eGFRs ranged from 25 to 75 mL/min/1.73 m2 with urine albumin-to-creatinine ratios from microalbuminuria to macroalbuminuria. The primary outcome was a composite of sustained eGFR decline of at least 50%, ESKD, or death from renal or cardiovascular causes.21

Overall, 9.2% (197/2152) of the dapagliflozin group and 14.5% (312/2152) of the placebo group met the primary outcome, although the trial was stopped 2 years early due to the overwhelmingly positive response to dapagliflozin.8,22 Statistical analysis of secondary outcomes also showed benefit from the dapagliflozin arm: lower rate of the composite of eGFR decline of at least 50%, ESKD, or death from renal causes; lower rate of composite of hospitalization for heart failure or death from cardiovascular causes; and less overall fatality.8 These positive results occurred in all patients with CKD, with or without T2DM. The conclusion is a simple one; patients with CKD, with or without T2DM, benefit from dapagliflozin with a sustained reduction in decline of the eGFR.8

The DAPA-CKD investigators of this study highlight the renoprotective properties of dapagliflozin with a deep and detailed statistical analysis. The implications of this trial go beyond simply having another tool to treat patients with CKD; we now have an option to reduce eGFR loss for those who are ACEi- or ARB-intolerant or need additional adjunctive therapy. Further, the DAPA-CKD trial confirmed the safety profile of dapagliflozin, with the overall incidence of adverse and serious adverse reactions similar between the treatment and placebo arms.

It is important to point out that patients with T1DM, polycystic kidney disease, autoimmune kidney diseases, and/or those on immunosuppressive therapy were excluded from the trial. Patients with New York Heart Association (NYHA) class IV heart failure and patients with recent cardiovascular events (including myocardial infarctions) were also excluded.21

While the FDA stated that patients with CKD who are at risk of disease progression can be treated with dapagliflozin. However, all patients in the DAPA-CKD trial were required to be receiving an ACEi or ARB prior to the trial start unless they had a documented intolerance.8 Therefore, it may be prudent to consider dapagliflozin as an adjunctive agent, rather than monotherapy in non-diabetic CKD. It would be reasonable to bolster a regimen with dapagliflozin that already has RAAS blockade therapies to further reduce eGFR decline.

Conclusion

When 37 million Americans have CKD and 1 in 3 are at risk for developing CKD, NPs need to be well-versed in the latest CKD diagnosis and management recommendations. It is known that aggressive management of HTN and patient-specific management of diabetes will slow progression of CKD as well as other major comorbidities, CVD, end organ failure, and/or stroke. Primary care NPs can have a major impact in CKD outcomes by utilizing KDIGO guidelines. The newest guidelines, diabetes management in CKD and hypertension management in CKD, combine the worldwide research of thousands of patients and practitioners.

Focus on initiation of therapies such as dapagliflozin, an SGLT2i, in the management of patients with CKD with or without diabetes will start at a primary care level. Staging of CKD and whether to use race as a modifier is still unclear. What is not in question is the importance of the primary care NP in diagnosis and management of the patient with CKD in the 21st century. It is imperative for NPs to stay up to date on future developments as they emerge.

REFERENCES

1. Center for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2021, https://www.cdc.gov/kidneydisease/pdf/Chronic-Kidney-Disease-in-the-US-2021-h.pdf, Accessed 12Jun2021
2. KDIGO announces increased priority on guideline updates. https://kdigo.org/kdigo-announces-increased-priority-on-guideline-updating/, Accessed 24Jun2021
3. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDGIO 2020 Clinical Practice Guidelines for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(4S):S1-S115
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5. ASN and NKF form joint task force to focus on use of race in eGFR. https://www.kidney.org/newsletter/nkf-and-asn-form-joint-task-force-to-focus-use-race-egfr, Accessed 24Jun2021.
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9. United States Renal Data System. 2020 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2020.
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13. Feldman HI, Briggs JP. Race and the Estimation of GFR: Getting it Right. J Am Soc Nephrol. 2021 Jun 1;32(6):1269–1270. doi: 10.1681/ASN.2021020206.
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15. National Kidney Foundation, Removing Race from Kidney Disease, letter to members, https://www.asn-online.org/g/blast/files/NKF-ASN-eGFR-March2021.pdf, Accessed 23May2021
16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. doi: 10.1159/000180580. PMID: 1244564.
17. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130(6):461–470.
18. Levey AS, Stevens LA, Schmid CH, et al; for the CKD-EPI (Chronic Kidney Disease Epidemiology) Collaboration. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604–12.
19. Kluger AY, Tecson KM, Barbin CM, et al. Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review. Rev Cardiovasc Med. 2018 Jun 30;19(2):41–49. doi: 10.31083/j.rcm.2018.02.907.
20. Sarraju A, Li J, Cannon CP, et al. Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: Results from the CREDENCE trial. Am Heart J. 2021 Mar;233:141–148. doi: 10.1016/j.ahj.2020.12.008
21. Heerspink HJL, Stefansson BV, Chertow GM, et al; for the DAPA-CKD Investigators. Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020 Feb 1;35(2):274–282. doi: 10.1093/ndt/gfz290.
22. Endocrine Today DAPA-CKD trial stopped early after ‘overwhelming benefit’ observed with dapagliflozin, https://www.healio.com/news/endocrinology/20200330/dapackd-trial-stopped-early-after-overwhelming-benefit-observed-with-dapagliflozin, Accessed 25Jun2021
Keywords:

chronic kidney disease; diabetes; diabetic kidney disease; glomerular filtration rate; hypertension; NKF-ASN task force; race and eGFR; SGLT2 inhibitors

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