Hot Topics in Nephrology

Ivonne Hernandez Schulman, MD

Professor of Clinical Medicine

Katz Family Division of Nephrology and Hypertension

Interdisciplinary Stem Cell Institute

University of Miami Miller School of Medicine

3-31-2019

Issues of Importance that Impact

Nephrology Patient Care and Research

• CKD/ESRD growing epidemic

• Shortage of nephrology fellow applicants

Projecting ESRD Incidence and Prevalence in the United States

through 2030 Keith P. McCullough et al., JASN, 2019 - used an open compartmental simulation model to

estimate the incidence and prevalence of ESRD in the United States through 2030 on the

basis of wide-ranging projections of population obesity and ESRD death rates

“The burden of ESRD will increase in the United States population through 2030 due to demographic, clinical, and

lifestyle shifts in the population and improvements in RRT. Planning for ESRD resource allocation should allow

for substantial continued growth in the population of patients with ESRD. Future interventions should be directed

to preventing the progression of CKD to kidney failure.”

The US Adult Nephrology Workforce 2016 Developments and Trends

Report on the Survey of 2018 Nephrology Fellows

Prepared for The American Society of Nephrology

by George Washington University Health Workforce

Institute

• Importance of nutrition (renal diet) in kidney disease

progression and comorbidities:

• education of nephrologists and patients,

• research funding,

• government and food industry awareness

• Need for more clinical trials for renal diseases

(Nephrotic syndromes, FSGS, ADPKD, etc.)

• Funding for Phase I/II clinical trials

• HTN guidelines specific for CKD and ESRD

populations: inclusion of CKD/ESRD patients in trials

Topics of Importance for Nephrology

A Pragmatic Step Forward: AKI and Beyond by Laura M. Dember, JASN, 2019

• Selby et al. report the results of “An organizational level program of intervention for

acute kidney injury: A pragmatic stepped-wedge cluster randomized trial”, a multicenter

trial of a multicomponent supportive care intervention for AKI.

• The trial was conducted in 5 hospitals in the United Kingdom over a 27-month period,

during which there were 24,059 episodes of AKI.

• The intervention had three components: • (1) an electronic health record alert for AKI events as defined by modified Kidney Disease

Improving Global Outcomes criteria;

• (2) a care bundle for assessing and managing AKI that included evaluating volume status,

optimizing BP, performing urinalysis, modifying medications, treating sepsis, and consulting

nephrology or critical care specialists; and

• (3) a program to educate health care personnel about AKI.

• The primary outcome was 30-day mortality, and secondary outcomes included AKI

progression, length of hospitalization, AKI recognition, and implementation of the care

bundle components.

• The intervention did not reduce 30-day mortality or progression of AKI, but it reduced

length of hospitalization and duration of AKI (a post-hoc outcome), and it increased the

recognition of AKI by clinicians as evidenced by greater use of AKI diagnosis codes.

AKI biomarkers, prevention, and treatment

• CVD complications and mortality in CKD/ESRD: Cardiorenal

syndromes

Topics of Importance for Kidney Research

Chronic Kidney Disease

http://www.usrds.org/2015/view/Default.aspx

• Approximately one in ten adults have CKD in the USA.

• Despite the magnitude of the resources committed to the

treatment of ESRD and the substantial improvements in the

quality of dialysis therapy, these patients continue to

experience significant mortality and morbidity and a reduced

quality of life.

• In general, CKD patients have worse survival across all of

the conditions reported.

Data source: Special analyses, Medicare 5 percent sample. January 1 of each reported year, point prevalent

Medicare patients age 66 and older. Adj: age/sex/race. Ref: 2012 patients. Abbreviation: CKD, chronic kidney

disease. This graphic also appears as Figure 3.1.

All-cause mortality rates (per 1,000 patient years at risk)

for Medicare patients aged 66+, by CKD status and year, 2001-2013

(b) Adjusted

USRDS Vol 1, CKD, Intro

Chronic Kidney Disease

http://www.usrds.org/2015/view/Default.aspx

• CKD patients have a greater burden of cardiovascular disease than

do their counterparts without a diagnosis of CKD.

• Cardiovascular diseases account for approx. 50% of deaths in CKD

patients regardless of biological age.

• The presence of CKD worsens the short- and long-term prognosis

for many common CVD, including heart failure, particularly HFpEF.

• CKD has been recognized as an independent risk factor for CVD and

has now been recognized as a CAD risk equivalent, similar to diabetes

mellitus.

• Heart failure is among the more frequently diagnosed types of CVD

among CKD patients.

• In 2015, the prevalence of CHF in CKD patients aged 66 and older was

nearly 30% compared to 6% among those without CKD. HFpEF

prevalence in CKD/ESRD may be as high as 80%.

Data Source: Special analyses, Medicare 5 percent sample. Patients aged 66 and older, alive, without end-

stage renal disease, and residing in the U.S. on 12/31/2013 with fee-for-service coverage for the entire calendar

year. Totals of patients for the study cohort: N=1,238,888; With CKD=132,840; Without CKD=1,106,048.

Abbreviations: AFIB, atrial fibrillation; AMI, acute myocardial infarction; ASHD, atherosclerotic heart disease;

CHF, congestive heart failure; CKD, chronic kidney disease; CVA/TIA, cerebrovascular accident/transient

ischemic attack; CVD, cardiovascular disease; PAD, peripheral arterial disease; SCA/VA, sudden cardiac arrest

and ventricular arrhythmias; VHD, valvular heart disease. This graphic also appears as Figure 4.1.

Cardiovascular disease in patients with or without CKD, 2013

USRDS Vol 1, CKD, Intro

Volume

Overload

Pressure

Overload

• Systemic arterial

resistance

• Elevated arterial

blood pressure

• Reduced large-

vessel compliance

• Neurohumoral

activation

• RAAS

• Aldosterone

Endothelial

dysfunction

FGF-23

• Na+ and

Fluid

retention

• Anemia

• Fistula

Correlation Between CKD and HFpEF:

Cardio Renal Syndrome (type IV)

Chronic

Inflammation

Urema

LVH

Cardiomyocyte

Hypertrophy

ECM

Fibrosis

Apoptosis

Capillary Loss

Efficacy and Safety of Spironolactone in Patients With HFpEF and

Chronic Kidney Disease

Iris E. Beldhuis et al, JACC: Heart Failure, 2019

Effect of Weight Loss Surgery on

CKD Risk

• Obesity is linked to the development and progression of CKD, but

whether bariatric surgery protects against CKD is poorly understood.

• In a study of 2144 adults who underwent weight loss surgery,

improvements in CKD risk (GFR and albuminuria) at 1 and 7 years after

surgery were observed in patients with moderate baseline CKD risk

(63% and 53%, respectively), high baseline risk (78% and 56%,

respectively), and very high baseline risk (59% and 23%, respectively).

• The proportion of patients whose CKD risk worsened was ≤10%.

• The findings support the consideration of CKD risk in evaluating the

appropriateness of bariatric surgery for individual patients.

J Am Soc Nephrol 29: 1289–1300, 2018.

Trend of overall improvement in CKD risk categories over 7-year

period after bariatric surgery.

Allon N. Friedman et al. JASN 2018;29:1289-1300

©2018 by American Society of Nephrology

• Gene expression studies to determine markers of kidney

disease risk.

Topics of Importance for Kidney Research

APOL1 High-Risk Genotype Linked with

Poor Renal Outcomes in Kidney Donors

• Among 136 black living kidney donors, APOL1 high-risk genotype was

associated with lower pre-donation and post-donation kidney function.

• At a median of 12 years after donation, donors with an APOL1 high-risk

genotype had an average eGFR of 57 mL/min per 1.73 m² compared with

67 mL/min per 1.73 m² in donors classified as APOL1 low-risk.

• Two donors reached ESRD, and both carried high-risk APOL1 genotypes.

• Outcomes did not differ between donors and matched nondonors stratified

by APOL1 status.

• APOL1 high-risk genotype may be associated with worse renal outcomes

in kidney donors, but the JASN findings require replication in a larger study.

J Am Soc Nephrol 29: 1309–1316, 2018

APOL1 High-Risk Genotype Linked with

Poor Renal Outcomes in Kidney Donors

J Am Soc Nephrol 29: 1309–1316, 2018

Technique Measures Gene Expression in

Thousands of Cells from Kidney Biopsies

• Researchers have established the feasibility of using single-cell

RNA-sequencing (scRNA-seq) to comprehensively measure gene

expression from thousands of cells from a single human kidney

biopsy.

• The investigators identified 16 separate cell types from just under

5000 single-cell libraries.

• Future improvements will likely enable the generation of 10-times as

many single-cell libraries from a single human biopsy, which should

allow for much finer cell type separation and deeper transcript

detection.

• In their JASN study, the scientists mapped previously defined genes

that associate with rejection outcomes to single cell types, and they

generated a searchable online gene expression database.

Haojia Wu et al. JASN 2018;29:2069-2080

©2018 by American Society of Nephrology

• Human developmental biology studies to understand/guide

development of regenerative stem cell treatments

Topics of Importance for Kidney Research

Conserved and Divergent Features of Mesenchymal Progenitor Cell

Types within the Cortical Nephrogenic Niche of the Human and Mouse

Kidney by Nils O. Lindström et al., JASN, 2018

• The nephrogenic niche of the developing kidney contains distinct progenitor cell

types for nephron, interstitial, and collecting duct lineages. Mouse studies have

defined these progenitor cell compartments and identified key regulatory

mechanisms acting within and between progenitor types to coordinate

developmental programs.

• Authors used a variety of molecular and cellular approaches to characterize the

nephron- and interstitial-forming compartments within the developing human

kidney.

• These studies reveal significant differences between their global transcriptional

profiles and distinct human and mouse differences in gene expression

patterns pointing to a likely evolutionary divergence in their

developmental programs.

• The insights and data resources generated here will facilitate efforts to generate

appropriate progenitor types for in vitro engineering of human kidney structures.

Conserved and Divergent Features of Mesenchymal Progenitor Cell

Types within the Cortical Nephrogenic Niche of the Human and Mouse

Kidney by Nils O. Lindström et al., JASN, 2018

• Unlike many organ systems where long lived stem cell populations generate and

regenerate functional mature cell types, the mammalian metanephric

(definitive, adult) kidney forms from a small subset of lineage-restricted

progenitor cell types that undergo expansion and commitment over a

limited period of fetal and neonatal development.

• Molecular, cellular, and genetic studies in the mouse have demonstrated that the

transcription factors Foxd1 and Six2 demarcate self-renewing, lineage restricted

interstitial and nephron progenitor cells, respectively.

• Each population occupies a unique position within the nephrogenic niche;

nephron progenitors closely associate with underlying collecting duct progenitor

cells, whereas interstitial progenitors localize between the nephron progenitors

and the renal capsule.

• Interactions among these progenitor pools drive the process of kidney

organogenesis.

Perico et al, JASN, 2017

Perico et al, JASN, 2017

Completed Clinical Trials of MSCs for CKD

Perico et al, JASN, 2017

Ongoing Clinical Trials of MSCs for CKD

Acknowledgements

• NIH/NHLBI Grants

• Starr Foundation

• Soffer Family Foundation

• Lipson Family Foundation and NHLBI R01

Interdisciplinary Stem Cell Institute