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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