Renal & Urology News - Spring 2023

HCTZ Fails to Prevent Stone Recurrence

The drug was no better than placebo in a randomized trial with a median follow-up of nearly 3 years

BY NATASHA PERSAUD

In a randomized study, the rate of symptomatic or radiologic recurrence of kidney stones over a median of 2.9 years did not differ significantly between placebo and hydrochlorothiazide, regardless of dose.

MMF Found Effective for IgAN

MYCOPHENOLATE mofetil (MMF) reduces the risk of disease progression in patients with immunoglobulin A nephropathy (IgAN), according to the findings of a recent study.

In the MAIN (The Effect of Mycophenolate Mofetil on Renal Outcomes in Advanced Immunoglobulin A Nephropathy) randomized controlled trial of 170 patients with IgAN, adding MMF to supportive care significantly reduced the risk of a composite outcome by 77% compared with supportive care alone, Fan Fan Hou, MD, PhD, of Nanfang Hospital, Southern Medical University in Guangzhou, China, and colleagues reported in JAMA Network Open The composite endpoint included creatinine doubling,

indication for kidney replacement therapy, or death due to a kidney or cardiovascular cause. The composite outcome occurred in 7.1% of the MMF group compared with 21.2% of the usual care group.

The addition of MMF also significantly reduced the risk of chronic kidney disease (CKD) progression by 77%, the investigators reported. CKD progression occurred in 8.2% of the MMF group compared with 27.1% of the usual care group. Progression was defined as a decline in estimated glomerular filtrate rate (eGFR) of 30% or more when baseline eGFR was 60 mL/min/1.73 m2 or higher or 50% of more when eGFR was less than 60 mL/min/1.73 m2

DESPITE BEING WIDELY used to prevent kidney stone recurrence, hydrochlorothiazide (HCTZ) does not exert this protective effect, regardless of dosage, according to investigators.

In the double-blind NOSTONE trial, investigators randomly assigned 416 patients with recurrent calciumcontaining kidney stones to receive HCTZ at a dosage of 12.5 mg, 25 mg, or 50 mg or placebo once daily. Patients also received dietary counseling. At baseline, 63% of patients had hypercalciuria, defined as a urinary calcium excretion rate of more than 200 mg in 24 hours.

Over a median of 2.9 years, the rate of symptomatic or radiologic recurrence

Nephrectomy Link to AKI, CKD Clarified

BY JODY A. CHARNOW PATIENTS

WITH preserved renal function who undergo surgery for localized renal masses are at increased risk for acute kidney injury (AKI) and clinically significant new-onset chronic kidney disease (CKD), especially if they have higher-complexity tumors, investigators reported at the 38th Annual Congress of the European Association of Urology in Milan, Italy.

of kidney stones did not differ significantly between the HCTZ and placebo groups: 59%, 56%, and 49% in the 12.5-mg, 25-mg, and 50-mg HCTZ groups vs 59% in the placebo group, Nasser A. Dhayat, MD, of the University of Bern in Switzerland, and colleagues reported in the New England Journal of Medicine The rate of symptomatic kidney stone recurrence alone also was comparable among groups: 38%, 40%, and 28%, respectively, vs 34% with placebo. The rate of radiologic recurrence was significantly lower in the 25- and 50-mg HCTZ groups compared with the placebo group: 32% and 34% vs 49%, respectively.

continued on page 9

IN THIS ISSUE

8 Urate levels vary by alcoholic beverage type consumed

8 High BP in CKD removes women’s cardiovascular risk advantage

10 Dietary potassium has minimal effect on potassium serum levels

11 Ultrasound renal denervation effective for hypertension

13 DGF is less likely with machine perfusion vs hypothermia

14 Circadian syndrome is associated with higher stone risk

17 CKD ups major hemorrhage risk in individuals older than 65 years continued on page 9

The findings are from a study of 2469 patients with localized renal masses, of whom 1063 (43%), 947 (38%), and 459 (19%) had low-, intermediate-, and high-complexity tumors, respectively.

All patients had an estimated glomerular filtration rate (eGFR) of 60 mL/ min/1.73 m 2 or higher and a normal contralateral kidney.

At hospital discharge, 8.7%, 14%, and 31% had AKI, respectively, investigator Alessio Pecoraro, MD, of the University of Florence in Italy, reported. At 60 months, 91%, 87%,

Dietary efforts to control hypertension in CKD go beyond sodium restriction.

EDITORIAL ADVISORY BOARD

Medical Director, Urology

Robert G. Uzzo, MD, MBA, FACS

G. Willing “Wing” Pepper Chair in Cancer Research

Professor and Chairman

Department of Surgery

Fox Chase Cancer Center Temple University School of Medicine Philadelphia

Urologists

Christopher S. Cooper, MD

Director, Pediatric Urology

Children’s Hospital of Iowa Iowa City

R. John Honey, MD

Head, Division of Urology, Endourology/Kidney Stone Diseases

St. Michael’s Hospital

University of Toronto

Stanton Honig, MD

Department of Urology

Yale University School of Medicine

New Haven, CT

J. Stephen Jones, MD

Chief Executive Officer

Inova Health System Falls Church, VA

Professor and Horvitz/Miller Distinguished Chair in Urologic Oncology (ret.)

Cleveland Clinic Lerner College of Medicine

Cleveland

Jaime Landman, MD

Professor of Urology and Radiology

Chairman, Department of Urology

UC Irvine School of Medicine

Orange, CA

James M. McKiernan, MD

John K. Lattimer Professor of Urology

Chair, Department of Urology

Director, Urologic Oncology

Columbia University College of Physicians and Surgeons

New York

Kenneth Pace, MD, MSc

Assistant Professor, Division of Urology

St. Michael’s Hospital

University of Toronto

Vancouver, Canada

Medical Director, Nephrology

Kamyar Kalantar-Zadeh, MD, PhD, MPH

Professor & Chief, Division of Nephrology, Hypertension & Kidney Transplantation

UC Irvine School of Medicine

Orange, CA

Nephrologists

Anthony J. Bleyer, MD, MS

Professor of Internal Medicine/Nephrology

Wake Forest University School of Medicine

Winston-Salem, NC

David S. Goldfarb, MD

Professor, Department of Medicine

Clinical Chief

New York University Langone Medical Center

Chief of Nephrology

NY Harbor VA Medical Center

Csaba P. Kovesdy, MD

Chief of Nephrology

Memphis VA Medical Center

Fred Hatch Professor of Medicine

University of Tennessee Health Science Center

Memphis

Edgar V. Lerma, MD

Clinical Associate Professor of Medicine

Section of Nephrology

Department of Medicine

University of Illinois at Chicago

College of Medicine

Chicago

Allen Nissenson, MD

Emeritus Professor of Medicine

The David Geffen School of Medicine at UCLA

Chief Medical Officer, DaVita Inc.

Denver

Rulan Parekh, MD, MS

Associate Professor of Pediatrics and Medicine

University of Toronto

Robert Provenzano, MD

Associate Professor of Medicine

Wayne State University School of Medicine

Detroit

Vice President of Medical Affairs, DaVita Healthcare

Denver

Renal & Urology News Staff

Editor Jody A. Charnow

Web editor Natasha Persaud

Production editor Kim Daigneau

Group creative director Jennifer Dvoretz

Senior production manager Krassi Varbanov

Vice president, sales operations and production Louise Morrin Boyle

National accounts manager William Canning

Vice president, content, medical communications Lauren Burke

Chief commercial officer James Burke, RPh

President, medical communications Michael Graziani

Chairman & CEO, Haymarket Media Inc. Lee Maniscalco

The Promise of Artificial Intelligence in Medicine

Artificial intelligence (AI) in medicine is evolving rapidly. Researchers are developing sophisticated machine-learning algorithms that could improve diagnostic accuracy. In this issue (see page 20), we report on such a development. It involves an AI algorithm that its developers say can effectively identify and distinguish between 2 lifethreatening heart conditions that are often easy to miss: hypertrophic cardiomyopathy and cardiac amyloidosis. The algorithm can pinpoint disease patterns that cannot be seen with the naked eye and then uses these patterns to predict the correct diagnosis. “By using AI, physicians can be more in tune with their intuition, and bring ‘curious’ findings to the forefront to reconsider and identify challenging diagnoses early,” said David Ouyang, MD, a cardiologist in the Smidt Heart Institute at Cedars-Sinai in Los Angeles, California, who is involved with algorithm’s development. This type of capability could have broad applicability across medicine. In particular, it could help reduce the number of outpatient diagnostic errors. And that number is troubling. According to a study published in BMJ Quality & Safety in 2014, the rate of outpatient diagnostic errors among US adults is 5%, which translates into approximately 12 million adults annually. A 2022 report issued by the Agency for Healthcare Research and Quality estimates that about 5.7% of emergency department visits, affecting 7.4 million patients, result in an incorrect diagnosis. Of these, 2.6 million experience an adverse event as a result, and about 370,000 suffer serious harms from diagnostic error, according to the report. Five conditions account for 39% of serious harms related to misdiagnosis: stroke, myocardial infarction, aortic aneurysm/dissection, spinal cord compression/injury, and venous thromboembolism.

There are multiple reasons why physicians sometimes arrive at an incorrect diagnosis. In outpatient venues such as emergency departments and urgent care centers, a contributing factor may be that clinicians making initial diagnoses typically are not specialists in the organ or other body part that is a source of a presenting patient’s complaints.

This is where AI can be an ally. By plugging patient data such as blood test results, medical history, radiologic and pathologic findings, and other particulars into an AI algorithm, non-specialist physicians in a busy emergency department or outpatient clinic could, perhaps in just a few minutes, confirm or zero in on a diagnosis that lies outside their area of expertise.

No doubt plenty of bugs remain to be worked out to keep false negatives and false positives to a minimum (ideally to zero, of course). But any technology, even if imperfect, that gives physicians an edge in diagnosing a medical problem deserves consideration.

Jody A. Charnow Editor

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Nephrology

8 Women With High BP Lose CV Advantage in CKD In the CKD population, women are at lower risk than men for cardiovascular events except when their systolic blood pressure is above 140 mm Hg.

8 Comfort vs Longer Life in Dialysis

Most patients receiving maintenance hemodialysis say they would prefer comfort-based rather than life prolongation-based care if they became serious ill, a survey found.

10 Dietary Potassium Weakly Linked to Serum Levels

New findings “are insufficient to support or oppose any dietary approaches to hyperkalemia,” investigator says.

13 Machine Perfusion vs Hypothermia Lowers

DGF Risk

In a randomized trial, the risk for delayed graft function among recipients of kidneys from brain-dead donors was 1.7-fold higher after hypothermia compared with machine perfusion.

Urology

14 Metabolic Risk Factors for Kidney Stones Revealed The likelihood of kidney stones is greater in individuals with circadian syndrome and low HDL cholesterol, researchers report.

14 Extended vs Standard LND in RC Compared Although extended lymph node dissection does not improve overall survival, it is associated with lower cancer-specific mortality, data suggest.

15 MDT Improves Outcomes in Recurrent PCa

Patients who received metastasis-directed therapy had a higher 3-year clinical recurrencefree rate compared with those who did not, a study found.

15 Survival Up in Metastatic Bladder CA

The median survival time increased from 9.9 months in 2004 to 12.5 months in 2018, investigators reported.

Editor’s note: The 2023 conference listings below include information provided by the sponsoring organizations on their websites as this issue went to press.

American Transplant Congress

June 3-7

San Diego, CA

European Renal Association

Annual Congress

June 15-18

Milan, Italy

American Society of Clinical Oncology

Annual Meeting

June 2-6

Chicago, IL

International Continence Society

Annual Meeting

September 27-29

Toronto, Canada

American Society of Nephrology

Kidney Week 2023

November 1-5

Philadelphia, PA

19

Departments

1 From the Editor The promise of artificial intelligence

3 News in Brief Lack of SLE follow-up tied to higher mortality

18 Renal Nutrition Update

Dietary approaches to BP control in CKD go beyond sodium restriction

19 Ethical Issues in Medicine

Why doctors may experience moral distress

20 Practice Management Artificial intelligence in medicine advances

The results of our study clearly demonstrate the significant interaction between systolic BP and cardiovascular risk in female patients with CKD.

Short Takes

Oral ED Drugs After RARP Tied to Improved Survival

Use of a phosphodiesterase-5 inhibitor (PDE5i) after robot-assisted radical prostatectomy (RARP) is associated with decreased death risk, according to a recent report in The World Journal of Men’s Health

The finding is from a retrospective cohort study that included 1843 men who underwent RARP from 2013 to 2021 at a single institution. Of these, 1298 were PDE5i users. From this group, investigators propensity score matched 529 PDE5i users with 529 nonusers. A propensity scorematched analysis showed that PDE5i use after RARP was significantly associated with a 57% lower risk for death, corresponding author Hyunho Han, MD, of Yonsei University College of Medicine in Seoul, Korea, and colleagues reported.

Federal Agency Announces Steps to Modernize OPTN

The Health Resources and Services Administration (HRSA), an agency of the US Department of Health and Human Services, announced major steps to reform and modernize the Organ

Procurement and Transplantation Network (OPTN).

“Every day, patients and families across the United States rely on the Organ Procurement and Transplantation Network to save the lives of their loved ones who experience organ failure,” said HRSA Administration Carole Johnson. “At HRSA, our stewardship and oversight of this vital work is a top priority. That is why we are taking action to both bring greater transparency to the system and to reform and modernize the OPTN.”

Risk of HD-Related Staph Bacteremia Varies by Race

An analysis by the Centers for Disease Control and Prevention has identified race and age disparities in the risk for hemodialysis-related Staphylococcus aureus bacteremia. After adjusting for state of residence, age, sex, and vascular access type, bacteremia risk was 1.4-fold higher in Hispanic compared with White patients and 1.7-fold higher in patients aged 18-49 years compared with those aged 65 years or older, according to findings published in Morbidity and Mortality Weekly Report

Survival Up in Men With mHSPC

Overall survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) increased from 2000 to 2019, according to a recent study of men with mHSPC in the SEER* database and in the Veterans Health Administration (VHA) system. Shown here are the median survival times in months.

Lack of SLE Follow-Up Is Linked to Higher Mortality

Older Medicare beneficiaries who do not receive timely follow-up care after hospital discharge for systemic lupus erythematosus have a higher likelihood of death, new data suggest.

In a 2014 Medicare sample including 8606 lupus-related hospitalizations (5403 patients), 35.5% lacked follow-up with a primary care physician or rheumatologist within 30 days of discharge, Christie M. Bartels, MD, MS, of the University of Wisconsin, Madison, and colleagues reported in Arthritis Care & Research A total of 38.6% of lupus-related hospitalizations involved adults aged 65 years and older. Follow-up was significantly associated with a 65% lower risk of mortality in this older age group. The death rate was 0.7% vs 3.9% among older adults who did and did not have follow-up visits, respectively.

NAC-Induced AKI Associated With Worse MIBC Outcomes

Acute kidney injury (AKI) during neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with worse oncologic outcomes, investigators reported at the American Society of Clinical Oncology’s 2023 Genitourinary Cancers Symposium in San Francisco, California.

Among 398 patients who received 2 to 4 cycles of NAC followed by radical cystectomy, AKI developed in 66 (17%). The AKI group had a significantly lower proportion of patients with less than ypT2 (38% vs 53%) and downstaging (53% vs 69%) compared with the no-AKI group, Naoki Fujita, MD, of Hirosaki University Graduate School of Medicine in Hirosaki, Japan, reported on behalf of his team. In adjusted analyses, patients with AKI had a significant 1.6-fold increased risk of recurrence, a 1.7-fold increased risk of cancer-related death, and a 1.8-fold increased risk of all-cause mortality.

Home Dialysis Up After ETC Payment Model Implemented

Home dialysis initiation marginally increased after implementation of The Centers for Medicare & Medicaid Services End-Stage Renal Disease Treatment Choices (ETC) payment model in January 2021. The ETC grants financial bonuses or penalties to mandated providers, such as dialysis facilities and nephrologists.

In the study of 750,314 adults with chronic kidney disease, use of home dialysis increased 1.0% more in markets randomly assigned to ETC vs not assigned, Kirsten L. Johansen, MD, of Hennepin Healthcare System Inc in Minneapolis, Minnesota, and colleagues reported in JAMA Network Open However, the annual rate of increase did not differ significantly between groups.

Home dialysis use in the US overall increased from 10.0% in January 2016 to 17.4% in June 2022. The annual rate of adoption increased from 0.86% to 1.66% per year.

According to the investigators, “these clinically relevant and statistically significant early increases in home dialysis initiation after ETC implementation are clearly not large enough to achieve ambitious targeted increases in home dialysis use by the end of the payment model in 2027.”

Serum Urate Levels Vary by Alcoholic Beverage Type, Investigators Report

Beer was associated with increased levels in both sexes

IN ADDITION TO ethanol content, alcoholic beverage type is a contributing factor to serum urate levels, a new study finds.

In a study of 78,153 Japanese adults (46.7% men) undergoing routine medical checkups, 45,755 (58.5%) regularly consumed alcoholic beverages. Among both men and women, regular drinkers had higher serum urate levels compared with infrequent drinkers, across alcoholic beverage types.

In adjusted analyses, each 1-unit increase in daily alcohol consumption (containing 20 g ethanol) was significantly associated with a 0.10 and 0.14 mg/dL increase in serum urate levels in men and women, respectively, Sho Fukui, MD, MPH, of ImmunoRheumatology Center, St Luke’s International Hospital in Tokyo, Japan, and colleagues reported in JAMA Network Open. Each 1-unit increase in beer consumption significantly increased serum urate levels by 0.12 and 0.21 mg/ dL in men and women, respectively. Each 1-unit intake of whiskey significantly increased levels by 0.19 and 0.16 mg/ dL, respectively. Wine significantly

increased levels by 0.10 mg/dL for each 1-unit increase in consumption in both sexes. Each 1-unit increase in shochu intake significantly increased levels by 0.08 and 0.09 mg/dL, respectively. Each 1-unit consumption of sake significantly increased levels by 0.06 mg/dL in men, but was not significantly associated with levels in women.

Besides ethanol, ingredients such as purines can affect urate levels.

Among a subset of patients who predominantly drank beer, each standard drink of beer consumed per day (500 mL) was significantly associated with a serum urate increase of 0.14 and 0.23 mg/dL in men and women, respectively.

“Higher beer consumption among men and women was consistently associated with higher serum urate levels, whereas sake was not associated with changes in serum urate levels,”

Dr Fukui’s team wrote. “Therefore, alcoholic beverage type, in addition to ethanol content, should be considered as a factor contributing to hyperuricemia.”

Ethanol increases uric acid production and decreases the elimination of uric acid in urine by modulating kidney tubule function, the investigators explained. Other ingredients in alcoholic beverages such as purines can also affect serum urate levels. Beer contains the highest amount of purines, while other beverages include small amounts.

At baseline, less than 15% of adults had hypertension, diabetes, or chronic kidney disease—known contributors to hyperuricemia. All models adjusted for these and other relevant factors. Heavy drinkers were excluded from this study.

To the best of their knowledge, the authors noted, their study is the largest to analyze the association of serum urate levels with alcohol consumption.

As their study was cross-sectional, the investigators pointed out, they “did not directly examine how changing the amount of alcohol intake or switching the dominant drink may impact future serum urate levels.” ■

Women With High SBP Lose CV Advantage in CKD

THE CARDIOVASCULAR risk advantage women with chronic kidney disease (CKD) have over men diminishes when their systolic blood pressure (SBP) exceeds 140 mm Hg, a new study finds. Investigators compared the risk of cardiovascular events between 1192 White women and 1635 White men with nondialysis-dependent CKD from 40 Italian nephrology clinics who participated in 4 prospective cohort studies. Over 4 years, 517 cardiovascular deaths or nonfatal cardiovascular events requiring hospitalization (ie, myocardial infarction, congestive heart failure, stroke, revascularization, peripheral vascular disease, and non-traumatic amputation) occurred in 199 women and 318 men.

In an adjusted multivariable Cox regression analysis, women had a 27% lower risk of cardiovascular events compared with men, Roberto Minutolo, MD, PhD, of University of Campania Luigi Vanvitelli in Naples, Italy, and colleagues reported in Nephrology

Dialysis Transplantation. However, they found a significant interaction between sex and SBP. Women with SBP levels less than 130 and 130-140 mm Hg had significant 50% and 28% lower risks for cardiovascular events, respectively, compared with men. At SBP levels above 140 mm Hg, the cardiovascular risk advantage in women disappeared.

In adjusted models, women with high vs normal SBP exhibited significantly increased risks of cardiovascular events, but men did not. Investigators observed no difference between the sexes in use of antihypertensive or cardioprotective drugs or regular nephrology care.

“Higher BP levels abolish the cardiovascular protection seen in female vs male patients with overt CKD. This finding supports the need for higher awareness of hypertensive burden in women with CKD,” Dr Minutolo’s team wrote.

Among the study’s limitations, the researchers could not explore the potential role of non-traditional risk factors,

Comfort vs Longer Life in Dialysis

MOST PATIENTS receiving maintenance dialysis say they would prefer a comfort-based rather than a life-prolongation approach to care if they should become seriously ill, the results of a recent survey suggest.

Regardless of their health care values, however, most patients did not document their treatment preferences or engage in other aspects of advance care planning, according to investigators.

The study included 933 patients, of whom 452 (48.4%) indicated they would value comfort-focused care and 179 (19.2%) longevity-focused care if they became seriously ill. The remaining 302 patients (32.4%) said they were unsure about the intensity of care they would value.

such as hypertensive pregnancy disorders, gestational diabetes, and radiation or chemotherapy for breast cancer. Since the entire cohort was White, results may not pertain to other racial and ethnic groups. Although the authors adjusted for the main Framingham traditional factors, residual confounding effects from unmeasured variables are possible.

“The results of our study clearly demonstrate the significant interaction between systolic BP and cardiovascular risk in female patients with CKD,” the authors wrote.

They stated that their findings are consistent with epidemiologic data from the general population demonstrating an increase cardiovascular risk among women compared with men at higher BP levels. They cited a study of 471,998 individuals in the UK Biobank published in 2018 in BMJ showing that the risk of myocardial infarction increased in parallel with BP in both sexes, but was consistently higher among women. ■

An estimated 47.5% of those who valued comfort-focused care and 28.1% of those who preferred longevity-focused care or were unsure indicated that they had completed an advanced directive, Susan P. Y. Wong, MD, MS, of the University of Washington in Seattle, and colleagues reported in JAMA Internal Medicine. In addition, 28.6% of the comfort-focused group compared with 18.2% of the longevity-focused or unsure groups discussed hospice, according to the investigators.

The proportion of patients indicating they had documented a surrogate decision-maker was significantly higher for those who would value comfortfocused care compared with those who would value longevity-focused care or were unsure (52.3% vs 45.4%).

Among patients who died during follow-up, 23.5% of the comfortfocused patients and 26.1% of those who preferred life-prolongation care or were unsure received an intensive procedure during the final month of life.

The authors concluded that “differences in how patients responded to the question about values did not translate into substantial differences in their engagement in advance care planning for the care they received at the end of life.” ■

HCTZ, stone recurrence

continued from page 1

“The results of our trial show that treatment with hydrochlorothiazide did not appear to differ substantially from placebo in preventing the recurrence of kidney stones in patients at high risk for recurrence,” the authors concluded.

Urine relative supersaturation ratios for calcium oxalate and calcium phosphate did not differ among groups at the end of the study.

Adverse events of special interest, including new-onset diabetes, hypokalemia, gout, skin allergy, and a plasma creatinine level exceeding 150% of

MMF effective for IgAN

continued from page 1

Once MMF was discontinued, kidney function declined faster. Annual eGFR decline was a mean 2.9 mL/ min/1.73 m 2 during MMF treatment compared with 6.1 mL/min/1.73 m 2 after discontinuation.

Up to 40% of patients with IgAN progress to end-stage kidney disease over 10 to 20 years. Immune and autoimmune activation in IgAN suggests a potential benefit of immunosuppression for treating the disease, Dr Hou’s team noted. Their findings are consistent with results from the TESTING trial, but differ from results from the observational STOP-IgAN study.

“Mycophenolate mofetil (MMF) is a potent immunosuppressive agent that is

Nephrectomy

continued from page 1

and 79% of patients in these groups were free of clinically significant CKD, which the investigators defined as an eGFR less than 45 mL/min/1.73 m 2

Partial vs Radical Nephrectomy

On multivariable analysis, patients with intermediate- and high-complexity tumors had significant 1.5- and 3.0fold increased odds of AKI compared with those who had low-complexity tumors. Patients with a history of hypertension had significant 1.3-fold increased odds of AKI. Compared with patients who underwent partial nephrectomy, those who underwent radical nephrectomy had significant 10.2-fold increased odds of AKI.

A Cox regression analysis showed that age-adjusted Charlson Comorbidity Index, preoperative eGFR, tumor

the baseline level occurred more frequently in the HCTZ group than placebo recipients. Serious adverse events occurred at a comparable frequency among groups.

the use of what has become the standard medical treatment — thiazide and thiazide-like diuretic agents — to reduce the risk of recurrence of kidney stones; accordingly, these findings should lead to further and larger studies to examine the usefulness of thiazides for the prevention of recurrence of kidney stones. However, these results may not bring about changes in clinical practice just yet.”

be developed for this common, costly medical problem.”

In an accompanying editorial, R. Todd Alexander, MD, PhD, of the University of Alberta in Canada, wrote, “These results call into question

relatively selective for lymphocytes and inhibits antibody production by B cells more strongly than any other immunosuppressant,” Dr Hou’s team stated.

“These results suggest that the addition of MMF to optimized [supportive care] was superior to [supportive care] alone in improving kidney outcomes and may be an alternative therapy for patients with IgAN, particularly those with CKD and subnephrotic proteinuria despite receiving [supportive care], as well as those not appropriate for steroid therapy.”

Serious adverse events were not more frequent with MMF compared with usual care. Infection, particularly pneumonia, and gastrointestinal symptoms, such as abdominal distension and diarrhea, were more common in the MMF group.

complexity, and RN significantly predicted the risk for clinically significant CKD. Each 10 mL increase in eGFR was associated with a 42% lower risk for clinically significant CKD. Compared with low-complexity tumors, intermediate- and high-complexity tumors were associated with 1.8- and 2.7-fold increases risks for clinically significant CKD, respectively. The risk was increased 3.9-fold among patients who underwent RN vs PN.

Risk ‘Not Clinically Negligible’

“The risk of acute kidney injury and de novo clinically significant CKD in elective patients with a localized renal mass and preserved baseline renal function is not clinically negligible, especially in those with highercomplexity tumors,” Dr Pecoraro told attendees. “While baseline nonmodifiable patient/tumor-related characteristics modulate this risk, partial

He noted that the study sample size may have been too small to detect differences in efficacy in subgroups.

According to Dr Alexander, “it is time for new, more effective medical therapies with fewer side effects to

At baseline, patients had a urinary protein excretion rate greater than 1 g/d and an eGFR of 30-60 mL/min/1.73 m2 or persistent hypertension. During a 12-week run-in period, all patients

With regard to trial limitations, Dr Dhayat and colleagues pointed out that it had an underrepresentation of women, and most patients were White. “Still, the prevalence of kidney stones is by far the highest among White men. The trial therefore directly informs treatment decisions for the most affected population,” they wrote. Noting that the median duration of the trial was nearly 3 years, they acknowledged that “we cannot rule out the possibility that hydrochlorothiazide has an effect on stone formation only after a longer treatment period.” ■

of 0.75 to 3.5 g/d to receive MMF plus supportive care or supportive care alone. The MMF group received 1.5 g/d oral MMF for 12 months, tapered to 0.75 to 1.0 g/d for at least 6 months.

Major exclusion criteria for the trial included secondary, familial, crescentic IgAN, other types of CKD, prior immunosuppressive therapy, baseline eGFR less than 30 mL/min/1.73 m 2 , and proteinuria greater than 3.5 g/d.

received supportive care, including optimal inhibition of the renin-angiotensin system with losartan, blood pressure control, lifestyle modification, and statins as needed. After the run-in phase, investigators randomly assigned 170 patients with persistent proteinuria

nephrectomy should be prioritized over radical nephrectomy to maximize nephron preservation if oncological outcomes are not jeopardized.”

The latest findings add to a growing literature on the effect of partial and radical nephrectomy on the risks for AKI and CKD. A retrospective study involving 528 patients who underwent unilateral radical or partial nephrectomy demonstrated that perioperative AKI independently predicts stage 3 or higher CKD, Xiaoqian Yang, MD, PhD, of Shanghai Jiao Tong University in Shanghai, China, and colleagues reported in Urologic Oncology. AKI developed in 232 (43.9%) patients and stage 3 or higher CKD developed in 47 patients (8.9%) during a median followup of 38 months. Of the 47 patients, 33 (70.2%) had postoperative AKI.

And in a study of US veterans undergoing partial or radical nephrectomy for kidney cancer, John T. Leppert,

Although the study was limited by its open-label design, Dr Hou and colleagues stated, the endpoints used were based on laboratory measurements and adjudicated by investigators blinded to treatment assignment. Moreover, the trial only included patients in China, “so caution should be used when generalizing findings to other populations.” ■

MD, of Stanford University School of Medicine in Stanford, California, and colleagues found that, among patients with normal or near-normal preoperative renal function (eGFR of 60 mL/min/1.73 m 2 or higher), partial

nephrectomy was significantly associated with an 85% decreased relative risk for clinically significant CKD (eGFR less than 45 mL/min/1.73 m 2 or receipt of dialysis) compared with radical nephrectomy. The authors published their findings in a 2018 article in the Journal of the American Society of Nephrology ■

New findings may raise questions about a standard medical treatment.

Serious adverse events with MMF did not occur more frequently vs usual care.

Greatest risk found among patients with intermediate- or highcomplexity tumors.

Dietary Potassium Weakly Linked to Serum Levels

DIETARY POTASSIUM IS not a major contributor to elevated serum potassium levels and hyperkalemia in patients with chronic kidney disease (CKD), new study findings suggest.

A team led by Shigeru Nakai, MD, PhD, of Fujita Health University School of Health Sciences in Aichi, Japan, studied the association between 24-hour urinary potassium excretion, an indicator of daily dietary potassium intake and serum potassium, in patients with CKD stages G3 to G5 who participated in the Multiple 24-hour Urine Collection Study. A total of 290 Japanese patients provided 3 urinary collections each for a total of 870 observations (3 times cohort). A subset of 220 Japanese patients provided 7 urinary collections each for a total of 1540 observations (7 times cohort).

In the 3 times cohort, serum potassium increased by a mean 0.12 mEq/L for every 10 mEq per day increase in

Recent findings are inadequate to inform dietary approaches to hyperkalemia.

24-hour urinary potassium excretion, the investigators reported in Kidney International Reports. Advancing CKD stage was associated with worse results.

Serum potassium increased 0.08, 0.12, and 0.16 mEq/L for every 10 mEq per day increase in 24-hour urinary potassium excretion at CKD stages 3, 4, and 5, respectively.

The odds of hyperkalemia significantly increased 2.1-fold per 10 mEq per day increase in 24-hour urinary potassium excretion, Dr Nakai and colleagues reported.

The researchers adjusted the 3 times cohort analysis for comorbidities such as diabetes and hypertension. They also adjusted for medications that could increase or decrease serum potassium levels. Medications that increase serum potassium included angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, renin inhibitors, and potassium supplements. Medications that decrease serum potassium included diuretics, sodium-glucose cotransporter-2 inhibitors, potassium binder, licorice extract, and bicarbonate.

An analysis of the 7 times cohort yielded similar results.

Dr Nakai’s team wrote that their findings “are insufficient to support or oppose any dietary approaches to hyperkalemia.” Besides nutrient intake from foods, urinary excretion of potassium also reflects transcellular shifts in potassium and potassium changes from medication use.

The study lacked specific dietary information, such as potassium additives in foods and plant intake, and relevant conditions affecting serum potassium, such as metabolic acidosis, constipation, and hyperglycemia.

Veterans Affairs in Orlando, Florida, and colleagues noted that the study adds to “a growing body of evidence that suggests a weak association of dietary potassium with serum potassium.” The latest finding “largely fits within existing knowledge of dietary potassium and its association with serum potassium.” ■

Ultrasound Renal Denervation May Ease HTN

ULTRASOUND RENAL denervation lowers systolic blood pressure (SBP) in patients with mild to moderate hypertension or resistant hypertension, according to recent studies.

In the RADIANCE II trial (A Study of the ReCor Medical Paradise System in Stage II Hypertension), ultrasound

renal denervation reduced mean daytime ambulatory SBP significantly more than sham renal angiography at 2 months: 7.9 vs 1.8 mm Hg, Michel Azizi, MD, PhD, of Université Paris Cité in Paris, France, and colleagues reported in JAMA. The team observed consistent effects during the day, overnight, and early morning.

The trial included 224 patients with stage 2 hypertension despite use of up to 2 antihypertensive medications (150 in the ultrasound renal denervation group and 74 in the sham group). Antihypertensive medications were withdrawn for the trial. In a separate study published in JAMA Cardiology, investigators

pooled data from 3 RADIANCE trials (RADIANCE II, RADIANCE-HTN SOLO, and RADIANCE-HTN TRIO) involving 506 patients (293 who received ultrasound renal denervation and 213 who had a sham procedure). Ultrasound renal denervation consistently lowered SBP during the day and night compared

Renal denervation

continued from page 11

with the sham procedure despite varying hypertension severity. At 2 months, mean daytime ambulatory SBP decreased significantly more in the renal denervation than sham group: 8.5 vs 2.9 mm Hg, Ajay J. Kirtane, MD, of Columbia University Medical Center/ New York-Presbyterian Hospital and the

Cardiovascular Research Foundation in New York City, and colleagues reported. The RADIANCE-HTN SOLO trial included patients with mild to moderate hypertension whose BP was controlled or uncontrolled with 0 to 2 medications before withdrawal of antihypertensive medications. The RADIANCE-HTN TRIO trial included patients with resistant hypertension taking 3 or more antihypertensive medications.

Across all trials, adult patients were required to have an estimated glomerular filtration rate of at least 40 mL/min/1.73 m2 with suitable renal artery anatomy. They had no significant comorbidities and low cardiovascular risk.

In the RADIANCE II trial, no major adverse events or renal artery stenosis greater than 70% occurred. In the pooled analysis, 1 periprocedural vasovagal event and a vascular access complication with

sequelae occurred in the ultrasound renal denervation group. One unrelated death also occurred in the intervention group. In an accompanying commentary, editors at JAMA Cardiology characterized the magnitude of BP reduction attributable to ultrasound renal denervation as similar to the addition of a single drug class or lifestyle modifications. Its role in treating hypertension still needs to be determined. ■

Machine Perfusion vs Hypothermia Lowers DGF Risk

MACHINE PERFUSION of kidneys from brain-dead donors better protects against delayed graft function (DGF) after transplantation compared with therapeutic hypothermia, new study findings suggest.

In the randomized trial, the risk for DGF was a significant 1.7-fold higher

after hypothermia compared with machine perfusion, Claus Niemann, MD, of the University of California San Francisco, and colleagues reported in the New England Journal of Medicine

The risk for dialysis initiation within the first 7 days of transplantation was a significant 1.6-fold higher after

hypothermia compared with combination therapy. “Our findings provide additional evidence that machine perfusion protects against delayed graft function as compared with static cold storage, even when the donor was undergoing therapeutic hypothermia,” Dr Niemann’s team wrote.

Adult brain-dead donors in the mild hypothermia group were externally cooled to 34-35°C with kidney perfusion. The machine perfusion group had donor normothermia, followed by ex situ hypothermic, nonoxygenated machine perfusion of the kidneys. The combination group had donor hypothermia and machine perfusion of a kidney. Among 725 adult brain-dead donors, 1349 kidneys were transplanted, including 359 kidneys in the hypothermia group, 511 in the machine-perfusion group, and 479 in the combined-therapy group. DGF occurred in a lower proportion of the machine-perfusion group compared with the hypothermia or combined-therapy groups (19% vs 30% vs 22%, respectively). Graft survival at 1 year was similar across the 3 groups, the investigators reported. Although transplant recipients “did not undergo randomization because kidneys were assigned to them through the usual organ-assignment process,” characteristics known to influence

kidney graft survival were well balanced among the 3 groups. The mean duration of renal replacement therapy prior to transplantation in the hypothermia, machine-perfusion, and combinationtherapy arms was 1813, 1692, and 1680 days, respectively. The median cold ischemia time was shorter in the hypothermia group compared with the machineperfusion and combination-therapy arms (16.7 vs 19.3 vs 19.1 hours, respectively).

In an accompanying editorial, Paulo Martins, MD, PhD, of the University of Massachusetts in Worcester, and Winfred Williams, MD, of Massachusetts General Hospital in Boston, pointed out that this trial did not include a control group representing current standard practice consisting of donor normothermia and cold static preservation alone. “Therefore, a head-to-head comparison of current-day, standard protocols for procurement and preservation is not possible,” they stated. Future trials “should incorporate mechanistic studies and report the procurement interval because these issues have ongoing implications for trial design, transplantation logistics, and outcomes.” ■

Findings are based on a randomized trial that included 1349 kidney transplant recipients.

Extended vs Standard LND in RC Compared

Bladder cancer-related death risk is reduced, but overall survival is not improved, study finds

BY JOHN SCHIESZER

EXTENDED LYMPH node dissection

(LND) during radical cystectomy (RC) for bladder cancer offers no advantage over standard LND with respect to time to progression (TTP) and overall survival (OS), but is significantly associated with decreased cancer-specific mortality, investigators concluded.

The findings emerged from longer follow-up of patients in a randomized phase 3 trial conducted at 16 highvolume RC centers in Germany. The trial included 401 patients with locally resectable T1G3 or muscle-invasive urothelial BCa (T2-T4aM0).

“Despite a much longer follow-up there is still no significant advantage in the primary endpoint TTP nor the secondary endpoint OS in these patients,” said study co-author Arnulf Stenzl, MD, of the University of Tuebingen, Germany. “There is a better CSS [cancer-specific survival], but does that mean a better quality of life or it is only a protraction of the actual visibility of tumor progression?”

Standard LND involved the obturator and internal and external iliac nodes. Extended LND also included the deep obturator and common iliac, presacral, paracaval, interaortocaval, and para-aortal nodes up to the inferior mesenteric artery. Patients in the standard and extended LND arms had a median 19 and 31 dissected nodes. The median follow-up duration of patients remaining alive without disease recurrence was 58.4 months.

Survival Outcomes

The study revealed no significant difference between extended and standard LND with respect to 5-year TTP (68% vs 60%) and 5-year OS (57% vs 51%). The 5-year CSS, however, was significantly higher in the extended group (76% vs 65%). Compared with standard LND, extended LND was significantly associated with a 35% decreased risk of cancer-specific mortality.

The investigators identified tumor recurrence in 123 patients (30%): 68 in the standard arm versus 55 patients

in the extended LND group. A total of 195 patients died (49%) — 105 (52%) in the standard arm and 90 (45%) in the extended group — including 100 patients (25%) who died from bladder cancer (60 in the standard arm and 40 in the extended group).

Mark Garzotto, MD, a professor of urology and radiation medicine at Oregon Health & Science University in Portland, said trials such as this one are important because in clinical practice there is so much variation that it is often impossible to know how much patients are being helped by different surgical approaches.

“Having high-quality trial data for surgical interventions is the best path

forward to uniformly improve clinical care,” said Dr Garzotto, chief of the urology section at the Portland VA Medical Center. “Second, in surgical oncology, historical precedent has been that the more radical the surgery is, the better the outcome. However, numerous contemporary trials have failed to show a benefit to more extensive surgery in a number of tumor types.”

No Replacement for Standard LND

Because this trial failed to meet its primary endpoint of TTP, he said, extended dissection should not be considered for replacement of a standard LND. “Although there was a slight improvement in CSS, the overall survival was not improved, which begs the question as to whether extended dissection was in some way harmful and negated any benefit of reduced cancer recurrence,” Dr Garzotto said. “I think as imaging techniques continue to improve, metastasesdirected therapy will become the new standard of care and replace extended LND for most if not all tumor types.” ■

Metabolic Risk Factors for Kidney Stones Revealed

NEW DATA from separate studies may provide insight into the role of metabolic processes in the development of kidney stones.

One study demonstrated an association between circadian syndrome and an increased risk for kidney stones. Another study found that elevated levels of high-density lipoprotein (HDL) cholesterol are significantly associated with a lower risk for kidney stones.

In a cross-sectional analysis of the 20072018 National Health and Nutrition Examination Survey (NHANES), 1559 of 4603 overweight adults (33.9%) had circadian syndrome. Kidney stone prevalence was significantly higher among individuals with vs without circadian syndrome: 14.5% vs 8.5%, Jianwei Cui, MD, and colleagues from West China Hospital of Sichuan University in Chengdu, China, reported. Similarly, circadian syndrome was more prevalent among adults who formed kidney stones compared with those who did not: 40.2% vs 26.9%. In a

fully adjusted model, circadian syndrome was significantly associated with 1.4-fold increased odds of kidney stones.

Certain groups had especially high risk. Among adults aged 35-49 years and women, those with circadian syndrome had 2.7- and 1.6-fold increased odds of kidney stones, respectively. Mexican Americans and adults of other

Circadian syndrome encompasses and possibly explains metabolic syndrome, according to emerging research. It links circadian rhythm disruption to poor lifestyle behaviors. Adults with circadian syndrome meet at least 4 of the following criteria: sleep less than 6 hours per night, depression symptoms, large waist circumference, elevated triglycerides, low HDL cholesterol, elevated blood pressure, and elevated fasting glucose.

HDL Cholesterol

The investigators noted that dysregulation of lipid metabolism is associated with kidney stones, but evidence related to the relationship between HDL cholesterol and kidney stones has been limited.

Metabolic Diseases

races with circadian syndrome had 3.8and 4.9-fold increased odds of kidney stones, respectively.

Avoiding circadian syndrome by adopting a healthy lifestyle may prevent or reduce the risk of developing kidney stones, according to the investigators.

In a separate analysis of 30,969 individuals aged 20 years or older who participated in the National Health and Nutrition Examination Survey from 2007 to 2018, the same research team found that individuals in the highest quartile of HDL cholesterol levels (28.44-105.12 mg/dL) had significant 13% reduced odds of kidney stone formation compared with those in the lowest quartile (2.88-18.54 mg/dL) in a fully adjusted model.

Further, in a Mendelian randomization study, Dr Cui and colleagues examined potential causal associations between 15 metabolic diseases and kidney stones in 462,933 individuals of European descent (2186 with a history of kidney stones). Their findings support a causal association between obesity-related traits, type 2 diabetes, fasting glucose levels, and inflammatory bowel disease in kidney stone formation, they concluded. They found no causal association between lipids and cardiovascular disease (atrial fibrillation, heart failure, and stroke) and kidney stone formation. Data suggest a possible causal role for coronary heart disease. ■

Formation of kidney stones is linked to circadian syndrome, data suggest.

Tumor recurrence rates at 5 years are similar for extended and standard LND.

MDT Improves Outcomes in Recurrent PCa

Finding is based on a study of patients with metastases documented on PSMA-PET/CT

BY JODY A. CHARNOW

METASTASIS-directed therapy (MDT) improves outcomes in men with prostate cancer who have metastases detected on PSMA-PET/CT scans following radical prostatectomy (RP), according to researchers.

A team led by Antony Pellegrino, MD, of IRCCS Ospedale San Raffaele VitaSalute, San Raffaele University in Milan, noted that little evidence exists regarding the role of MDT in this patient population and the effect of MDT on patterns of subsequent clinical recurrence (CR). To address this gap, he and his colleagues retrospectively studied 226 patients with positive 68Ga-PSMAPET/CT findings after post-RP biochemical recurrence. MDT consisted of stereotactic ablative radiation therapy focused on nodal, bony, or visceral metastatic sites. The investigators defined CR as development of any new metastases detected on follow-up PSMAPET/CT scans. Of the 226 patients, 109 received MDT and 117 did not.

Shock Wave Treatments Improve ED

REAL-WORLD data confirm the efficacy of low-intensity extracorporeal shock wave treatment (LI-ESWT) in treating vascular erectile dysfunction.

Antonio Pedro Fernandes Carvalho, MD, of Trofa Saude Hospitals in Braga, Portugal, and colleagues retrospectively studied 171 men with erectile dysfunction who underwent LI-ESWT. Patients had a median age of 61 years and 69% were on concomitant phosphodiesterase-5 inhibitor therapy. Of the 171 men, 79.5% had 5 treatment sessions, 16.4% had 10 sessions, and 4.1% had more than 10 sessions. The median score on the Sexual Health Inventory for Men tool increased significantly from 10.0 to 13.0, with 77.9% of men reporting overall improvement in their erections. ■

At a median follow-up of 24 months after initial PSMA-PET/CT scans, 73 patients had CR. The 3-year CR-free rates were 51% in the MDT group and 28% in the no MDT group, said Dr Pellegrino, who reported study findings on behalf of his team. At CR, the men who did not receive MDT had a significantly higher rate of distant metastases compared with those who did (86% vs 77%). The MDT group had a significantly lower proportion of distant metastases (67% vs 76%).

“Interestingly, the pattern of recurrence was influenced by the use of MDT with a lower rate of clinical recurrence to non-pelvic distant sites,” Dr Pellegrino told attendees. “Therefore, salvage therapies may alter patterns of prostate cancer dissemination.”

The investigators observed no statistically significant differences between the groups in the distribution of metastatic sites found on the initial or postCR PSMA-PET scans.

The latest study adds to a growing literature on MDT for recurrent prostate

Compared with men who did not receive metastasis-directed therapy (MDT), those who did had a significantly higher 3-year clinical recurrence (CR)-free rate and significantly lower proportion of patients with distant metastasis at CR, a study found.

cancer guided by PSMA-PET. Data supporting the use of 68Ga-PSMA-PET/ CT to guide MDT for oligometastatic prostate cancer emerged from a retrospective study published in 2019 in the World Journal of Urology The study included 20 patients diagnosed with oligometastatic disease on 68Ga-PSMAPET/CT and treated with metastasis-

directed radiotherapy. The median follow-up was 15 months. The biochemical recurrence-free survival rate was 53% at 2 years. The ADT-free survival rate at 2 years was 74%. The authors concluded that metastasis-directed radiotherapy based on 68 Ga-PSMAPET/CT may be a valuable treatment for patients with oligometastatic PCa. ■

Survival Up in Metastatic Bladder CA

MEDIAN overall survival of patients with metastatic bladder cancer improved from 2004 to 2019, a trend possibly related to the advent of immune-checkpoint therapies, investigators reported.

A team from University of Texas Health in San Antonio studied 10,895 patients with newly diagnosed metastatic bladder cancer from 2014 to 2019 identified using the National Cancer Database. They analyzed changes in the first-line systemic treatment and changes in 1-year overall survival. Of

these patients, 9229 received systemic chemotherapy and 1666 received systemic immunotherapy.

The use of systemic immunotherapy increased significantly from 2.3% in 2007 to 36.5% in 2019, whereas use of systemic chemotherapy declined significantly from 98.2% in 2004 to 63.5% in 2019, Furkan Dursun, MD, reported on behalf of his colleagues. The median survival time and the 1-year overall survival rate increased from 9.9 months and 38.6%, respectively, in 2004 to

12.5 months and 50.8%, respectively, in 2018.

In addition, from 2009 to 2018, the 1-year overall survival rate rose gradually from 38.3% to 53.6% among recipients of systemic chemotherapy and from 44.4% to 46.3% among recipients of systemic immunotherapy.

The authors acknowledged study limitations, including the retrospective design, lack of information on cancerspecific survival and causes of death, and the possibility of confounding variables. ■

Prostate Cancer Found at Cystectomy Usually Indolent

INCIDENTAL prostate cancer found at radical cystectomy for bladder cancer is typically indolent, new research suggests.

Chi Hang Yee, MBBS, and colleagues from S.H. Ho Urology Centre, The Chinese University of Hong Kong, reviewed data from 193 men at their institution without evidence of prostate cancer who underwent cystoprostatectomy from 1998 to 2017. Of the cohort,

31 patients (16.1%) had incidental prostate cancer, Dr Yee reported. All prostate cancers were pT2a stage with Grade Group 1.

Patients with vs without prostate cancer had a significantly higher mean age: 71.1 vs 67.5 years, according to Dr Yee. They also had numerically higher preoperative PSA (4.47 vs 2.84 ng/mL), but the difference was not significant.

On multivariate analysis, older age was significantly associated with 11% increased odds of incidental prostate cancer at radical cystectomy. Among the variables studied—age, use of neoadjuvant therapy, preoperative PSA, margin status of the bladder tumor, and bladder cancer T stage and grade, only older age independently predicted incidental prostate cancer. ■

Source: Pellegrino A, Gandaglia G, Stabile A, et al. Exploring the effect of metastasis-directed therapy on progression patterns of patients with positive 68Ga-PSMA PET/CT and biochemical recurrence from prostate cancer. Presented at: EAU23, Milan, Italy, March 10-13, 2023. Abstract A0264.

CKD Ups the Risk of Major Hemorrhage Among Patients Older Than 65 Years

Preemptive strategies such as stopping unnecessary aspirin use are warranted

CHRONIC kidney disease (CKD) is associated with an increased risk of major hemorrhage among older adults, a new study finds.

“Given the association of CKD and bleeding in older persons, preemptive strategies to reduce bleeding risk such as discontinuation of unnecessary aspirin use, smoking cessation, and blood pressure control are warranted,” investigators concluded in a paper published in Kidney International Reports

In a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) trial, major hemorrhage occurred at a higher rate among adults older than 65 years with than without CKD: 10.4 vs. 6.3 per 1000 person-years, Suzanne E. Mahady, MBBS, PhD, of Monash University in Melbourne, Australia, and colleagues reported. In adjusted analyses, CKD was independently associated with a 37% increased risk of bleeding compared with no CKD. By component, albuminuria was significantly associated with a 74% increased risk of bleeding once the urinary albumin to creatinine ratio (UACR) reached 3 mg/mmoL or higher. As a continuous

variable, each doubling of the UACR increased bleeding risk by 18%. Bleeding risk also increased when the estimated glomerular filtration rate (eGFR) fell below 40 mL/min/1.73 m2

Bleeding risks were higher among patients who were aged 80 years or older, male, smokers, hypertensive, and aspirin users. Aspirin use did not

Among 17,976 participants in ASPREE, 11.5% had a UACR of at least 3 mg/ mmoL and 18.4% had an eGFR less than 60 mL/min/1.73 m2. Patients with anemia were excluded from this study.

The investigators noted that bleeding scoring systems such as HASBED (Hypertension, Abnormal liver/ renal function, stroke history, bleeding history or predisposition, Labile INR, Elderly, Drug/alcohol usage) use reduced eGFR to indicate CKD, but “albuminuria may be a more sensitive predictor.”

Kidney Graft Loss Linked to BKPyVAN

BK POLYOMAVIRUS-associated nephropathy (BKPyVAN) may increase the risk for graft loss among kidney transplant recipients, according to recent study findings.

mediate the relationship between CKD and bleeding, the investigators reported.

Major hemorrhage included intracranial or extracranial bleeding and hemorrhagic stroke requiring transfusion, hospitalization, or surgery or resulting in death. A total of 595 patients experienced 244 gastrointestinal bleeding events, 169 intracranial bleeding events, and 250 “other” bleeding events including hematuria, trauma-related bleeding, epistaxis, and gynecological bleeding.

Study strengths include a large sample size, prospective event capture, and physician review of records and adjudication of bleeding events, “ensuring minimal misclassification bias and missed events,” the authors noted. Limitations included reliance on eGFR and UACR values based on single spot collections “which may result in misclassifying participants in either direction.” In addition, “eligibility criteria focused on community-dwelling, otherwise healthy older people and may limit generalizability to a CKD population in tertiary care with a high prevalence of comorbidities.” ■

Hyperkalemia in CKD Less Likely With Finerenone

IN PATIENTS WITH moderate to severe chronic kidney disease (CKD) and treatment-resistant hypertension, finerenone is associated with less systolic blood pressure reduction, greater proteinuria reduction, and lower rates of hyperkalemia compared with spironolactone with or without a potassium binder. The findings are from an indirect posthoc comparison of the placebocontrolled FIDELITY pooled analysis (FIDELIO-DKD and FIGARO-DKD trials) and the uncontrolled AMBER trial evaluating these respective mineralocorticoid receptor antagonists (MRA). Investigators identified a subset of patients with an estimated glomerular filtration rate (eGFR) of 25 to 45 mL/min/1.73 m 2, near-normal serum potassium of 4.3 to 5.1 mmol/L, and mean automated office systolic blood pressure (SBP) of 135 to 160 mmHg despite use of 3 or more antihypertensive drugs, including a diuretic

at baseline. After matching 624 patients from FIDELITY and 295 patients from AMBER, investigators evaluated the relative efficacy and safety of finerenone, a nonsteroidal MRA, and spironolactone, a steroidal MRA, at approximately 17 weeks and 12 weeks, respectively (the nearest timepoints with data).

Mean office systolic blood pressure declined 1.3 mm Hg in the placebo group, 7.1 mm Hg in the finerenone group, 10.8 mm Hg in the spironolactone group, and 11.7 mm Hg in the spironolactone plus patiromer potassium binder group at 3-4 months, Rajiv Agarwal, MD, of the Richard L. Roudebush VA Medical Center and Indiana University in Indianapolis, and colleagues reported in Clinical Kidney Journal. Although the absolute reduction in urinary albumin to creatinine ratio (UACR) was greater with finerenone, baseline UACR differed among groups, so more data are needed to

clarify the relative effects of the drugs on this outcome, the investigators noted.

Rates of eGFR decline and hypotension appeared lower with finerenone than with spironolactone with or without patiromer.

Hyperkalemia (defined as serum potassium of 5.5 mmol/L or more) occurred in 3.3% of a placebo group, 11.6% of the finerenone group, 35.4% of the spironolactone plus patiromer group, and 64.2% of the spironolactone-only group. Treatment discontinuation due to hyperkalemia occurred in 0.3%, 7.0%, and 23% of the MRA groups, respectively. Treatment discontinuation for any reason was lowest with finerenone.

According to Dr Agarwal’s team, these data suggest that finerenone may be associated with a lower magnitude of systolic blood pressure reduction and a lower risk of hyperkalemia during the first 4 months of treatment than spironolactone, with or without a potassium-binding agent. ■

Among 14,697 kidney transplant recipients from the Australia and New Zealand Dialysis and Transplant registry (ANZDATA), BKPyVAN occurred in 460 patients (3.3%) within a median 4.8 months of transplant surgery. Compared with patients who did not have BKPyVAN, those who did had significantly higher rates of graft loss (35% vs 21%), graft rejection (42% vs 25%), and death (18% vs 13%). In addition, recipients with vs without BKPyVAN had a 1.8- and 2.5-fold increased risk of all-cause and deathcensored graft loss, respectively, Ryan Gately, MBBS, of Princess Alexandra Hospital in Queensland, Australia, and colleagues reported in Kidney International Reports

The risk for BKPyVAN was higher for men and recipients aged 70 years or older (vs younger than 20 years), the investigators reported. It developed more often in recipients with blood type A (vs B), tacrolimus use, and transplantation at a lowvolume center. Older donor age and donor ethnicity mismatch were also associated with higher risks of the condition.

“The key challenge for transplant clinicians in managing BKPyVAN is determining the optimal degree of immunosuppression reduction that prevents viral replication while balancing the risk of inducing allograft rejection,” Dr Gately’s team wrote.

Study strengths included the large, binational cohort with contemporaneous data collected over a 15-year period, “allowing for prolonged follow-up and detailed analysis of patient and graft survival and immunosuppression changes,” the authors wrote. Limitations include the study’s observational nature and lack of an independent audit process to validate data accuracy as well as missing data for some variables. ■

Researchers report an independent 37% increased likelihood of serious bleeding.

Renal Nutrition Update

Dietary approaches to blood pressure control in chronic kidney disease extend beyond sodium restriction

BY LINDSEY ZIRKER MS, RD, CSR

Nutrition often plays a role in the management of hypertension via a low sodium diet. Studies consistently show that sodium restriction is an effective way to support healthy blood pressure.1 Blood pressure control is achieved through different mechanisms and biochemical pathways. Recent research supports this and indicates that there are additional nutrition interventions that can support healthy blood pressure beyond a sodium restriction.

Potassium

In the non-CKD population, potassium is regularly recommended as a heart-healthy blood pressure-lowering mineral. The American Heart Association recommends a minimum of 4700 mg of potassium daily to achieve these benefits. 2 Studies considering higher potassium diets have shown improved blood pressure in those with CKD, although it is difficult to know if this is due to higher potassium intake or some other factor in high potassium diets, like increased fiber or antioxidant intake.3

There is historically a concern about high potassium intake leading to high

Magnesium

Magnesium is an important cofactor for many different enzymes and processes — such as vascular tone and calcium and potassium ion channels — which in turn can impact blood pressure levels. Historically, magnesium intake has been restricted in those with CKD due to some evidence showing that declining function resulted in increased magnesium levels. More recent evidence suggests that low magnesium is common in CKD patients,

Nutrition interventions to control hypertension should include managing potassium and magnesium intake in addition to reducing sodium consumption.

serum levels of this nutrient. While there is a growing body of evidence that eases this concern, it is also worth considering that there are many medications used to manage blood pressure that are known to raise potassium levels. Providers recommending these medications use clinical judgment and monitoring to ensure patient safety. The same can be done with higher potassium diets and dietitian counseling to achieve optimal blood pressure and safe potassium levels.

and that those with magnesium levels in the “high to high normal” range are more likely to have improved survival and endothelial function and reduced vascular calcification, which supports better blood pressure control.4

Causes of low magnesium in those with CKD are related to losses during dialysis, metabolic acidosis, and medications like diuretics.5 Also, it is estimated that fewer than 50% of Americans eat the estimated average requirement of magnesium.6 Another

reason for low magnesium is the frequent use of proton pump inhibitors, which further increase the risk of magnesium deficiency, in addition to other micronutrients.7 Magnesium can increase the effectiveness of many antihypertensive medications, which not only can improve outcomes but also reduce dosage needed for optimal blood pressure levels.5

Stress management

While not a nutrition intervention, a discussion of blood pressure control beyond sodium and medications would be incomplete without any mention of stress management.

Ample evidence acknowledges the negative impact of stress on kidney health and healthy blood pressure management.8 Asking patients about what they do to help manage their stress (and referring out to therapists or social workers as needed) can help providers create a well-rounded plan for blood pressure control.

Below are some tips for achieving adequate blood pressure control.

Medication review: Are there medications that are counteracting your goals (like antacids or proton pump inhibitors)? Could the patient make dietary/ lifestyle changes to reduce the dose of a medication?

Mineral recommendations: Sodium intake should be less than 2300 mg daily9 and fruit and vegetable intake should be increased.9 Potassium intake should be based on patients’ individual needs and clinician judgment,9 but several studies recommend 3500-4700 mg daily.2,10 The recommended magnesium intake is 500-1000 mg/day.6 Magnesium oxide should be avoided, as it is poorly absorbed and can cause diarrhea. Magnesium citrate or magnesium glycinate are better and more easily available options.11 Ensure availability of the right tools: This can be as easy as a referral to a dietitian or other provider, but it is critical as a provider to think through the implementation of the intervention and ensure that patients have the tools to be successful. ■

Lindsey Zirker MS, RD, CSR is a renal dietitian who works with the Kidney Nutrition Institute in Titusville, Florida. She specializes in autoimmune kidney disease and advanced practice medical nutrition therapy for people with kidney disease.

REFERENCES

1. Cobb M, Pacitti D. The importance of sodium restrictions in chronic kidney disease. J Ren Nutr. 2018;28(5):e37-e40. doi:10.1053/j.jrn.2018.02.001.

2. American Heart Association. https://www.heart.org/en/ health-topics/high-blood-pressure/changes-you-can-maketo-manage-high-blood-pressure/how-potassium-canhelp-control-high-blood-pressure. Accessed 1/18/23.

3. Song Y, Lobene AJ, Wang Y, Hill Gallant KM. The DASH diet and cardiometabolic health and chronic kidney disease: A narrative review of the evidence in East Asian countries. Nutrients. 2021;13(3):984. doi:10.3390/nu13030984.

4. Leenders NHJ, Vervloet MG. Magnesium: A magic bullet for cardiovascular disease in chronic kidney disease? Nutrients. 2019;11(2):455. doi:10.3390/nu11020455.

5. Kopple J, Massery S, Kalantar-Zadeh K, Fouque D. Nutritional Management of Renal Disease. 4th ed. 2022. Cambridge, MA:Elsevier.

6. Houston M. The role of magnesium in hypertension and cardiovascular disease. J Clin Hypertens (Greenwich). 2011;13(11):843-847. doi:10.1111/j.17517176.2011.00538.x.

7. Al-Aly Z, Maddukuri G, Xie Y. Proton pump inhibitors and the kidney: Implications of current evidence for clinical practice and when and how to deprescribe. Am J Kidney Dis. 2020;75(4):497-507. doi:10.1053/j.ajkd.2019.07.012.

8. Bruce MA, Griffith DM, Thorpe RJ Jr. Stress and the kidney. Adv Chronic Kidney Dis. 2015;22(1):46-53. doi:10.1053/j.ackd.2014.06.008.

9. Ikizler TA, Burrowes JD, Byham-Gray LD, et al. KDOQI Nutrition in CKD Guideline Work Group. KDOQI clinical practice guideline for nutrition in CKD: 2020 update. Am J Kidney Dis. 2020;76(3)(suppl 1):S1-S107. doi:10.1053/j.ajkd.2020.05.006

10. Poorolajal J, Zeraati F, Soltanian AR, Sheikh V, Hooshmand E, Maleki A. Oral potassium supplementation for management of essential hypertension: A meta-analysis of randomized controlled trials. PLoS One. 2017;12(4):e0174967. doi:10.1371/journal. pone.0174967.

11. Lord R, Bralley A. Laboratory Evaluations for Integrative and Functional Medicine. 2nd ed. Duluth, GA: Metamatrix Institute. 2012.

Increasing intake of fruits and vegetables may help control hypertension in patients with CKD.

Ethical Issues in Medicine

BY DAVID J. ALFANDRE, MD, MSPH

Acolleague of mine recently shared a story with me from her training. She told me that when she started caring for patients during her 3rd year medical school clerkship rotations, a resident sat her down and instructed her, “It’s not about you anymore.” For her, that was the first of many steps in forming her professional identity as a physician, when she learned that physicians should put their patients first. She learned that the authority, legitimacy, and respect that the medical professional enjoys are grounded in its obligation to ensure that the patient’s well-being comes before individual self-interest. The patient should be the center of all of a physician’s efforts. At the same time, she learned that her needs or her feelings were still relevant and important because they could serve as crucial clinical data to use in service of better patient care. Moreover, her ability to care for herself would allow her to take better care of her patients.

I found this story useful because it effectively illustrated some of the challenges with how moral distress can be misunderstood and misused by health professionals. In my previous column I introduced moral distress, which is described as a perceived violation of one’s core values and duties, concurrent with a feeling of being constrained from taking ethically appropriate action. Because there is often moral ambiguity or moral diversity with ethical disagreements, defining moral distress as what one individual believes to be “wrong” can be misleading and often distracts from achieving a resolution.

Professional vs Personal Values

Distinguishing between health care workers’ professional and personal values is central to appropriately responding to moral distress in health care because both should be addressed differently. Health care professionals identify, practice, and profess the shared values of the profession—a commitment, for example, to competence,

truth telling, respect for persons, beneficence, and so forth. Put another way, those are the core tenets of the profession that help to maintain the integrity of the profession. Individual members of a profession, however, each have their own diverse personal values that are central to their personal integrity, but are not necessarily shared by every member of a profession.

COVID-19 Pandemic

As discussed in the last column, moral distress rooted in professional values is particularly concerning. Such moral distress developed among some health care professionals during the COVID pandemic when they believed that they could not appropriately care for patients according to usual standards of practice either because of resource constraints or simply because of the necessary isolation requirements for safe patient care. This distress was not based on a moral position just held by an individual, but rather by the entire profession—that the medical profession should provide high quality care to all patients. Attempting to provide care without adequate resources or according to established standards of care was contrary to the broad shared values of the profession.

a particular treatment from a patient simply because it is contrary to a physician’s personal values would be ethically problematic. Withholding that same treatment because providing it would violate a clear professional standard, however, is more likely to be ethically supportable.

Support the Physician

A central objective of addressing moral distress is to enable clinicians to perform their professional functions

At the same time, some clinicians may feel moral distress as a result of their own deeply held personal values. This can be more challenging for these health care professionals because of their obligations to put their patients’ interests before their own self-interest. These professionals are often aware that their personal values are not determinative when helping patients make their own decisions. So, for example, deciding to withhold

effectively and thus better help patients. Clinicians and the institutions that support them are responsible for ensuring that any moral distress does not affect the quality of their care or inadvertently shift providers away from their primary commitment to patients. Responding to moral distress, however, depends on whether it is based on one’s personal moral integrity versus distress based on violation of one’s professional integrity. With distress based on a violation of

personal moral integrity, the goal is to support individual clinicians in their distress while ensuring the provision of the requested, appropriate care. Consider a physician who is morally distressed over a patient with a substance use disorder who chooses to leave the hospital prematurely. This provider’s distress is based on their idea that drug use is immoral, and they wonder how much effort they are expected to expend in caring for such patients. The physician should be empathically supported in caring for patients who may be “difficult to help” because of a substance use disorder by confidentially helping the provider process their concerns and helping them manage their values in the context of providing needed care. This supports the clinician who is ultimately, and most importantly, the one who is best positioned to support the patient. ■

David J. Alfandre, MD, MSPH, is a health care ethicist and an Associate Professor in the Department of Population Health at the NYU School of Medicine in New York. The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the VA National Center for Ethics in Health Care or the US Department of Veterans Affairs.

A central objective of addressing moral distress is to enable clinicians to perform their professional functions effectively and thus better help patients.

Successfully coping with moral distress can enable health care providers to deliver better patient care

Some clinicians may feel moral distress as a result of their own deeply held personal values.

Practice Management

BY JOHN SCHIESZER

Physicians are using artificial intelligence (AI) for a host of diagnostic and treatment purposes, but they should make sure the software they use improves patient care and does not simply create a burden with having to learn another workflow and adopting the use of another application, according to David Ouyang, MD, a cardiologist in the Smidt Heart Institute at Cedars-Sinai in Los Angeles, California.

Physicians and investigators at the institute have created an AI tool that can effectively identify and distinguish between 2 life-threatening heart conditions that are often easy to miss: hypertrophic cardiomyopathy and cardiac amyloidosis. Dr Ouyang said these 2 conditions are challenging for even expert cardiologists to accurately identify, and patients often go for years or even decades before receiving a correct diagnosis. The new AI algorithm can pinpoint disease patterns that cannot be seen by the naked eye, and then uses these patterns to predict the right diagnosis.

“AI can allow for faster and more precise diagnosis. Often, in medical imaging there are suspicious signs that pique the interest of physicians, but insufficient to definitively diagnose a disease,”

thickness of heart walls and the size of heart chambers. This allowed them to efficiently flag certain patients as suspicious for having the potentially unrecognized cardiac diseases.

Without comprehensive testing, cardiologists find it challenging to distinguish between similar appearing diseases and changes in heart shape and size that can sometimes be thought of as a part of normal aging. The new algorithm accurately distinguished not only abnormal from normal, but also between which underlying potentially life-threatening cardiac conditions may be present. Getting an earlier diagnosis may enable patients to begin effective treatments sooner and prevent adverse clinical events.

Dr Ouyan and colleagues reported their study findings last year in JAMA Oncology

Clinical trials now are underway for patients flagged by the AI algorithm for suspected cardiac amyloidosis. Many types of AI software are now being quickly developed for a host of conditions, often with the goal of enhancing patient quality of life by improving diagnosis or treatment. Physicians need to be careful, however, when adopting this new technology. “Too often there are AI software offers that

tailored multi-cancer screening approach that assesses a person’s individual risk and identifies cancer signals in order to provide patients with a clear path forward. Freenome uses a multiomics platform that combines tumor and nontumor signals with machine learning to detect cancer in its earliest stages using a standard blood draw.

can’t keep pace. This is why there’s a lot of value in cloud computing, artificial intelligence and machine learning,” Dr Baldo said.

Freenome plans to enroll approximately 8000 patients in a study to evaluate their novel machine-learning approach in screening for multiple cancers.

Dr Ouyang said. “By using AI, physicians can be more in tune with their intuition, and bring ‘curious’ findings to the forefront to reconsider and identify challenging diagnoses early.”

In a study, the 2-step novel algorithm was used on more than 34,000 cardiac ultrasound videos from Cedars-Sinai and Stanford Healthcare’s echocardiography laboratories. By adding these clinical images, the algorithm identified specific features related to the

seek to optimize billing or provide assessments that aren’t useful in clinical care,” Dr Ouyang said. “At the same time, there is often much overselling, claiming software is AI when it’s simply software and the AI is just window dressing.”

Detecting Cancer

Freenome, a privately held biotech company in San Francisco, California, recently announced it is developing a

“When applied thoughtfully, machine learning or AI can take volumes of data from many sources, including electronic health records, clinical studies, claims data, and process and organize the data to derive actionable insights,” said Freenome’s Chief Medical Officer Lance Baldo, MD. “For example, at Freenome, we’re developing a risk prediction tool for payers and health systems that leverages multiple layers of data to identify and surface patients who may be at a higher risk for colorectal cancer.”

This type of innovation may offer significant benefits because current risk tools for cancer screening only look at high-level demographic variables, such as age or family history. Those variables are important, but there are hundreds of other factors that could more accurately predict an individual’s cancer risk. “The rate of scientific advancement is happening so quickly that traditional methods of applying those data

Engineers at the University of Waterloo have developed AI technology to predict if a woman with breast cancer would benefit from chemotherapy prior to surgery. The new AI algorithm, part of the open-source CancerNet initiative, could help unsuitable candidates avoid the serious side effects of chemotherapy and pave the way for better surgical outcomes for those who are suitable.

The AI software was trained with images of breast cancer made with a new MRI modality called synthetic correlated diffusion imaging (CDI). With knowledge gleaned from CDI images of old breast cancer cases and information on their outcomes, the AI software can predict if pre-operative chemotherapy treatment would benefit new patients based on their CDI images. ■

Artificial intelligence can enable a speedier and more precise diagnosis.

Artificial intelligence is expanding its reach into medical practice and has the potential to improve patient care

Researchers report promising results with an AI algorithm that can distinguish between 2 heart conditions that challenge even expert cardiologists.