Renal & Urology News - Winter 2023

KDIGO Hepatitis C Guidelines Updated

Advances in antiviral therapies cited

BY NATASHA PERSAUD

PROMPTED by advances in the management of hepatitis C virus (HCV) and increased use of HCV-positive kidney grafts, the Kidney Disease: Improving Global Outcomes (KDIGO) organization reexamined and updated its 2018 guideline recommendations for preventing and managing hepatitis C in patients with chronic kidney disease (CKD).

The KDIGO 2022 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease, published in Kidney International, provides additional

recommendations for diagnosing and managing kidney diseases associated with hepatitis C.

Direct-Acting Antivirals

Members of the KDIGO work group that updated the guidelines highlighted the important impact of direct-acting antiviral (DAA) therapies, which they noted are highly effective and welltolerated for treating HCV-infected patients across all CKD stages, including those on dialysis and kidney transplant recipients, with no dose adjustment needed. The efficacy and safety

ESKD Risk Tied to Retinal Age Gap

RETINAL AGE GAP, a marker of biological aging, may identify patients at increased risk for end-stage kidney disease (ESKD), investigators suggest.

“The retina has long been considered as a window to the kidney, as common microvascular structures, physiological pathways and pathogenic pathways are shared between the two organs, inextricably linking

them in many diseases,” Zhuoting Zhu, MD PhD, of the Centre for Eye Research Australia in Melbourne, and colleagues explained. Common risk factors for retinal and kidney diseases include smoking, diabetes, hypertension, and high cholesterol.

They also observed: “The association of retinal age gap with incident ESKD could be interpreted as a byproduct of accelerated vascular ageing in kidney,” the authors wrote.

Using a deep learning prediction model, the investigators assessed future ESKD risk among 35,864 adults with retinal fundus images from the UK Biobank study. They calculated the retinal age gap for each individual,

continued on page 12

of DAA therapies have “profoundly changed the landscape of HCV management in patients with CKD and necessitated an update to the KDIGO 2018 guideline on HCV in CKD,” Paul Martin, MD, of the Division of Digestive Health and Liver Diseases at

Stone Risk Linked to Fat Distribution

EXCESSIVE ABDOMINAL fat is associated with increased kidney stone risk, according to investigators.

The finding is from a study examining the association between androidto-gynoid fat ratio (A/G ratio) and kidney stone prevalence. The android region includes the abdomen and areas of the torso, whereas the gynoid region encompasses the buttocks and part of the thighs.

In a study of 10,858 participants aged 20 to 59 years who participated in the 2011-2018 National Health and Nutrition Examination Survey (NHANES) database, investigators found that each 1-unit increase in the A/G ratio significantly increased the likelihood of kidney stones by 2.75-fold in a fully adjusted model.

Compared with patients in the lowest tertile of the A/G ratio, those in the highest tertile had a significant 1.4-fold increased likelihood of kidney stones.

An increase in the A/G ratio usually represents abnormal fat content

the University of Miami’s Miller School of Medicine, and coauthors wrote.

Pangenotypic DAA therapies, including sofosbuvir-based regimens, and genotype-specific regimens are safe and effective for stage 4-5 CKD, including

IN THIS ISSUE

3 Post-op acetaminophen lowers risk of severe AKI

4 Antegrade procedures may be best for kidney graft stones

5 Risk factors for CKD-related pruritus identified

5 Nonsteroidal MRAs lower risk for adverse renal outcomes

6 Global warming could increase kidney stone prevalence

11 Living in the US ‘stroke belt’ identified as CKD risk factor

12 Post-transplant anemia is linked to higher kidney graft loss risk

Retinal imaging may be useful in predicting kidney failure risk.

DIRECT-ACTING ANTIVIRALS are effective for treating hepatitis C across all CKD stages.

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

The Return of Renal Nutrition Update

In December 2022, Renal & Urology News brought back Renal Nutrition Update, which had been a regular monthly department before it was discontinued more than a decade ago. Its reprise is a response to the apparent growing importance of renal nutrition in the care of patients with kidney disease, as reflected in part by the surging medical literature on the topic. For example, a PubMed search using the search terms renal or kidney and nutrition or diet retrieved 9067 citations in 2000, 18,155 in 2010, and 34,503 in 2022. Further, dietary issues related to kidney care seem to be gaining in prominence at nephrology conferences in terms of sessions and poster and oral presentations.

The return of Renal Nutrition Update in print begins with this issue (page 14). The article deals with KDOQI’s 2020 revision of potassium intake recommendations for patients with chronic kidney disease that suggest an individualized approach to patients’ needs. The department appears monthly on our website (renalandurologynews.com).

Also in this issue is an article about the possible effect of climate change on kidney stone prevalence (page 6). Rising temperatures, especially in urban areas, may increase the likelihood of dehydration. This could lead to greater concentrations of stone-forming substances in urine such as calcium, oxalate, phosphate, and uric acid. Kidney stone prevalence has already been on the rise, and a warming earth could exacerbate the problem.

And be sure to read our report on a study showing that people who live in the so-called stroke belt of the United States (a region of the southeast including Alabama, Arkansas, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, and Tennessee) are at higher risk for chronic kidney disease compared with individuals who live elsewhere independent of conventional risk factors (page 11). The investigators wrote that people who live in the stroke belt may have different environmental exposures compared with those who inhabit other regions.

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

Editorial director, Haymarket Oncology Lauren Burke

Vice president, content, medical communications Kathleen Walsh Tulley

Chief commercial officer James Burke, RPh

President, medical communications Michael Graziani

Chairman & CEO, Haymarket Media Inc. Lee Maniscalco

Lastly, I would like to highlight our article about the 2022 Advanced Prostate Cancer Consensus Conference in which a multidisciplinary international panel of experts offered their opinions on how to approach controversial areas in prostate cancer management (page 8). The goal was to help supplement evidence-based guidelines. Notably, the panel reached consensus on the appropriate use of PSMA PET in various clinical situations. For example, the panel favored its upfront use, in addition to prostate MRI, with or without subsequent conventional imaging for systemic staging of clinically localized prostate cancer. The panel strongly agreed not to recommend PSMA PET for the majority of patients with clinically localized favorable intermediate-risk localized prostate cancer. These and other consensus statements no doubt are welcome guidance at a time of rapid advancements in therapeutics and imaging, when it may take a while to determine their optimal use.

Jody A. Charnow Editor

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Nephrology

4 Stone Treatment in Kidney Grafts Characterized Antegrade approaches may yield the highest stone-free rates for patients with de novo nephrolithiasis in kidney grafts.

5 CKD-Related Pruritus Risk Factors ID’d Older individuals, those with a higher body mass index, and current smokers among those with a greater likelihood of the condition.

6 Global Warming Could Lead to More Kidney Stones

Higher temperatures can cause dehydration, which concentrates substances in urine that can foster development of kidney stones.

11 CKD Risk Higher in the American ‘Stroke Belt’ Inhabitants have a significant 14% higher risk for incident CKD compared with those who do not.

Urology

4 Long-Term PCa Outcomes Worse With AS Prostate cancer-specific survival at 10 years is slightly lower among men with low-grade disease undergoing active surveillance vs definitive initial treatment

5 Statin Use During Prostate Cancer ADT Ups Survival

A systematic review and meta-analysis demonstrated that concurrent statin use was significantly associated with a 27% reduced risk of all-cause mortality.

13 PCA vs Partial Nephrectomy for cT1b Renal Tumors Both procedures offer comparable distant oncologic outcomes, but percutaneous cryoablation is associated with a higher local recurrence rate, data show.

13 Use of 5-ARIs Increases Risk for Dementia Finasteride and dutasteride are significantly associated with a 22% and 10% increased risk of all-cause dementia, respectively.

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

Annual Dialysis Conference

March 3-6

Kansas City, MO

European Association of Urology

Annual Congress

March 10-13

Milan, Italy

National Kidney Foundation

Spring Clinical Meetings

April 11-15

Austin, TX

American Urological Association

Annual Meeting

April 28-May 1

Chicago, IL

1

14

15

16

There’s no question that global warming and climate change contribute to increasing temperatures in urban environments.

Short Takes

UI Tied to Artificially Sweetened Drinks

Women who drink 1 or more servings per day of artificially sweetened beverages are 10% more likely to report having mixed urinary incontinence (UI) compared with women who drank less than 1 serving per week or never drank these beverages, according to study findings published in Menopause

The finding is from a secondary analysis of data from 80,388 women in the Women’s Health Initiative Observational Study.

Investigators found no association between the quantity of artificially sweetened beverages consumed and stress or urgency UI symptoms.

Gene Therapy Approved for High-Risk NMIBC

The US Food and Drug Administration has approved a novel gene therapy called nadofaragene firadenovec-vncg (Adstiladrin, Ferring Pharmaceuticals) for adult patients with high-risk nonmuscle-invasive bladder cancer (NMIBC) that is unresponsive to bacillus Calmette-Guérin (BCG) therapy, according to a news release from the agency.

Nadofaragene firadenovec-vncg is a non-replicating adenoviral vectorbased gene therapy. It is administered every 3 months into the bladder via a urinary catheter. The safety and effectiveness of the therapy were evaluated in a multicenter trial that included 157 patients with high-risk BCG-unresponsive NMIBC.

Post-Op Acetaminophen

Cuts Risk of Severe AKI

Acetaminophen given soon after cardiac surgery is associated with a lower risk for severe acute kidney injury, investigators reported in the American Journal of Kidney Diseases

The study included 9631 patients from 2 registries who underwent cardiac surgery: 5791 in the Medical Information Mart for Intensive Care (MIMIC)-III and 3840 in the eICU Collaborative Research Database (eICU). Acetaminophen was administered in the early postoperative period to 4185 patients (72%) and 2737 patients (71%), respectively. On multivariable analysis, early acetaminophen use was significantly associated with a 14% and 16% reduced risk for severe AKI in the MIMIC-III and eICU groups, respectively.

Prostate Cancer AS On the Rise

Hyperkalemia More Likely With TMP/SMX vs Amoxicillin

Antibiotic treatment with oral trimethoprim-sulfamethoxazole (TMP/SMX) rather than amoxicillin is associated with a more than 3-fold higher risk of a hospital encounter with hyperkalemia, especially among patients with nondialysisdependent chronic kidney disease.

The finding is from a population-based cohort study of adults aged 66 years and older in Ontario, Canada. Investigators compared 58,999 matched pairs of outpatients initiating oral TMP/SMX vs oral amoxicillin from 2008 to 2020. Median prescription duration for both antibiotics was 7 days. The primary outcome, an emergency department visit or hospital admission with hyperkalemia (defined as serum potassium level of 5.5 mmol/L or greater) within 14 days, occurred in a higher proportion of patients treated with TMP/SMX vs amoxicillin: 0.46% vs 0.14%, Y. Joseph Hwang, MD, MSc, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues reported in Nephrology Dialysis Transplantation TMP/SMX recipients had a significant 3.4-fold increased relative risk of a hospital encounter with hyperkalemia.

Bladder Cancer Risk Higher After PCa Radiation vs RP

Prostate cancer treatment with radiation is associated with a greater risk for bladder cancer compared with surgery, investigators concluded in a presentation at the Society of Urologic Oncology’s 23rd annual meeting in San Diego, California. In a study of 2000 to 2019 data from 418,053 patients in the Surveillance, Epidemiology, and End Results (SEER) database, Steven Monda, MD, from UC Davis Health in Sacramento, California, and colleagues found that brachytherapy and external beam radiation therapy (EBRT) were significantly associated with an approximately 2.4- and 2.5-fold increased risk for bladder cancer, respectively, compared with radical prostatectomy (RP), in adjusted analyses. RP followed by EBRT was significantly associated with a 1.5-fold increased risk for bladder cancer compared with RP alone.

Air Pollution Ups ESKD Risk in IgA Nephropathy

Exposure to air pollution consisting of fine particulates less than 2.5 microns (PM2.5) in diameter independently predicts development of end-stage kidney disease (ESKD) among patients with IgA nepropathy (IgAN), new findings suggest.

Jingyuan Xie, MD, PhD, of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine in China, and colleagues studied PM2.5 exposure across regions in China from 1998 to 2016 using satellite data on aerosols. Among 1979 patients with biopsy-proven IgAN at 7 Chinese centers, ESKD developed in 207. Each 10 μg/m3 increase in annual average concentration of PM2.5 exposure was significantly associated with a 14% increased risk of ESKD before study entry and a 10% increased risk after study entry, Dr Xie’s team reported in Kidney International. When patients were exposed to PM2.5 pollution above the median both before and after study entry (defined as 52.7 and 52.3 μg/m3, respectively), patients had a significant 54% increased risk for ESKD.

Active surveillance rates for prostate cancer increased sharply from 2014 to 2019 for patients with low- and intermediate-risk disease, according to data presented at the Society of Urologic Oncology’s 23rd annual meeting in Orlando, Florida.

Long-Term PCa Outcomes Worse With AS

Investigators find increased 10-year

PROSTATE CANCER-specific survival at 10 years is slightly lower among men with low-grade disease undergoing active surveillance (AS) compared with definitive initial treatment, according to population-based data.

“Although outcomes on AS are excellent, these results do suggest that some men are misclassified or may miss an opportunity for cure,” Antonio Finelli, MD, of the Princess Margaret Cancer Centre at the University of Toronto in Canada and colleagues wrote in The Journal of Urology.

In the retrospective study, investigators compared long-term cancer outcomes among 21,282 men with Grade Group 1 cancer receiving AS or definitive initial treatment with radiation or surgery in Ontario, Canada from 2002 to 2014. At 10 years, only 39% of men remained on AS, the investigators reported. The 10-year prostate cancer-specific survival rates were 98.1% with AS and 99.1% in the initial treatment group. The 10-year metastasis-free survival rates were 94.2% and 95.8%, respectively, and the

Cardiac Risks Higher in Men With Priapism

PRIAPISM IS associated with an increased risk for cardiovascular and cerebrovascular events in the years following an episode of the condition, investigators reported in The Journal of Urology.

In a study that included 10,459 men with priapism (mean age 51.1 years), a team led by Michael L. Eisenberg, MD, of Stanford University School of Medicine in Palo Alto, California, found that these men had a 24% increased risk for both ischemic and other heart disease and 33% increased risk for cerebrovascular disease in the years following a priapism diagnosis compared with a matched group of men with other sexual dysfunctions.

The rate of cardiovascular disease and thromboembolic events was higher among men with more priapism episodes. ■

risks compared with initial definitive treatment

10-year overall survival rates were 88.7% and 89.9%, respectively.

In a landmark analysis, AS was significantly associated with a 66% increased risk of prostate cancer-specific mortality, 34% increased risk of metastasis, and 12% increased risk of all-cause mortality compared with initial treatment, Dr Finelli’s team reported. In a propensity-score matched analysis, AS was significantly associated with a 28%, 12%, and 87% increased risks of these outcomes, respectively, compared with initial treatment.

The investigators calculated that 125 men on AS would need to receive initial treatment to prevent 1 prostate cancer death at 10 years. They cautioned that overtreatment is associated with potential urinary, bowel, and sexual-related harms.

The findings highlight “a need for a careful discussion between patient and clinician to balance treatment-related side effects and impact on quality of life vs the modest decrease in PC-specific mortality associated with intervention,” Dr Finelli’s team wrote.

vs Treatment: Long-Term

Men on active surveillance (AS) for low-grade prostate cancer had lower rates of 10-year prostate cancer-specific, metastatis-free, and overall survival compared with patient who had definitive initial treatment.

Study strengths included the size of the cohort, length of follow-up, and use of population-based outcomes within the context of universal health care, according to Dr Finelli’s team. Further, unlike in many prior published studies, they distinguished AS from watchful waiting, which are dissimilar approaches that result in different oncologic outcomes, they noted.

They also acknowledged study limitations. For example, they inferred AS if there was no definitive treatment claim. In addition, data on prostate cancer stage and PSA levels were incomplete, and most men were diagnosed before widespread use of pre-biopsy prostate magnetic resonance imaging, according to the investigators. ■

ADT Shown to Increase Fracture Risk

ALL FORMS OF androgen deprivation therapy (ADT) for prostate cancer are significantly associated with an increased risk for bone fracture, according to a recent population-based study published in PLoS ONE The risk is highest among men who undergo orchiectomy.

An analysis of 2001-2008 data from the Taiwan National Health Insurance Research Database showed that patients who received injection formulations of ADT (gonadotropin-releasing hormone agonists and antagonists) had a 55% increased risk of bone fracture

compared with a matched group of control patients without cancer after adjusting for multiple variables. Men who underwent orchiectomy and those who took oral antiandrogens had a 95% and 37% increased risk, respectively.

Patients who underwent only radical prostatectomy (RP) had a significant 49% decreased risk of fracture. Those who received osteoporosis medications had a significant 74% decreased risk.

The study also demonstrated that older age and various comorbidities, including stroke, heart failure, and

pulmonary and renal disease, significantly increased the risk of fracture in men with prostate cancer. Stroke, heart failure, pulmonary disease, and renal disease increased the risk of fracture by 15%, 24%, 22%, and 33%, respectively.

“For patients receiving long-term prostate cancer castration therapy, doctors should always keep this complication in mind and arrange proper monitoring and provide timely osteoporosis medication,” Wei-Cheng Chen, MD, of Taichung Veterans General Hospital in Taichung, Taiwan, and colleagues concluded. ■

Stone Treatment in Kidney Grafts Characterized

ANTEGRADE treatment approaches may yield the highest stone-free rates for patients with de novo nephrolithiasis in kidney grafts, according to new study findings.

In a systematic review of 37 retrospective studies, investigators identified 553 patients with de novo stones in the transplanted kidney. Of the 612 procedures, 20 were antegrade ureteroscopy, 154 retrograde

ureteroscopy, 118 percutaneous nephrolithotomy (PCNL), 25 open surgery, 155 extracorporeal shock wave lithotripsy (ESWL), and 140 surveillance/ medical treatment. The stone-free rate at 3 months was 96% with open surgery, 95% with antegrade ureteroscopy, 86% with PCNL, 81% with retrograde ureteroscopy, and 75% with ESWL, Alberto Breda, MD, of University Autonoma of Barcelona

in Spain, and colleagues reported in European Urology Focus.

“As opposed to the management of nephrolithiasis in native kidney, an antegrade approach should be considered more in renal transplant patients,” they wrote. Study findings support a minimum of annual imaging of the renal graft, they noted.

The mean stone size on diagnosis was 11 mm. ■

Source: Timilshina N, et al. Long-term outcomes following active surveillance of low-grade prostate cancer: A population-based study using a landmark approach. J Urol. 2022; published online ahead of print.

Nonsteroidal MRAs Reduce Renal Risks

NONSTEROIDAL mineralocorticoid receptor (MR) antagonists (MRAs) reduce the risk of renal and cardiovascular outcomes in patients with and without chronic kidney disease (CKD), findings from a new systematic review and meta-analysis suggest. Use of the drugs may also reduce albuminuria and blood pressure.

“Overactivation of [the] MR promotes inflammation, oxidative stress and fibrosis and is one of the key factors leading to the development and progression of kidney and cardiovascular damage,” Jingwei Zhou, MD, of Dongzhimen Hospital of Beijing University of Chinese Medicine in China and colleagues explained in Diabetes Research and Clinical Practice MRAs, they noted, “can directly target aldosterone to play an anti-inflammatory and antifibrotic role and can provide cardiorenal protection, including beneficial effects in hypertension,

heart failure and chronic kidney disease (CKD),” they wrote.

The investigators pooled data from 11 randomized controlled trials and 1 meta-analysis including 17,517 patients. Of the cohort, 92.6% had stage 1-5 CKD, 91.0% had type 2 diabetes, and 92.1% had hypertension. Most patients (15,607) were treated with finerenone, whereas 1456 received esaxerenone, 292 apararenone, and 162 KBP-5074.

The primary endpoint was a composite renal outcome of a sustained 40% or greater or 40% or greater decrease in estimated glomerular filtration rate (eGFR) from baseline, doubling of baseline serum creatinine, end-stage kidney disease (ESKD), or renal death.

Finerenone use was significantly associated with a 17% reduced risk of the renal composite endpoint compared with control, Dr Zhou and colleagues reported. By component, nonsteroidal MRA use was significantly associated with a 23% lower

Statin Use During Prostate Cancer ADT Ups Survival

STATIN USE during androgen-ablative therapies may improve survival among men with advanced prostate cancer.

In a systematic review and metaanalysis of 25 cohorts including 119,878 men, concurrent statin use was significantly associated with a 27% reduced risk of all-cause mortality and a 35% reduced risk of prostate cancerspecific mortality, Robert J. Hamilton, MD, MPH, of the University of Toronto in Canada, and colleagues reported in JAMA Network Open. Overall, 65,488 men (55%) were taking statins.

In subgroup analyses, men receiving androgen-receptor axis targeted therapy (ie, abiraterone or enzalutamide) had a significantly greater reduction in prostate cancer mortality risk with concurrent statin use compared with men taking androgen deprivation therapy (ADT) alone: 60% vs 32% reduced risk.

“We observed a consistent overall and prostate cancer-specific survival advantage for statin users undergoing androgen-ablative therapies, independent of patient age, baseline metastasis

status, prior use of chemotherapy, or primary treatment type,” Dr Hamilton’s team explained. “For overall mortality, the observed benefit was independent of hormone sensitivity status and type of androgen-ablative therapy.”

The investigators acknowledged substantial heterogeneity among studies and a low confidence in the evidence according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

With respect to plausible mechanisms of action, the investigators noted that statins may inhibit inflammation, angiogenesis, cell proliferation, migration, adhesion, and invasion and promote apoptosis. Statins may also work synergistically with androgen-ablative therapies to lower circulating and intraprostatic androgen precursors.

Given the limitations of observational research, Dr Hamilton’s team encouraged randomized clinical trials to evaluate the effect of statins on prostate cancer survival and to determine the optimal statin class and dose. ■

risk for ESKD, a 20% decreased risk of a decline in eGFR to less than 15 mL/ min/1.73 m2, and 17% decreased risk of a greater than 40% decline in eGFR.

In addition, the risk of cardiovascular composite endpoints significantly

CKD-Related Pruritus Risk Factors ID’d

OLDER AGE, higher body mass index (BMI), and current smoking are among the risk factors for moderate to severe pruritus in patients with nondialysis chronic kidney disease (CKD), according to investigators.

In a study of 1951 participants with CKD in the Chronic Renal Insufficiency Cohort (CRIC) study who did not have pruritus at baseline, moderate to severe pruritus — defined as a response of 3 or higher on a Likert scale of 1 to 5 — developed in 660 patients (34%) over a median follow-up duration of 6 years, Kendra Wulczyn, MD, of the nephrology division at Massachusetts General Hospital in Boston, and colleagues reported in the Clinical Journal of the American Society of Nephrology. Patients aged 65 years or older had a significant 31% increased risk for moderate to severe pruritus compared with those aged 44 to 64 years, according to the investigators. Each 5 kg/m2 increase in BMI was associated with a 10% increased risk. Current smokers had a 60% increased risk compared with patients who were not current smokers.

decreased by 14% and all-cause mortality by 13% with use of nonsteroidal MRAs, Dr Zhou’s team reported.

The investigators also found evidence that nonsteroidal MRAs reduce albuminuria. Compared with controls, patients taking nonsteroidal MRAs experienced a urinary albumin to creatinine ratio (UACR) decline of 32%, a 2.9-fold greater likelihood of a 30% or more decrease in UACR, or an absolute UACR reduction of 105.13 mg/g. Systolic blood pressure decreased by an additional 2.58 mm Hg and diastolic blood pressure by an additional 1.82 mm Hg with use of the nonsteroidal MRAs compared with control.

With respect to safety, the investigators found no significantly greater risks of hyperkalemia, elevated serum potassium, hypotension, hypoglycemia, or urinary tract infection with nonsteroidal MRAs.

The investigators judged the quality of the evidence to be low to moderate and encouraged more well-controlled trials. ■

Opioid use was associated with a 27% increased risk for moderate to severe pruritus compared with nonuse. Patients with moderate depressive symptoms had a 46% increased risk compared with those who had no depressive symptoms. An iPTH level of 65 pg/mL or higher was associated with a 30% increased risk compared with lower levels. Patients with a serum calcium level less than 9 mg/dL had a 20% decreased risk compared with those who had a level of 9.0-9.4 mg/dL.

Increased risk observed among patients aged 65 years or older.

“We suggest that providers caring for patients with CKD should anticipate a high likelihood that their patients may develop pruritus and, thus, incorporate frequent screening for pruritus and associated risk factors into routine clinical care,” Dr Wulczyn and colleagues concluded.

Depressive symptoms and weight, they wrote, “warrant further investigation as potentially modifiable risk factors that could be targets for a multifaceted approach to the treatment of pruritus in CKD.” ■

Finerenone was significantly associated with a 17% reduced risk of a composite renal endpoint

MRA use is associated with improved kidney and cardiovascular outcomes, a study found.

Global Warming Could Lead to More Kidney Stones

Higher temperatures can cause dehydration, which increases the likelihood of nephrolithiasis

BY JODY A. CHARNOW

Climate change is thought to be responsible for much of the extreme weather affecting people around the world, such as stronger hurricanes and other storms that dump increasing amounts of rain and cause catastrophic flooding, unprecedented heat waves, and prolonged droughts that imperil agriculture and human health. Extreme weather events generate headlines and dramatic images, so some of the subtle effects of rising global temperatures on human health may get little attention.

One plausible effect could be an increase in kidney stone risk. Higher temperatures can increase water loss through perspiration and cause dehydration. This lowers urine volume and concentrates substances in urine that can form kidney stones, such as calcium, oxalate, phosphate, and uric acid.

“So it’s not hard to conclude that greater exposure to heat, even for relatively short periods of time, is likely to increase kidney stone prevalence,” said nephrologist David S. Goldfarb, MD, Professor of Medicine at the NYU Grossman School of Medicine and Director of the Kidney Stone Prevention Program at NYU Langone Health in New York. Studies have clearly demonstrated a link between higher temperatures and elevated kidney stone risk. Pediatric urologist Gregory E. Tasian, MD, MSc, Associate Professor of Surgery at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia, led one of those studies. He and his colleagues looked at the effect of temperature and kidney stone presentation in 5 major US cities with diverse climates. They discovered that a daily mean temperature of 30 vs 10 degrees C (86 vs 50 degrees F)

was significantly associated with a 38%, 37%, 36%, and 47% increased risk for kidney stone presentations in Atlanta, Chicago, Dallas, and Philadelphia, respectively, according to their 2014 report in Environmental Health Perspectives. 1 The investigators found a nonsignificant 11% increased risk in Los Angeles. The study also revealed a short lag between daily temperatures and medical visits for kidney stones, with the maximum risk occurring within 3 days of temperature exposure.

Other studies in the United States, the Middle East, and elsewhere have documented that emergency department visits for kidney stones occur more frequently in summer than winter.

Kidney stone prevalence already has been on the rise. In the United States, the overall prevalence of kidney stones increased from 3.2% in 1980 to 10.1% in 2016, Api Chewcharat, MD, and Gary

Curhan, MD, ScD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, reported in a 2020 paper in Urolithiasis 2 At the American Urological Association’s 2022 annual meeting, Shirley Y. Zhang, a medical student at the University of Alabama School of Medicine in Birmingham, reported on a study by her and her collaborators showing that the prevalence of symptomatic kidney stones among children in the southeastern United States increased 84.4% from 2006 to 2020.

The precise reasons for the upward trend are unclear, but researchers have cited dietary changes and an increasing prevalence of diabetes and obesity among the underlying causes. Now, global warming is considered to be in the mix of risk factors.

The effect of higher temperatures on kidney stone risk would be especially pronounced in urban areas because

they tend to be warmer than rural environments, said Dr Goldfarb, who has advanced a hypothesis that urban heat islands contribute to a growing prevalence of kidney stones.3 As he explained in an interview with Renal & Urology News, the asphalt, concrete, and other building materials that make up the urban milieu absorb more heat during the day and give up that heat to the atmosphere at night compared with rural settings, he said. This results in areas characterized not only by higher daytime temperatures but less dipping of temperatures at night compared with rural areas. Consequently, urbanites may have prolonged exposure to higher temperatures compared with their rural counterparts, Dr Goldfarb said.

“Our urban heat island hypothesis suggests that the temperatures in cities are really much more of an issue than the average temperature of the Earth,” Dr Goldfarb said. “There’s no question that global warming and climate change contribute to increasing temperatures in urban environments.”

And cities are where most of the world’s people live. According to the United Nations Department of Economic and Social Affairs, 55% of the world’s population live in urban areas, and this proportion is expected to rise to 68% by 2050. The proportion of city dwellers is much higher in the United States, where 80.7% of the nation’s population lived in urban areas in 2010, according US Census data.

Dr Goldfarb acknowledged that it is difficult to disentangle the effect of heat from other factors that influence development of kidney stones. He noted, for example, that city residents may have different diets, activities, and occupations that increase their risk for kidney

Urban areas may be at especially higher risk for kidney stones from global warming.

stones compared with people who live in rural communities. In addition, access to medical and imaging modalities and intensity of medical surveillance for kidney stones may be greater in cities, suggesting that evidence for increased kidney stone prevalence in urban settings could be related to greater detection rather than a true increase in prevalence.

Dr Tasian, who also is Surgical Director of the Pediatric Kidney Stone Center at the Children’s Hospital of Philadelphia, pointed out that established associations between temperature and kidney stone presentations could be complicated by changes in human behavior in response to higher temperature. For example, he and his collaborators observed a ceiling effect in Dallas, where temperatures above 30 degrees C did not result in an increased risk for kidney stone presentations. It could be that the city’s population adapted to the local climate such that residents spend more time indoors in air conditioned rooms and increase their fluid intake at higher temperatures, Dr Tasian postulated.

What would happen, then, in places where air conditioning is not widely used, such as in Europe? According to Inaba-Denko, a company that manufactures air conditioning products, air conditioning is present in only 20% of households in Europe, with much lower proportions in some countries, such as the United Kingdom (about 3% of residential homes), France (about 5%), and Germany (about 3%). Much of Europe has experienced record-breaking heat waves with temperatures above 100 degrees F this summer, with climate change widely blamed for the phenomenon. Dr Goldfarb and Dr Tasian say it is plausible that the effect of global warming on kidney stone prevalence could be more pronounced in these and other places where air conditioning is uncommon. Although stronger storms, massive floods and wildfires, and property destruction are among the attentiongrabbing events attributed to global warming, an increase in the prevalence of kidney stones brought on by rising temperatures could be among the underappreciated threats to human health. n

REFERENCES

Local Failure After Prostate Cancer RT Predicts Distant Metastases

BY JOHN SCHIESZER

LOCAL TREATMENT failure following radiation therapy for intermediate- and high-risk prostate cancer independently predicts an increased risk for development of distant metastases, but in most cases, metastases occur without detectable local recurrence, according to a recently published meta-analysis.

The latest findings, published in European Urology, could help better guide clinicians and their patients with aggressive cancers who appear to have a reasonable chance of harboring micrometastatic disease even at diagnosis. The findings suggest that local treatment may need to be integrated into a multimodality plan that includes systemic therapy, according to investigators.

The meta-analysis included pooled data from 6245 men with intermediaterisk and 6288 with high-risk prostate cancer enrolled in 18 randomized trials. The trials were conducted from 1985 to 2015 within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. The median follow-up was 11 years.

Among intermediate-risk patients, 449 men (7.2%) experienced local failure and 451 men (7.2%) developed distant metastases. Among high-risk patients, local failure occurred in 795 men (13%) and distant metastases occurred in 1288 (21%). Overall, 81% of distant metastases developed in patients who had no prior detectable local recurrence (clinically relapse-free [cRF state]). Presumably, these metastases start off as micrometastatic disease not detected at the time of diagnosis, according to investigators.

“A local failure may not mechanistically lead to most distant metastases, but it is a poor prognostic factor and there certainly are a subset of distant metastases in later years that appear subsequent to a local failure,” said corresponding author Amar U. Kishan, MD, Chief of the Genitourinary Oncology Service for the Department of Radiation Oncology at the David Geffen School of Medicine at UCLA and the UCLA Jonsson Comprehensive Cancer Center in Los Angeles, California. “So for highgrade cancers at least, an optimization of

local and systemic therapy is important. However, local therapy intensification should not be pursued at the expense of systemic therapy intensification.”

Dr Kishan said the current study largely confirms a prior analysis by his team of 6 trials that focused on high-grade prostate cancer. “This was a much larger effort, including many more patients and trials, and therefore help establish the patterns of failure we document as a recurrent theme in prostate cancer natural history,” he said.

In high-risk patients, local failure was significantly associated with an approximately 1.2-fold increased risk for allcause mortality, a 2.0-fold increased risk for prostate cancer-specific death, and 1.9-fold increased risk for development of distant metastasis. In intermediaterisk patients, local failure was significantly associated with a nearly 1.6-fold increased risk for distant metastasis, but was not significantly associated with overall survival.

Dr Kishan’s team acknowledged limitations of their analysis, including the small size of some treatment subgroups. In addition, the included studies exhibited heterogeneity in the definition of local failure and distant metastases. “Some trials did not specify the definition, while some were reliant on digital rectal examination to determine the local failure status.”

Judd W. Moul, MD, of the Division of Urologic Surgery at the Duke Cancer Institute in Durham, North Carolina, said these findings are clinically relevant because they represent a large cohort of patients from numerous prior RCTs with long-term follow-up. “All the patients in this meta-analysis were treated in the pre-PET scan era of staging,” Dr Moul said. “As more and more newly diagnosed high risk men receive PET imaging for initial work-up, the management of prostate cancer will change to more up-front treatment intensification.”

The team examined the effect of androgen deprivation therapy (ADT) and RT dose on various transition states and found that ADT significantly reduced the incidence (24% vs 16%) and delayed the onset of distant metastasis from a cRF state (27.1 vs 48.5 months) in highrisk patients. The findings differed for intermediate-risk patients, with ADT failing to significantly reduce the rates of distant metastasis from the cRF state (6.4% vs 5.4%) or delay the time from the cRF state to distant metastasis (60.3 vs 61.8 months).

In both groups, ADT significantly decreased the local failure rate from a cRF state (6.2% vs 7.8% for intermediate-risk patients and 11% vs 20% for high-risk patients). These data show that the vast majority of distant metastases develop without a preceding clinically detectable local failure, Dr Kishan said.

Glenn Bauman, MD, a professor in departments of oncology and medical biophysics at the Western University’s Schulich School of Medicine and Dentistry in London, Ontario, Canada, said there has been considerable investigation into safely escalating radiation doses to the prostate based on the hypothesis that improved local control will ultimately improve survival by reducing metastases from persistent disease in the prostate. “This has been a difficult question to answer, and the current paper is a very important exploration of this issue and the conclusion that there is a need to optimize both local and systemic control is an important message,” Dr Baumann said.

These findings can now be coupled with modern imaging for designing boosted doses to the prostate that may improve outcomes. Current clinical trials may offer even greater insights into disease progression through more rigorous imaging.

“PSMA PET/CT or other molecular imaging techniques might allow us to better understand patterns of failure and correlate with dose response as well as better identify men upfront who need intensified systemic therapy or intensified locoregional treatment,” Dr Bauman said. n

1. Tasian GE, Pulido JE, Gasparrini A, et al. Daily mean temperature and clinical kidney stone presentation in five U.S. metropolitan areas: A time-series analysis. Environ Health Perspect. 2014;122(10):1081-1087. doi:10.1289/ehp.1307703

2. Chewcharat A, Curhan G. Trends in the prevalence of kidney stones in the United States from 2007 to 2016. Urolithiasis. 2021;49(1):27-39. doi:10.1007/ s00240-020-01210-w

3. Goldfarb DS, Hirsch J. Hypothesis: Urbanization and exposure to urban heat islands contribute to increasing prevalence of kidney stones. Med Hypotheses. 2015;85(6):953-957. doi:10.1016/j. mehy 2015.09.003

In 81% of cases, there is no prior detectable local recurrence

In high-risk patients, local failure increased the risk of death from prostate cancer 2-fold.

Expert Panel Offers Guidance on PCa Controversies

BY JOHN SCHIESZER

FINDINGS arising from a consensus conference may help clinicians navigate controversial areas in the treatment of men with advanced prostate cancer (PCa).

The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed an international panel of experts for their opinions about key dilemmas in clinical management to help supplement evidence-based guidelines.

The consensus conference is convened to address only controversial areas in which high-level evidence is scant. “We specifically go for these topics with our questions,” said first author Silke Gillessen, MD, of the Oncology Institute of Southern Switzerland, EOC, Bellinzona. “Therefore, clinicians who have less experience with prostate cancer because they treat a wide variety

PSMA PET

The panel reached consensus on the use of prostate-specific membrane antigen-positron emission tomography (PSMA PET) in various clinical situations. For systemic staging of clinically localized PCa, in addition to prostate magnetic resonance imaging (MRI),

78% of panelists voted to recommend upfront PSMA PET with or without subsequent conventional imaging, according to the report’s authors. For patients with clinically localized PCa with PSMA-positive findings consistent with bone metastases on the computed tomography (CT) component of

upfront PSMA PET, 78% of panelists voted not to recommend additional imaging such as MRI or bone scintigraphy. For patients with clinically localized high-risk PCa, 77% of panelists voted to recommend PSMA PET.

The panel reached strong consensus for not recommending PSMA

of different tumors, can check in the report what world experts are doing in specific situations where there is no strong evidence. We hope that therefore their patients will profit from the transfer of ‘concentrated knowledge’ of experts to their treating physician.”

Multidisciplinary Panel

Before the conference, a multidisciplinary international panel of 117 PCa experts developed multiple-choice consensus questions related to 7 controversial areas. At the conference, 105 panelists voted on the questions. Of this group, 50% were medical oncologists, 29% were urologists, and 21% were clinical oncologists and radiation oncologists. The panel defined consensus as 75% or greater agreement on an answer option and strong consensus as 90% or greater agreement.

Survey findings are detailed in a report in European Urology. The authors wrote that “although this report captures what experts in the field think today, it should be interpreted and integrated into clinical practice with the same scrutiny that any other major paper would receive, and with the knowledge that consensus does not constitute or substitute for evidence.”

Experts reach consensus on appropriate use of PSMA PET.

PET in the majority of patients with clinically localized favorable intermediate-risk (according to the National Comprehensive Cancer Network definition) localized PCa. The panel also reached a strong consensus not to recommend whole-body, diffusionweighted MRI for systemic staging in the majority of men with clinically localized intermediate- or high-risk disease.

The survey revealed no consensus as to whether to give systemic therapy along with salvage radiotherapy, or for how long, even though this is a relatively common clinical scenario, Dr Gillessen said. “In terms of hormonal treatments, we found that there is consensus to check for drug-drug interactions when starting an ARPI [androgen receptor pathway inhibitor],” she said. “Interestingly, only a minority of panelists voted for an ECG

or more intensive cardiac evaluation before starting treatment with hormonal treatment for the majority of patients.”

A Welcome Effort

“I believe that expert panels are beneficial to brainstorm and synthesize the evidence and help identify knowledge gaps,” said Nirmish Singla, MD, Director of Translational Research in GU Oncology and an Associate

Professor of Urology and Oncology, Johns Hopkins Medical Center, Baltimore, Maryland. “It is important to have a well-balanced, multidisciplinary panel given the role for multimodal approaches in managing advanced prostate cancer.” Further, he noted that a panel made up of experts in urology, medical oncology, and radiation oncology is critical to ensure a balanced discussion and mitigate bias.

Expert panel

continued from page 9

There has been a recent emergence of several new agents and treatment approaches for men with advanced prostate cancer in a variety of settings, Dr Singa said. The challenge for clinicians, however, is deciding on the optimal strategy at the individual patient level.

“As a clinician, I found the paper useful as the survey questions represent scenarios that patients and physicians face every day,” said Saum Ghodoussipour, MD, a urologic oncologist who is an assistant professor of surgery at Rutgers Robert Wood Johnson Medical School and Director of the Bladder and Urothelial Cancer Program at Rutgers Cancer Institute of New Jersey in New Brunswick. “The

varied consensus reflects limitations in the existing literature and most importantly, the new gaps in understanding that we are fortunate to face with the development of advanced imaging modalities and novel androgen receptor pathway inhibitors and antaghonists.”

While the findings of this panel do not fill any knowledge gaps or provide “guideline level” evidence, they suggest that most of the questions raised can be

better addressed through PSMA PET, novel drugs, genomic classifiers, and patient reported outcomes in ongoing trials. Dr Ghodoussipour said the needle is likely to continue to move in PCa care and new questions will arise. “Expert consensus statements like this will always be welcomed so that we can push to provide the best treatments and outcomes for our patients,” Dr Ghodoussipour said. ■

CKD Risk Higher in the American ‘Stroke Belt’

LIVING IN THE so-called stroke belt of the southeastern United States is an independent risk factor for development of chronic kidney disease (CKD), according to a recent study.

Individuals who inhabit that region, which includes Alabama, Arkansas, Georgia, Louisiana, Mississippi,

North Carolina, South Carolina, and Tennessee, have a significant 14% higher risk for incident CKD compared with those who do not, in a fully adjusted model, Katharine L. Cheung, MD, PhD, of the Larner College of Medicine at The University of Vermont in Burlington, and colleagues reported

in the American Journal of Kidney Diseases. Residence in the stroke belt also is a risk factor for decline in estimated glomerular filtration rate (eGFR).

The investigators also found that albuminuria is a stronger risk factor for CKD in the stroke belt compared with other regions.

“It is noteworthy that the increased risk of CKD among residents of the US stroke belt was independent of established CKD risk factors that disproportionately impact the southeastern US, including smoking, diabetes, low socioeconomic status and cardiovascular disease,” Dr Cheung’s team wrote. “These findings suggest that other factors may contribute to the development of incident CKD in those residing in the US stroke belt.”

Compared with the rest of the United States, people living in the southeast may experience differences in environmental exposures such as heat, air pollution, or water quality, all of which have been linked to kidney disease, the investigators explained.

The findings emerged from an observational longitudinal cohort study that included 7799 White and 4198 Black individuals aged 45 years or older who participated in the prospective REGARDS (REasons for Geographic and Racial Differences in Stroke) study, which enrolled participants from 2003 to 2007.

During a mean follow-up of 9.4 years, incident CKD developed in 1067 participants (9%), with minimal differences by sex and race groups, the investigators reported. The probability of incident CKD, however, differed by age strata, ranging from 4% for individuals aged 45 to 54 years to 18% for those aged 75 years or older.

The study revealed that traditional CKD risk factors account for the higher risk for incident CKD and eGFR decline among Black vs White adults, “supporting the focus on addressing modifiable risk factors such as diabetes, hypertension and obesity in reducing disparities in CKD.”

In a demographics-adjusted model, Black vs White race was independently associated with a 39% increased risk for CKD. Black race, however, was no longer associated with incident CKD in a fully-adjusted model that took into account systolic blood pressure, body mass index, diabetes, albuminuria, hyperlipidemia, cardiovascular disease, and use of ACE inhibitors, angiotensin receptor blockers, and nonsteroidal anti-inflammatory drugs, among other variables. ■

People living in the southeast may differ in their environmental exposures.

Post-Tx Anemia Linked to Higher Graft Loss Risk

ANEMIA AFTER kidney transplantation may increase the risk of graft loss, cardiovascular events, and death from cardiovascular and other causes, investigators reported in Progress in Transplantation

Poemlarp Mekraksakit, MD, of Texas Tech University Health Sciences Center

KDIGO guidelines update

continued from page 1

those on dialysis and receiving kidney transplant.

“Since the publication of the KDIGO 2018 HCV guideline, evidence has mounted that sofosbuvir, a key component of several regimens, is safe for all stages of CKD, including for individuals with low glomerular filtration rate (GFR) or undergoing dialysis,” the authors wrote. “This development is important because in many nations, the only available DAA regimens are those that are sofosbuvir-based.”

If pangenotypic regimens are not available, determine the patient’s hepatitis C genotype and use the genotypespecific treatment. The full report lists DAA regimens with evidence of effectiveness for various CKD populations. Protease inhibitors such as simeprevir, paritaprevir, and grazoprevir are contraindicated in patients with ChildPugh B and C cirrhosis.

DAA regimens can interact with immunosuppressive agents, such as calcineurin

Stone risk link

continued from page 1

in the android region, Guoxiang Li of The First Affiliated Hospital of Anhui Medical University in Hefei, China, and colleagues explained in Frontiers in Endocrinology. The authors cited research showing that fat accumulation

in Lubbock, Texas, and colleagues conducted a systematic review and metaanalysis of 17 studies published from August 2006 to April 2019 including 16,463 kidney transplant recipients.

Post-transplant anemia was significantly associated with a 2.3-fold increased risk of graft loss and a 1.7-fold increased

and mTOR inhibitors. The guideline suggests consulting http://www.hepdruginteractions.org before using these regimens in kidney transplant recipients.

Since the publication of the KDIGO 2018 HCV guideline, evidence has mounted that sofosbuvir, a key component of several regimens, is safe for all stages of CKD, including for individuals with low glomerular filtration rate (GFR) or undergoing dialysis. This development is important because in many nations, the only available DAA regimens are those that are sofosbuvir-based.

Test for Hepatitis B Virus

Hepatitis B virus can reactivate during and after treatment with DAAs, so the guideline recommends testing beforehand for serologic markers, such as hepatitis B surface antigen, total core antibody, and antibody to hepatitis B surface antigen. If hepatitis B surface antigen is present, clinicians should assess the patient for hepatitis B therapy. If hepatitis B surface antigen is absent, but markers of prior hepatitis B infection (positive for total core antibody

Subgroup analyses revealed that the association between high A/G ratio and increased kidney stone risk was more pronounced among women than men, individuals without vs with diabetes, Mexican-American and White adults vs Black adults and other races, participants aged 40 to 59 years, and patients with hypertension.

When analyzed by diabetes status, the investigators found no correlation between A/G ratio and KSD among patients with diabetes. “This may be because several glucose-lowering drugs can prevent kidney stone formation,” they wrote.

risk of all-cause mortality. Anemia occurring within 6 months of transplantation carried greater risks of graft loss (2.96- vs 2.22-fold increased risk) and all-cause mortality (2.63- vs 1.73-fold increased risk) compared with anemia that occurred later, the investigators reported. Post-transplant anemia was significantly

associated with a 1.3-fold increased risk of major adverse cardiovascular events and a 2.1-fold increased risk of cardiovascular death compared with no anemia. As post-transplant anemia has myriad causes, prompt assessment and appropriate management are crucial, according to Dr Mekraksakit’s team. ■

with or without antibody to hepatitis B surface antigen) are detected, clinicians should perform hepatitis B DNA testing if levels of liver function tests rise during direct-acting antiviral therapy.

Transplant Candidates

In addition, kidney transplant candidates with hepatitis C should be screened for liver disease severity and portal hypertension. Results from this assessment will help guide the decision between kidney transplantation alone and simultaneous kidney-liver transplantation.

The guideline recommends administering DAA therapy to all kidney transplant candidates infected with hepatitis C. The decision to treat before or after transplantation should be guided by donor type (living vs deceased donor), wait-list times by donor type, center-specific policies, and the severity of liver fibrosis.

Living kidney donors should be screened for hepatitis C with immunoassay and undergo nucleic acid testing if seropositive.

Kidneys from hepatitis C-infected donors can be offered to potential

ESKD, retinal age gap

continued from page 1

defined as the difference between the retinal age predicted by artificial intelligence and chronological age. The mean age of the cohort was 56.8 years, and 93.2% were White.

recipients who are positive or negative in accordance with national and regional laws.

Research shows that kidney transplantation from hepatitis C-infected donors to uninfected recipients who are treated immediately or early with direct-acting antivirals leads to favorable outcomes. Education and informed consent are required.

Patients with hepatitis C presenting with immune-complex glomerulonephritis do not need a confirmatory kidney biopsy, according to the guideline. They should be treated with DAAs. Clinicians should consider biopsy if kidney function or proteinuria worsens, and before immunosuppressive therapy.

Patients with cryoglobulinemic flare or rapidly progressive glomerulonephritis can be treated with both DAAs and immunosuppressive agents, with or without plasma exchange. Rituximab is generally used as the first-line immunosuppressive treatment, although steroids should also be considered in rapidly progressive glomerulonephritis. ■

low compliance rate to kidney disease screening,” Dr Zhu’s team concluded. The predictive ability of retinal age gap has been demonstrated for other diseases. For example, in a 2022 paper in Stroke, investigators reported study

in the liver, pancreas, and kidneys can have adverse effects. For example, fat accumulation in the liver and pancreas is associated with indicators of inflammation, and inflammation is strongly linked to kidney stone formation, they wrote.

“Based on a cross-sectional study of a US population, we found that a high A/G ratio was associated with an increased prevalence of kidney stones,” the authors concluded. “This may have significant implications for the prevention and treatment of kidney stones.” ■

After a median 11 years, 115 (0.32%) individuals were diagnosed with ESKD. Each 1-year increase in retinal age gap was independently associated with a 10% increase in ESKD risk, Dr Zhu and colleagues reported in the American Journal of Kidney Diseases. Patients with higher retinal age gaps in the fourth quartile had a significant 2.8-fold increased risk of developing ESKD compared with those in the first quartile.

“The non-invasive, fast and costeffective features of retinal imaging enable the utility of retinal age gap as a screening and triage tool for ESKD, thus potentially improving the current

findings showing that each 1-year increase in retinal age gap was associated with a 3% increased risk for incident cardiovascular disease. In another study, described in a 2022 paper in Age and Ageing, researchers found that each 1-year increase in retinal age gap was associated with a 10% increased risk for Parkinson’s disease. ■

An increased A/G ratio is associated with a higher risk for kidney stones.

ESKD risk rose by 10% with each 1-year increase in retinal age gap.

PCA vs Partial Nephrectomy for cT1b Renal Tumors

PERCUTANEOUS cryoablation (PCA) offers distant oncologic outcomes comparable to partial nephrectomy (PN) for cT1b renal tumors, although PCA is associated with a higher local recurrence rate, recent study findings suggest.

A team led by Takafumi Yanagisawa, MD, PhD, of The Jikei University School of Medicine in Tokyo, Japan, retrospectively analyzed data from 119 patients who underwent PCA (29 patients) or PN (90 patients) for cT1b renal tumors. The median follow-up was 43 months in the PCA group and 36.5 months in the PN group. The investigators noted residual unablated tumor and local recurrence in 2 and 4 patients, respectively, in the PCA group and local recurrence in 4 PN patients. In an inverse probability weighting (IPW) analysis, PCA was significantly associated with worse local recurrence-

Use of 5-ARIs Increases Risk for Dementia

USE OF 5α-reductase inhibitors (5-ARIs) for benign prostatic hyperplasia (BPH) and androgenic alopecia increases the risk for dementia and depression, study findings suggest. The risk for dementia, however, observed at the start of treatment diminishes over time, indicating that other factors probably underlie this association.

In a Swedish national registry of 2,236,876 men aged 50 to 90 years, 70,645 (3.2%) initiated finasteride and 8774 (0.4%) initiated dutasteride. Finasteride and dutasteride users had a significant 22% and 10% increased risk of all-cause dementia, a 20% and 28% increased risk of Alzheimer’s disease, a 44% and 31% increased risk of vascular dementia, and a 61% and 68% increased risk of depression, respectively, compared with nonusers. While the risk for depression persisted, the risks of the other neurologic conditions diminished after 4 years, Miguel Garcia-Argibay, PhD, of Örebro University in Sweden, and colleagues reported in JAMA Network Open. At no point was 5-ARI use associated with suicide. ■

free survival (LRFS) compared with PN. An IPW-adjusted restricted mean survival time (RMST) analysis revealed that, within a 100-month window, the PCA group had an LRFS that was 22.7 months shorter than in the PN group, Dr Yanagisawa and colleagues reported in Urologic Oncology.

The IPW-adjusted RMST for metastasis-free, cancer-specific, and overall survival did not differ between the groups.

“Our analyses revealed that PCA has a substantially relevant disadvantage regarding local recurrence in patients with cT1b renal tumors compared to PN,” the authors concluded. “We

found no differences in complication rates or renal function preservation rates between the 2 procedures.”

The investigators wrote that their findings suggest that PCA “can be an alternative treatment for elderly, comorbid patients, even those with cT1b renal tumors. ■

Renal Nutrition Update

Potassium management is a key part of nephrology care and is generally carefully monitored given the risk of cardiac arrhythmias that can occur with potassium imbalance. This fear tends to make potassium restriction a hallmark for the renal diet and is often the first diet recommendation for those with chronic kidney disease (CKD). More recent evidence, however, challenges this restriction with a call for more individualized and liberal recommendations.

In 2020, the KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines released updated guidance on potassium management with the following recommendations:1

• It is reasonable to adjust dietary intake to maintain serum potassium within the normal range.

• In adults with hyper- or hypokalemia, we suggest dietary or supplemental potassium intake be based on a patient’s individual needs and clinician judgment.

These guidelines shift our potassium recommendations from “everyone with CKD needs a potassium restriction” to basing potassium recommendations on a patient’s individual needs and serum

fixed, clinicians should consider looking at potassium as a red flag that something upstream might need to be addressed. Multiple studies indicate benefits for a more liberal potassium diet in those with CKD, including improved blood pressure and lower risk for stroke, arrhythmia, myocardial infarction, and death related to cardiovascular events.2 This is an important consideration given that adverse cardiovascular

difficulties related to following the renal diet are that its recommendations are complex and it contradicts a healthy eating pattern, conflicts with other dietary recommendations for disease (such as for improving heart health), fails to achieve desired results despite adhering to recommendations, and alienates patients from others at cultural or social events or even their own family due to having to make separate meals. A more liberalized diet can improve the nutrition quality of life for CKD patients and may increase adherence to other recommendations.6

—Mild to moderate CKD: 4.7g/day with normal serum potassium levels

—Advanced CKD: <3g/day if serum levels are elevated despite high fiber intake

—Dialysis < 3g/ day and encourage high fiber intake

3. Consider that most of the potassium in diets comes from intake of potatoes, savory snacks, fruit juice, coffee, tea, beer, animal protein, and dairy.8 Restricting fruits and vegetables is less likely to have a positive impact if potassium is high due to intake.

4. Clarify follow-up with patients and staff on lab redraws or follow-up visits so that potassium issues can be resolved in a timely manner.

5. If potassium is high (or low), refer out to a renal dietitian. Many of the root causes of high potassium can be resolved with a nutrition approach. Dietitians and other nephrology providers can work as a team to provide optimal support for CKD patients. ■

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

levels and clinician judgment, which may prompt consideration of interventions other than dietary restriction to achieve normal serum levels when appropriate.

The rationale for this more individualized approach for potassium recommendations is meant to remind nephrology providers that the KDOQI workgroup found no clinical trials on how modifying diet can influence serum potassium levels in patients with CKD and that there are multiple factors for serum potassium changes.1 Instead of seeing high potassium as the problem that needs to be

events are the current leading cause of death in those with CKD not on dialysis as well as on dialysis.3,4

Other benefits of a more liberal potassium diet are slower progression of CKD due to improved control of metabolic acidosis and reduced inflammation and fibrosis, 2 improved gut health and reduced production of uremic toxins,5 reduced age-related bone loss, and decreased risk of kidney stones.2

A survey of patients on dialysis found helpful insights into the patient perspective of the renal diet. Common

More liberal, individualized potassium recommendations can improve patient outcomes and quality of life. Some guidelines and tips for implementing these recommendations are as follows:

1. Consider these questions to help pinpoint the root issue of high potassium:

—Is this potassium level consistent with the current trend?

—Does this patient take medications that impact potassium (or had a recent medication dose change)?

—Has the patient been losing muscle mass or having a reduced appetite?

—What foods has the patient been eating recently?

2. Guidelines for potassium intake based on stage and serum level:7

1. Ikizler TA, Burrowes JD, Byham-Gray LD, et al. KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update. Am J Kidney Dis. 2020;76(3 Suppl 1):S1S107. doi:10.1053/j.ajkd.2020.05.006. Erratum in: Am J Kidney Dis. 2021 Feb;77(2):308.

2. Terker A, Saritas T, McDonough A. The highs and lows of potassium intake in chronic kidney disease Does one size fit all? J Am Soc Nephrol. 2022;33(9):16381640. doi:10.1681/ASN.2022070743.

3. National Institute of Health. Kidney disease statistics for the United States. https://www.niddk.nih.gov/ health-information/health-statistics/kidney-disease. Accessed 10/29/21.

4. Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol. 2015;26(10):2512-2520. doi:10.1681/ASN.2014101034

5. Lau WL, Kalantar-Zadeh K, Vaziri ND. The gut as a source of inflammation in chronic kidney disease. Nephron 2015;130(2):92-98. doi:10.1159/000381990.

6. Stevenson J, Tong A, Gutman T, et al. Experiences and perspectives of dietary management among patients on hemodialysis: An interview study. J Ren Nutr. 2018;28(6):411-421. doi:10.1053/j.jrn.2018.02.005. Epub 2018 Apr 22. PMID: 29691161.

7. Kalantar-Zadeh K, Fouque D. Nutritional management of chronic kidney disease. N Engl J Med. 2017;377(18): 1765-1776. doi:10.1056/NEJMra1700312.

8. Lanham-New SA, Lambert H, Frassetto L. Potassium. Adv Nutr. 2012;3(6):820-821.

In 2020, KDOQI released revised recommendations for patients with chronic kidney disease that suggest an approach based on a patient’s individual needs.

Potatoes are among the major dietary sources of potassium.

Updated guidelines suggest a need to change how potassium intake in patients with CKD is managed BY LINDSEY ZIRKER MS, RD, CSR

Ethical Issues in Medicine

Moral distress can disengage health care professionals from their patients or their colleagues

BY DAVID J. ALFANDRE, MD, MSPH

In the last few years, there has been a burgeoning interest in the role of moral distress and moral injury in health care. This column and the next will examine moral distress by clarifying the term, demonstrating how to apply the concept in consistent, practical, and meaningful ways, and describing how to support colleagues who have moral distress.

Having moral distress is sometimes colloquially defined as knowing the “right thing to do,” but being unable to do it. Unfortunately, this definition can lack the conceptual clarity needed to help people manage their distress. A nurse may report moral distress because an attending physician’s treatment plan fails to account for the nursing staff’s concerns about what is in the patient’s best interest. A physician may experience moral distress because their patient has chosen to decline an uncomplicated surgical treatment that could extend their life.

More Than One ‘Right Thing to Do’

Moral distress, however, can easily be confused with general distress or helplessness. In the examples above, there are multiple options that could be ethically justifiable. In the second example, the patient accepting or declining surgery could be ethically justifiable as part of an adequate informed consent process. For this reason, it is critical to distinguish moral distress from moral ambiguity or moral diversity, particularly when the individual assumes they already know what is the right thing to do.1 Given the ethical standards and the preferences and values of the various moral agents, there often may be more than one “right thing to do.”

When we identify moral distress, we are actually identifying moral ambiguity or moral diversity and the need for an ethics consultation that can mediate the conflict over values. This process identifies the range of ethically acceptable options and provides support for the health care professional when their moral position or decision isn’t followed. Not all moral distress is as complicated to define. Contrast the aforementioned examples with the unambiguous

and unfortunately frequent moral distress felt during the COVID-19 pandemic. Some health care professionals felt that they could not adequately care for patients according to usual standards either because of resource constraints or simply because of the isolation requirements needed to safely care for patients. There is no moral ambiguity there, just helplessness at the sometimes impossible situations.

Addressing moral distress means not just obtaining ethics consultations as needed but also dealing with the feeling of powerlessness that often accompanies it. If the original narrative with moral distress was about some health care professions attempting to free themselves from the oppression of others in medicine, more recent discussions have approached the issue similarly. For example, physicians might feel moral distress when constrained by their patient’s choices.

Examine Power Dynamics

What is the experience of powerlessness for those in moral distress? Is it lost power or never attained power? Loss of power to act or power to influence? Is it a part of the normal helplessness many health care professionals sometimes feel when caring for patients?2 Rather

diversity leading to multiple ethically justifiable options, what if they focused on what has led to the power dynamics and what can be done about it? Did the nurses have no power in this scenario and if so, what is specifically limiting it? What specific power does the attending hold?

Course of Action

What can individual health care professionals do when feeling morally distressed? First, consider calling an ethics consultation. Second, anyone can

A significant risk of moral distress is that it can disengage health care professionals from their patients or their colleagues and divert them away from their core commitment to patients. This is not an accusation of blame, but rather an assertion that they have considerable agency, choice, and ultimately control to effect change. Health care professionals will often need support through ethics consultation, their colleagues, or their institution to help them adequately address their moral distress. That will be good for them and ultimately for their patients.

The next column will discuss the risks for moral distress affecting patient outcomes. ■

than focusing on the moral ambiguity or the moral indignation that can sometimes be a part of moral distress, it can be useful to uncover and examine the power dynamics of moral distress.

A nurse or a medical student might be feeling morally distressed when a physician advocates for a treatment plan that doesn’t promote their conception of what is in the patient’s best interest. Rather than anchoring to “the right thing to do,” because there could be reasonable moral

and should try to recognize their current internal state—am I feeling anxious, angry, sad, or helpless? Are those feelings about me or the patient? Next, one can allow themselves to experience that distress without avoidance and take perspective on it and the situation that may have led to it. Following this model, and with time and support, health care professionals can find it easier and more productive to react mindfully to future challenges.

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.

REFERENCES

1. Repenshek M. Moral distress: Inability to act or discomfort with moral subjectivity? Nurs Ethic s. 2009;16(6):734-742. doi:10.1177/0969733009342138

2. Brody H. The Healer’s Power. London: Yale University Press: 1992.

A physician may experience moral distress because their patient has chosen to decline an uncomplicated surgical treatment that could extend their life.

Moral distress is often accompanied by a feeling of powerlessness.

Practice Management

Private medical practices wrestling with widespread shortages of qualified

health care personnel

Ahealth care worker shortage may be one of the biggest problems facing physicians in private practice. Medical practice management teams are assessing their systems and processes to make sure they are as efficient as possible because of the never-ending changes in the marketplace. While medical practices want to deliver superior care, at times that can be at odds with a strong financial performance. Managing and growing a medical practice has become challenging due to regulatory mandates and record-breaking staffing shortages.

Evan R. Goldfischer, MD, President of the Large Urology Group Practice Association (LUGPA), said practicing medicine today is becoming increasingly more difficult for the nation’s independent physicians. “The challenges that we face stem in part, from the escalating physician shortage in the United States,” Dr Goldfischer said. “Due to the number of retiring urologists, the workforce shortage is projected to become more severe over time.”

Urologist Numbers in Decline

A 2021 study published in JAMA Network Open estimated that there will be a continued decline in the number of urologists per capita in the United States

BY JOHN SCHIESZER

an epidemic in itself,” Dr Goldfischer said. “These workforce shortages lead to longer wait times for appointments and other inconveniences for our patients.”

Job vacancies for various types of nursing personnel increased by up to 30% between 2019 and 2020, according to an analysis by the American Hospital Association. The report notes that staff turnover due to COVID-19 pressures increased from 18% to 30% for some hospital departments (emergency, intensive care units, and nursing) during this same period. Data suggest that there could be a critical shortage of 3.2 million health care workers by 2026.

Why Clinicians Leave

Patricia Pittman, PhD, Fitzhugh Mullan Professor of Health Workforce Equity at George Washington University’s Milken Institute School of Public Health in Washington, DC, said the biggest hurdles facing physicians and outpatient independent medical practices today are a combination of increasing patient needs and decreasing control over their clinical practice. “On the demand side, the pandemic has created a backlog of medical visits, and an accompanying worsening of complex chronic conditions, both behavioral and physical,” Dr Pittman said. “On the supply side, there are pressures

some are leaving independent practice and even clinical practice entirely,” Dr Pittman said. “The workforce shortage has become a vicious cycle. As clinicians get fed up with the system and leave, those who remain behind are witnessing worsening quality and patient safety.”

Many clinicians know that major changes are warranted to turn around the worsening morale and the impetus to quit clinical practice. “It’s time for a whole range of stakeholders to reconsider the ways in which the status quo is driving clinicians out, and to make the health worker experience of providing care a central consideration in reviewing how they do business,” Dr Pittman said.

Inflation

through 2060, based on the current growth of the profession. That number is projected to decline from 3.99 urologists per 100,000 in 2019 to 3.3 and 3.1 per 100,000 by 2060, respectively.

In addition to the challenges in the physician workforce, recruiting and retaining a good staff are also problematic. “Since the pandemic, the lack of availability of qualified personnel, due to people leaving the workforce or changing careers, has become almost

created by the continuation of a volume driven payments system, combined with just enough value driven payment that quality reporting requirements are experienced as an additional unfair burden.”

In addition, greater use of electronic health records that add more work to the day, along with unprecedented administrative burdens on clinicians, are taking time away from patient-facing activities. “Clinicians are tired and angry, and so it’s not surprising that

On top of an escalating shortage of urologists, many independent practices are currently experiencing the effects of high inflation along with the 2% Medicare Physician Fee Schedule (MPFS) payment cut, Dr Goldfischer said. “The MPFS is also the only payment method within Medicare without an annual inflationary update, which is particularly destabilizing for clinicians who are small business owners,” he said. “The long‐term consequence of failing to prevent these cuts will be a decrease in patient access to care.”

Rising Labor Costs

Due to the health care worker shortage, more and more practices are experiencing big increases in labor costs, and Medicare rates have not kept up with these costs. Some experts contend that consolidation in the health care industry is continuing to jeopardize not only independent practices, but also patient access to quality care. “Federal aid at the beginning of the COVID-19 pandemic favored hospital systems, despite vows from policymakers to fight consolidation,” Dr Goldfischer said. “Therefore, hospitals continued to combine or buy up smaller practices, resulting in colossal hospital systems that create fewer choices for where patients can seek health care. This decrease in competition will increase the cost of care for patients.”

LUGPA is advocating on Capitol Hill to decrease regulatory burdens and level the playing field between hospital and independent physician reimbursement. Independent urologists must do all they can to educate policymakers on the benefits of integrated urologic care to ensure all patients have access to high-quality, affordable and efficient overall care, Dr Goldfischer said. ■

Physician retirements and challenges in recruiting and retaining staff are among the reasons medical practices are struggling with labor shortages.

Imperiled patient safety may be among the consequences of an exodus of health providers.