Management of Presumed

Acute Kidney Injury during

Hypertensive Therapy: Stay
Calm and Carry on?
Teresa K. Chena, Chirag R. Parikh

The American Journal of Nephrology

2020
Introduction
In 2014, the Eighth Joint National Committee guidelines
recommended a blood pressure goal:
• Adults aged <60 years  <140/90 mmHg
• Adults aged ≥60 years  <150/90 mmHg

In 2015, the landmark Systolic Blood Pressure Intervention Trial

(SPRINT)  <120 mmHg:
1. Lower risk of a composite cardiovascular outcome (25%)
2. Lower risk of all-cause mortality (27%)
However, development of acute kidney injury (AKI), defined by
changes in serum creatinine concentration, was 64% (95% CI 1.30–
2.09) more likely in participants randomized to the intensive versus
standard treatment group
Introduction
• Despite this reported increase in AKI risk,
hypertension guidelines have already begun to
move toward lower blood pressure goals.
• For example, The American College of Cardiology
and American Heart Association now
recommend a blood pressure target <130/80
mm Hg for individuals with hypertension and any
of the following: diabetes mellitus, CKD, or a 10-
year atherosclerotic cardiovascular disease risk
of ≥10%.
Introduction
This review aims to:
1. Describe the limitations of serum creatinine as
a marker of kidney injury;
2. Discuss the utility of urinary biomarkers in
discerning presumed from actual kidney injury
in hypertension trials; and
3. Propose an approach to managing presumed
AKI during hypertension therapy.
Pitfalls of Serum Creatinine
as a Marker of Kidney Injury
The ideal filtration marker  freely filtered by the
glomerulus and not secreted, reabsorbed, or
metabolized by the renal tubule. In addition, the
marker should be nontoxic, physiologically inert,
and not bound to proteins.
• “Gold Standard” : INULIN , but:
Process of measuring inulin clearance is
laborious, requiring an intravenous infusion and
repeated sample collections
Pitfalls of Serum Creatinine
as a Marker of Kidney Injury
Alternative filtration markers  Serum Creatinine.
Creatinine, an endogenous 113 Dalton breakdown
product of muscle metabolism, is less expensive and
easier to measure compared to inulin. Freely filtered
and not protein bound or metabolized by the
kidneys, creatinine possesses many of the qualities
of a good filtration maker but also has several
important limitations
Pitfalls of Serum Creatinine
as a Marker of Kidney Injury
1. Production of creatinine varies between and within
individuals over time.
2. Creatinine is secreted by the proximal tubules, which
can lead to an overestimation of the glomerular
filtration rate.
3. Extrarenal elimination of creatinine occurs in severe
renal insufficiency.
There are also situations where a rise in serum creatinine does
not reflect kidney injury but rather a change in glomerular
hemodynamics.
1. Initiation of ACEI and ARB : Rise in serum creatinine
2. Patients with type 2 diabetes, hypertension, and CKD:
initiation of losartan was associated with a greater acute
fall in creatinine-based eGFR compared to placebo in the
first 3 months of treatment.
3. Patients with left ventricular dysfunction (mean eGFR 66
mL/min/1.73 m2), early worsening renal function (de-
fined as a ≥20% decrease in eGFR within 2 weeks of ini-
tiating therapy) was independently associated with in-
creased mortality in the placebo group but not the enalapril
group
4. Withdrawal of an ACEI, even after years of therapy, can lead
to a return in measured GFR toward baseline values. Taken
together, the results of these studies suggest that an acute
decline in eGFR that occurs following ACEI or ARB initiation may
be a marker of therapeutic responsiveness rather than a safety
concern.
5. Analysis of SPRINT, investigated the clinical implications of an
early decline in eGFR attributed to intensive blood pressure
control.
6. African American Study of Kidney Disease and Hy- pertension
(AASK) and the Modification of Diet in Renal Disease (MDRD)
trial, reported that acute declines in eGFR <20% (from baseline
to 3 months for AASK; from baseline to 4 months for MDRD)
were not associated with an increased risk of subsequent end-
stage renal disease (ESRD) among participants randomized to
the intensive treatment arms (MAP ≤92 mm Hg for AASK; MAP
<92 or <98 mm Hg for MDRD).
 Era of Urinary Biomarkers

In best-case scenarios, serum creatinine-based AKI

definitions correctly identify the absence (no kidney
injury) or presence (clinical acute tubular injury) of
structural kidney injury. Conversely, serum creatinine-
based AKI definitions may fail to detect structural
kidney injury when present (subclinical AKI) or
categorize patients as having AKI when no such dam-
age exists (hemodynamic AKI).
 Era of Urinary Biomarkers

Presence of structural
  kidney injury
No Yes

No No kidney Subclinical
AKI based on injury AKI
serum
creatinine
change Yes Hemodynamic Clinical ATI
AKI

Possible scenarios of AKI as defined by serum creatinine and structural kidney injury.
Adapted from Moledina et al.
*AKI, acute kidney injury; ATI, acute tubular injury.
 Era of Urinary Biomarkers
• Subclinical AKI can tran- spire in a variety of settings.
1. 48–72- hour lag in serum creatinine elevation following kidney
injury.
2. Ongoing kidney injury may be masked if uninjured nephrons
are able to compensate for their in- jured counterparts and
maintain GFR
3. Serum creatinine concentrations may remain relatively stable
despite ongoing kidney injury as a result of decreased
creatinine production from low muscle mass or dilution from
intravenous fluid administration.
Era of Urinary Biomarkers
 Category Biomarker Clinical correlates beyond AKI
Glomerular
structure and UACR Incident CKD; eGFR decline; CVD ; mortality
injury
Proximal tubular B2M ESRD , CVD , mortality, eGFR decline CVD
function A1M mortality, allograft function

Proximal tubular KIM-1 Incident CKD; ESRD ; CVD ; mortality

injury IL-18 Mortality
Loop of Henle UMOD* eGFR decline; CVD; mortality
injury
Distal tubular NGAL CKD progression; ESRD; CVD; mortality
injury
Incident CKD; eGFR decline ; CVD
Inflammation MCP-1
and repair YKL-40 mortality; allograft function
Mortality; allograft function
* Associated with lower risk.
AKI, acute kidney injury; CKD, chronic kidney disease; CVD, cardiovascular disease;
ESRD, end-stage renal disease.
 Utility of Urinary Biomarkers
in Hypertension Clinical Trials
Conclusions