87 Renal Insufficiency and Ischemic Nephropathy
Joshua Augustine, MD, Alvin C. Wee, MD, Venkatesh Krishnamurthi, MD, and David A. Goldfarb, MD
ACUTE KIDNEY INJURY
Acute kidney injury (AKI) in is defined by an acute rise in serum
creatinine (SCr) and/or an acute decline in urine output. This
abrupt decline in kidney function occurs over hours to days and
results in the accumulation of byproducts of metabolism and the
dysregulation of electrolyte homeostasis, acid/base, and volume
status. Changes in blood urea nitrogen (BUN) and SCr have been
used as surrogate markers for changes in kidney function. BUN can
be altered by other factors and may be disproportionately elevated
in states of volume depletion, in hypercatabolic states, or in marked
increased in protein loads seen with gastrointestinal bleeding or
total parenteral nutrition. Creatinine is a metabolite of muscle and
is used to calculate the estimated glomerular filtration rate (GFR),
using GFR equations that also account for age, gender, and black
race. The two equations most commonly used and often reported
with routine lab values include the Modification of Diet in Renal
Disease (MDRD) and the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) equations (Levey et al., 1999, 2009). The
CKD-EPI equation is a modification of the MDRD formula and is
less likely to underestimate true GFR in patients with early stages
of chronic kidney disease (CKD) (Levey et al., 2009). It is more
predictive of mortality associated with CKD than the MDRD equation
(Matsushita et al., 2012).
Because of its dependence on muscle mass, SCr may overestimate
kidney function in cases of muscle wasting, such as in patients with
cirrhosis or prolonged intensive care unit (ICU) stays (Schetz et al.,
2014; Skluzacek et al., 2003). Alternatively, at extremes of high muscle
mass, SCr may underestimate kidney function. Another marker of
kidney function that has been compared with SCr is the measurement
of cystatin C, a low-molecular-weight protein that is a member of
the cystatin superfamily of cysteine protease inhibitors (Newman
et al., 1995). Unlike creatinine, cystatin is not secreted by renal
tubules, although it does undergo renal tubular metabolism. Cystatin
C does not appear to be as strongly correlated with muscle mass
and thus may improve the accuracy of estimating kidney function
in patients with extremes of muscle mass and nutrition, such as
patients with cirrhosis (Pöge et al., 2006). However, cystatin C levels
appear to be altered in states of inflammation, thyroid disease, and
smoking, making it an imperfect replacement for SCr (Knight et al.,
2004; Manetti et al., 2005). Combining formulas that estimate GFR
using both SCr and cystatin C leads to improved precision and
accuracy compared with using either variable alone (Inker et al.,
2012). Online calculators that allow for combining of such formulas
are available. See The National Kidney Foundation website at https://
www.kidney.org/professionals/KDOQI/gfr_calculator.
It is also important to recognize that changes in SCr may lag in
appearance after an episode of AKI. For example, contrast nephropathy,
which may induce kidney injury immediately after contrast exposure,
is often associated in a change in SCr evident only after 24 to 48
hours (Rich et al., 1990). For this reason, it is inappropriate to
estimate GFR using a single SCr value in a hospitalized patient
whose SCr is fluctuating. For example, a patient whose SCr doubles
from 1 to 2 mg/dL in 24 hours may have advanced kidney failure
with lower clearance than a patient with a stable SCr of 2 mg/dL.
Conversely, a patient recovering from AKI or after kidney transplanta-
tion with an SCr falling from 6 mg/dL to 3 mg/dL in 24 hours has
a better GFR than would be reflected by a stable SCr of 3 mg/dL.
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Such fluctuation in kidney function can create challenges in drug
dosing in the hospital setting (Lewis et al., 2016). In addition, drug
dosing has historically relied on outdated methods of measurement
of kidney function, such as SCr alone or the calculation of creatinine
clearance using formulas such as Cockcroft-Gault. The Cockcroft-Gault
formula uses patient weight but does not account for morbid obesity,
which may positively skew the estimation of creatinine clearance
well above the true GFR (Bouquegneau et al., 2016).
Another method occasionally used to estimate kidney function
in the hospital setting is a 24-hour urine collection for creatinine
clearance. Twenty-four–hour urine is often imprecise and may result
in errors related to over- or undercollection. It may be used to assess
kidney function in a patient who is suspected of having impaired
kidney function beyond that reflected by the SCr alone, or to screen
for renal recovery in a patient with nonoliguric AKI. However, in
addition to errors in collection, the percentage of creatinine excreted
in the tubules can vary and tends to be a higher percentage of total
creatinine excretion at lower levels of GFR. Tubular secretion of
creatinine may account for more than a third of creatinine measured
in the urine and thus may artificially inflate creatinine clearance
relative to true GFR (Doolan et al., 1962).
The gold standard for evaluating kidney function is a measure-
ment of GFR using a marker of pure glomerular filtration (Stevens
et al., 2009). Inulin has been used historically but is no longer
available in the United States. GFR is more often measured by nuclear
medicine testing using iothalamate or other isotopes. Few hospitals
routinely use nuclear measurement of GFR, but it has been a valuable
tool particularly in research designed to derive estimation formulas.
It has also been used in some kidney transplant centers to evaluate
kidney function in living kidney donor candidates.
One set of criteria used to define AKI is known as the Risk, Injury
Failure, Loss of kidney function, and End-stage kidney disease (RIFLE)
criteria (Bellomo et al., 2004; Table 87.1), which divides AKI and
chronic kidney failure into stages based on severity and duration.
The Kidney Disease: Improving Global Outcomes (KDIGO) definition
of AKI is also widely used and is described in Table 87.2. Contrasting
from the RIFLE criteria, KDIGO includes an acute rise in SCr more
than 0.3 mg/dL within 48 hours as a definition of AKI, along with
a rise in SCr of at least 1.5 times baseline within 7 days, or urine
volume below 0.5 mL/kg/h for 6 consecutive hours (KDIGO, 2012).
Unlike RIFLE, the KDIGO criteria do not include scoring related to
prolonged kidney failure or end-stage renal disease (ESRD).
Use of these AKI definitions does not account for the cause of
AKI, which may be rapidly correctable in cases of volume depletion,
or more severe and sustained in cases of intrinsic ischemic kidney
injury. Therefore staging alone has some prognostic capability but
should optimally be subdivided into cause of AKI. In addition, it is
not always clear whether a patient had a normal baseline SCr before
AKI, or developed “acute on chronic” kidney injury with underlying
CKD. Patients with CKD have a greater risk for AKI (Chawla et al.,
2012). AKI may develop before a hospital admission, with an eleva-
tion in SCr on presentation, thus affecting definitions that use the
change in SCr from admission to a later hospital date. Regardless, it
is recommended that the practitioner identify AKI early in its course
because even small changes in SCr may indicate a significant change
in kidney function. Early consultation with nephrology may also
improve outcomes in hospitalized patients with AKI (Balasubramanian
et al., 2011).
1921
1922 PART VIII Renal Physiology and Pathophysiology

TABLE 87.1 The Risk, Injury Failure, Loss of Kidney TABLE 87.3 Cause of Hospital-Acquired Acute Kidney
Function, and End-Stage Kidney Disease Injury in 748 Patients in Thirteen Tertiary
(RIFLE) Criteria for Acute Kidney Injury Care Centers in Madrid, Spain

RIFLE CRITERIA: STAGES CAUSE PERCENTAGE

Stage I Increase in serum creatinine 50%–99% OR Acute tubular necrosis 45

Urine output < 0.5 mL/kg/h for 6–12 h
Stage 2 Increase in serum creatinine of 100%–200% OR
Urine output < 0.5 mL/kg/h for 12–24 h
Failure Increase in serum creatinine ≥ 200% OR
Increase in serum creatinine > 0.5 mg/dL to >
4 mg/dL OR
Urine output < 0.3 mL/kg/h for >24 h or anuria for
>12 h OR
Initiation of renal replacement therapy
Loss Need for renal replacement therapy for >4 weeks
End stage Need for renal replacement therapy for >3 months
TABLE 87.2 The Kidney Disease: Improving Global
Outcomes (KDIGO) Definition of Acute
Kidney Injury
KDIGO CRITERIA: STAGES
Stage 1 Increase in serum creatinine ≥ 0.3 mg/dL or
50%–99% OR
Urine output < 0.5 mL/kg/h for 6–12 h
Stage 2 Increase in serum creatinine of 100%–200% OR
Urine output < 0.5 mL/kg/h for 12–24 h
Stage 3 Increase in serum creatinine ≥ 200% OR
Increase in serum creatinine ≥ 0.3 mg/dL to ≥
4 mg/dL OR
Urine output < 0.3 mL/kg/h for > 24 h or anuria for
≥ 12 h OR
Initiation of renal replacement therapy
In patients < 18 y/o: a decline in estimated
glomerular filtration rate < 35 mL/min/1.73 m2
A classic way to divide AKI is by “prerenal,” “intrinsic,” and
“postrenal” or obstructive causes. However, prolonged prerenal
physiology may lead to intrinsic kidney ischemia and injury, such
as is seen with prolonged hepatorenal syndrome (HRS). Prolonged
obstruction can also lead to intrinsic kidney damage. The greatest
proportion of hospital acquired AKI is secondary to acute tubular
necrosis (ATN). A Spanish analysis of 748 cases of AKI in 13 tertiary
care hospital centers revealed that ATN accounted for 45% of all
AKI (Liaño et al., 1996). Alternatively, immune-mediated AKI from
glomerulonephritis or acute interstitial nephritis accounted for less
than 10% of cases (Table 87.3).
Prerenal Kidney Injury
Prerenal AKI is caused by new renal hypoperfusion that leads to a
fall in GFR typically with urinary sodium avidity, as noted by a
reduction in urinary sodium or the fractional excretion of sodium
(FeNa) in the urine. The hallmark of prerenal disease is its revers-
ibility after treatment of the underlying cause, with absence of
structural damage to the kidney if treatment promptly. Recovery
of renal function within 24 to 72 hours of volume resuscitation or
correction of renal hemodynamics helps to define prerenal AKI in
isolation.
Prerenal disease 21
Acute on chronic kidney disease (primarily 13
resulting from acute tubular necrosis or
prerenal)
Obstructive disease 10
Glomerulonephritis or vasculitis 4
Acute interstitial nephritis 2
Atheroembolic disease 1
The kidney can maintain normal renal blood flow and GFR with
systemic perfusion pressures as low as 55 to 60 mm Hg under normal
conditions (Walsh et al., 2013), although such autoregulation of
kidney blood flow may be compromised in CKD, making patients
with chronic disease more susceptible to AKI. In the setting of low
systemic blood pressure, renal angiotensin II, which has selective
vasoconstriction on the efferent (postglomerular) arteriole, and
vasodilatory prostaglandins, which dilate the afferent (preglomerular)
arteriole, play an important role in maintaining glomerular hydrostatic
pressure and GFR. Drugs that inhibit angiotensin, such as
angiotensin-converting enzyme (ACE) inhibitors and angiotensin
receptor blockers (ARBs), exert a vasodilatory effect on the efferent
arteriole and thus reduce glomerular pressure and filtration frac-
tion. Such agents are of great value in treatment of diabetic
nephropathy and congestive heart failure and help to reduce
proteinuria and convey renal protection in proteinuric kidney
disease. However, they may increase the risk of prerenal AKI as
well as hyperkalemia during periods of hypotension and hypo-
perfusion and are thus often held in the hospital setting after
identification of AKI. In addition, drugs that inhibit prostaglandins
such as nonsteroidal anti-inflammatory drugs (NSAIDs) can contribute
to the risk of prerenal and intrinsic AKI (Whelton, 1999).
Although prerenal AKI may often occur as a result of volume
depletion such as after hemorrhage or GI losses, it can also occur
in instances of total body overload. For example, congestive heart
failure and cirrhosis often occur with total body overload, edema
and/or ascites and yet are defined by prerenal AKI typically with
a low urine sodium concentration and low FeNa. Other causes of
prerenal AKI related to volume overload include third spacing related
to low albumin states, sepsis, and burn injury. These conditions can
create a reduction in “effective” circulating volume. Such prerenal
states are difficult to manage because administration of crystalloid
only worsens total body volume overload and third spacing. Treatment
is directed toward treating the underlying disease states in an
effort to optimize systemic hemodynamics and renal perfusion.
In heart failure, paradoxically, prerenal AKI may improve with diuresis
using agents such as loop diuretics. Improvement in right heart
function (Testani et al., 2010) and reduction in venous back pressure
on the kidneys (Bock and Gottlieb, 2010) may explain improved
kidney function with diuresis in heart failure.
The sympathetic nervous system and the renin-angiotensin cascade
are activated in prerenal AKI in the face of reduced blood flow.
In addition, hypotension is a powerful stimulus for the release of
antidiuretic hormone (ADH) from the posterior pituitary gland.
ADH release is triggered by baroceptor activation in response to low
systemic blood pressure, and it causes free water retention even in the
face of normal or low serum sodium concentrations (Bankir et al.,
2017). ADH binds to V2 receptors in the distal collecting tubule
of the kidney, leading to increased transcription and insertion of
aquaporin-2 water channels and free water absorption, often leading
to hyponatremia. The most common cause of hyponatremia in the
hospital setting is related to such “hypovolemic” hyponatremia, as

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 Chapter 87
opposed to other conditions such as the syndrome of inappropriate
ADH secretion (SIADH). It is important to assess volume status
through measurements of urine sodium, FeNa in the urine, and
other measures such as orthostatic blood pressure monitoring. In
hyponatremia related to volume depletion, urinary sodium, and
FeNa tend to be low (UNa < 20 mEq/L, FeNa < 1%). Serum sodium
levels correct quickly with volume repletion, typically with the use of
normal saline or other isotonic crystalloid therapy. Hyponatremia in
patients with volume overload but ineffective circulating volume is
also typically associated with low urine sodium. It is more difficult
to manage and often requires diuresis and free water restriction.
Tolvaptan, an arginine vasopressin receptor antagonist, blocks the
V2 receptor and leads to a rapid water diuresis in patients with a
high ADH response. It has been used in patients with SIADH and
in patients with congestive heart failure (Konstam et al., 2007). The
use of tolvaptan has been curtailed somewhat by the rapid correction
of serum sodium that can be seen, high cost of the agent, and a
“black box” warning against its use in patients with liver impairment,
leading to avoidance in cirrhotic patients.
HRS represents a unique and severe form of prerenal AKI in
patients with cirrhosis, acute hepatitis, or any acute form of hepatic
decompensation. HRS can be seen in the hospital setting, and the
risk increases with additional known risk factors, including bacterial
peritonitis and gastrointestinal bleeding (Wu et al., 2006). Dilation
of the splanchnic vasculature mediated by nitric oxide appears to
drive HRS pathophysiology (Iwakiri, 2007). Temporary improvement
in AKI associated with HRS has been associated with the use of
albumin, along with midodrine, an α1 agonist, which mediates
vasoconstriction, and octreotide, a somatostatin analogue that
decreases splanchnic blood flow (Angeli et al., 1999). Terlipressin,
a vasopressin analogue, has been shown to improve renal function
in HRS relative to midodrine and octreotide (Cavallin et al., 2015),
but it can cause intestinal ischemia and is currently not available in
the United States. The gold standard therapy for HRS is liver trans-
plantation, which can result in reversal of HRS pathophysiology and
recovery of kidney function (Gonwa et al., 1991). Prolonged HRS,
however, may result in permanent kidney injury, and the decision
to allocate a kidney allograft with a liver (simultaneous liver kidney
transplantation) is in part related to the duration of AKI related to
HRS. Recent guidelines for combined liver kidney allocation define
advanced AKI with an eGFR of 25 mL/min or less and/or dialysis
dependence for 6 consecutive weeks as an appropriate duration of
AKI to warrant a combined liver and kidney transplant rather than
liver transplant alone (Formica et al., 2016).
Postrenal Kidney Injury
Obstruction of the urinary tract can be a cause of AKI and can
be acute or chronic, complete or partial, and involve any area of
the lower urinary tract. Obstructive uropathy often occurs in the
outpatient setting, and patients often are seen in the clinic or hos-
pital with functional impairment (Gottlieb et al., 1997). Unilateral
obstruction may initially go unnoticed in terms of kidney function
and changes in SCr, although patients may gradually lose function
in a single kidney, rendering them with reduced kidney mass and
GFR. Chronic obstruction, whether partial or complete, may lead
to tubule-interstitial atrophy and fibrosis, with irreversible loss of
kidney function (Klahr, 1991). Patients may develop a distal renal
tubular acidosis, with hyperkalemia, mild sodium wasting, and
reduced serum bicarbonate levels (Batlle and Arruda, 2018). The
duration of obstruction predicts recovery of kidney function, and
ideally obstruction should be relieved as soon as possible and within
a week of onset at most (Better et al., 1973).
Bilateral obstruction presents dramatically, often with oligoanuria,
advanced kidney failure, and electrolyte perturbations. Common
causes of bilateral obstruction include congenital posterior urethral
valves in a younger population, bladder dysfunction including
neurogenic bladder, and prostatic disease in men. Oligoanuria
is a diagnostic sign that suggests complete obstruction and is an
uncommon feature of AKI overall. Other causes of anuric AKI
include shock, which is readily apparent upon presentation, severe
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Renal Insufficiency and Ischemic Nephropathy 1923
ATN, bilateral vascular occlusion, hemolytic-uremic syndrome, or
severe cases of crescentic glomerulonephritis such as anti-glomerular
basement membrane (GBM) disease.
A kidney ultrasound is a sensitive test for identifying hydronephro-
sis related to obstruction. However, there is a high false-positive rate,
which can vary depending upon the index of suspicion (Kamholtz
et al., 1989). The negative predictive value is high, although false-
negative tests may also be seen with early obstruction. In addition,
metastatic malignancies involving the ureters or retroperitoneal
fibrosis may mask hydronephrosis by restricting the ability of
the ureters to expand (Somerville et al., 1992). Further imaging
may be indicated, such as computed tomography (CT) scanning,
with noncontrast imaging if there is suspicion or concern for kidney
stones. A simple bladder scan may reveal a distended bladder resulting
from bladder outlet obstruction. Foley catheter placement relieves
obstruction related to bladder outlet obstruction and allows for
sampling of the urine for urinalysis (UA) and culture. Dilation at
the level of the ureteropelvic junction with minimal bladder filling is
more typically a result of a kidney stone or ureteropelvic malignancy.
One challenge that urologists commonly face after the relief of
obstructive uropathy is “postobstructive diuresis.” This usually
represents an appropriate response to prolonged obstruction with
elimination of excess fluid and sodium. However, there may be
dysregulation with inappropriate water loss resulting from tubular
injury or an osmotic effect created by excretion of elevated blood
urea nitrogen (Schlossberg and Vaughan, 1984). This is a condition
that typically lasts 24 to 72 hours and can result in dehydration and
hypernatremia, as well as electrolyte wasting. Generally it is recom-
mended to replace one-half of the urine output using hypotonic
solutions, such as one-half normal saline and to monitor electrolytes
closely during this interval. Intravenous (IV) replacement with free
water in dextrose may be appropriate in hypernatremic patients.
Intrinsic Kidney Injury
Acute Tubular Necrosis Resulting From Ischemic Injury
Overall, AKI may occur in 2% to 7% of hospitalized patients in
tertiary care centers, and the incidence in surgical or medical ICUs
may exceed 25% to 35%. The type of AKI in hospitalized patients
is ATN in the majority of cases (Myers and Moran, 1986; Uchino
et al., 2005). Hypoperfusion and ischemic injury most commonly
cause ATN in the hospitalized setting related to operative bleeding
and intraoperative hypotension, sepsis, and shock.
Contrast Nephropathy
Contrast-induced tubular injury (contrast nephropathy) is common
in the hospital setting. It is a type of ATN that is generally reversible
but can contribute to patient morbidity, mortality, and long-term
kidney impairment. Patients who develop contrast nephropathy are
more likely to be older with more comorbidities, including diabetes.
Despite general reversibility of AKI, one analysis found a higher
30-day mortality rate in patients with contrast nephropathy than those
without after controlling for other factors (Giacoppo et al., 2015).
Iodinated contrast, particularly with higher osmolarity, has been
shown to induce renal vasoconstriction and medullary ischemia and
also cause direct toxic effects at the proximal renal tubules (Persson
et al., 2005). Contrast nephropathy may occur with a low FeNa (<1%)
because of constrictive or renal tubular obstructive effects (Schwab
et al., 1989). An increase in SCr is generally observed at 24 to 48
hours after contrast exposure, and the AKI is typically nonoliguric.
Muddy brown casts may be seen on urinary sediment.
Risk factors for contrast nephropathy include older age, preexist-
ing CKD, diabetic nephropathy, congestive heart failure, hemo-
dynamic instability, high osmolar contrast (Lautin et al., 1991),
NSAID usage, higher volume of contrast, and volume depletion
before contrast exposure. Preventive measures should be used in
patients with CKD. NSAIDs, which can induce vasoconstriction,
should be avoided for 24 hours before contrast exposure. Generally,
diuretics are held before the procedure as well to avoid volume
1924 PART VIII Renal Physiology and Pathophysiology

depletion. The use of isotonic IV fluids before and after contrast
is a staple in the prevention of contrast nephropathy despite only
limited data on protection (Jurado-Román et al., 2015; Luo et al.,
2014). There are various strategies related to IV hydration, but in
general normal saline is given either in bolus form at 3 mL/kg for
an hour or 1 mL/kg for 6 to 12 hours before contrast exposure,
followed by 1 to 1.5 mL/kg for 4 to 12 hours after contrast exposure.
Sodium bicarbonate solutions may be used, although studies have
been mixed in terms of any additional benefit over normal saline.
Outcomes with the use of N-acetylcysteine have also been mixed.
One large randomized trial with a 2×2 design was unable to dem-
onstrate benefit with either sodium bicarbonate or N-acetylcysteine
compared to standard normal saline administration (Weisbord et al.,
2018). Iso-osmolar contrast agents (e.g., iodixanol) are preferred in
patients with preexisting kidney disease, with slight benefit seen in
one recent meta-analysis (Eng et al., 2016). Limiting contrast volume
to the lowest amount possible is recommended in high risk patients,
and diagnostic angiography may often be performed with minimal
contrast (10–20 mL).
One important differential diagnosis in patients with AKI after
arterial instrumentation is atheroembolic kidney injury. Athero-
embolic disease should be suspected in patients who have other
evidence of embolic injury such as lesions in fingers or toes (e.g.,
“blue toe syndrome”) or symptoms of gut ischemia such as pain,
nausea, and vomiting. Patients may develop transient eosinophilia
(Scolari et al., 2007) and hypocomplementemia (Lye et al., 1993).
The natural history is different from contrast nephropathy, in that
kidney injury may be gradual and unremitting, exhibiting a stuttering
pattern and progressing to advanced kidney failure. On biopsy,
needle-shaped clefts from cholesterol emboli that dissolve during
fixation may be seen. These clefts are often surrounded by inflam-
matory cells, including eosinophils.
Pigment-Related Kidney Injury
function. As stated earlier, aggressive volume resuscitation may prevent
or curtail kidney injury.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is a condition seen in the presence of
high tumor burden that may cause AKI in part because of precipitation
of uric acid crystals in renal tubules causing urate nephropathy. TLS
is most commonly seen after treatment for high-grade lymphomas
and leukemias but has also been reported in cases of solid tumors,
including renal cell and transitional cell carcinomas (Lin et al., 2007;
Norberg et al., 2014). Prophylactic use of agents such as rasburicase, a
urate-oxidase enzyme that converts uric acid to allantoin, has greatly
reduced the incidence of urate nephropathy associated with TLS.
Hyperphosphatemia with subsequent hypocalcemia and calcium-
phosphate deposition remain features of TLS and may contribute
to AKI by causing nephrocalcinosis. Renal replacement therapy may
be required if the calcium-phosphorus product (Ca × Phos) exceeds
70 mg2/dL2 (Coiffier et al., 2008; Howard et al., 2011). Potassium levels
may also become critically high. Cardiac monitoring and frequent
assessment of electrolytes are essential in the management of TLS.
Drug Toxicity as a Cause of Acute Kidney Injury
Nephrotoxic pharmacologic agents are a common source of kidney
injury through direct toxic effects or by causing inflammation (intersti-
tial nephritis). Drugs and agents known to cause direct tubular toxicity
are shown in Table 87.4. Some, like aminoglycosides, amphotericin B,
cisplatin, and ifosfamide, cause renal proximal tubular toxicity, which
is cumulative with repeated dosing. Patients with proximal tubular
toxicity may initially have a “Fanconi syndrome,” with evidence
of proximal tubular wasting, including acidosis with an alkaline
urine (proximal renal tubular acidosis), phosphorus wasting, and
renal glycosuria.

Pigment injury related to hemoglobin or myoglobin may be

suspected in the appropriate clinical situation, such as severe TABLE 87.4 Drugs/Agents Known to Cause Direct
hemolysis or muscle breakdown related to trauma, toxicity, or Renal Tubular and Interstitial Toxicity
surgical injury, causing rhabdomyolysis. Muscle breakdown is
associated with elevation in creatine phosphokinase (CPK) in the Antibacterial/antifungal/antiviral
bloodstream along with high levels of phosphorus, potassium, and Aminoglycosides
uric acid related to cellular breakdown. Metabolic acidosis is common
Amphotericin B
and hypocalcemia can be severe related to cellular entry, and phos-
phorus binding is often seen. Myoglobin may cause positive testing Polymyxin, colistin
for blood by urine dipstick testing in the absence of true hematuria. Vancomycin
Myoglobinuria may also be seen early in the course and can contribute Acyclovir
to the production of red-brown–tinged urine. The risk of AKI is Foscarnet
related to the severity of muscle injury as well as volume status. Cidofovir
Early aggressive fluid resuscitation may prevent or limit the extent Indinavir
of kidney injury after muscle injury. Forced alkaline diuresis with Ritonavir
bicarbonate based therapy is controversial and requires close monitor- Tenofovir
ing of arterial pH and serum calcium levels every 2 hours ideally in Pentamidine
an ICU setting. Bicarbonate therapy may worsen hypocalcemia and
Iodinated contrast
promote calcium-phosphorus precipitation.
In urology, two specific clinical circumstances have been identified Nonsteroidal anti-inflammatory drugs
in association with rhabdomyolysis. The first relates to protracted Chemotherapeutic agents
exaggerated lithotomy positioning, as used in urethral stricture surgery Cisplatin
(Anema et al., 2000; Vijay et al., 2011) and robotic-assisted radical Carboplatin
prostatectomy (Keene et al., 2010). Gluteal muscles are often affected, Ifosfamide
and long exposure to lithotomy positioning greater than 5 hours Gemcitabine
appears to convey greater risk for muscle injury. Attention to padding, Methotrexate
positioning, and any maneuver that can reduce the duration of Immunosuppressive/immunomodulating therapy
exaggerated positioning help prevent this complication. A second Cyclosporine
type of surgery that has been associated with rhabdomyolysis is
Tacrolimus
laparoscopic nephrectomy, including after living kidney donor surgery
(Deane et al., 2008; Glassman et al., 2007; Kuang et al., 2002). Intravenous immunoglobulin
Prolonged lateral decubitus positioning appears to be a risk factor Psychotropics
for downside iliopsoas muscle injury, and risk factors also include Lithium
high body mass index. Unusually severe muscle pain early after Mannitol
surgery along with darkened red-brown urine should prompt an Zoledronic acid
early evaluation with blood CPK levels and measurement of kidney

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 Chapter 87
Some examples of agents recently identified as causing nephrotoxic-
ity include a number of chemotherapeutic agents that have shown
great promise in treating and stabilizing various metastatic malignan-
cies. For example, tyrosine kinase inhibitors, including sorafenib
and sunitinib, inhibit vascular endothelial growth factor (VEGF),
and are known to cause hypertension, proteinuria (typically subne-
phrotic), and AKI in certain patients. Inhibition of VEGF has been
shown to predispose animal models to thrombotic microangiopathy
(TMA) (Eremina et al., 2008), and TMA has been a finding on kidney
biopsy in patients with tyrosine kinase inhibitor–related kidney injury
(Bollée et al., 2009). Tyrosine kinase inhibitors are approved for
the treatment of metastatic renal cell carcinoma, and urologists
involved with treatment should be aware of the potential neph-
rotoxicity associated with such agents.
Another newer group of chemotherapeutic agents that may
induce AKI are the so-called checkpoint inhibitors, which are
immunomodulatory agents designed to enhance the immune
response against various malignancies. One class, known as pro-
grammed cell death receptor-1 (PD-1) inhibitors, includes medications
such as nivolumab and pembrolizumab. These agents are used in
metastatic renal cell and urothelial carcinomas, along with other
malignancies. PD-1 inhibitors may cause immune mediated side effects
including skin rash, colitis, hepatotoxicity, and pneumonitis. They
are also known to cause AKI with acute interstitial nephritis (AIN)
and occasionally immune complex glomerular disease manifesting
with heavy proteinuria (Cortazar et al., 2016; Izzedine et al., 2017).
AKI associated with these agents may require cessation of drug
therapy and/or corticosteroid treatment.
Recent epidemiologic data have also linked proton pump inhibitors
(PPIs) to acute and chronic kidney disease. PPIs have long been
known to cause AIN in a small percentage of patients (Geevasinga
et al., 2006). More recently, studies of large patient populations have
linked PPIs to CKD and ESRD (Lazarus et al., 2016; Xie et al., 2016).
Duration of PPI usage appeared to correlate with risk. It is not entirely
clear whether such studies are flawed by residual confounding, but
there may be incidences of subacute AIN that go undetected in some
patients. It appears prudent to limit PPI usage in patients who can
otherwise be managed with dietary changes and/or the use of
histamine-2 receptor antagonists. Alternatively, patients with a history
of peptic ulcer or esophageal ulceration would likely retain benefit
that exceeds risk with maintenance PPI therapy.
In general, interstitial nephritis is common in the hospital
setting and can occur acutely (AIN), often related to antibiotic
therapy, or chronically, often related to the long-term use of
NSAIDs. Table 87.5 lists common drugs associated with AIN. The
acute presentation is classically described as including a rash, fever,
and eosinophilia. However, a report on AIN in 128 patients described
a rash in only 15%, fever in 27%, and eosinophilia in only 23%,
and these findings were less common in AIN related to NSAIDs or
PPIs (Baker and Pusey, 2004). Urinary eosinophils are commonly
measured but are neither sensitive nor specific for AIN (Muriithi
et al., 2013). The most common urinary findings are pyuria and
hematuria, although a bland urine sediment does not exclude AIN.
Thus the diagnosis of AIN requires a high index of suspicion. Sterile
pyuria and white cell casts on urine sediment support the diagnosis,
and confirmation is made by kidney biopsy. A Spanish registry analysis
found AIN in 12.9% of those biopsied for AKI, and the prevalence
of AIN appeared to be increasing in the more recent era, particularly
in elderly patients (Goicoechea et al., 2013).
Non–drug-related AIN may be seen in various infections and
rheumatologic diseases, including systemic lupus, sarcoidosis, and
Sjögren syndrome. Another emerging disease entity that may cause
AIN is so-called IgG-4 related disease, characterized by an inflam-
matory infiltration predominantly containing IgG-4–positive
plasma cells. Manifestations may include pancreatitis, lymph-
adenopathy, salivary or orbital involvement, cholangitis, and involve-
ment of other organ systems. Patients may have AKI related to
retroperitoneal fibrosis, which can mimic the appearance of a
tumor and cause obstructive uropathy. IgG-4–related disease may
also cause intrinsic kidney injury with a dense AIN displaying a
nodular pattern of inflammation on biopsy that can mimic tumor
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Renal Insufficiency and Ischemic Nephropathy 1925
TABLE 87.5 Drugs Known to Cause Acute
Interstitial Nephritis
Antibiotics
Penicillins
Cephalosporins
Sulfonamides
Ciprofloxacin
Rifampin
Nonsteroidal anti-inflammatory drugs
Including cyclooxygenase-2 inhibitors
Proton pump inhibitors
Checkpoint inhibitor chemotherapeutic agents
Allopurinol
Loop and thiazide diuretics
Anticonvulsants
Phenytoin
Carbamazepine
Phenobarbital
Indinavir
Cimetidine
Mesalamine
infiltration (Saeki et al., 2010). Patients with kidney involvement
often have extrarenal manifestations. Serum IgG-4 levels are elevated
in the majority of patients, and serum complement levels are often
low, suggesting complement activation. Treatment with corticosteroid
therapy and other immunosuppressive agents has been proven effective
(Khosroshahi et al., 2015).
Renal Vein Thrombosis
Renal vein thrombosis is a condition occasionally seen in nephrotic
patients and patients with malignancy. Renal vein thrombosis is
most commonly associated with membranous glomerulonephritis
and is more common with glomerular disease associated with
malignancy. Loss of anticoagulation factors such as anti-thrombin
III and an increase in procoagulant factors predispose nephrotic
patients to venous clotting (Loscalzo, 2013). The classic clinical
findings include flank pain (usually unilateral), microscopic or
gross hematuria, elevated lactate dehydrogenase (LDH), and an
enlarged, swollen kidney on imaging. Severe AKI is seen in cases
of bilateral acute renal vein thrombosis.
Urologists may see renal vein thrombosis associated with renal
cell carcinoma with renal vein involvement or external compression
or postoperative thrombosis related to manipulation of the renal
circulation (partial nephrectomy or renal transplantation). Catheter-
directed local thrombolytic therapy has been used with success in
cases of AKI (Kim et al., 2006) and in renal transplantation (Fulton
et al., 2011). In cases of renal malignancy, nephrectomy with removal
of the tumor thrombus is usually the therapy of choice.
Clinical Approach to the Differential Diagnosis
of Acute Kidney Injury
Distinguishing among prerenal, intrinsic, and postrenal causes
of AKI should be feasible with appropriate attention to the history,
physical, laboratory, and imaging results. A thorough history and
physical examination to assess volume status, cardiovascular hemo-
dynamics, potential nephrotoxic insults, and evidence of systemic
disease should be undertaken in patients with AKI. All interventions
and drug therapies surrounding an AKI event should be outlined
against the timeline of changes in kidney function. Risk factors
associated with AKI such as advanced age, heart failure, liver failure,
baseline CKD, diabetes, and recent surgery should be identified.
Exposures including radiocontrast and potential inciting pharma-
cologic agents may offer clues as to the cause. In perioperative AKI,
1926 PART VIII Renal Physiology and Pathophysiology
the duration of the procedure, blood loss, hemodynamic instability,
integrity of the urinary tract, and intraoperative drug treatment are
critical to review.
Vital signs and hemodynamic parameters should be assessed,
including the measurement of orthostatic hypotension, correctly
performed, which may identify volume depletion and prerenal AKI.
Hypertension and third spacing of volume identify patients who
would benefit from diuresis or possible renal replacement therapy.
Daily weights and accurate intake and output are essential in the
management of AKI in hospitalized patients. Central venous pressure
monitoring may also be beneficial, particularly after major surgery
and in an ICU setting.
Examination of the UA and urinary studies is fundamental to
the evaluation of the patient with AKI (Perazella and Parikh, 2009).
A basic UA may distinguish between various causes of AKI. A urine
sediment should also be examined. The nephrologist may assist in
identifying cells and casts after urine cytospin because relying on
automated laboratory reporting of urinary casts from UA samples
is unreliable (Cavanaugh and Perazella, 2018). Heavy proteinuria,
hematuria, and red cell casts on urinary sediment are classic findings
of acute glomerulonephritis, which may require a prompt biopsy
and institution of immunosuppressive therapy. Proteinuria can further
be quantified by a spot urinary protein to creatinine or albumin to
creatinine ratio or by 24-hour urine collection. Nephrotic range
proteinuria (>3.5 g protein/24 h) is highly suggestive of glomerular
disease and typically prompts a biopsy, unless there is a high suspicion
for diabetic nephropathy or a contraindication to biopsy. Alternatively
and more commonly in the hospital setting, a bland urine is noted
on UA, and “muddy brown” casts may be seen on urine microscopy,
helping to confirm the diagnosis of ATN. Sterile pyuria and hematuria
in association with white blood cell casts on urine microscopy is
suggestive of AIN and should prompt a careful review of medication
exposure and consideration for kidney biopsy and/or treatment.
Tuberculosis, chlamydia, ureaplasma, and mycoplasma are infectious
agents that may also cause sterile pyuria.
The urine sodium and FeNa are helpful in delineating prerenal
physiology in AKI. Typically, a urine sodium under 20 mEq/L and
a FeNa under 1% are markers of a prerenal state and are usually
associated with a bland UA (Table 87.6). The FeNa is superior to
measurement of urinary sodium alone because it does not vary by
urinary volume. Low sodium and FeNa may also be seen in shock,
heart failure, HRS, contrast nephropathy, rhabdomyolysis, or acute
GN. One caveat to urinary sodium analysis is that patients on diuretic
therapy may have higher values despite volume depletion. An alterna-
tive measurement that may be undertaken is the fractional excretion
of urea (FeUrea) (see Table 87.6). FeUrea is typically less than 35%
in prerenal disease and 50% to 65% in ATN (Carvounis et al., 2002;
Pépin et al., 2007). Renal reabsorption of urea relies on intact proximal
tubular function and may not be accurate in the face of hyperglycemia
or other causes of osmotic diuresis.
Imaging is typically incorporated in the evaluation of AKI. As
mentioned earlier, renal ultrasound is instrumental in identifying
most cases of obstructive uropathy and can also identify chronic
changes that may be seen after prolonged kidney injury and CKD.
Total kidney size reduction and loss of cortical echogenicity correlate
with tubular atrophy and interstitial fibrosis and may guide interven-
tion. For example, a chronically obstructed kidney that is small and
atrophied may not recover significant function after ureteral stenting
or surgical intervention. CT imaging with low radiation dose is a
highly sensitive test to identify or confirm stone disease and can be
used in the absence of IV contrast in patients with AKI. CT has
TABLE 87.6 Formulas for the Fractional Excretion of
Sodium and Urea
FeNa, % = UNa × SCr / SNa × UCr × 100
FeUrea, % = Urea × SCr / SBUN × UCr × 100
B, Blood; BUN, blood urea nitrogen; Cr, creatinine; Fe, fractional excretion;
Na, sodium; U, urine.
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improved sensitivity in identifying kidney stones relative to plain
abdominal radiography and avoids the contrast required for IV
urography (Pfister et al., 2003).
Management of Acute Kidney Injury
The management of AKI focuses on reversing any prerenal condi-
tion, restoring and maintaining euvolemia, and eliminating
nephrotoxic drugs when clinically appropriate. Early consultation
with a nephrologist improves the outcome of AKI in some studies
of critically ill patients (Mehta et al., 2002; Ponce et al., 2011). During
the initial evaluation, it is imperative to search for reversible causes
such as volume depletion, obstruction, and vascular occlusion. A
trial of parenteral hydration with isotonic fluids may correct AKI
secondary to prerenal causes (Prowle et al., 2014). Thereafter fluid
status should be monitored vigilantly to maintain euvolemia. In
patients with oliguria, special attention must be provided to avoid
excessive hydration and volume overload, which could precipitate
the need for renal replacement therapy.
Diuretic therapy is commonly used in patients with AKI and
volume overload. Response to diuretic therapy may depend on
the severity of kidney injury, but diuretic therapy used appropriately
neither hinders nor hastens recovery from AKI. Response to diuretic
therapy is a favorable prognostic sign in AKI (Cosentino, 1995).
When dosing loop diuretics such as furosemide, a response to an
IV bolus can be assessed within 60 minutes of administration. If
there is no significant augmentation in urine output, the dose should
be increased to find the threshold dose for a given patient. If a dose
response is established, IV furosemide may be dosed every 6 to 8
hours at the amount required to elicit a diuretic response. Alternatively,
a continuous infusion may be administered. For example, if a patient
responds to 60 mg of IV furosemide bolus, he or she may be converted
to a 10 mg/h continuous infusion. Continuous infusions increase
the area under the curve of therapeutic efficacy, allowing for more
consistent dosing. In one comparison study of heart failure patients
there was a trend for increased dosage requirement with bolus dosing
compared with continuous therapy, and there was a trend for fewer
complications with continuous infusion as well (Felker et al., 2011).
Bumetanide and torsemide are alternative loop diuretic agents
and have the advantage of increased potency and improved oral
bioavailability compared with furosemide. Torsemide also exhibits
a longer duration of action compared with furosemide. Comparison
of dosing of loop diuretics is shown in Table 87.7. Ethacrynic acid
is occasionally used when patients have exhibited drug allergies to
the sulfonamide component of loop diuretics. However, ethacrynic
acid may be more ototoxic than the sulfonamide diuretics at high
doses, and it is difficult to administer intravenously because of the
relative insolubility. Patients who fail to respond to high doses of
loop diuretics may respond to the addition of a low dose of thiazide
diuretic, such as metolazone 2.5 to 5 mg/d. Distal sodium absorp-
tion may be augmented, particularly in patients on chronic loop
diuretic therapy, and an impressive increase in diuresis may be
observed by combining loop and thiazide diuretic therapy. Close
monitoring of electrolytes is essential with such dual diuretic therapy
because hypokalemia and metabolic alkalosis are common side
effects. If there is minimal response to high-dose loop diuretic therapy
combined with a thiazide in an oliguric patient, then dialysis or
ultrafiltration therapy should be considered.
Other agents such as low-dose dopamine and fenoldopam
have not been shown to improve outcomes in AKI. One randomized
trial assigned 328 critically ill patients to low-dose dopamine (2 μg/
kg/min) versus placebo. There were no differences in renal recovery,
need for dialysis, hospital stay, or mortality between groups (Bellomo
et al., 2000). Even “renal” dose dopamine may precipitate cardiac
arrhythmias and should be used with caution. A large randomized
trial using fenoldopam, a selective dopamine receptor-1 agonist,
similarly did not show any improvement in AKI compared with
placebo (Bove et al., 2014). The study included 667 cardiac surgical
patients with early AKI who were randomized to fenoldopam versus
placebo. There were no differences in rates of dialysis or mortality,
and patients on fenoldopam had a higher rate of hypotension.
 Chapter 87
TABLE 87.7 Comparison of Dosing, Bioavailability, and Half-Life of Various Loop Diuretics
DRUG BIOAVAILABILITY EQUIVALENT DOSING
Furosemide oral 50% with variability 40 mg
Furosemide IV 100% 20 mg
Bumetanide oral 80%–90% 1 mg
Bumetanide IV 100% 1 mg
Torsemide oral 80%–90% 20 mg
Torsemide IV 100% 20 mg
Ethacrynic acid oral 100% 50 mg
Ethacrynic acid IV 100% 50 mg
IV, Intravenous.
Electrolyte abnormalities are common after AKI, and hyper-
kalemia is the most common and dangerous electrolyte abnormality
in the AKI setting (Fordjour et al., 2014; Hoorn et al., 2013). If
serum potassium levels exceed 6 mEq/L, an electrocardiogram (ECG)
should be obtained and evaluated. Peaked T waves may be observed
with broadening of the PR interval, which may lead to QRS broadening
and the potential for maturation into a sine waveform. The goals
for treatment of hyperkalemia in the face of ECG changes include
stabilization of the cardiac conduction system, shifting potassium
intracellularly, and eventual elimination of excess potassium from
the body. Stabilizing the cardiac membrane may be achieved by
immediate administration of calcium salts. Shifting potassium into
cells may be accomplished by insulin therapy (usually with glucose
to prevent hypoglycemia), sodium bicarbonate, or β2-adrenergic
agonist therapy. A cationic binding resin such as sodium polystyrene
sulfonate (SPS) may be used to augment potassium excretion in the
gut. SPS appears to have modest efficacy (Hagan et al., 2016). There
are reported cases of intestinal necrosis with SPS, with or without
the concomitant use of sorbitol (Goutorbe et al., 2011). Its use should
be avoided in patients with postoperative ileus, intestinal obstruction,
or active colitis.
Two newer agents have been approved that augment the excre-
tion of potassium and are the first agents available since SPS was
approved for use in 1958. Patiromer is a nonabsorbed polymer
that exchanges potassium for calcium in the gastrointestinal tract.
It has efficacy in dropping potassium levels over days by approximately
0.75 mEq/L in patients with CKD, with minimal adverse effects
including constipation and hypomagnesemia (Bushinsky et al., 2015;
Weir et al., 2015). It is taken in powder form mixed with water and
must be separated from other oral medications. However, because
of its delayed onset of action, patiromer is not indicated for the
treatment of severe acute hyperkalemia. A second agent, sodium
zirconium cyclosilicate (ZSC), was approved for use in the United
States in 2018. It is also a nonabsorbed inorganic cation exchange
agent that works in the gastrointestinal tract by exchanging potas-
sium for hydrogen and sodium. It also can lower potassium over
48 hours and is not approved for emergent treatment of severe
hyperkalemia but holds promise as an agent with minimal adverse
effects (Hoy, 2018).
Despite medical intervention, dialysis therapy may be required
for patients with severe, persistent AKI. The indications for initiation
of dialysis therapy include volume overload, severe hyperkalemia,
severe metabolic acidosis, pericarditis, selected poisonings and drug
overdoses, and uremic symptomatology. There are disparate outcomes
from studies examining the utility of starting dialysis earlier in the
course of AKI in the ICU setting. One study in patients with septic
shock and advanced failure by RIFLE criteria (see Table 87.1) were
randomized to early renal replacement therapy within 12 hours
versus delaying more than 48 hours if there was no urgent indication
for dialysis. Mortality rates were similar at 90 days between groups,
and dialysis was avoided altogether in 38% of the delayed group
(Barbar et al., 2018). A theoretical concern exists that the dialysis
treatment may have a detrimental impact on recovery of AKI. A drop
in urine output is often seen during and after intermittent dialysis
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Renal Insufficiency and Ischemic Nephropathy 1927
DURATION OF ACTIVITY DOSING INTERVAL
6h Daily to q6h
6h Daily to q6h
6h Daily to q12h
6h Daily to q12h
8–12 h Daily to q12h
8–12 h Daily to q12h
6h Daily to q8h
6h Daily to q8h
therapy, and hypotension often occurs during therapy. There may
be a greater risk for ischemic injury during dialysis treatment, and
efforts should be made to avoid exacerbating hypotension and
hemodynamic instability. Slower, continuous dialysis modalities are
often used in the ICU setting, particularly in hypotensive patients
or in patients dependent on pharmacologic vasopressor support.
KEY POINTS: ACUTE KIDNEY INJURY
• AKI is defined by an acute rise in SCr and/or an acute
decline in urine output. This abrupt decline in kidney
function occurs over hours to days and results in the
accumulation of byproducts of metabolism and the
dysregulation of electrolyte homeostasis, acid/base, and
volume status.
• A classic way to divide AKI is by “prerenal,” “intrinsic,”
and “postrenal” or obstructive causes. The hallmark of
prerenal disease is its reversibility after treatment of the
underlying cause, with absence of structural damage to the
kidney if treatment promptly.
• Prolonged prerenal physiology may lead to intrinsic
kidney ischemia and injury. The greatest proportion of
hospital-acquired AKI is secondary to ATN.
• Nephrotoxic pharmacologic agents are a common source
of kidney injury through direct toxic effects or by causing
inflammation (interstitial nephritis).
• Examination of the UA and urinary studies, including
measurement of electrolytes and protein concentration, are
fundamental to the evaluation of the patient with AKI.
CHRONIC KIDNEY DISEASE
CKD is defined as kidney impairment sustained beyond 3 months
with a reduction in GFR, structural abnormalities in the kidneys,
and/or proteinuria (often defined specifically by albuminuria).
As described earlier, estimations in GFR may be derived from the
MDRD and CKD-EPI equations and should be used when kidney
function and SCr are at steady state. The 2012 KDIGO guidelines
included albuminuria in the definition of CKD to emphasize the
prognostic implications related to abnormal urinary protein excretion.
For example, a patient with diabetic nephropathy who has a GFR
of 60 mL/min/1.73 m2 and is excreting 3 g/day of albuminuria is
more likely to progress to ESRD than a patient with a GFR of 45 mL/
min/1.73 m2 related to prior kidney injury and no albuminuria.
The interplay between albuminuria and GFR as outlined by the 2012
KDIGO guidelines is shown in Fig. 87.1.
The presence of CKD has implications in terms of greater risk
for AKI, and recognizing that CKD is a risk factor for AKI should
lead to measures taken to prevent AKI in the hospital or office setting.
Precautions should be taken in CKD patients to avoid nephrotoxic
drugs, avoid or limit iodinated contrast exposure, and to dose
medications appropriately with adjustment for level of kidney func-
tion. Conversely, it is important to recognize that AKI often leads
1928 PART VIII Renal Physiology and Pathophysiology

CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO

CKD is defined as abnormalities of kidney structure or function, present for more than 3 months, with
implications for health, and CKD is classified based on cause, GFR category, and albuminuria category (CGA).
Prognosis of CKD by GFR and albuminuria category

Persistent albuminuria categories

description and range

Prognosis of CKD by GFR A1 A2 A3

and albuminuria categories:
KDIGO 2012 Normal to mildly Moderately Severely
increased increased increased
<30 mg/g 30–300 mg/g >300 mg/g
<3 mg/mmol 3–30 mg/mmol >30 mg/mmol

G1 Normal or high ≥90

GFR categories (mL/min/1.73 m2)

G2 Mildly decreased 60–89

description and range

Mildly to moderately
G3a 45–59
decreased
Moderately to
G3b 30–44
severely decreased

G4 Severely decreased 15–29

G5 Kidney failure <15

Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk;
Orange: high risk; Red: very high risk.

Fig. 87.1. Chronic kidney disease (CKD) risk for progression based on Kidney Disease: Improving Global
Outcomes (KDIGO) 2013 classification of glomerular filtration rate (GFR) and albuminuria. (From KDIGO
Committee: KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney
Disease. Kidney Int Suppl 3[1]:2012.)

to CKD that will require monitoring after renal recovery (Lewington
et al., 2013; Pannu, 2013).
Deficits in nephron number may predispose to progressive kidney
disease and hypertension. Nephron number averages approximately
600,000 ± 200,000 per normal kidney. Loss of kidney mass through
ablation or partial nephrectomy may trigger progressive glomerular
injury in the remnant kidney. The injury is associated with hyperfiltra-
tion, glomerular hypertrophy, and systemic hypertension (Brenner
and Mackenzie, 1997). Proteinuria appears to correlate with degree
of nephron loss and time from the loss (Novick et al., 1991). Reduced
birth weight or solitary kidney from birth may similarly lead to
kidney injury over time because of low nephron number (Bhathena
et al., 1985; Hughson et al., 2003; Lopes and Port, 1995). In general,
monitoring of kidney function, albuminuria, and blood pressure
should be undertaken after loss of kidney mass. This includes living
kidney donors, although the typical natural history in kidney donors
is an improvement in GFR and lack of proteinuria in the years after
donation (Fehrman-Ekholm et al., 2011). The development of
albuminuria should lead to targeted therapy in patients with reduced
renal mass. The use of ACE inhibitors or ARBs appears to be protective
and can reduce proteinuria in a “remnant kidney” model (NDT 9:
131, 1994), (Novick and Schreiber, 1995).
The causes of progressive CKD parallel the most common causes
of ESRD. Table 87.8 lists the incident causes of ESRD from the US
Renal Data System (USRDS, 2013). Diabetes mellitus and hyperten-
sion account for the largest percentage of cases (63%) followed by
glomerular diseases (14%). A caveat to such reporting is that many
patients go without kidney biopsy and lack a definitive cause of
ESRD. Genetic disease or other occult kidney diseases may com-
monly go undiagnosed or unrecognized, resulting in the labeling
of “hypertensive” kidney disease in the absence of a definitive
TABLE 87.8 Incidence of Reported Causes of
End-Stage Renal Disease
DIAGNOSIS PERCENTAGE
Diabetes mellitus 38
Hypertension 25
Glomerulonephritis 14
Cystic kidney disease 5
Urologic disease 2
Other/missing/unknown 15
diagnosis. This is particularly common in the black community, in
which the diagnosis of hypertensive kidney failure is increasingly
being recognized to correlate with genetic risk of CKD.
Accordingly, special mention should be made to the identifica-
tion of genetic risk for CKD in a subset of black patients, which
relates to variants in apolipoprotein genetics. Polymorphisms
in the genes that encode apolipoprotein L1 (APOL1) are found
in patients of sub-Saharan African ancestry, and two separate vari-
ants have been identified: G1 and G2. These gene variants appear
to convey protection against African sleeping sickness caused by
Trypanosoma parasitic infection, whether inherited as a single or dual
variant (Vanhamme et al., 2003). Inheritance of two APOL1 gene
variants of any combination (G1/G1, G1/G2, or G2/G2) appears to
greatly increase the risk of CKD related to hypertensive kidney
disease, focal sclerosis, diabetic nephropathy, lupus nephritis, and
human immunodeficiency virus associated nephropathy (HIVAN) in
patients of African descent (Cohen et al., 2017; Larsen et al., 2013;

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 Chapter 87
Parsa et al., 2013). Two gene variants are found in approximately
13% of the black population (Friedman et al., 2011) and explain to
a large extent the increased risk of CKD and ESRD seen in blacks
in the United States (Freedman et al., 2018). Although APOL1 is a
circulating protein, it has also been localized to the podocyte, proximal
tubule, and vasculature of the kidney (Madhavan et al., 2011). The
idea that the integrity of the kidney may be affected by APOL1 gene
variation is suggested by studies in kidney transplantation, which
demonstrate reduced allograft survival when kidneys came from
deceased donors with high-risk gene variants (Freedman et al., 2016).
The long-recognized risk of inferior transplant outcomes with kidneys
from black deceased donors also appears to be entirely explained by
the disproportionate risk related to the smaller percentage of donors
with two APOL1 gene variants (Julian et al., 2017).
Glomerulonephritis
Glomerulonephritis is evolving in terms of accuracy of diagnosis
and identification of cause. The diagnosis of focal segmental glo-
merulosclerosis (FSGS) may represent a primary immune process
or a secondary pattern of injury. Secondary forms of FSGS may
develop for many reasons, including loss of renal mass such as after
partial or total nephrectomy, genetic risk such as APOL1 gene variants
in blacks, a consequence of morbid obesity (Goumenos et al., 2009),
or as a consequence of other prior drug or immune-mediated injury.
In addition, primary FSGS may be familial rather than immune
mediated. Familial FSGS is suggested by a positive family history of
disease and an onset of nephrotic syndrome at a very young age
(Sadowski et al., 2015). Identifying such secondary or genetic forms
of FSGS is critical because these patients would not be expected to
benefit from immunotherapy with medications such as corticosteroids
or calcineurin inhibitors. Diffuse podocyte effacement on electron
microscopic biopsy in the absence of genetic association may
alternatively point to a primary FSGS for which immunotherapy
would potentially convey benefit (De Vriese et al., 2018). Such primary
FSGS patients are more likely to be young adults, Caucasian, and
have heavy proteinuria in the nephrotic range.
Nephrotic syndrome is a clinical presentation that may be caused
by FSGS or other primary or secondary glomerular diseases. It is
characterized clinically by a urinary protein excretion of greater than
3.5 g/day, hypoalbuminemia, and peripheral edema. Primary diseases
that may cause nephrotic syndrome include FSGS; minimal change
disease, which is especially common in children; membranous
nephropathy; and certain types of membranoproliferative diseases.
Secondary nephrotic syndrome may be seen in secondary FSGS related
to infection such as HIV infection, lupus-associated membranous
nephropathy, hereditary diseases, and amyloid or light chain deposi-
tion caused by monoclonal proteins.
Abnormal monoclonal proteins in the absence of defined
myeloma or amyloidosis may be seen with variable nephrotic
and nephritic presentations in the kidneys and has been termed
monoclonal gammopathy of renal significance (MGRS) (Leung et al.,
2012). Accordingly, testing for monoclonal proteins as a potential
cause of glomerular disease is essential, with risk for MGRS increasing
with age. Serum and urine electrophoresis along with measurements
of free light chains kappa and lambda may detect low level mono-
clonal proteins that may be involved in renal glomerular or tubular
pathology. Treatment with agents used to treat myeloma may be
indicated even in the absence of other organ disease if renal pathology
is present (Sethi and Rajkumar, 2013).
Membranous nephropathy is one of the most common causes
of nephrotic syndrome in adults. The diagnosis and treatment of
membranous nephropathy have improved because of the discovery
of a target antibody against a podocyte protein that is positive
in 70% to 80% of idiopathic membranous disease cases. The
antibody targets the M-type phospholipase A2 receptor (PLA2R),
a transmembrane receptor that is highly expressed in glomerular
podocytes (Beck et al., 2009). This antibody may be identified in
the glomerulus on kidney biopsy by immunofluorescence or immu-
nohistochemistry staining and may be detected in the circulation
by ELISA or other methods. Monitoring of PLA2R Ab titers is useful
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Renal Insufficiency and Ischemic Nephropathy 1929
to guide treatment of membranous nephropathy because clearance
of the antibody often precedes a reduction in proteinuria and is
predictive of remission (Beck et al., 2011). Reemergence of antibodies
may also predict disease recurrence (Ruggenenti et al., 2015). Other
antibodies have been identified that are present in a minority of
membranous cases, including one targeting thrombospondin type-1
domain-containing 7A (THSD7A), another podocyte transmembrane
protein. THSD7A antibodies have been detected in 10% of patients
with membranous who lack antibodies to PLA2R (Ren et al., 2018).
Some cases of membranous nephropathy with antibodies against
THSD7A have been associated with malignancy, and clearance of
the antibody leading to remission of glomerular disease has been
described with the use of chemotherapy targeting the malignancy
directly (Hoxha et al., 2016).
End-Stage Renal Disease Demographics
and Treatment Options
There continues to be a steady growth of ESRD patients on renal
replacement therapies (RRTs) throughout the world. In the United
States the incidence rate for ESRD in 2016 was 373 new cases per
million people (US Renal Data System, 2018). The prevalence of
ESRD patients has continued to increase since 2006, and the number
of patients with ESRD in the United States in 2016 was approximately
726,000. The number of kidney transplants performed annually in
the United States has increased slightly and in 2016 was just more
than 20,000, with approximately one-third of transplants coming
from living kidney donors. Rates of living donation have declined
slightly since 2004 and remained relatively level in more recent
years. In 2016, 87% of patients with incident ESRD in the United
States started hemodialysis, 10% started on peritoneal dialysis, and
3% received a preemptive kidney transplant (before any dialysis
therapy). By the end of 2016, 63% of prevalent ESRD patients were
on hemodialysis, 7% were on peritoneal dialysis, and 30% had a
functioning kidney transplant. Although home hemodialysis is a
modality that has demonstrated improved survival (Mailloux et al.,
1996) and cost effectiveness (McGregor et al., 2000), only 2% of
hemodialysis patients received home treatments in 2016.
Poor long-term survival of ESRD patients is illustrated by compar-
ing the expected remaining lifetime on dialysis or transplant with
the general US population. The expected survival for dialysis patients
was less than one-third of those age-matched in the general popula-
tion, whereas the expected survival in transplant patients was 69%
to 85% of that in the general population. The adjusted mortality
rate in patients on dialysis was 164 per 1000 patient-years, whereas
the rate in transplant recipients was 29 per 1000 patient-years.
Importantly, however, survival is improving for patients on dialysis
and with transplantation. Between 2001 and 2016, adjusted mortality
rates decreased in dialysis patients by 29%. Such improved survival
is contributing to the growing prevalence of ESRD patients. This
improvement in survival was similar to that seen in non-dialysis
patients on Medicare with diabetes and cancer. In transplant patients,
the adjusted mortality rates between 2001 and 2016 decreased by
40%. The transplant population is aging. In 2001, 8% of transplant
recipients were over the age of 65, and in 2016 the rate increased
to 24% (USRDS, 2018).
Outcome comparisons suggest that kidney transplantation is
still the best overall treatment for ESRD patients, despite advances
in dialysis care and modalities. The time on dialysis (vintage) has
an impact on transplant outcomes, with inferior outcomes seen with
longer dialysis vintage (Meier-Kriesche et al., 2000). This finding
likely relates in part to progressive vascular disease on dialysis therapy
but also reflects socioeconomic status and timeliness of listing (Schold
et al., 2010). Patients who progress to stage IV CKD with an estimated
or measured GFR of 20 mL/min/1.73 m2 or less are eligible for active
transplant listing in the United States and should be counseled and
referred for transplant evaluation. Patients at advanced age or with
severe medical comorbidities or problems with medical adherence
may be excluded from transplant listing. For those approved, preemp-
tive transplantation, before initiation of dialysis therapy, should
be the goal. Because of long waiting times for deceased donor
1930 PART VIII Renal Physiology and Pathophysiology
transplantation, preemptive transplant is most likely to be achieved
with kidney donation from a living donor.
Atherosclerotic Renal Artery Stenosis
Atherosclerotic renal artery stenosis, a recognized cause of severe,
secondary hypertension and impaired renal function, is present in
approximately 7% of individuals older than 65 years (Hansen et al.,
2002) and in 40% to 50% of patients with atherosclerotic disease
in other vascular beds (Miralles et al., 1998). Clinically relevant
complications, specifically resistant hypertension and/or renal atrophy
with progressive decline in renal function, develop in 15% to 20%
of cases of atherosclerotic renal artery stenosis (Caps et al., 1998;
Chabova et al., 2000). In addition, atherosclerotic renal artery stenosis
appears to be an independent risk factor for adverse cardiovascular
events and increased cardiovascular mortality. In 3 recent studies,
patients with atherosclerotic renal artery stenosis had between a
two- and fivefold increases in mortality compared with healthy
age-matched normotensive control patients (Conlon et al., 2001;
Edwards et al., 2005; Johansson et al., 1999). Moreover, the increased
risk profile appears to remain despite anatomic correction of ath-
erosclerotic renal artery stenosis.
Atherosclerotic renal artery stenosis accounts for 90% of the
lesions that impede blood flow within the renal artery. Fibromuscu-
lar dysplasias, vasculitides, congenital bands, and intrinsic and extrinsic
causes make up the remaining 10% of causes. Atherosclerosis typically
involves the ostium and proximal one-third of the renal artery and can
also involve the adjacent aorta. Involvement of segmental renal arteries
and higher-order branches is uncommon. Because atherosclerosis
is a systemic condition, atherosclerotic renal artery stenosis most
often occurs in patients with risk factors for atherosclerosis, such as
hypertension, hyperlipidemia, diabetes mellitus, and tobacco use.
Early studies determined the prevalence of renal artery disease in
autopsy series. In patients older than 60 years and with a history of
hypertension, moderate to severe renal artery stenosis was found in
approximately 50% of patients (Holley et al., 1964; Schwartz et al.,
1964). Because atherosclerosis-related complications are a leading
cause of death, autopsy studies may overestimate the prevalence of
atherosclerotic renal artery disease but nonetheless suggest a direct
relationship to increasing patient age and severity of hypertension.
The clinical prevalence of atherosclerotic renal artery stenosis,
which is frequently identified in patients with cerebrovascular, coro-
nary, and peripheral arterial disease depends on the radiographic
definition (percent of renal artery luminal narrowing), imaging
technique, and the patient population being studied. In a general
population of patients older than 65 years of age the prevalence was
noted to be 6.8%, when assessed with duplex Doppler ultrasonography
(Hansen et al., 2002). In a systematic review of studies using more
sensitive imaging techniques and defining atherosclerotic renal artery
stenosis as at least 50% luminal narrowing, the prevalence ranged
between 10.5% in consecutive patients undergoing coronary angi-
ography to 54.1% in patients with congestive heart failure (de Mast
et al., 2009). In patients with underlying atherosclerotic conditions,
atherosclerotic renal artery stenosis can be anticipated in approxi-
mately 10% to 20% of cases. With these sensitive imaging techniques
the prevalence of bilateral atherosclerotic renal artery stenosis is
4.2%, in contrast to 0.8% when identified by duplex ultrasonography
(de Mast et al., 2009; Hansen et al., 2002).
Pathophysiology of Hypertension in Atherosclerotic Renal
Artery Stenosis
Basic Concepts in Arterial Physiology. Blood flows throughout
the circulatory system primarily because of differences in total fluid
energy but from a functional standpoint, blood flow can be attributed
to differences in pressure gradients. A pressure gradient is maintained
by cardiac contractions and elasticity of the arterial system. The basic
concept that describes the relationship between blood pressure (and/
or flow) and blood vessel diameter follows Pouiseuille’s law, which
states that the pressure difference between two points along a tube
is directly proportional to the flow velocity (Q), length of tube (L),
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110.0
100.0
Available blood flow (%)
90.0
80.0
70.0
60.0 Systolic blood flow (%)
50.0 Diastolic blood flow (%)
40.0
30.0
20.0
10.0
0.0
0 10 20 30 40 50 60 70 80 90 100
% Area stenosis
Fig. 87.2. Relationship of blood flow to increasing arterial stenosis.
and fluid viscosity (η) and is inversely proportional to the second
power of the radius of the tube.
Pouiseuille’s law = ∆P = Q8Lη r 2
Viewed simplistically, this relationship shows that as the radius (or
diameter) of a tube decreases, the difference in pressure increases
exponentially. Therefore, as the diameter of a blood vessel decreases,
the decline in pressure, ΔP, increases.
The second important concept relates to the relationship between
luminal diameter and cross-sectional area. The cross-sectional area
of a tube, which is equal to that of a circle, is expressed as A=πr2.
This can be further expanded to consider diameter or A=π (d/2)2 or
πd2/4. Again showing that as the diameter of a vessel decreases, the
luminal area decreases by the square of the diameter reduction. Early
experiments have conclusively shown that clinically significant vascular
stenosis, specifically those that cause a pressure drop, occur when
the luminal area is reduced by more than 70%, also expressed as
“70% stenosis” (May et al., 1963; Fig. 87.2). This corresponds to a
diameter reduction of approximately 50% because such a diameter
reduction will result in a reduction in cross-sectional area to 25%
of the original area.
Given that a constant amount of fluid (blood) circulates through
the vascular system, another basic assumption is that blood flow
(volume of blood per time) is maintained in all parts of the circulatory
system. Extending from the Bernoulli equation, as the diameter of
tube decreases, the velocity of the moving fluid increases to maintain
the conservation of energy principle of flowing fluids. Importantly,
these concepts are based on laminar flow of frictionless fluids through
rigid tubes, markedly different from the human circulatory system.
Flow is maintained in human arteries by increasing velocity until
a critical level of stenosis or approximately a 70% decrease in area.
Beyond 70%, flow begins to decrease rapidly, and beyond a 90%
stenosis flow and velocity are reduced, compatible with “trickle-flow”
(Fig. 87.3).
Based upon this relationship, flow decreases markedly at critical
levels of stenosis (>70%). Under normal systolic blood pressures
(120 mm Hg) there is an approximately 40- to 60-mm Hg pressure
drop to the level of the afferent arterioles within the kidney (Fig. 87.4).
De Bruyne et al. (2006) have shown that as the degree of stenosis
increases to approximately 50%, the pressure in the renal artery
distal to stenosis is 60 to 70 mm Hg. It is likely therefore that at
this lower perfusion pressure, the pressure and flow, at the afferent
arteriole reaches precipitously low levels, thus initiating the patho-
physiologic processes.
The pathophysiologic basis for hypertension resulting from
impaired renal blood flow was first elegantly described more than
75 years ago (Goldblatt et al., 1941). These initial studies stimulated
numerous experiments that outlined the hormonal basis for the
kidney’s role in blood pressure control. Adding to these initial studies,
it is now well outlined that a reduction in renal perfusion leads to
a decrease in glomerular filtration. Consequently, the reduction in
distal tubular sodium chloride (NaCl) delivery to the macula densa
 Chapter 87 Renal Insufficiency and Ischemic Nephropathy 1931

600 perfusion pressure, which, in turn, promotes a natriuresis and volume

loss. Therefore maintenance of hypertension in unilateral renal
artery stenosis and normal contralateral kidney is driven primarily
500 by renin and angiotensin. In contrast, in the setting of bilateral
Flow (mL/min) – velocity (cm/sec)

renal artery stenosis or renal artery stenosis affecting a solitary

Velocity
kidney, sodium and volume retention are not modified to the
400
extent of having a normal contralateral kidney. Renin and angio-
tensin levels do not remain elevated, and hypertension remains
Flow sodium and volume dependent.
300
Given the transient elevation in renin and angiotensin, several
other pressor pathways participate in the development of hypertension.
These pathways include sympatho-adrenergic activation, oxidative
200
stress pathways, and impaired vasodilatory responses within the
kidney and systemic microcirculation (Lerman et al., 2001).
100
Pathophysiology of Ischemic Nephropathy in Atherosclerotic
100 90 80 70 60 50 40 30 20 10 0 % Decrease in area
Renal Artery Stenosis
80 70 60 50 40 30 20 10 0 % Decrease in diameter A reduction in renal perfusion resulting from atherosclerotic renal
artery disease, which in turn leads to renal parenchymal loss and
Fig. 87.3. Correlation of percent diameter reduction with increases in blood declining renal function, describes a condition known as ischemic
flow velocity (cm/sec) and reduction in volume flow (mL/min) in arteries. Note nephropathy. Several interrelated pathophysiologic mechanisms are
that a high-grade (>95%) diameter-reducing stenosis causes volume flow to likely responsible for the renal structural and functional changes
decrease toward zero, whereas the velocity within the stenosis may be minimally that occur in atherosclerotic renal artery disease. The impairment in
elevated. microvascular blood flow, in combination with conditions that
contribute to the atherosclerotic milieu, such as hypercholesterolemia,
diabetes mellitus, and hypertension, lead to vascular dysfunction,
120 which is mediated by endothelial injury, reduced bioavailability of
BP Interlobular nitric oxide, and increased vascular tone resulting from the predomi-
artery nance of vasoconstrictors, primarily angiotensin II. Concomitant
100
cellular activation leads to migration of mononuclear cells and release
Pressure (mm Hg)

Arcuate inflammatory mediators including nuclear factor kappa-B (NF-κB).

80
artery
Afferent
60
arteriole
Glomerular
40
capillaries
Efferent
20
arteriole
0 artery stenosis in which tissue hypoxia may occur, there is preferential
Fig. 87.4. Hydraulic pressure profile in the renal vasculature based on a variety
of micropuncture studies in superficial nephrons of the rat and squirrel monkey
as well as values obtained by micropuncture of juxtamedullary nephrons in
the rat. For these latter studies, the arcuate artery was perfused with whole
blood at normal arterial pressures, and hydraulic pressures were measured
at downstream sites, including the interlobular artery, the proximal and distal
portions of the afferent arteriole, the glomerular capillaries, the proximal and
late segments of the efferent arteriole, the peritubular capillaries, and the
renal vein.
cells of the juxtaglomerular apparatus initiates an epithelial response
that consists of activation of multiple mitogen-activated protein
kinases and stimulation of cyclooxygenase-2 activity and induction
of cyclooxygenase-2 expression. This is subsequently followed by
the appearance in the juxtaglomerular interstitium of prostaglandin
E2 and the suppression of adenosine. Prostaglandin E2 activates
receptors on granular cells which then results in adenylate cyclase
activation and phosphokinase A-mediated renin secretory and
transcriptional activation (Schnermann et al., 2003).
Renin, in turn, cleaves hepatically-produced angiotensinogen to
produce angiotensin I, which is then converted by the angiotensin
converting enzyme in the pulmonary vasculature to angiotensin II.
In addition to causing hypertension via its potent vasoconstrictive
effects, angiotensin II stimulates adrenal synthesis of aldosterone,
which further results in sodium and fluid retention.
In the classic 2-kidney, 1-clip model, increased renin release from
the affected kidney leads to hypertension and sodium retention.
However, the contralateral (unaffected) kidney senses increased
Upregulated tubular and glomerular expression of profibrotic factors,
including transforming growth factor β (TGF-β), tissue inhibitor of
metalloproteinase-1, and plasminogen activator inhibitor-1 leads
Peritubular
capillaries Renal to structural changes of tubulointerstitial fibrosis, vascular changes
and/or glomerulosclerosis (Chade et al., 2003; Lerman et al., 2009).
venules
Changes in intrarenal blood flow have been identified using blood
oxygen level–dependent (BOLD) magnetic resonance imaging (MRI)
analysis. Gloviczki et al. (2013) found that in cases of severe renal
redistribution of blood flow away from the renal cortex and toward the
medulla. At the same time, there are changes in metabolic processes
to preserve oxygen (Eirin et al., 2013).
Studies sampling renal vein blood from patients with atheroscle-
rotic renal artery stenosis compared with those with essential
hypertension found multiple markers reflecting active inflammation,
suggesting kidney injury and reduced function. Endothelial progenitor
cells expressing the markers CD34 and KDR were sequestered in
kidneys with atherosclerotic renal artery stenosis, whereas levels of
E-selectin, vascular cell adhesion molecule-1, and several inflammatory
molecules were increased (Eirin et al., 2013).
In summary, atherosclerotic renal artery stenosis, in combination
with other atherosclerotic risk factors, results in progressive loss of
renal function through a complex interplay between inflammatory
and immune responses, angiotensin II, oxidative stress, vascular
rarefaction, and fibrosis. These molecular and cellular level processes
ultimately lead to renal atrophy and diminished renal function.
Diagnostic Evaluation of Atherosclerotic Renal
Artery Stenosis
Clinical Features. The primary goal when undertaking diagnostic
evaluation for suspected atherosclerotic renal artery stenosis is
to identify patients who, if found to have a lesion, are most likely
to benefit from treatment. Given that most patients with athero-
sclerotic renal artery stenosis are asymptomatic, the decision to pursue
diagnostic assessment, particularly with invasive studies, should be
driven by the probability that renovascular disease is a significant
contributor to the patient’s condition and will result in potential
clinical consequences. If blood pressure and renal function are

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1932 PART VIII Renal Physiology and Pathophysiology
satisfactorily controlled with medical therapy, further diagnostic
evaluation may not lead to treatment gains.
In general, the clinical criteria that should prompt evaluation are
(1) early onset of hypertension (age < 30 years), (2) accelerated
hypertension, (3) severe hypertension, or (4) hypertension resistant
to optimal medical therapy, (5) asymmetric kidney size with more
than 1.5 cm difference in craniocaudal length, (6) unexplained loss
of kidney function, (7) rapid or recurrent decline in GFR in association
with systemic blood pressure reduction, and (8) decline in GFR (SCr
at least 30% from pretreatment level) after initiation of ACE inhibitors
or ARBs. In addition, although most likely unrelated to atherosclerosis,
all children with unexplained hypertension should be screened for
renal artery stenosis.
Other clinical features that are often present in patients with ath-
erosclerotic renal artery stenosis are typical for patients with systemic
atherosclerotic disease. These include advanced age; atherosclerotic
risk factors, including hypertension, CKD, hyperlipidemia, diabetes
mellitus, tobacco exposure; and history of atherosclerotic disease in
the coronary, cerebral, and/or the peripheral arterial circulation. On
physical examination these patients often have severe hypertension
and may also have fewer common signs, such as diminished lower
extremity pulses, peripheral edema, and abdominal bruits.
To generate uniformity, the American Heart Association proposed
the following classification scheme in patients with renal artery disease
(Rocha-Singh et al., 2008):
Grade I: Renal artery stenosis present, but no clinical manifestations
(normotensive and normal renal function)
Grade II: Renal artery stenosis present, but patients have medically
controlled hypertension and normal renal function
Grade III: Renal artery stenosis present and patients have evidence
of abnormal renal function, medically refractory hypertension,
or evidence of volume overload
Laboratory Features
Apart from decreased GFR, patients with atherosclerotic renal artery
stenosis typically do not have notable laboratory abnormalities. The
urine analysis is likely to be unremarkable. On routine chemistry
panels, patients may have low or low normal serum potassium because
of aldosterone secretion.
Ritchie et al. (2014) retrospectively reviewed 467 patients with at
least 50% atherosclerotic renal artery stenosis and noted that nearly
half of their patient group was asymptomatic. One or more “high-risk
presentations,” defined as flash pulmonary edema, refractory hyperten-
sion (>140 mm Hg systolic and/or >90 mm Hg diastolic) despite use
of 3 or more different classes of antihypertensive agents, or rapidly
declining kidney function (SCr level more than 1.2-fold or 1.14 mg/
dL greater than baseline within the previous 6 months) was present in
51% of the patients, and 30% to 40% had a history of angina, previous
myocardial infarction, cerebrovascular accident/transient ischemic attack,
peripheral arterial disease, or diabetes (Ritchie et al., 2014)
These data underscore a guiding principle for diagnostic evalu-
ation in atherosclerotic renal artery stenosis. Patients who are
asymptomatic, have normal renal function, and have satisfactory
blood pressure control likely do not need evaluation. Alternatively,
patients who fail to improve or who decline while on medical
therapy may benefit from additional diagnostic testing.
Radiographic Assessment of Atherosclerotic Renal
Artery Stenosis
Radiographic evaluation of suspected atherosclerotic renal artery
stenosis should begin with noninvasive imaging studies. Given the
wide availability, low cost, ease to the patient, and diagnostic accuracy,
duplex ultrasonography should be considered the screening test
of choice. Duplex ultrasonography combines anatomic information
(B- or brightness-mode and color Doppler imaging) with acquisition
of blood flow.
The primary diagnostic advantage of duplex ultrasonography is
the ability to accurately determine blood flow velocity. A duplex
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ultrasonographic examination for renal artery stenosis should be
done by an experienced technologist, and patients should undergo
an overnight fast to minimize bowel gas. Imaging is performed from
anterior and flank (lateral decubitus) approaches, with attention
directed to the perirenal aorta, looking for aneurysmal change,
stenosis, or occlusion. The lateral decubitus position may aid in the
obese patients and/or in the setting of excessive bowel gas. Peak
systolic velocity in the aorta is recorded. Subsequently each renal
artery is imaged, and velocities and waveforms are recorded from
the proximal, mid, and distal segments of the renal arteries. Duplex
ultrasonography with color-flow and Doppler imaging is used to
determine the patency and phasicity of the renal veins. Velocity
measurements within the superior, mid, and lower poles of the
kidneys are used to calculate resistive indices and acceleration times.
Last, the duplex ultrasonographic study determines renal parenchymal
anatomic details including kidney size, parenchymal thickness and
echogenicity, and potentially unanticipated findings such as masses,
calculi, and/or hydronephrosis.
The most commonly measured duplex ultrasonographic parameters
include peak systolic velocity (PSV), end diastolic velocity (EDV),
and adjacent aortic peak systolic velocity. The ratio of velocity in
the main renal artery to the aorta (renal aortic ratio, RAR) and
resistive index within the renal parenchyma (RI = [(PSV−EDV)/PSV])
can be derived from these measurements. In addition, arterial blood
flow characteristics such as tardus/parvus, acceleration time, and
acceleration index can be determined within the main, accessory,
and intraparenchymal renal arteries.
The accuracy of duplex ultrasonography for the diagnosis of renal
artery stenosis varies according to predetermined velocity thresholds,
which in turn, depend on individual vascular laboratory experience.
AbuRahma et al. (2012) reviewed their institution’s large experience
and found that a PSV of 285 cm/s or a RAR of 3.7 alone had the
best overall accuracy in diagnosing at least 60% stenosis when
compared with angiography. Using these thresholds, these investigators
were able to achieve more than 80% accuracy. Lower velocity
thresholds, although more sensitive, were less accurate. These findings
reinforce the notion that clinicians should recognize the expertise
in their individual vascular laboratories and use the data to screen
patients who require more invasive examination.
Computed tomography (CT) and magnetic resonance imaging (MRI)
have sensitivity of more than 90% in detecting atherosclerotic renal
artery stenosis, and MRI has a specificity of 91% (Eklof et al., 2006).
CT and MRI provide excellent anatomic detail; however, the blood
flow changes that result from the stenosis cannot be determined. The
functional consequences of these lesions may be indirectly determined
by the findings of parenchymal atrophy. Another drawback of CT is
the cost and need for intravenously administered radiographic contrast
agents. Because many patients with suspected atherosclerotic renal
artery disease may have co-existent renal insufficiency, administration
of iodinated contrast agents raises concerns of contrast nephropathy.
Patients with estimated glomerular filtration rate (GFR) below 50 mL/
min should receive IV hydration before contrast administration and
those with GFR below 30 mL/min should not receive iodinated contrast
as part of a diagnostic procedure (contrast should be reserved for use
during a therapeutic procedure). Administration of IV gadolinium
for magnetic resonance angiography (MRA) in patients with GFR
below 30 mL/min should be avoided because it is associated with
the development of nephrogenic systemic fibrosis.
Renal arteriography, the “gold standard” for the diagnosis of
atherosclerotic renal artery stenosis, can also provide detailed imaging
of the aorta, segmental renal arteries, and intrarenal vasculature.
Digital subtraction improves resolution and allows a reduction in
the amount of contrast material. Angiography is an invasive study
with risks of bleeding from arterial puncture, arterial dissection,
arterial spasm, and thromboembolism. Additionally iodinated contrast
material cannot be administered in patients with contrast allergy or
significant renal dysfunction, and use of carbon dioxide may reduce
the amount of contrast.
Two additional diagnostic studies that warrant discussion are
radionuclide renography and plasma renin determination. With
radionuclide or nuclear renography, a radiopharmaceutical agent,
 Chapter 87
either diethylenetriaminepentaacetic acid (DTPA) or mercaptoacet-
yltriglycine (MAG 3), is administered intravenously, and images are
reviewed to determine a renal functional difference, delay in time
to peak uptake of the radioisotope, or delayed excretion of the isotope.
Additional imaging after administration of captopril, an ACE inhibitor,
may show decreased function (GFR), suggesting the influence of
angiotensin II maintaining glomerular filtration. Radionuclide
renography has largely fallen out of favor because of its unreliability.
In addition to diagnostic limitations in patients with diminished
renal function (SCr > 2.0 mg/dL) or bilateral arterial disease, these
imaging studies have poor sensitivity and specificity (Vasbinder et al.,
2001). Currently the primary role of renography in evaluating patients
with hypertension may be to determine differential function before
recommending nephrectomy.
Plasma renin activity or determination of renin level from the
renal vein has been suggested to be highly diagnostic for the presence
of renal artery stenosis, but these studies are limited by their invasive-
ness and stringent testing conditions. The patient’s volume status
must be optimized, concurrent medications must be addressed, and
blood pressure must be tightly controlled. Last, and as mentioned
previously, renin may be elevated early in the course of atherosclerotic
renal artery stenosis and likely declines over time as other pathophysi-
ologic processes maintain the hypertensive state.
Therapeutic Options for Atherosclerotic Renal
Artery Stenosis
Medical Management. Medical management makes up the founda-
tion of atherosclerotic renal artery stenosis treatment. The general
objectives of therapy are control of blood pressure, preservation of
renal function, and prevention of atherosclerosis-related complica-
tions. Antihypertensive treatment with ACE inhibitors or ARBs are
the first-line approach for blood pressure control and for their
beneficial effect on cardiovascular risk reduction (Heart Outcomes
Prevention Evaluation Study Investigators, 2000). Use of these agents
may initiate concerns of renal insufficiency from loss of glomerular
filtration as a result of blockade of the AII-induced efferent arteriolar
constriction. However, significant renal function decline is uncommon
in most series and, when it occurs, is almost diagnostic of renal
artery stenosis. If additional antihypertensive agents are needed,
beta-blockers, diuretics, and calcium-channel blockers can be added.
Given the presence of systemic atherosclerosis, many patients
with atherosclerotic renal artery stenosis also have pre-existing
cardiovascular risk factors, including essential hypertension, diabetes
mellitus, dyslipidemia, and smoking. Established additional related
therapies include glycemic control, statins, antiplatelet agents, and
lifestyle modifications, including tobacco cessation.
Procedural Management. Whether all patients with atherosclerotic
renal artery stenosis should undergo renal revascularization in addition
to medical therapy remains a controversial practice, although recent
trials do not support this procedure. Renal revascularization, with
open surgical renal artery bypass and percutaneous transluminal
angioplasty with or without stent placement, has been the subject
of several randomized prospective trials. Numerous single-center
retrospective studies have reported on various techniques of open
surgical revascularization and have shown durable long-term patency
rates (Cambria et al., 1996; Cherr et al., 2002; Darling et al., 1999;
Fergany et al., 1995; Hansen et al., 2000; Marone et al., 2004; Paty
et al., 2001). Notwithstanding these results, open surgical renal artery
repair is associated with considerable perioperative mortality (5%)
and morbidity (20%) rates and therefore is generally reserved for
young patients and those with hemodynamically significant athero-
sclerotic renal artery stenosis and significant juxtarenal or suprarenal
aortic disease (Edwards et al., 2009).
Renal revascularization with percutaneous transluminal renal
artery angioplasty (PTRA) has been compared with medical therapy
in three randomized controlled trials, none of which showed improved
renal function, hypertension management, or survival with PTRA
(Plouin et al., 1998; van Jaarsveld et al., 2000; Webster et al., 1998).
These trials enrolled small numbers of patients, excluded patients
with severe renal functional impairment, had extensive crossover
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Renal Insufficiency and Ischemic Nephropathy 1933
between treatment groups, and did not use current medical therapy,
thus making the results difficult to apply to current practice.
When compared with PTRA alone, percutaneous transluminal
renal artery angioplasty with stenting (PTRS) was found to have
superior technical success rates, increased patency rates, and decreased
restenosis rates, leading to widespread adoption of PTRS as the
standard endovascular management for atherosclerotic renal artery
stenosis during the 1990s and early 2000s (Liang et al., 2013; van
de Ven et al., 1999). A comparison of PTRS and medical manage-
ment for atherosclerotic renal artery stenosis has been the subject of
several randomized controlled trials. In three of these trials, which
were presented or published in 2009, nearly 1000 patients with
atherosclerotic renal artery stenosis were enrolled and followed for
2 to 4 years (Bax et al., 2009; Kumbhani et al., 2011; Wheatley et al.,
2009). Aside from a slight reduction in number of antihypertensive
medications, no significant improvement in systolic or diastolic blood
pressure, renal function decline, or adverse cardiovascular events
was seen with PTRS and medical management in comparison with
medical management alone. Despite the randomized prospective
design, these trials have faced several criticisms, including discrepan-
cies in atherosclerotic renal artery stenosis diagnosis, flaws in the
intention-to-treat analysis, and inclusion of patients with wide-ranging
degrees of stenosis.
The NIH sponsored Cardiovascular Outcomes in Renal Atheroscle-
rotic Lesions, or CORAL, trial attempted to correct these limitations
and definitively answer whether revascularization of hemodynamically
significant atherosclerotic renal artery stenosis in hypertensive patients
prevents adverse cardiovascular and renal events when added to
optimal medical therapy (Cooper et al., 2014). The CORAL study
enrolled 947 patients with atherosclerotic renal artery stenosis
and hypertension between 2005 and 2010 and randomly assigned
these patients to medical therapy plus renal artery stenting or
medical therapy alone. After a median follow-up period of 43
months, the rate of the primary composite end point, made up of
cardiovascular and renal sequelae, was not significantly different
between participants who underwent stent placement in addition
to medical therapy versus those who received medical therapy alone
(Cooper et al., 2014). Although the limitations of these studies
continue to be debated, the conclusions reached by the CORAL
study reliably show the lack of benefit of renal artery stenting in
most patients with atherosclerotic renal artery stenosis.
Complications of PTRS, although generally less frequent than
those seen with open surgical revascularization, can still account
for significant morbidity. Periprocedural mortality rate is approxi-
mately 0.7%, and renal artery complications range from 1% to 10%
(Kumbhani et al., 2011).
In contrast to asymptomatic patients who are found to have
high-grade atherosclerotic renal artery stenosis, a subgroup of patients
who appear to benefit from renal artery revascularization are those
with flash pulmonary edema. As stated earlier, randomized prospective
trials included mostly asymptomatic patients. Ritchie et al. (2014)
evaluated outcomes between medical management alone compared
with medical management plus percutaneous renal artery revascu-
larization with stent placement in patients with high-risk clinical
presentation, defined as flash pulmonary edema, rapidly declining
renal function, or refractory hypertension. In this large analysis, flash
pulmonary edema appeared to be an adverse prognostic marker
with increased risk of death and cardiovascular events in medically
treated patients, whereas the combination with renal artery revas-
cularization reduced the risk of death (Ritchie et al., 2014).
Nonatherosclerotic Renal Artery Diseases
Fibromuscular Dysplasia
Fibromuscular dysplasia (FMD) is a nonatherosclerotic, noninflam-
matory vascular disease that most often affects small to medium
arteries. Unlike atherosclerosis, FMD mostly involves the mid- to
distal renal artery and can affect segmental renal artery branches.
FMD has a female predominance and typically occurs in patients
between 20 and 60 years of age but can occur in older and pediatric
1934 PART VIII Renal Physiology and Pathophysiology
patient populations. Asymptomatic patients are most often diagnosed
on imaging studies. Symptomatic patients can experience sequelae
of arterial disease such as stenosis, occlusion, arterial dissection, or
aneurysm. Although FMD can occur in any arterial bed in the body,
involvement of the renal artery is most common.
Epidemiology of Renal Artery Fibromuscular Dysplasia. Because
many patients with FMD remain asymptomatic, the true prevalence
of FMD is difficult to assess. The overall prevalence can be estimated
from the evaluation of renal donors, a suitable representation of
healthy adult population. The prevalence of FMD in renal donors
ranges between 2.6% to 6.6% with the variance most likely resulting
from differences in imaging technique and patient populations (Cragg
et al., 1989; McKenzie et al., 2013; Neymark et al., 2000). Bilateral
renal artery involvement is seen in approximately one-third of FMD
cases (McKenzie et al., 2013; Olin et al., 2011). FMD has a marked
female preponderance: nearly 90% of cases occur in women. Several
causative factors, including hormonal and environmental causes,
have been proposed for the development of FMD; however, the
prevailing thought is that FMD is idiopathic.
Histopathology of Fibromuscular Dysplasia. FMD is classified
according to the affected layer of arterial wall; specifically, the intima,
media, and adventitia. FMD involving the media occurs most
commonly and can be further subdivided into medial fibroplasia,
perimedial fibroplasia, and medial hyperplasia. The latter two condi-
tions are very uncommon, whereas medial fibroplasia accounts
for 90% of all types of FMD. Medial fibroplasia is characterized
by multiple diaphragm-like thickened areas of media that result in
segments of arterial stenosis and poststenotic dilatation, typically
seen as a “string of beads” appearance on CT angiography (Fig. 87.5).
Accounting for the remaining 10% of cases of FMD, intimal
fibroplasia is due to collagen deposition within the intima with
resultant fragmentation of the intimal layer. On angiography, intimal
fibroplasia often appears as a concentric stenosis and, occasionally,
as a long, diffuse narrowing.
Clinical Presentation. As mentioned previously, the diagnosis of
renal artery FMD is often made in asymptomatic patients undergoing
abdominal imaging for other reasons. The most common symptomatic
presentation is a middle-age woman with new-onset or difficult-
to-control hypertension. Other clinical presentations of renal artery
FMD include flank pain and/or hematuria, both of which can result
from dissection or occlusion of the renal artery and aneurysmal
changes involving the artery. Interestingly, unless dissection occurs,
medial fibroplasia rarely results in renal dysfunction. Intimal and
perimedial fibroplasia may be associated with renal dysfunction,
arterial dissection, and progression to occlusion (Stokes et al., 1996).
Diagnostic Evaluation. As with atherosclerotic renal artery stenosis,
angiography remains the gold standard to diagnose and evaluate
renal artery FMD. Catheter-based angiography provides excellent
resolution of the main and segmental renal arteries and can identify
luminal changes such as aneurysm formation and dissection that
may affect the smaller vessels. More recently intravascular ultrasound
has been used as an adjunct to angiography and can depict pressure
Fig. 87.5. “String of beads” appearance of the right renal artery typical of
fibromuscular dysplasias.
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gradients and even provide virtual histology of the arterial lumen
(Prasad et al., 2009). CT and MRA are able to suggest the diagnosis
of FMD in main renal vessels but are limited by poor visualization
along branch renal vessels.
Management of Fibromuscular Dysplasia. The primary treatment
goals in patients with renal artery FMD are control of hypertension
and prevention of secondary complications of hypertension. Because
ischemic nephropathy is not a sequela of FMD, preservation of renal
function is not a consideration in the treatment of FMD. The primary
factors in considering which patients with FMD merit treatment are
patient age, temporal relationship between onset of hypertension
and diagnosis of FMD, adequacy of blood pressure control with
anti-hypertensive agents, and duration of hypertension.
Asymptomatic, normotensive patients with renal artery FMD
should be followed for the development of hypertension. Young,
otherwise healthy patients in whom FMD is diagnosed proximate
to the onset of hypertension should be referred for PTRA, which
provides immediate and long-term blood pressure control in nearly
75% of patients (Davies et al., 2008; Trinquart et al., 2010). Patients
in whom hypertension has been present for many years should be
continued on antihypertensive medications as long as blood pressure
control is satisfactory. Dopper ultrasound–based surveillance of kidney
length and cortical thickness should be done once or twice per year.
If blood pressure control becomes difficult, medication side effects
become intolerable, or renal size or function decrease, PTRA should
be performed (Olin, 2011). Balloon angioplasty alone is a very effective
treatment for renal artery FMD, thereby making stent placement
unnecessary. Surgical revascularization is reserved for cases not
amenable to percutaneous approaches such as those with aneurysms
or FMD involving distal extrarenal branches. Indications for stent
placement in FMD are inability to eliminate a pressure gradient with
angioplasty alone and intimal dissection.
Treatment success is fairly similar between PTRA and surgery.
Approximately 50% of patients have cure of hypertension, but the
complications are markedly fewer after PTRA. Major complication
rates after PTRA are approximately 12%, in contrast to 17% after
surgery (Trinquart, 2010).
Restenosis can occur after PTRA, particularly if the angioplasty
was inadequate. Most instances of restenosis can be successfully
treated with repeat angioplasty. Use of intravascular ultrasound (IVUS)
in this setting can document resolution of a pressure gradient. Similar
to patients on antihypertensive medications, patients are advised to
continue with routine surveillance for recurrence of hypertension
and for Doppler ultrasound of renal length and cortical thickness.
Routine use of aspirin (81 mg) is advised for all patients with renal
artery FMD (Olin, 2011).
KEY POINTS: CHRONIC KIDNEY DIEASE
• CKD is defined as kidney impairment sustained beyond 3
months with a reduction in GFR, structural abnormalities
in the kidneys, and/or proteinuria.
• There continues to be a steady increase in the number of
patients with ESRD on RRTs throughout the world.
Outcome comparisons suggest that kidney transplantation
is still the best overall treatment for ESRD patients, despite
advances in dialysis care and modalities.
• Hemodynamically significant narrowing in the renal artery,
or renal artery stenosis, can result in secondary
hypertension and/or diminishing renal function.
• Atherosclerotic vascular disease accounts for 90% of causes
of renal artery stenosis, and fibromuscular dysplasias
account for the remaining 10%.
• Renal artery stenosis can lead to renal parenchymal loss
and diminished renal function, a condition known as
ischemic nephropathy.
• Although the limitations of these studies continue to be
debated, the conclusions reached by the CORAL study
reliably show the lack of benefit of renal artery stenting in
most patients with atherosclerotic renal artery stenosis.
 Chapter 87 Renal Insufficiency and Ischemic Nephropathy 1935

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