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.

References1 . Vaamonde CA, Oster JR. Strauss J: The kidney in sickle cell

disease. In: The Kiclne� in Systemic Disease, edited by Suki WN,

Eknoyan 0, New York, Wiley, 1981, pp 159-1952. De Jong PE. Van Eps LWS: Sickle cell nephropathy: New

insights into its pathophysiology. Kidney Jut 27: 71 1-717, 1985

3. Allon M: Renal abnormalities in sickle cell disease. Arc/i Intern

Med 150: 501-504, 1990

4. Falk Ri. Jennette SC: Sickle cell nephropathy. Adv Nephro/ 23:

133-147, 1994

5. Sears DA: The morbidity of sickle cell trait. Aiti J Med 64:

1021-1036, 1978

6. Lange RD. Minnich V. Moore CV: Effect of oxygen tension and

pH on the sickling and mechanical fragility of erythrocytes from

patients with sickle cell anemia and sickle cell trait. J Lab C/in

Med 37: 789-801. 1957

7. Van Eps LW, Pinedo-Veels C, DeVries OH, DeKoning J: Nature

of concentrating defect in sickle-cell nephropathy: Microangio-graphic studies. Laticet I : 450-45 1 , 1970

8. Mostofi FK, Under Brueggs C, Diggs LW: Lesions in kidneys

removed for unilateral hematuria in sickle cell disease. Arch

Pat/wlLabMed63: 336-351, 1957

9. Van Eps LW, Schouten H. Romeny-Wachter C, LaPorte-Wijs-man L: The relationship between age and renal concentratingcapacity in sickle cell disease and hemoglobin C disease. C/in

Chi,n Aeta 27: 501-51 1, 1970

10. Oster JR. Lespier LE. Lee SM, Pellegnni EL, Vaamonde CA:

Renal acidification in sickle cell disease. J Lab C/in Med 99:

389-401, 1976

I 1 . Keitel HG, Thompson D. Itano HA: Hyposthenuria in sickle cell

anemia: A reversible renal defect. J C/in Invest 35: 998-1007,

I956

12. Levitt MF, Hauser AD, Levy MS. Polimeros D: The renal

concentrating defect in sickle cell disease. Am J Med 29: 61 1-

622, 1960

I 3. Oster JR. Lanier DC, Vaamonde CA: Renal response to potas-

sium loading in sickle cell trait. Arch Intern Med 140: 534-536,1980

14. DeFranzo RA, Tarfield PA, Black J: Impaired renal tubularpotassium excretion in sickle cell disease. Ann Intern Med 90:

310-316, 1979

15. Walker BR, Alexander F: Uric acid excretion in sickle cell

anemia. fAin MedAssoc 215: 255-258, 197116. Diamond HS, Meisel AD, Sharon E, Holden D, Cacatian A:

Hyperuricosuria and increased tubular secretion of urate in sickle

cell anemia. Am J Med 59: 796-802, 1975

18. Richie JP, Kerr WS: Sickle cell trait: Forgotten cause of hema-tuna in white patients. J Urol 122: 134-135, 1979

19. Eckert DE, Jonitlis AJ, Davidson AJ: The incidence and mani-festations of urographic papillary abnormalities in patients with S

hemoglobinopathies. Radiology I 13: 59-63, 197420. Pandya KK, Koshy M, Brown N, Pressman D: Renal papillary

necrosis in sickle cell hemoglobinopathies. J Urol 1 15: 497-501,

19762 1 . Mapp E, Karasick S. Pollack H, Wechsler Ri, Karasick D:

Uroradiological manifestations of S-hemoglobinopathy. Seinin

Roentgenol 22: 186-194, 1987

22. Vaamonde CA: Renal papillary necrosis in sickle cell hemoglo-

binopathies. Setnin Nephro/ 4: 48-64, 198423. Whalley PJ. Martin FG, Pritchard JA: Sickle cell trait and urinary

tract infection during pregnancy. J Am Med Assoc 189: 903-906,I 964

24. Maryniek SP, Ramsey EJ, Knochel JP: The effect of bicarbonate

and distilled water on sickle trait hematuria and in vitro studies

on the interaction of osmolality and pH on erythroeyte sickling insickle cell trait. J Urol I 18: 793-796, 1977

25. Melnnes BK: The management of hematuria associated withsickle hemoglobinopathies. J Urol 124: 171-174. 1980

26. Meyerfeld SA, Morganstern SL, Seery W, Cole AT: Medical

management of refractory hematuria in sickle-cell trait. Urology

8: 112-113, 1976

27. Nilsson IM, Andersson L, Bjorkman SE: Epsilonamino-eaproic

acid (E-ACA) as a therapeutic agent based on 5 years clinical

experience. Acta Med Scand Suppi 448: 10-15, 1966

28. Pariser S. Katz A: Treatment of sickle cell trait with oral urea.

J Urol 151: 401-403, 1994

29. Gong MB. Davidson AJ: Development and progression of renal

papillary necrosis in SA hemoglobinopathy. Urol Radiol 2: 55-

56, 1980

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

teaching hospitals affiliated with the Medical School: the Erie County Medical Center and the Veterans Administration

Medical Center, but uses other hospitals as necessary to enhance teaching and research. Our large faculty, with varied

interests and backgrounds, affords fellows the opportunity to be exposed to a variety of approaches to nephrologie

problems. Trainees develop competence in all aspects of clinical nephrology in compliance with the special requirements

for training programs in nephrology. These include structured and focused training, comprehensive instruction, and active

participation in various dialysis modalities, renal transplantation, and continuous renal replacement therapy. The nephrol-

ogy fellows are also trained in procedures such as percutaneous renal biopsy and dialysis catheter insertions. Experience

in the care of end-stage renal disease (ESRD) patients is offered through direct involvement of the fellows in the ESRD

team approach to management of both hospitalized and nonhospitalized ESRD and transplant patients. The opportunity for

both clinical and basic research is available and encouraged for the fellows. The program prepares the nephrology trainees

for clinical practice of nephrology, subspecialty board examination, and academic medicine or research. The length of the

program is 2 yr with the possibility for extension, if desired, to continue research training. During this 2-yr period, fellows

are able to organize a work system that will be conducive to an efficient and productive experience for inpatient care

delivery, training, and education. Constant growth in education is accomplished through journal clubs, teaching respon-

sibilities, research experience, and attendance and participation in regional and national nephrology scientific meetings.