RNP

Pendahuluan
Renal papillary necrosis (RPN) is characterized by coagulative necrosis of the renal medullary
pyramids and papillae brought on by several associated conditions and toxins that exhibit
synergism toward the development of ischemia. The clinical course of renal papillary necrosis
varies depending on the degree of vascular impairment, the presence of associated causal factors,
the overall health of the patient, the presence of bilateral involvement, and, specifically, the
number of affected papillae.
Renal papillary necrosis can lead to secondary infection of desquamated necrotic foci, deposition
of calculi, and/or separation and eventual sloughing of papillae, with impending acute urinary
tract obstruction. Multiple sloughed papillae can obstruct their respective calyces or can
congregate and embolize to more distal sites (eg, ureteropelvic junction, ureter, ureterovesical
junction). Previously undiagnosed congenital anomalies (eg, partial ureteropelvic junction
obstruction) can provide a narrowed area where the sloughed papilla can nest and obstruct.
Renal papillary necrosis is potentially disastrous and, in the presence of bilateral involvement or
an obstructed solitary kidney, may lead to renal failure. The infectious sequelae of renal papillary
necrosis are more serious if the patient has multiple medical problems, particularly diabetes
mellitus.

History of the Procedure

In 1877, Friedrich first described renal papillary necrosis in a patient with urinary obstruction
resulting from hypertrophy of the prostate.[1] Later, Gunther[2] and Edmondson et al[3] described
renal papillary necrosis as a lesion associated with diabetes. Since then, researchers have
reported that 17-90% of all patients with renal papillary necrosis have diabetes and that 25-73%
of patients have severe urinary tract obstructions. In 1945, Spuhler and Zollinger documented the
first description of analgesic nephropathy. [4] Since then, analgesic abuse has been increasingly
significant in the development of papillary necrosis, particularly in Australia, England, and
Scandinavia.
Ludwig von Beethoven's 1827 autopsy report predates all of these descriptions. The original
Latin autopsy protocol by Johann Wagner was translated into German by von Seyfried in 1832
and has only recently been rediscovered.
Reports indicate that Beethoven, the highly regarded musical genius and arguably the best
composer of all time, was a long-term abuser of alcohol and analgesics. Beethoven was prone to
headaches, back pain, and attacks of rheumatism or gout. His physician often prescribed salicin,
a commonly used analgesic substance at that time, which was made from dried and powdered
willow bark. His alcohol abuse was compounded by a viral hepatitis infection that led to liver
cirrhosis and chronic pancreatitis. Davies postulated that Beethoven developed diabetes mellitus
secondary to chronic pancreatitis. Beethoven had no reported history of urinary obstruction, nor
was it mentioned in his autopsy report.

Wagner's autopsy, as translated by von Seyfried into German, reported "calcareous concretions"
filling every calyx of both kidneys. He described the concretions as "symmetrical and soft like a
pea cut across the middle." According to Davies and Schwarz, this finding is so typical of renal
papillary necrosis that the diagnosis is as near to certain as possible without a histological
examination. Researchers postulate that Beethoven's renal papillary necrosis was most likely a
consequence of analgesic abuse and decompensated liver cirrhosis, which ultimately caused his
death. Davies contests that Beethoven also had diabetes and that this illness was the primary risk
factor for him developing renal papillary necrosis. Indeed, all 3 conditions may have been
synergistic factors. In any case, Wagner's protocol from his autopsy of Beethoven represents the
first description of papillary necrosis recorded in the literature.

Problem
Renal papillary necrosis is sometimes classified as one end of a spectrum of changes associated
with pyelonephritis and tubulointerstitial nephritis. Renal papillary necrosis is often considered a
complication or extension of severe pyelonephritis that is more devastating than usual because of
associated disease states, particularly diabetes and urinary tract obstructions. Other sources
believe this consideration is inaccurate and archaic because renal papillary necrosis does not
usually occur with florid pyelonephritis.
Indeed, pyelonephritis and an ascending urinary tract infection are conditions that are commonly
associated with renal papillary necrosis. Infection is a frequent and important finding in most
cases, contributing significantly to the clinical presentation of renal papillary necrosis (ie, fever
and chills in approximately two thirds of patients, positive urine culture results in 70%).
However, renal papillary necrosis can occur in the absence of infection, indicating that infection
may not be the primary process in the pathogenesis. Conversely, infection is likely a
complication of renal papillary necrosis; the necrotic papillae act as a nidus for infection and
lithogenesis. Infection within necrotic material and calculi is often difficult to definitively treat
with antibiotics alone, and infection often recurs as renal papillary necrosis progresses to chronic
pyelonephritis.
Renal papillary necrosis is considered a sequela of ischemia occurring in the renal papillae and
the medulla. Various insults generate this ischemia, one of which may be infection. The boggy
inflammatory interstitium of the pyelonephritic kidney compresses the medullary vasculature
and, thus, predisposes the patient to ischemia and renal papillary necrosis. This vasculature can
become compressed, attenuated, or impaired from several other associated diseases, most notably
diabetes mellitus, urinary tract obstruction, and analgesic nephropathy. Therefore, renal papillary
necrosis is a distinct clinical and pathophysiological entity primarily caused by ischemia that can
develop without pyelonephritis or urinary tract infection and is likely a focus for infectious
complications. Renal papillary necrosis has a well-documented association with several diseases
that predispose a patient to ischemia.
Renal papillary necrosis is primarily a bilateral process, as is expected considering the systemic
nature of the associated diseases and the ischemic pathophysiologic mechanism of renal papillary
necrosis. Reports indicate that, among patients in whom a single kidney is involved at initial
presentation, the contralateral kidney will develop renal papillary necrosis within 4 years.

Physicians diagnose true unilateral renal papillary necrosis when the patient's predisposing factor
is infection or obstruction that is limited to one kidney, as is the scenario in a patient with
congenital ureteropelvic junction obstruction.

Epidemiology
Frequency

Renal papillary necrosis generally affects individuals who are in the middle decades of life or
older. The typical patient is aged 53 years, with nearly half of cases occurring in individuals
older than 60 years and more than 90% of cases occurring in individuals older than 40 years.
Renal papillary necrosis is uncommon in individuals younger than 40 years and in the pediatric
population, except in patients with sickle cell hemoglobinopathies, hypoxia, dehydration, and
septicemia.
In general, renal papillary necrosis is more common in women than in men. Mandel organized
the first comprehensive review to focus attention on renal papillary necrosis. [5] In his series,
which examined 160 cases of renal papillary necrosis from the world literature, 96 patients
(60%) had diabetes mellitus, 48 patients (30%) had urinary tract obstruction, and 15 patients
(9.4%) had both. In the group with diabetes, women outnumbered men, and in the group of
patients without diabetes, men outnumbered women, further reflecting the frequency and
significance of urinary tract obstructions in elderly men with renal papillary necrosis. An autopsy
report from 1957 by Simon and associates documented the presence of acute or chronic
pyelonephritis in 95%.[6]
Analgesic nephropathy, another associated condition and causal factor of renal papillary
necrosis, is also more common in women than in men. Analgesic nephropathy is particularly
prevalent in individuals with recurrent headaches or chronic, unremitting muscle and joint pain
and in patients with psychoneuroses.
Occupational risks are not associated with developing renal papillary necrosis.

Etiology
Generally, any condition associated with ischemia predisposes an individual to papillary
necrosis. Important general considerations include shock, massive fluid sequestration (eg, as in
pancreatitis), dehydration, hypovolemia, and hypoxia. Certain conditions have a known
association with renal papillary necrosis, and the underlying mechanism of these conditions is
ischemia, which ultimately leads to renal papillary necrosis.
A useful mnemonic device for the conditions associated with renal papillary necrosis is
POSTCARDS, which stands for the following:

Pyelonephritis
Obstruction of the urinary tract

Sickle cell hemoglobinopathies, including sickle cell trait

Tuberculosis
Cirrhosis of the liver, chronic alcoholism
Analgesic abuse
Renal transplant rejection, radiation
Diabetes mellitus
Systemic vasculitis

More than half the patients with renal papillary necrosis have 2 or more of these causative
factors. Thus, renal papillary necrosis in most patients is multifactorial in origin, and physicians
must consider the pathogenesis of renal papillary necrosis a combination of detrimental factors
that overlap and operate in concert to cause renal papillary necrosis (see image below).
.

In this figure, the multifactorial

nature of renal papillary necrosis is represented by 5 of the disease's most frequently associated
conditions: infection, obstruction, diabetes mellitus, analgesic abuse, and sickle cell disease.
Each circle represents a condition. Note how the conditions overlap; the red areas show the
coexistence of 2 conditions, and the black areas represent 3 coexistent conditions. Multiple
conditions exhibit synergism and, therefore, worsen both the severity of the disease and the
prognosis.
One of the most common and most preventable etiologic factors is the use of analgesics. A
classic factor is phenacetin, with its highly toxic metabolite, p-phenetidin. Recently, however,
the rising popularity of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly those that
inhibit cyclooxygenases (ie, COX-1, COX-2) has led to a relatively high frequency of adverse
events in patients at risk for renal papillary necrosis.
In healthy individuals in whom renal arterial blood flow is not compromised, NSAIDs have little
effect unless they are used in excess. This is mostly true because the kidney is not relying on the
vasodilatory effects of prostaglandin to supply adequate perfusion. However, in patients who are

predisposed to renal hypoperfusion, local prostaglandin synthesis protects the glomeruli and
tubules from ischemia. The inhibition of prostaglandin synthesis by NSAIDs that inhibit COX-1
and, as recently reported, COX-2, removes this protective mechanism and predisposes the kidney
to further renal hypoperfusion and, ultimately, ischemia. An extremely important precaution is to
strictly monitor patients with prior renal disease or any of the above-mentioned etiologic
conditions when prescribing NSAIDs.
Additionally, note that a short course of NSAIDs has caused papillary necrosis and nonoliguric
renal failure in otherwise healthy individuals as young as age 17 years. A case such as this may
be an anomaly, but caution is warranted when prescribing NSAIDs, and adequate hydration is
recommended.
These precautions should also be extended to patients receiving specific COX-2 inhibitors.
Touted as being safer than COX-1 inhibitors because they spare the gastrointestinal tract, COX-2
inhibitors have been shown to significantly decrease renal medullary prostaglandin levels.
Therefore, care should be exercised when administering even the COX-2 inhibitors to patients
with a predisposition to renal disease or renal papillary necrosis, and otherwise healthy patients
should maintain adequate hydration and avoid physiologic stress while on these medications.
Recently, multiple publications have described indinavir-induced renal papillary necrosis. In one
study, diagnosis was delayed as the initial symptoms were attributed to suspected urinary
tuberculosis. These studies demonstrate the necessity of renal function monitoring during HIV
treatment above that of calculus monitoring.[7, 8]

Pathophysiology
Renal papillary necrosis is classified as focal (ie, involving only the tip of the papilla) or diffuse
(ie, involving the whole papilla and areas of the medulla), depending primarily on the patient's
degree of impaired vasculature. Renal papillary necrosis may simply affect a single papilla, or
the entire kidney may be grossly involved. Once again, renal papillary necrosis is more often a
bilateral process; many of the predisposing factors are systemic. Renal papillary necrosis never
involves the entire medulla; the disease is always strictly limited to the inner, more distal zone of
the medulla and the papilla.
Researchers recognize 2 pathologic forms of renal papillary necrosisthe medullary form and
the papillary form. The pathogenic form is dictated by the degree of vascular impairment. The
medullary form is characterized by intact fornices, discrete grain-sized necrotic areas, and later
defects in the papillae. Clinicians often observe sinus tracts extruding from irregular medullary
cavities. In the papillary form, the calyceal fornices and the entire papillary surface are
destroyed, demarcated, and sequestered. If these fornices and papillary surfaces are not sloughed,
they reepithelialize and acquire a smoother appearance.
Patients with medullary ischemia develop decreased glomerular filtration rates, salt wasting, an
impaired ability to concentrate, and polyuria because the vasa rectae supply the medulla and
serve the countercurrent exchange mechanism.

The pathologic findings on a cut section include gray-white to yellow necrosis that resembles
infection on the tips or distal two thirds of the pyramids. Microscopically, the tissue shows
characteristic coagulative infarct necrosis, with preserved tubule outlines. The leukocytic
response is limited to the junctions between preserved and destroyed tissue. After the acute
phase, scars that can be observed on the cortical surface as fibrous depressions replace the
inflammatory foci. This pyelonephritic scar is usually associated with inflammation, fibrosis, and
a deformation of the underlying calyces and pelvis.
Papillary necrosis is easily induced experimentally by administering a combination of aspirin and
phenacetin, usually to subjects in a water-depleted state. The phenacetin metabolite p-phenetidin
exhibits high renal toxicity; it injures cells by covalent binding and oxidative damage. These
papillotoxins target interstitial cells via hydroperoxidase-mediated activation. Aspirin induces its
potentiating effect by inhibiting the vasodilatory effects of prostaglandin, thus predisposing the
papilla to ischemia. Therefore, papillary damage may be the result of a combination of the direct
toxic effects of phenacetin metabolites and ischemic injury to both tubular cells and vessels.
Grossly, the cortex exhibits depressed areas that represent cortical atrophy overlying the raised
necrotic papillae. The papillae within the kidney show various stages of necrosis with
calcification, fragmentation, desquamation, and sloughing.
This development contrasts with the papillary necrosis observed in patients with diabetes, whose
papillae are generally at the same stage of acute necrosis at any given time. Microscopically, the
individual papillary changes range from a patchy appearance to the advanced form, wherein the
entire papilla is necrotic. When the papillae remain attached, they are structureless masses with
ghosts of tubules and foci of dystrophic calcification. These tubules and calcifications
subsequently fragment and slough, becoming potential obstructive entities. The cortical columns
of Bertin that contain the glomeruli characteristically remain uninvolved. Certain papillotoxins
target interstitial cells, resulting in hydroperoxidase-mediated activation with subsequent
inflammatory, degradative, and necrotic cell changes

Presentation
Renal papillary necrosis has a variable clinical course that ranges from a chronic, protracted, and
relapsing form to an acute, rapidly progressive form. The acute progressive form is particularly
rare, but the effects are devastating, resulting in death from septicemia and renal failure. Patients
with the more common chronic form may remain asymptomatic until diagnosed incidentally
through the appearance of a ring shadow on a radiographic image, by the passage of sloughed
papillae in the urine, or during autopsy. The symptomatic form manifests as episodes of
pyelonephritis and hydronephrosis, and it mimics nephrolithiasis.
The most common presenting symptoms in symptomatic patients include fever and chills, flank
and/or abdominal pain, and hematuria. Acute renal failure with oliguria or anuria is rare; when
these symptoms develop, the disease may be fulminant, requiring dialysis and potentially
resulting in death.

If renal function deteriorates suddenly in a patient with confirmed diabetes or in a patient with a
known history of chronic obstruction and/or pyelonephritis, consider the diagnosis of papillary
necrosis, even if the patient is asymptomatic.
Acute ureteral obstruction from sloughed papillae manifests as flank pain and colic due to
hydronephrosis or pyonephrosis; hematuria is invariably present. Pyonephrosis or secondary
acute or relapsing pyelonephritis compounds the presentation with fever, chills, prostration, and
sepsis.

Indications
The differential diagnoses of flank pain or hematuria includes a plethora of conditions with
infectious, neoplastic, congenital, metabolic, and hematogenous sources. Intraluminal and
extraluminal lesions may result in ureteral obstruction.
If acute ureteral obstruction manifests as hematuria, colic, and flank pain, consider that
nephrogenic calculi may have embolized to the ureter. Approximately 15% of all calculi,
particularly uric acid stones, are not radiopaque (ie, visible on radiographs); therefore, the
examining clinician needs to perform further imaging studies for an accurate identification.
CT scanning is an excellent imaging modality for identifying all calculi (including uric acid
stones), except for the rare indinavir (Crixivan) crystal concretions that form in the ureters of
patients with HIV infection who are taking this protease inhibitor. If calculi are not seen on a CT
scan, consider the possibility of an obstructing urothelial tumor; cytology and endoscopic
procedures help to determine this diagnosis.
Blood coagulum downstream from a bleeding source in the kidney (eg, renal cell carcinoma,
angioma, angiomyolipoma, arteriovenous malformation, trauma to a pyelonephritic or
multicystic kidney) can also manifest with a similar clinical picture. If a patient has acute ureteral
obstruction with fever and leukocytosis, the preferred treatment is drainage of the system.
Pyonephrosis may or may not be present; therefore, the initial short-term management of an
obstructed system should be conservative, with resuscitation, drainage, and intravenous
antibiotics. Further diagnostic studies can be performed later, once the physician is certain that
the system is sterile. This strategy prevents further clinical deterioration.
Extraureteric causes of ureteral obstruction include retroperitoneal lymphadenopathy from
metastatic tumors or lymphoma, retroperitoneal fibrosis, uterine myoma, bladder masses, and
high-stage pelvic tumors (eg, cervical cancer).
Anything that causes severe bladder outlet obstruction leads to bilateral hydronephrosis or
hydronephrosis of a solitary kidney. Congenital anomalies can also directly obstruct or provide
stasis that may lead to pyelonephritis and papillary necrosis. Duplicate collecting systems,
vesicoureteral reflux, and ureteroceles are important offenders to consider.

In the clinical scenario of fever, chills, prostration, and sepsis without hydronephrosis, the
differential diagnoses include pyelonephritis, perinephric abscess, renal hemorrhage,
tubulointerstitial nephritis, and glomerulonephritis.
In asymptomatic patients who present with acute renal failure characterized by azotemia, the
physician must consider bilateral obstruction or the presence of a solitary obstructed kidney.
Renal ultrasonography is a wise first test in this scenario, along with tests for urine and plasma
urea, creatinine, sodium, and osmolality. After excluding postrenal causes, consider prerenal and
renal sources.

Relevant Anatomy
Briefly reviewing basic renal anatomy and histology allows a clear understanding of the
pathophysiology of the underlying ischemia of renal papillary necrosis and how this ischemia is
distributed.
The renal papilla is the rounded apex of each medullary pyramid and represents the confluence
of the collecting ducts from each nephron within that pyramid. An individual minor calyx cups
each papilla; these calyces represent the most proximal aspect of the renal collecting system and
are lined with transitional cells.
The renal papillary blood supply is derived from 2 sources: the vasa rectae, which disperse blood
from the efferent arteriole, and the interlobar branches of the renal artery, which run within the
adventitia of the minor calyces. The vasa rectae arise from the efferent arteriole within the renal
cortex and form wide and plentiful vascular bundles at the base of the medullary pyramid. The
bundles taper as they continue distally toward the apex and papilla. This process results in the
papillary tip receiving only a marginal supply of blood, which appears to be a predisposing factor
for the central role of ischemia in the development of renal papillary necrosis.
The already tenuous vasculature is further impaired by several pathophysiologic states, including
the above-described boggy inflammatory interstitium of pyelonephritis, the microangiopathy of
diabetes mellitus, the increased pyelovenous pressure of urinary obstruction, the chronic
hyperbilirubinemia of liver cirrhosis, the oxidative damage of analgesic nephropathy, and the
intraluminal stasis of sickle cell disease.

Contraindications
Patients with known or suspected renal papillary necrosis should limit or completely avoid the
use of analgesics. Other nephrotoxic medications should also be avoided. The routine use of
indwelling catheters should be discouraged except when clinically indicated. Clean intermittent
catheterization, although more time-consuming, is equally effective for the purpose of
monitoring output is less likely to cause nosocomial urinary tract infection.
In patients with obstructed collecting systems who are hemodynamically unstable, obtunded, and
floridly septic, avoiding any retrograde instrumentation of the ureter, such as stent placement,

should be seriously considered. Unnecessary retrograde instrumentation is discouraged because

of the risk of irrigating purulent or contaminated urinary inoculum from the lower urinary tract
into the renal pelvis and pyelovenous system, exacerbating urosepsis.
In general, patients who are more ill should preferably be treated with antegrade percutaneous
nephrostomy placement. However, an uncorrectable concomitant coagulopathy may preclude
any percutaneous procedures, considering the potential morbidity of renal hemorrhage. Attempt
correction of any coexisting coagulopathy prior to percutaneous nephrostomy. In patients with
hemodynamic instability who have a grossly infected and obstructed collecting system with an
uncorrectable coagulopathy, the problem is more dire and a truly effective treatment remains
elusive. These patients are probably best treated with retrograde stent placement to avoid a
potentially lethal renal hemorrhage. In the severely ill patient, perform the quickest and safest
procedure to establish drainage of the hydronephrotic section. This means that carefully
considered retrograde procedures are sometimes the preferred modalities.
Broad-spectrum intravenous antibiotics administered immediately prior to any retrograde study
may have a protective effect.
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