917
ASSOCIATION OF RENAL PAPILLARY
NECROSIS AND ANKYLOSTNG
SPONDYLITIS
SETH H. LOURIE, SUSAN J. DENMAN, and EDWARD T. SCHROEDER
Three patients with ankylosing spondylitis devel-
oped renal papillary necrosis. All had received prosta-
glandin synthetase inhibitors including phenylbutazone,
indomethacin, or ibuprofen. One patient had sickle trait.
These drugs are not commonly associated with papillary
necrosis in man, but may adversely effect renal medullary
blood flow. An underlying renal vascular abnormality
related to ankylosing spondylitis is also considered.
Patients with ankylosing spondylitis who are taking pros-
taglandin synthetase inhibitors should be routinely screened
for hematuria.
In the past 4 years we have observed 3 patients
with ankylosing spondylitis and renal papillary necrosis.
A n association between these two processes has not
been previously noted. Etiologic considerations include
the effects of medications, an underyling renal lesion
related to ankylosing spondylitis, and the presence of
sickle trait in 1 patient. We have examined the possible
interaction of these factors to produce the renal lesions
seen in our patients.
From the State University of New York Upstate Medical
Center, Syracuse, New York.
Seth H. Lourie, M.D.: Assistant Professor of Internal Medi-
cine and Rehabilitation Medicine (Rheumatology): Susan J. Denman.
M.D.: formerly student at State University of New York Upstate
Medical Center, presently House Officer, Baltimore City Hospital,
Baltimore, Maryland: Edward T. Schroeder, M.D.: Associate Profes-
sor of Internal Medicine (Nephrology).
Address reprint requests to Seth H. Lourie, M.D., S U N Y
Upstate Medical Center, 750 East Adams Street, Syracuse, New York
13210.
Submitted for publication September 10, 1976; accepted De-
cember 23. 1976.
Arthritis and Rheumatism, Vol. 20, No. 4 (May 1977)
CASE REPORTS
Case 1
A 26-year-old white male was hospitalized on July
30, 1973, for gross hematuria and right flank pain of 1 week
duration. He had noted pain in his back, shoulders, and left
knee for I year. Ankylosing spondylitis was diagnosed on the
basis of sclerotic sacroiliac joints on X ray and decreased
spinal movement. He was treated with phenylbutazone, 100
mg three times a day, from December 1972 to March 1973.
when he noted a brief episode of painless, gross hematuria
lasting about 12 hours. This episode was not further evaluated
at that time, but the phenylbutazone was decreased to 100 mg
daily. In June 1973 penicillin was given for a culture-proven
streptococcal throat infection. He had no history of urethritis,
conjunctivitis, bowel disease, or rash.
On physical exam his BP was 108/75 and he was
afebrile. Schober's index was 2 cm of movement on forward
bending, and chest expansion was 3.1 cm. There was no costo-
vertebral angle tenderness and the remainder of the exam-
ination was unremarkable. Urine showed 30 mg/dl albumin
and greater than 100 RBCs/HPF. Urine cultures were nega-
tive. Serum creatinine and BUN were normal and creatinine
clearance was I13 ml/min. Renal diluting and concentrating
capacities were normal. HLA typing was positive for antigen
B27. Coagulation studies were normal. Rheumatoid factor,
LE prep, and ANA were all negative. An intravenous pyelo-
gram showed deformity and destruction of part of the calyceal
system of the right kidney, with filling defects and extrava-
sation of contrast material into the renal parenchyma (Figure
1 ). The left kidney showed less extensive calyceal deformities.
Percutaneous renal biopsy was performed and the findings are
discussed below.
Phenylbutazone was discontinued and the hematuria
gradually cleared. Since his discharge from the hospital he has
been treated with aspirin and propoxyphene in addition to
courses of hydroxychloroquine, ibuprofen, and diazepam
918
Fig 1. Case I : Pyelogram showing contrast material outside the renal
calyx due to papillary necrosis.
without recurrence of hematuria or deterioration of renal
function. His ankylosing spondylitis is particularly severe and
has progressed to involve his cervical spine, and he now has
bilateral flexion contractures of his hips and knees. No cardiac
lesions have been noted. In the past year he has developed a
rash resembling psoriasis.
Case 2
A 23-year-old white male was admitted to the State
University Hospital in September 1973 because of intermittent
episodes of painless, gross hematuria. He had a history of back
pain for 6 years. Ankylosing spondylitis was confirmed by
sacroiliac sclerosis, decreased chest expansion, and positive
family history. He was treated with propoxyphene and inter-
mittent aspirin. I n the fall of 1969 he developed his first epi-
sode of painless, gross hematuria. H e was evaluated at another
hospital, where intravenous pyelography showed possible ob-
struction of the right uretero-pelvic junction, but cytoscopy
and retrograde pyelogram were normal, and urine cultures
were negative. The hematuria subsided and he continued his
medications. In September 1970 indomethacin was added but
was discontinued after 2 weeks because of headaches and
dizziness. lndomethacin was restarted in February I973 be-
cause of increased back pain and was continued until late
August 1973, when his urine became brown.
On physical exam his BP was 142/70 and he was
afebrile. There was minimal tenderness to percussion over the
lower lumbar spine, but the remainder of the exam was unre-
markable. Urinalysis revealed greater than 100 RBCs/HPF.
L O U R I E ET AL
Fig 2. Case 2: Extravasated dye on pyelogram.
Creatinine clearance was 149 ml/min. Urine concentrating
and diluting capacities were normal, and urine cultures were
negative. Coagulation studies were normal. HLA antigen B27
was absent. A pyelogram showed mild bilateral papillary ne-
crosis (Figure 2). A percutaneous renal biopsy was performed
and the findings are discussed below.
The hematuria subsided over a few weeks and he has
been treated with phenylbutazone and propoxyphene since
January 1974. He has been testing his urine for occult blood,
and has had a few episodes of microscopic hematuria, but no
return of gross urinary bleeding.
Case 3
A 26-year-old black male with sickle trait noted the
onset of gross hematuria associated with fatigue and left flank
pain in late August 1972. He had intermittent pain in his back
and left hip for 12 years. Ankylosing spondylitis was diag-
nosed in December 1970 based on sclerosis of sacroiliac joints,
fusion of L3-LS posterior joints, and bilateral hip disease.
HLA typing showed that antigen B27 was present. H e was
PAPILLARY NECROSIS IN SPONDY LITIS
Fig 3. Case 3: Blunting of calyces and extramsation of dye on pyelogram.
treated with indomethacin, 25 mg twice daily, from December
1970 to May 1972 when phenylbutazone was instituted. The
phenylbutazone was discontinued for lack of effect and in-
domethacin was restarted at 25 mg four times a day in June
1972.
Microscopic hematuria developed first, followed by
gross hematuria. left flank pain, mild urgency, and urinary
frequency. BP was 110/60 and he was afebrile. There was
flexion and general stiffness of the dorsal spine and decreased
range of motion of the hip joints bilaterally. There was no
costovertebral angle tenderness, and the rest of the exam-
ination was unremarkable. Urinalysis showed greater than 100
RBCs/HPF: urine cultures were negative. Creatinine clear-
ance was 76 ml/min. Renal tubular function studies and histo-
compatibility typing were not done. Coagulation studies were
normal. Intravenous pyelography showed a filling defect in a
right calyx and general irregularities of the collecting system
bilaterally consistent with papillary necrosis (Figure 3).
After indomethacin was discontinued, the hematuria
gradually disappeared over the next few months. H e was
treated with aspirin and propoxyphene without recurrence of
hematuria until November 1974, when a trial of ibuprofen was
instituted. His urine became reddish-brown within 1 week and
cleared when he discontinued the drug. He restarted the
ibuprofen with the same result. Urinalysis showed 80
919
RBCs/HPF, and creatinine clearance was 69 ml/min. His
urinalysis returned to normal within 1 week of discontinuing
the ibuprofen. Since January 1975 he has been treated with
aspirin and propoxyphene without recurrence of hematuria.
DISCUSSION
The diagnosis of ankylosing spondylitis in these 3
patients was based on bilateral sacroiliitis and lumbar
pain in accordance with the New York criteria ( I ) .
HLA-B27 was present in 2 of the 3 patients. The diag-
nosis of papillary necrosis was based on gross hematuria
and typical intravenous pyelography findings in all the
patients, and on flank pain in 2.
Papillary necrosis has been associated with
urinary tract obstruction, diabetes mellitus, long-term
ingestion of aspirin-phenacetin mixtures, and hemoglo-
bin S disorders (2-4). Papillary necrosis related to
urinary tract infection and diabetes is associated with
decreased renal function and usually progresses to
uremia (2). Patients with papillary necrosis related to
analgesic ingestion and hemoglobin S often have more
mild disease with well preserved renal function, as was
seen in our patients. There was no evidence of diabetes,
obstruction, or chronic urinary tract infection in these
patients. Case 3 was complicated by the presence of
sickle trait; however the occurrence of gross hematuria
was apparently directly related to the use of an antiin-
flammatory drug, as shown by drug challenge.
Renal morphologic lesions associated with pa-
pillary necrosis have been well studied in patients with a
history of excessive ingestion of analgesic drugs contain-
ing aspirin and phenacetin ( 5 , 6 ) . Despite radiologic evi-
dence of papillary necrosis, histologic findings vary from
no change to severe interstitial fibrosis, tubular atrophy,
sclerosis of the medulla, and slomerular fibrosis. The
earliest lesion consists of increased collagen fibers
around the tubules and vasa rectae (5). Our two biop-
sied patients had few histologic renal abnormalities. N o
tubular lesions or increased collagen was noted in either
biopsy. Minimal lesions were seen on electron micros-
copy. Case 1 had a few small epimembranous glomeru-
lar deposits; however he had no clinical evidence of
glomerulitis and no vascular changes were seen. In Case
2 there were focal hyalin deposits in the intima and
media of the arteriolar walls. Similar lesions have been
seen in hypertension, diabetes, and advanced age (7,B).
It is especially interesting that these deposits have been
reported in ankylosing spondylitis. Pasternack et a/ (9)
found hyalin deposits between the intima and media of
arterioles and small arteries on light microscopy in 67%
of renal biopsies of 24 patients with spondylitis with
920
normal renal function. The deposits seen in case 2 may
represent an early stage of such a lesion.
Our patients used antiinflammatory drugs that
are not commonly known to cause papillary necrosis
(Case 1-phenylbutazone; Case 2-indomethacin, pro-
poxyphene HCI, and aspirin; and Case 3-indomethacin
and ibuprofen). Papillary necrosis following phenyl-
butazone has been reported in one prior case, an elderly
man with osteoarthritis and nephrolithiasis who devel-
oped anuria, papillary necrosis, and obstructive urop-
athy after 5 months of therapy (10). Biopsy tissue was
interpreted as “chronic pyelonephritis,” but further de-
scription is not available.
There are several other case reports of transient
anuria following fairly short courses of phenylbutazone
therapy (11-14). These patients, some of whom had
microscopic hematuria, appeared to be idiosyncratic hy-
persensitivity reactions. Renal biopsies were reported as
“tubular necrosis” ( 1 1 ), generalized “nephrosclerosis”
(13). and “tubulo-interstitial nephritis” (14). There was
no evidence of papillary necrosis in these cases. Studies
in animals have shown that renal lesions can be pro-
duced with these compounds. Studies in animals have
shown that renal lesions can be produced with these
compounds. Small daily doses of phenylbutazone, for 8
to 20 weeks, produced papillary necrosis in rats (15).
Arnold et a1 (16) have produced the same lesion in rats
with a single high dose of phenylbutazone or in-
domethacin. lndomethacin has been associated with mi-
croscopic hematuria in some patients with juvenile rheu-
matoid arthritis (17). Papillary necrosis has been noted
at autopsy in rheumatoid arthritis, although it is often
unclear what criteria were used to make the diagnosis
(18-20). Clinically evident papillary necrosis as seen in
our patients, however, has not been specifically de-
scribed.
The mechanism by which drugs cause papillary
necrosis remains controversial. Arnold et a1 (16) favored
a toxic etiology based on the finding that papillary ne-
crosis could be produced in rats within 2 hours of oral
phenylbutazone without evident vascular lesions. Other
data suggest a vascular etiology. Kincaid-Smith et a1
(21 ) used an aspirin-phenacetin-caffeine(APC) mixture
to produce papillary necrosis in rats. The earliest mor-
phologic lesions they found were increases in the num-
ber and density of reticulin and collagen fibers of the
vasa rectae and decreased vascular lumina. Measure-
ments of renal medullary blood flow in APC-fed rats
show that medullary ischemia is present before any his-
tologic lesions occur (22). A similar reduction in medul-
lary blood flow has been found in rats following in-
domethacin (23.24).
LOURIE ET AL
ltskoritz and coworkers (25) have demonstrated
a correlation between the effect of indomethacin on
inhibition of prostaglandin production and a decrease in
the ratio of inner cortical blood flow to outer cortical
blood flow. Phenylbutazone and ibuprofen as well as
indomethacin inhibit prostaglandin synthetase (26), and
they might therefore produce similar effects on distribu-
tion of renal blood flow. However, other workers have
not been able to document a decreased medullary blood
flow in dogs following prostaglandin synthetase inhibi-
tion (27).
The mechanism for the development of papillary
necrosis in our 3 patients is not clear. Their normal renal
function suggests analgesic nephropathy as opposed to
other causes. However the analgesics our patients
used-phenylbutazone, indomethacin, ibuprofen, aspi-
rin, and propoxyphene-are not commonly associated
with papillary necrosis in humans. All these drugs, ex-
cept propoxyphene, inhibit prostaglandin synthetase.
This inhibition may have been a factor in our patients by
causing a decrease in medullary blood flow as noted in
the animal models. Unfortunately no direct evidence of
alteration of renal blood flow has been shown in man.
Furthermore, these compounds are used in a wide vari-
ety of diseases, and no other reports suggest that they
substantially increase the incidence of papillary necrosis.
These facts lead us to speculate that a combination of
factors may be necessary for a significant lesion to de-
velop.
In Case 3 the presence of sickle trait may certainly
have contributed t o papillary necrosis, as mentioned
above. The tendency for increased sickling in the vasa
rectae (4) may have been exacerbated by the postulated
reduction in renal medullary blood flow. The association
of the papillary necrosis with ankylosing spondylitis in our
cases is interesting. Spondylitis is hereditary, with auto-
soma1 dominant transmission and a uniquely high asso-
ciation with histocompatibility antigen HLA-B27. Al-
though much speculation suggests that the underlying
lesion is immunologic, no proof exists and other tissue
defects can be hypothesized. There may be a vascular
abnormality i n ankylosing spondylitis, perhaps unre-
lated to HLA antigens, which might predispose them to
drug-induced papillary necrosis.
Although a mechanism for our finding remains
speculative, certain implications can be drawn. In the 3
patients we studied there appears to have been an associ-
ation between ankylosing spondylitis and papillary ne-
crosis. The renal lesions may have resulted from a com-
bination of factors including the drug therapy, the
underlying disease process, and in one case the presence
of sickle trait. Perhaps there are more patients similar to
PAPILLARY NECROSIS IN SPONDYLITIS
ours in whom the diagnosis of papillary necrosis is
missed. We would encourage routine screening of anky-
losing spondylitis patients for hematuria. Further eval-
uation including intravenous pyelography and renal
tubular function should be done if any bleeding is
found*Patients with ankylosing spondylitis and espe-
cially those with sickling disorders should be carefully
monitored while taking prostaglandin synthetase inhib-
itors because they may be more prone to develop pa-
pillary necrosis.
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