renal papillary necrosis inapatient withsickle celltrait
TRANSCRIPT
Renal Papillary Necrosis in a Patient with Sickle Cell Trait
GINO ZADEII and JAMES W. LOHR
Department of Medicine, State University of New York at Buffalo, Buffalo, New York, and the Veterans Affairs
Medical Center, Buffalo, New York.
Abstract. A patient with sickle cell trait who presented with
gross hematuria and was subsequently found to have renal
papillary necrosis is presented. The hematuria resolved with
conservative therapy consisting of bed rest and hydration with
hypotonie intravenous fluids. The pathophysiology of renal
abnormalities associated with sickle cell trait is described. The
management of the primary clinical manifestations of this
disorder, hematuria and papillary necrosis, are discussed.
(J Am Soc Nephrob 8: 1034-1040, 1997)
A variety of renal abnormalities have been described in pa-
tients with sickle hemoglobinopathies (1-5). Most of the liter-
ature has dealt with patients with homozygous sickle cell
anemia (HbSS), although the incidence of heterozygous sickle
cell trait in the United States has been estimated to be 40 times
as great (1).
We report a case of a patient with sickle cell trait presenting
with gross hematuria, who was subsequently found to have
papillary necrosis on intravenous pyelography. A discussion of
the renal abnormalities associated with sickle cell trait and the
approach to management of these disorders is presented.
Case ReportAn African-American man 66 yr of age presented to the
Buffalo Veterans Affairs Medical Center with a 2-d history of
gross hematuria. He denied having experienced fever and
chills, dysuria, or flank pain. He had no history of recent
trauma or nephrolithiasis. Past medical history was significant
for hypertension, hypereholesterolemia, and benign prostatie
hypertrophy, which had been evaluated in the previous year
and found not to be causing any urinary tract obstruction. He
also had sickle cell trait, diagnosed by AS pattern on hemo-
globin eleetrophoresis in 1986. The patient was taking lisino-
pril and eolestipol. He denied taking any nonsteroidal inflam-
matory drugs.
The physical examination revealed a well-developed man in
no acute distress. Blood pressure was 140/70 mmHg, pulse was
76 beats/mm, and temperature was 36.5#{176}C. Examination of the
abdomen showed no evidence of hepatosplenomegaby. No cos-
tovertebral tenderness was noted. The physical examination
was otherwise unremarkable except for a symmetric, mildly
enlarged prostate gland. Laboratory tests showed normal com-
plete blood cell counts, clotting studies, and electrolytes. Blood
urea nitrogen was I 2 mg/dl. and serum ereatinine was I .3
Received March 7. 1996. Accepted October 9. 1996.
Correspondence to Dr. James W. Lohr. Department of Medicine ( I 1 1A),
Veterans Affairs Medical Center. 3495 Bailey Avenue. Buffalo. NY 14215.
1046-6673/0806- l034$03.00/0
Journal of the American Society of Nephrology
Copyright 0 1997 by the American Society of Nephrology
mg/dl. Urine dipstick revealed a specific gravity of I .020, pH
5.5, 3+ blood, 3+ protein, and was negative for glucose,
ketones, and leukocyte esterase. The microscopic exam
showed many red blood cells (RBC), but no RBC casts or
white blood cells were seen. Urine culture showed no growth.
The patient was evaluated by a urologist, and an intravenous
pyelogram was performed that showed bilateral papillary ne-
erosis (Figure 1 ). The patient was placed at bed rest and given
intravenous half-normal saline at a rate of 150 mlIh. The
hematuria cleared on day 4. Before discharge, he had cystos-
copy that was unremarkable. Retrograde urogram could not be
completed due to patient discomfort.
The patient has not had any recurrent hematuria in the 9 mo
since discharge.
DiscussionSeveral renal abnormalities have been described in patients
with sickle cell disorders. These vary depending on whether
the patient has sickle cell disease or sickle cell trait. In sickle
cell disease, there are two abnormal genes related to hemoglo-
bin production, with at least one being the gene for hemoglobin
S. These include sickle cell anemia, sickle cell-hemoglobin C
disease, sickle cell-thabassemia, and some less common disor-
ders. Nephropathy associated with sickle cell disease has been
well reviewed (1-4). In sickle cell trait, there is a normal gene,
along with the gene for hemoglobin S. This is the most corn-
mon hernogbobinopathy in the United States, present in more
than 2 million people. This discussion will be restricted to renal
findings in sickle cell trait, with only a mention of the con-
trasting features of sickle cell anemia.
Pat hophysiologv
The renal medullary interstitium may achieve an osmolarity
of 800 to 1200 mosmol/kg based on the countercurrent mech-
anism, which involves the loops of Henle and the blood supply
of the mideortical juxtarnedullary nephrons. The medullary
interstitium is made hypertonic by reabsorption of sodium
chloride without water in the ascending limb of the loop of
Henle. Solute is transferred from the tubular lumen into the
rnedullary interstitial fluid, raising the osmotic concentration of
the interstitial fluid relative to tubular fluid. The hyperosmotie
Papillary Necrosis and Sickle Cell Disorders 1035
Figure 1. Intravenous pyelogram showing bilateral papillary necrosis in patient with sickle cell trait.
medullary interstitium causes removal of water from the de-
scending limb of the loop of Henle and raises the osmolality of
the tubular fluid as it approaches the tip. Urea also contributes
to the hyperosmolabity of the medullary interstitium by diffu-
sion from the inner rnedullary collecting tubule. The vasa recta
are vessels with hairpin-like construction that lie near the loops
of Henle and carry blood through the medullary tissue at a
much slower rate than cortical vessels. Thus, this blood comes
into contact with the hypertonic medullary interstitial fluid
through the capillary wall.
In patients with sickle cell trait, the hyperosmolar interstitial
fluid draws water from the cells, resulting in an increased
concentration of sickle cell hemoglobin, the most important
determining factor for sickling (Figure 2). Another factor that
may contribute to red blood cell sickling is the low oxygen
tension present in the medulla. Along with the fact that the
medulla receives less than 10% of the renal blood flow, the
configuration of the vasa recta capillaries results in a loss of
oxygen as the blood enters the medulla with subsequent uptake
by the opposing ascending capillaries leaving the medulla. This
can result in oxygen tensions of 20 mmHg or less in the
medulla, with sickling often occurring at less than 45 mmHg
due to polymerization of sickle cell hemoglobin. This hypoxia,
along with the acidic rnedullary pH, also promotes sickling of
RBC (6). As sickling occurs, there is an increase in blood
viscosity, which may further slow the blood flow in the rued-
ullary capillaries.
Initiably, capillaries become engorged with erythrocytes.
Subsequently, RBC sickling in the vasa recta causes formation
of rnicrothrombi, infarction, and formation of collateral vessels
(7). Capillaries develop increased permeability, allowing RBC
to leak into the collecting system. This results in a reduced
number of vasa recta and loss of the normal medullary archi-
tecture as revealed by microangiographic studies (7).
Eventually, these events may lead to papillary necrosis. The
papillary necrosis usually involves the tip of the papilla, with
no involvement or destruction of the fornices. Gross pathologic
exam shows one or more papillae with areas of necrosis,
usually involving one-third of the papilla (8). Calcification
may be seen in old areas of necrosis. Microscopic examination
reveals total or partial necrosis of tubular and collecting duct
epithelium in the area of necrosis. There may be evidence of
expansion of the interstitial space with fibrosis.
The functional renal changes (Table 1 ) that are seen in sickle
cell trait are primarily due to the loss of vasa recta, which
disrupts the countercurrent exchange system. This results in an
impaired ability to concentrate the urine in patients with sickle
cell trait (9-12). This appears to be reversible early in life, but
there is a continual gradual decrease throughout life, which
then becomes fixed. In patients over 50 yr of age, maximum
urine osmolality generally will not exceed 450 mosmol (9).
The ability to dilute the urine has been found to be normal in
patients with sickle cell trait (12).
Patients with sickle cell trait have been found to have a
normal ability to excrete acid in response to ammonium chlo-
ride loading ( 10). This is in contrast to those with sickle cell
disease who frequently have an incomplete distal renal tubular
acidosis ( 10). Potassium excretion has also been studied and
was found to be normal in patients with sickle cell trait,
whereas it was frequently impaired in those with sickle cell
anemia (13.14). Sodium handling is thought to be normal in
patients with sickle cell trait. although this has not been well
1036 Journal of the American Society of Nephrology
Renal Medullaiy
Acidosis Hypertonicity Hypoxia
sickling of RBC
in vasa recta
�Irt blood viscosity
,,�,,medullary blood flow
Imicrothrombi formation
infarction of vasa rectaformation of collateral vessels
papillary necrosis defect in countercurrent
exchange
loss of rena concentrating ability
Figure 2. Effects of renal medullary red blood cell sickling. Modifiedfrom reference 22.
studied ( 1 ). The tubular reabsorption of phosphate is normal in
patients with sickle cell trait, but increased in those with sickle
cell anemia ( 10). In some studies, the fractional excretion of
uric acid does not differ between sickle cell anemia, sickle cell
trait, and control subjects ( 15), whereas others show increased
rate of uric acid clearance in sickle cell anemia (16).
In contrast to sickle cell disease, in which there is an early
increase in glomerular filtration rate in younger patients with a
subsequent decrease in later life, glomerular filtration rate has
been found to be normal in patients with sickle cell trait (10).
However, the filtration fraction is decreased as it is in sickle
cell disease. This is due to a small increase in renal plasma
flow (10).
Clinical Presentation
Hematuria. Patients with sickle cell trait will most corn-
monly present with gross hematuria in the third or fourth
decade, although microscopic hematuria may be picked up on
routine urinalysis (1 ). The hematuria is generally painless,
although patients may present with flank or abdominal pain
due to sloughing of papilla. The left kidney appears to be
involved approximately 80% of the time because of increased
venous drainage into the left renal vein, which may elevate the
venous pressure and lead to stasis (17).
Recurrent episodes of hematuria in affected people are corn-
mon (8,17). Hematuria due to sickle cell trait must be consid-
ered a diagnosis of exclusion, particularly in patients present-
ing with hernaturia for the first time. Thus, the work-up should
include urinalysis and urine culture, urinary acid-fast bacilli,
urinary cytology, hematologic work-up for coagulation abnor-
malities, intravenous pyelogram, and cystoscopy . Hemoglobin
electrophoresis should be performed in all patients with hema-
tuna of unknown etiology, as sickle cell trait is not exclusively
seen in African-American patients (18).
Papillary Necrosis. Renal papillary necrosis may occur in
up to 50% of patients with sickle cell trait who present for
evaluation (19,20). It is generally discovered during evaluation
of hematuria. It must be differentiated from the other common
causes of papillary necrosis listed in Table 2. Various patterns
of papillary abnormalities have been described on excretory
urography (intravenous pyebogram and/or retrograde pyebo-
gram) (19-22). The most common pattern seen in sickle he-
mogbobinopathies is a medullary type of partial papillary ne-
erosis, which appears as a cavity within the papilla (20,21).
Papillary necrosis is most commonly identified in sickle cell
trait at 30 to 40 yr of age, but initial presentation in older
patients, such as in this case report, is not uncommon. There
does not seem to be a sex predominance in the incidence of the
disease.
The clinical presentation of papillary necrosis in sickle cell
trait is quite variable (22). It may appear as gross hematuria
with or without renal colic. Patients may have symptoms of
urinary tract infection or sepsis. There may be minor episodes
of hematuria with years of asymptomatie periods. The patients
may be totally asymptomatie with the papillary necrosis found
incidentally during radiographic studies. Urinary findings may
include the presence of white blood cells in addition to red
blood cells. The urine should be strained and examined for the
presence of sloughed papillae.
Other Renal Abnormalities. An increased incidence of
pyelonephritis during pregnancy has been well demonstrated in
sickle cell trait (23). Patients have presented with perinephric
hernatoma thought to be associated with bleeding into the renal
capsule after cortical infarction. Other findings that have been
reported in patients with sickle cell trait in which causality has
not been proven include nephrotic syndrome, renal vein throm-
bosis, and chronic renal failure.
Treatment
Hematuria. Although usually responsive to conservative
measures, treatment of gross hernaturia in patients with sickle
hernogbobinopathies may be quite challenging. A number of
different approaches have been tried in the past.
One early approach involved the administration of distilled
water intravenously along with oral bicarbonate solution (24).
This was found to be effective in stopping the hematuria.
Although one might expect intravascular hemolysis to occur,
this was not observed. Treatments such as vitamin K, vaso-
pressin, and hyperbaric oxygen have been used with varying
degrees of success. Urologic interventions have included in-
gation of the renal pelvis with sodium oxychlorosene, silver
nitrate, or aminocaproic acid and use of ureteral catheters in an
effort to tarnponade the bleeding.
Table 3 outlines the current approach to management of
hernaturia in sickle cell trait involving measures designed to
eliminate the underlying pathophysiologic conditions leading
to sickling (25). Thus, an effort is made to reduce the tonieity,
Papillary Necrosis and Sickle Cell Disorders 1037
Table I. Renal features of sickle cell trait (SCT) and sickle cell anemia (SCA)a
Type Control SCT SCA Reference
Physiologic
GFR (inubin clearance) (mb/mm per 1.73 rn2) 99 ± 5 95 ± 9 125 ± 1 1 10
renal plasma flow (PAH clearance) (ml/min per 1.73 m2) 454 ± 21 514 ± 59 837 ± 34L� 10
filtration fraction (%) 22 ± 1 19 ± 1h 15 ± I” 10
urinary concentrating ability (mosrnol/kg H2O) 994 ± 54
1055 ± 24
593 ± 35�’
745 ± 33b
447 ± 1O’�
� � 16b
1011
urinary acidificationc (p�eq/min) 79 ± 4 74 ± 6 60 ± 5” 10
urinary potassium excretion�’ (jieq/rnin)
tubular reabsorption of phosphate (%)
136 ± 14
153±41
88 ± 2
127 ± 7
88 ± 2
ll4±l4h
93 ± I
13
14
10
fractional excretion of uratee (%) 6 6 6 15
Pathologic
disruption of medullary architecture Present Present 1-3, 7, 8
papillary necrosis Present Present 1-3, 8
gbomerular disease and nephrotie syndrome Absent Present I , 3, 4
renal insufficiency Absent Present 1, 3, 4
a PAH, para-aminohippurate; p.eq, microequivalent.h p < 0.05 versus control; values are presented as mean ± SEM.
C Net acid excretion after ammonium chloride load.d Maximum potassium excretion after potassium chloride load.C Urate clearance/ereatinine clearance X 100.
Table 2. Common causes of renal papillary necrosis
Diabetes mellitus
Analgesic abuse
Pyelonephritis
Urinary tract obstruction
Sickle hemogbobinopathy
Tuberculosis
increase the pH, and increase the oxygen tension of the renal
medulla. Hypotonic intravenous solutions are administered,
along with a loop diuretic (such as furosemide), which will
reduce medullary tonicity and maintain a high rate of urine
output. The use of a loop diuretic may also reduce oxygen
consumption and increase medullary oxygen tension. Urinary
alkalinization may be achieved by giving 8 to 1 2 g of sodium
bicarbonate daily (26). Addition of acetazolamide will further
alkalinize the urine (25). Patients are generally kept at bed rest
to avoid dislodging of blood clots.
If these measures are unsuccessful in halting the bleeding,
epsilon aminocaproic acid (EACA) may be given intrave-
nously or orally. This is an inhibitor of urokinase, the urinary
enzyme that activates plasminogen. Thus, EACA prevents
formation of excess plasmin responsible for fibrinolysis. The
recommended dose of EACA is 3 to 4 g three to four times
daily, which will usually result in the clearing of the urine
within a few days (27). Common side effects include nausea,
vomiting, and diarrhea, along with the rare complication of
causing clot formation within the urinary excretory system.
The administration of oral urea has also been found to be
Table 3. Medical management of hematuria in sickle cell
disorders�’
Maintain high urine flow rate
hypotonie fluid intake (4 L/l .73 m2 per d) either po or iv
furosemide 40 mg po BID
Urinary alkalinization
NaHCO3 2 to 3 g QID
± acetazolarnide 250 rug
If bleeding persists after 72 h:
urea 40 g QID
or
EACA 3 to 4 g QID
a � by mouth: iv, intravenously; BID. twice daily: QID, four
times daily: EACA. epsilon aminocaproic acid.
effective in the treatment of persistent sickle trait hematuria
(28). Oral urea is given at a dose of 160 g daily in four divided
doses. This will generally increase the blood urea nitrogen to
greater than 80 mg/dl by day 3, and the hematuria resolves.
Urea has been demonstrated to decrease the viscosity and
gelation of deoxygenated sickle hemoglobin, and has been
found to prevent or reverse sickling. The osmotic diuretic
effect of urea may also lower medullary osmolality.
If bleeding remains uncontrolled, arteriography with local
embolization of the involved kidney region may be used. In
rare instances, nephreetorny may be required.
Papillary Necrosis. The treatment of renal papillary ne-
crosis in patients with sickle cell trait does not differ from that
1038 Journal of the American Society of Nephrology
of other causes of papillary necrosis (22). Aggressive antibiotic
therapy for treatment of infection and early relief of obstruction
due to sloughed papilla is essential. Other factors that may
contribute to the development of papillary necrosis, such as
nonsteroidal anti-inflammatory drugs, should be avoided. Use
of nonionie contrast agents for radiographic studies may be less
likely to cause sickling of RBC than ionic contrast.
The outcome of papillary necrosis in sickle cell trait is
generally good. Papillae seem to be affected one at a time.
Serial follow-up intravenous pyelograrns of a case of sickle-
cell trait with hematuria revealed initially unilateral, then bi-
lateral, evidence of partial papillary necrosis (29). Despite
bilateral lesions involving one or two papillae in each kidney,
there is sufficient uninvolved kidney tissue (the average is
eight pyramids per kidney) to maintain normal renal function.
The impairment of concentrating ability that occurs in sickle
hemoglobinopathies may protect against further injury due to
sickling.
In summary, we have presented a case of papillary necrosis
due to sickle cell trait that presented as gross hematuria. Sickle
cell trait should be included in the differential diagnosis of any
patient who presents with unexplained hematuria.
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Papillary Necrosis and Sickle Cell Disorders 1039
State University of New York at Buffalo Nephrology Training Program
The Nephrology Training Program at the State University of New York at Buffalo is focused at two of the major
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