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What's new in nephrology and hypertension

What's new in nephrology and hypertension
Authors:
John P Forman, MD, MSc
Albert Q Lam, MD
Literature review current through: Feb 2022. | This topic last updated: Feb 22, 2022.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ACUTE AND CHRONIC KIDNEY DISEASE

Finerenone in patients with type 2 diabetes and less severe diabetic kidney disease (January 2022)

Patients with type 2 diabetes and diabetic kidney disease (DKD) should generally be treated with an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) plus a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Finerenone, a nonsteroidal selective mineralocorticoid receptor antagonist (MRA), was shown to slow the progression of kidney function loss in a large trial of patients with type 2 diabetes and severe DKD. In a similar trial that tested the effects of this drug in over 7000 patients with less severe DKD, finerenone, compared with placebo, reduced the risk of heart failure hospitalization and nonsignificantly lowered the rate of kidney failure and all-cause mortality; the benefit from finerenone was similar in those treated and not treated with an SGLT2 inhibitor [1]. As a result of these two trials, some experts add finerenone, where available, to SGLT2 therapy provided the patient has a normal serum potassium while taking an ACE inhibitor or ARB. (See "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)

Daprodustat for anemia treatment in nondialysis chronic kidney disease (November 2021)

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) are a novel class of oral erythropoiesis-stimulating agents (ESAs) that are being evaluated for treatment of anemia in patients with chronic kidney disease (CKD). In a trial of nearly 4000 patients with nondialysis CKD and anemia that compared the safety and efficacy of the HIF PHI daprodustat with darbepoetin, hemoglobin concentrations increased more with daprodustat at approximately two years [2]. However, major cardiovascular events (a composite of death, nonfatal stroke, and nonfatal myocardial infarction) were also more frequent with daprodustat, a difference that was statistically significant during the active treatment period but not by the end of post-treatment follow-up. Although these data indicate that anemia can be effectively treated with daprodustat, they raise some safety concerns about this drug. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Investigational agents'.)

Revised equation to estimate glomerular filtration rate without using a race coefficient (September 2021)

The creatinine-based chronic kidney disease epidemiology (CKD-EPI) equation, commonly used to estimate glomerular filtration rate (GFR), has recently been revised and no longer contains a term for race [3]. Compared with the original equation, the 2021 equation is less accurate, generally underestimating measured GFR in Black individuals and overestimating measured GFR in other individuals, but is reasonable and acceptable for clinical use. When applied to the general population, the 2021 CKD-EPI equation results in a higher estimated prevalence of chronic kidney disease (CKD) among Black individuals and a lower estimated prevalence of CKD among other individuals. The revised equation also impacts clinical aspects of care, such as candidacy for certain cancer treatments, drug dosing, listing for kidney transplantation, and others. (See "Assessment of kidney function", section on 'Estimation of GFR'.)

Glomerular filtration rate estimation without inclusion of a race coefficient (September 2021)

Previously, the chronic kidney disease epidemiology (CKD-EPI) equation used to estimate glomerular filtration rate (GFR) included a term for race such that, for any given age, sex, and serum creatinine, a Black individual would have a higher estimated GFR. The American Society of Nephrology and National Kidney Foundation reevaluated the inclusion of race in estimating GFR and determined that a revised creatinine-based equation (ie, the 2021 CKD-EPI equation) that did not include race was sufficiently accurate for clinical use [4]. We now suggest using the 2021 revised CKD-EPI equation to estimate GFR (calculator 1). The equation applies to people with stable kidney function. (See "Assessment of kidney function", section on 'Estimation of GFR'.)

DIALYSIS

Daprodustat for anemia in patients on dialysis (January 2022)

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) are a novel class of oral erythropoiesis-stimulating agents (ESAs) that are being evaluated for treatment of anemia in patients with chronic kidney disease (CKD). In a trial that compared the efficacy and safety of the HIF PHI daprodustat and an injectable ESA (epoetin or darbepoetin) in over 2900 patients on dialysis, the mean change in hemoglobin concentration was 0.28 g/dL with daprodustat and 0.10 g/dL with ESA therapy over a median of 2.5 years [2]. Rates of major adverse cardiovascular events were similar between the treatment groups, as were rates of other adverse events. While these data suggest that daprodustat can effectively treat anemia in patients on dialysis, this drug is not yet approved for use outside of Japan. (See "Treatment of anemia in dialysis patients", section on 'Investigational agents'.)

FLUID, ELECTROLYTES, AND ACID-BASE BALANCE

Fluid resuscitation with saline or a buffered crystalloid in adults (September 2021)

The choice between normal saline and a buffered crystalloid for initial fluid resuscitation in adults is debated. A recent two-by-two-factorial randomized trial of >11,000 critically ill patients (mostly surgical) treated with normal saline or a buffered crystalloid found that neither the fluid type nor the rate of administration had an impact on 90-day mortality or the incidence of acute kidney injury (AKI) [5,6]. However, the trial may have been underpowered, only small volumes of fluids were administered, and fluid was administered prior to randomization, all of which decrease confidence in the results. We suggest that the choice between fluids be individualized and re-evaluated following initial resuscitation. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Choosing between 0.9 percent saline and buffered crystalloid'.)

GLOMERULAR DISEASE AND VASCULITIS

Macrophage infiltration and response to immunosuppression in IgA nephropathy (December 2021)

In patients with IgA nephropathy (IgAN), immunosuppressive therapy is generally reserved for those who are at high risk for disease progression; however, tools to identify which patients are likely to benefit from treatment are lacking. In a study of over 600 Chinese patients with IgAN at high risk for disease progression who received immunosuppressive therapy for a median of 18 months, higher levels of macrophage infiltration within glomeruli on kidney biopsy were associated with a markedly increased probability of response to immunosuppression when compared with lower levels [7]. Combining the intensity of macrophage infiltration with clinical and histologic data accurately predicted the response to immunosuppression. While these findings may help identify patients who will benefit from immunosuppressive therapy, additional validation in other patient populations is needed. (See "IgA nephropathy: Treatment and prognosis", section on 'Immunosuppressive therapy in high-risk patients'.)

Anti-nephrin antibodies in minimal change disease (November 2021)

Minimal change disease (MCD) is a common cause of the nephrotic syndrome in children and adults, but the underlying pathogenesis remains unclear. In a recent study of over 60 adults and children with biopsy-proven MCD and no known genetic basis, circulating autoantibodies targeting nephrin, an essential component of the glomerular slit diaphragm, were identified in approximately one-third of patients with active disease [8]. Punctate immunoglobulin G (IgG) deposits colocalized with nephrin in the kidney biopsies of patients who were serologically positive for anti-nephrin antibodies, whereas no deposits were present in those who were serologically negative. These findings suggest a possible autoimmune etiology for MCD in a subset of patients. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Role of B cells'.)

New antineutrophil cytoplasmic antibody-associated vasculitis guideline (September 2021)

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a group of diseases that involve inflammation of small and medium-sized vessels and include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The American College of Rheumatology (ACR)/Vasculitis Foundation has recently published guidelines for the management of the ANCA-associated vasculitides [9]. These guidelines provide recommendations for induction and maintenance therapy for GPA, MPA, and EGPA, which are largely consistent with our approach. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Initial treatment approach'.)

HYPERTENSION

Antihypertensive effect of chlorthalidone in advanced chronic kidney disease (November 2021)

It is a commonly held belief that thiazide diuretics are not effective in patients with advanced chronic kidney disease (CKD); however, several studies indicate that thiazide diuretics are effective in such patients. In a randomized trial of 160 patients with advanced CKD (estimated GFR 15 to 29 mL/min/1.73 m2) and uncontrolled hypertension despite antihypertensive therapy, chlorthalidone substantially reduced 24-hour ambulatory blood pressure (by 10.5/3.9 mmHg) compared with placebo [10]. Hypokalemia, hyponatremia, and dizziness were more common with chlorthalidone. These data confirm findings from other studies and indicate that thiazide diuretics can be effective in controlling blood pressure among patients with advanced CKD. (See "Thiazides versus loop diuretics in the treatment of hypertension", section on 'Patients with chronic kidney disease'.)

Randomized trial of goal blood pressure in older adults (October 2021)

UpToDate recommends intensive blood pressure lowering in hypertensive older adults, based in part upon findings from the Systolic Pressure Intervention Trial (SPRINT). In the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial, more than 8000 Chinese adults aged 60 to 80 years were randomly assigned to either a more intensive (goal systolic pressure <130 mmHg) or a less intensive (goal systolic pressure <150 mmHg) blood pressure lowering strategy [11]. Those assigned to more intensive blood pressure lowering had modestly lower rates of stroke, acute coronary syndrome, and heart failure at approximately three years; major adverse events were similar between the groups. The STEP trial findings are broadly consistent with those from SPRINT and support our recommendation for intensive blood pressure lowering in hypertensive older adults. (See "Goal blood pressure in adults with hypertension", section on 'Older adults'.)

Effect of a salt substitute on cardiovascular events and mortality (September 2021)

Strong evidence supports that dietary sodium reduction can lower blood pressure, but few trials have directly assessed the effects of sodium reduction on long-term cardiovascular outcomes and mortality. In the recent Salt Substitute and Stroke Study (SSaSS), which randomly assigned over 20,000 older adults at high cardiovascular risk to use a potassium-enriched salt substitute at home or to continue using regular salt, those assigned to the reduced sodium intervention had a lower risk of stroke and all-cause mortality at five years [12]. These findings support our recommendation to reduce dietary sodium intake. (See "Salt intake, salt restriction, and primary (essential) hypertension", section on 'Effects of sodium on cardiovascular disease'.)

TRANSPLANTATION

Additional COVID-19 vaccine primary series dose for immunocompromised individuals (August 2021, Modified February 2022)

COVID-19 vaccines are less effective among patients with certain immunocompromising conditions than in the general population; additional vaccine doses have been associated with improved effectiveness in this population. We agree with recommendations from the Advisory Committee on Immunization Practices (ACIP) in the United States that individuals with such conditions (table 1) receive an additional mRNA vaccine dose as part of their primary COVID-19 vaccine series (eg, following two doses of an mRNA vaccine or one dose of Ad26.COV2.S vaccine) [13,14]. This additional primary series dose is distinct from the booster dose, which such patients should additionally receive, although at a shorter interval than recommended for the general population. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

Mode of delivery and pregnancy outcomes in kidney transplant recipients (January 2022)

Most pregnant kidney transplant recipients will undergo a cesarean delivery, but there is no clear evidence to support its routine use. In a registry study of over 1400 female kidney transplant recipients with live births, approximately two-thirds underwent a trial of labor (most with a vaginal delivery) and one-third had a scheduled cesarean birth [15]. Compared with scheduled cesarean birth, a trial of labor was not associated with an increase in severe maternal morbidity and was associated with lower odds of neonatal morbidity. Among kidney transplant recipients, vaginal birth is the preferred mode of delivery, and cesarean birth should be reserved for patients with obstetric indications only. (See "Kidney transplantation in adults: Sexual and reproductive health after kidney transplantation", section on 'Mode of delivery'.)

Fourth dose of COVID mRNA vaccine in solid organ transplant recipients (January 2022)

In solid organ transplant recipients, a third dose of a COVID-19 mRNA vaccine appears to improve the immune response; however, many have a weak response even after three prior doses. Data from three independent case series suggest that a fourth dose of an mRNA vaccine may increase antibody levels in some of these patients [16-18]. In the largest of these studies, approximately half of the 92 kidney transplant recipients who received a fourth dose mounted an appropriate serologic response (antispike IgG titer >143 binding antibody units); however, similarly robust responses were not seen across all studies. Among patients who did not respond to previous doses, the likelihood of response to additional doses was low. Administration of more than three doses of mRNA vaccine is not routinely performed; for patients who are unable to respond to multiple vaccine doses, other strategies may be required to achieve immunity. (See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

Neutralization of SARS-CoV-2 variants in transplant recipients after three doses of mRNA vaccine (December 2021)

In transplant recipients, administration of a third COVID-19 mRNA vaccine dose has been shown to improve the immune response without causing short-term adverse events; however, data on vaccine immunogenicity against SARS-CoV-2 variants are limited. In a secondary analysis of a recent randomized trial, sera obtained from participants after receipt of the third vaccine dose had greater ability to neutralize wild-type SARS-CoV-2 and Alpha, Beta, and Delta variants when compared with sera obtained after the second dose and sera from participants who received placebo [19]. The third dose was well tolerated; no cases of rejection were reported, and graft function remained stable in all patients for three months after the third dose. These findings support administering a three-dose primary vaccine series among transplant recipients and other immunocompromised patients. (See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

REFERENCES

  1. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med 2021; 385:2252.
  2. Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis. N Engl J Med 2021; 385:2325.
  3. Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med 2021; 385:1737.
  4. Delgado C, Baweja M, Crews DC, et al. A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. Am J Kidney Dis 2022; 79:268.
  5. Zampieri FG, Machado FR, Biondi RS, et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA 2021.
  6. Zampieri FG, Machado FR, Biondi RS, et al. Effect of Slower vs Faster Intravenous Fluid Bolus Rates on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA 2021; 326:830.
  7. Xie D, Zhao H, Xu X, et al. Intensity of Macrophage Infiltration in Glomeruli Predicts Response to Immunosuppressive Therapy in Patients with IgA Nephropathy. J Am Soc Nephrol 2021.
  8. Watts AJB, Keller KH, Lerner G, et al. Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology. J Am Soc Nephrol 2022; 33:238.
  9. Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Care Res (Hoboken) 2021; 73:1088.
  10. Agarwal R, Sinha AD, Cramer AE, et al. Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease. N Engl J Med 2021; 385:2507.
  11. Zhang W, Zhang S, Deng Y, et al. Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension. N Engl J Med 2021; 385:1268.
  12. Neal B, Wu Y, Feng X, et al. Effect of Salt Substitution on Cardiovascular Events and Death. N Engl J Med 2021; 385:1067.
  13. CDC - An Additional Dose of mRNA COVID-19 Vaccine Following a Primary Series in Immunocompromised People. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-08-13/02-COVID-Dooling-508.pdf (Accessed on August 14, 2021).
  14. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html (Accessed on February 24, 2022).
  15. Yin O, Kallapur A, Coscia L, et al. Mode of Obstetric Delivery in Kidney and Liver Transplant Recipients and Associated Maternal, Neonatal, and Graft Morbidity During 5 Decades of Clinical Practice. JAMA Netw Open 2021; 4:e2127378.
  16. Alejo JL, Mitchell J, Chiang TP, et al. Antibody Response to a Fourth Dose of a SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Transplantation 2021; 105:e280.
  17. Kamar N, Abravanel F, Marion O, et al. Assessment of 4 Doses of SARS-CoV-2 Messenger RNA-Based Vaccine in Recipients of a Solid Organ Transplant. JAMA Netw Open 2021; 4:e2136030.
  18. Caillard S, Thaunat O, Benotmane I, et al. Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series. Ann Intern Med 2022.
  19. Kumar D, Ferreira VH, Hall VG, et al. Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine : Secondary Analysis of a Randomized Trial. Ann Intern Med 2022; 175:226.
Topic 8352 Version 10977.0

References

1 : Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.

2 : Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.

3 : New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

4 : A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease.

5 : Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

6 : Effect of Slower vs Faster Intravenous Fluid Bolus Rates on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

7 : Intensity of Macrophage Infiltration in Glomeruli Predicts Response to Immunosuppressive Therapy in Patients with IgA Nephropathy.

8 : Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology.

9 : 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

10 : Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease.

11 : Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension.

12 : Effect of Salt Substitution on Cardiovascular Events and Death.

13 : Effect of Salt Substitution on Cardiovascular Events and Death.

14 : Effect of Salt Substitution on Cardiovascular Events and Death.

15 : Mode of Obstetric Delivery in Kidney and Liver Transplant Recipients and Associated Maternal, Neonatal, and Graft Morbidity During 5 Decades of Clinical Practice.

16 : Antibody Response to a Fourth Dose of a SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series.

17 : Assessment of 4 Doses of SARS-CoV-2 Messenger RNA-Based Vaccine in Recipients of a Solid Organ Transplant.

18 : Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series.

19 : Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine : Secondary Analysis of a Randomized Trial.