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Renal Papillary Necrosis in a Patient with Sickle Cell Trait

GINO ZADEII and JAMES W. LOHR Department of , 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 abnormalities associated with sickle cell trait is described. The gross and was subsequently found to have renal management of the primary clinical manifestations of this papillary necrosis is presented. The hematuria resolved with disorder, hematuria and papillary necrosis, are discussed. conservative consisting of bed rest and hydration with (J Am Soc Nephrob 8: 1034-1040, 1997) hypotonie intravenous fluids. The pathophysiology of renal

A variety of renal abnormalities have been described in pa- mg/dl. Urine dipstick revealed a specific gravity of I .020, pH tients with sickle hemoglobinopathies (1-5). Most of the liter- 5.5, 3+ blood, 3+ protein, and was negative for glucose, ature has dealt with patients with homozygous sickle cell ketones, and leukocyte esterase. The microscopic exam (HbSS), although the incidence of heterozygous sickle showed many red blood cells (RBC), but no RBC casts or cell trait in the United States has been estimated to be 40 times white blood cells were seen. Urine culture showed no growth. as great (1). The patient was evaluated by a urologist, and an intravenous We report a case of a patient with sickle cell trait presenting pyelogram was performed that showed bilateral papillary ne-

with gross hematuria, who was subsequently found to have erosis (Figure 1 ). The patient was placed at bed rest and given papillary necrosis on intravenous pyelography. A discussion of intravenous half-normal saline at a rate of 150 mlIh. The the renal abnormalities associated with sickle cell trait and the hematuria cleared on day 4. Before discharge, he had cystos- approach to management of these disorders is presented. copy that was unremarkable. Retrograde urogram could not be completed due to patient discomfort. Case Report The patient has not had any recurrent hematuria in the 9 mo An African-American man 66 yr of age presented to the since discharge. Buffalo Veterans Affairs Medical Center with a 2-d history of gross hematuria. He denied having experienced fever and Discussion chills, dysuria, or flank pain. He had no history of recent Several renal abnormalities have been described in patients trauma or nephrolithiasis. Past medical history was significant with sickle cell disorders. These vary depending on whether for , hypereholesterolemia, and benign prostatie the patient has or sickle cell trait. In sickle hypertrophy, which had been evaluated in the previous year cell disease, there are two abnormal genes related to hemoglo- and found not to be causing any urinary tract obstruction. He bin production, with at least one being the gene for also had sickle cell trait, diagnosed by AS pattern on hemo- S. These include sickle cell anemia, sickle cell-hemoglobin C globin eleetrophoresis in 1986. The patient was taking lisino- disease, sickle cell-thabassemia, and some less common disor- pril and eolestipol. He denied taking any nonsteroidal inflam- ders. Nephropathy associated with sickle cell disease has been matory drugs. well reviewed (1-4). In sickle cell trait, there is a normal gene, The revealed a well-developed man in along with the gene for hemoglobin S. This is the most corn- no acute distress. Blood pressure was 140/70 mmHg, pulse was mon hernogbobinopathy in the United States, present in more 76 beats/mm, and temperature was 36.5#{176}C. Examination of the than 2 million people. This discussion will be restricted to renal abdomen showed no evidence of hepatosplenomegaby. No cos- findings in sickle cell trait, with only a mention of the con- tovertebral tenderness was noted. The physical examination trasting features of sickle cell anemia. was otherwise unremarkable except for a symmetric, mildly enlarged prostate gland. Laboratory tests showed normal com- Pat hophysiologv plete blood cell counts, clotting studies, and . Blood The renal medullary interstitium may achieve an osmolarity nitrogen was I 2 mg/dl. and serum ereatinine was I .3 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 . The medullary Received March 7. 1996. Accepted October 9. 1996. interstitium is made hypertonic by reabsorption of sodium Correspondence to Dr. James W. Lohr. Department of Medicine ( I 1 1A), Veterans Affairs Medical Center. 3495 Bailey Avenue. Buffalo. NY 14215. chloride without water in the ascending limb of the loop of

1046-6673/0806- l034$03.00/0 Henle. Solute is transferred from the tubular lumen into the Journal of the American Society of Nephrology rnedullary interstitial fluid, raising the osmotic concentration of Copyright 0 1997 by the American Society of Nephrology 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- to leak into the collecting system. This results in a reduced scending limb of the loop of Henle and raises the osmolality of number of vasa recta and loss of the normal medullary archi- the tubular fluid as it approaches the tip. Urea also contributes tecture as revealed by microangiographic studies (7). to the hyperosmolabity of the medullary interstitium by diffu- Eventually, these events may lead to papillary necrosis. The sion from the inner rnedullary collecting tubule. The vasa recta papillary necrosis usually involves the tip of the papilla, with are vessels with hairpin-like construction that lie near the loops no involvement or destruction of the fornices. Gross pathologic of Henle and carry blood through the medullary tissue at a exam shows one or more papillae with areas of necrosis, much slower rate than cortical vessels. Thus, this blood comes usually involving one-third of the papilla (8). Calcification into contact with the hypertonic medullary interstitial fluid may be seen in old areas of necrosis. Microscopic examination through the capillary wall. reveals total or partial necrosis of tubular and collecting duct In patients with sickle cell trait, the hyperosmolar interstitial epithelium in the area of necrosis. There may be evidence of fluid draws water from the cells, resulting in an increased expansion of the interstitial space with fibrosis. concentration of sickle cell hemoglobin, the most important The functional renal changes (Table 1) that are seen in sickle determining factor for sickling (Figure 2). Another factor that cell trait are primarily due to the loss of vasa recta, which may contribute to sickling is the low oxygen disrupts the countercurrent exchange system. This results in an tension present in the medulla. Along with the fact that the impaired ability to concentrate the urine in patients with sickle medulla receives less than 10% of the renal blood flow, the cell trait (9-12). This appears to be reversible early in life, but configuration of the vasa recta capillaries results in a loss of there is a continual gradual decrease throughout life, which oxygen as the blood enters the medulla with subsequent uptake then becomes fixed. In patients over 50 yr of age, maximum by the opposing ascending capillaries leaving the medulla. This urine osmolality generally will not exceed 450 mosmol (9). can result in oxygen tensions of 20 mmHg or less in the The ability to dilute the urine has been found to be normal in medulla, with sickling often occurring at less than 45 mmHg patients with sickle cell trait (12). due to polymerization of sickle cell hemoglobin. This hypoxia, Patients with sickle cell trait have been found to have a along with the acidic rnedullary pH, also promotes sickling of normal ability to excrete acid in response to ammonium chlo- RBC (6). As sickling occurs, there is an increase in blood ride loading ( 10). This is in contrast to those with sickle cell viscosity, which may further slow the blood flow in the rued- disease who frequently have an incomplete distal renal tubular ullary capillaries. acidosis ( 10). Potassium excretion has also been studied and Initiably, capillaries become engorged with erythrocytes. was found to be normal in patients with sickle cell trait, Subsequently, RBC sickling in the vasa recta causes formation whereas it was frequently impaired in those with sickle cell of rnicrothrombi, infarction, and formation of collateral vessels anemia (13.14). Sodium handling is thought to be normal in (7). Capillaries develop increased permeability, allowing RBC patients with sickle cell trait. although this has not been well 1036 Journal of the American Society of Nephrology

Renal Medullaiy 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 Acidosis Hypertonicity Hypoxia seen in African-American patients (18). Papillary Necrosis. Renal papillary necrosis may occur in sickling of RBC up to 50% of patients with sickle cell trait who present for evaluation (19,20). It is generally discovered during evaluation in vasa recta of hematuria. It must be differentiated from the other common Ir causes of papillary necrosis listed in Table 2. Various patterns of papillary abnormalities have been described on excretory blood viscosity t urography (intravenous pyebogram and/or retrograde pyebo- gram) (19-22). The most common pattern seen in sickle he- ,,,,medullary blood flow mogbobinopathies is a medullary type of partial papillary ne- I erosis, which appears as a cavity within the papilla (20,21). microthrombi formation Papillary necrosis is most commonly identified in sickle cell infarction of vasa recta trait at 30 to 40 yr of age, but initial presentation in older formation of collateral vessels patients, such as in this case report, is not uncommon. There does not seem to be a sex predominance in the incidence of the papillary necrosis defect in countercurrent disease. exchange The clinical presentation of papillary necrosis in sickle cell trait is quite variable (22). It may appear as gross hematuria

loss of rena concentrating ability with or without renal colic. Patients may have symptoms of urinary tract or sepsis. There may be minor episodes Figure 2. Effects of renal medullary red blood cell sickling. Modified of hematuria with years of asymptomatie periods. The patients from reference 22. 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 studied ( 1 ). The tubular reabsorption of phosphate is normal in blood cells. The urine should be strained and examined for the patients with sickle cell trait, but increased in those with sickle presence of sloughed papillae. cell anemia ( 10). In some studies, the fractional excretion of Other Renal Abnormalities. An increased incidence of uric acid does not differ between sickle cell anemia, sickle cell during pregnancy has been well demonstrated in trait, and control subjects ( 15), whereas others show increased sickle cell trait (23). Patients have presented with perinephric rate of uric acid clearance in sickle cell anemia (16). hernatoma thought to be associated with bleeding into the renal In contrast to sickle cell disease, in which there is an early capsule after cortical infarction. Other findings that have been increase in glomerular filtration rate in younger patients with a reported in patients with sickle cell trait in which causality has subsequent decrease in later life, glomerular filtration rate has not been proven include , renal vein throm- been found to be normal in patients with sickle cell trait (10). bosis, and chronic renal failure. However, the filtration fraction is decreased as it is in sickle cell disease. This is due to a small increase in renal plasma Treatment flow (10). Hematuria. Although usually responsive to conservative measures, treatment of gross hernaturia in patients with sickle Clinical Presentation hernogbobinopathies may be quite challenging. A number of Hematuria. Patients with sickle cell trait will most corn- different approaches have been tried in the past. monly present with gross hematuria in the third or fourth One early approach involved the administration of distilled decade, although microscopic hematuria may be picked up on water intravenously along with oral bicarbonate solution (24).

routine urinalysis (1 ). The hematuria is generally painless, This was found to be effective in stopping the hematuria. although patients may present with flank or abdominal pain Although one might expect intravascular hemolysis to occur, due to sloughing of papilla. The left appears to be this was not observed. Treatments such as vitamin K, vaso- involved approximately 80% of the time because of increased pressin, and hyperbaric oxygen have been used with varying venous drainage into the left renal vein, which may elevate the degrees of success. Urologic interventions have included in- venous pressure and lead to stasis (17). gation of the with sodium oxychlorosene, silver Recurrent episodes of hematuria in affected people are corn- nitrate, or aminocaproic acid and use of ureteral catheters in an mon (8,17). Hematuria due to sickle cell trait must be consid- effort to tarnponade the bleeding. ered a diagnosis of exclusion, particularly in patients present- Table 3 outlines the current approach to management of ing with hernaturia for the first time. Thus, the work-up should hernaturia in sickle cell trait involving measures designed to include urinalysis and urine culture, urinary acid-fast bacilli, eliminate the underlying pathophysiologic conditions leading urinary cytology, hematologic work-up for coagulation abnor- 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 ± 54 593 ± 35’ 447 ± 1O’ 10 11 1055 ± 24 745 ± 33b 16b urinary acidificationc (peq/min) 79 ± 4 74 ± 6 60 ± 5” 10 urinary potassium excretion’ (jieq/rnin) 136 ± 14 127 ± 7 13 153±41 ll4±l4h 14 tubular reabsorption of phosphate (%) 88 ± 2 88 ± 2 93 ± I 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 Table 3. Medical management of hematuria in sickle cell disorders’ mellitus Analgesic abuse Maintain high urine flow rate Pyelonephritis hypotonie fluid intake (4 L/l .73 m2 per d) either po or iv Urinary tract obstruction furosemide 40 mg po BID Sickle hemogbobinopathy Urinary alkalinization Tuberculosis NaHCO3 2 to 3 g QID ± acetazolarnide 250 rug

If bleeding persists after 72 h: increase the pH, and increase the oxygen tension of the renal urea 40 g QID medulla. Hypotonic intravenous solutions are administered, or along with a loop diuretic (such as furosemide), which will EACA 3 to 4 g QID reduce medullary tonicity and maintain a high rate of urine output. The use of a loop diuretic may also reduce oxygen a by mouth: iv, intravenously; BID. twice daily: QID, four consumption and increase medullary oxygen tension. Urinary times daily: EACA. epsilon aminocaproic acid. 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 effective in the treatment of persistent sickle trait hematuria to avoid dislodging of blood clots. (28). Oral urea is given at a dose of 160 g daily in four divided If these measures are unsuccessful in halting the bleeding, doses. This will generally increase the blood urea nitrogen to epsilon aminocaproic acid (EACA) may be given intrave- greater than 80 mg/dl by day 3, and the hematuria resolves. nously or orally. This is an inhibitor of urokinase, the urinary Urea has been demonstrated to decrease the viscosity and enzyme that activates plasminogen. Thus, EACA prevents gelation of deoxygenated sickle hemoglobin, and has been formation of excess plasmin responsible for fibrinolysis. The found to prevent or reverse sickling. The osmotic diuretic recommended dose of EACA is 3 to 4 g three to four times effect of urea may also lower medullary osmolality. daily, which will usually result in the clearing of the urine If bleeding remains uncontrolled, arteriography with local within a few days (27). Common include nausea, embolization of the involved kidney region may be used. In vomiting, and diarrhea, along with the rare complication of rare instances, nephreetorny may be required. causing clot formation within the urinary excretory system. Papillary Necrosis. The treatment of renal papillary ne- The administration of oral urea has also been found to be 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 Renal acidification in sickle cell disease. J Lab C/in Med 99: therapy for treatment of infection and early relief of obstruction 389-401, 1976 due to sloughed papilla is essential. Other factors that may I 1 . Keitel HG, Thompson D. Itano HA: Hyposthenuria in sickle cell anemia: A reversible renal defect. J C/in Invest 35: 998-1007, contribute to the development of papillary necrosis, such as I956 nonsteroidal anti-inflammatory drugs, should be avoided. Use 12. Levitt MF, Hauser AD, Levy MS. Polimeros D: The renal of nonionie contrast agents for radiographic studies may be less concentrating defect in sickle cell disease. Am J Med 29: 61 1- likely to cause sickling of RBC than ionic contrast. 622, 1960 The outcome of papillary necrosis in sickle cell trait is I 3. Oster JR. Lanier DC, Vaamonde CA: Renal response to potas- generally good. Papillae seem to be affected one at a time. sium loading in sickle cell trait. Arch Intern Med 140: 534-536, Serial follow-up intravenous pyelograrns of a case of sickle- 1980 cell trait with hematuria revealed initially unilateral, then bi- 14. DeFranzo RA, Tarfield PA, Black J: Impaired renal tubular lateral, evidence of partial papillary necrosis (29). Despite potassium excretion in sickle cell disease. Ann Intern Med 90: bilateral lesions involving one or two papillae in each kidney, 310-316, 1979 there is sufficient uninvolved kidney tissue (the average is 15. Walker BR, Alexander F: Uric acid excretion in sickle cell eight pyramids per kidney) to maintain normal renal function. anemia. fAin MedAssoc 215: 255-258, 1971 16. Diamond HS, Meisel AD, Sharon E, Holden D, Cacatian A: The impairment of concentrating ability that occurs in sickle and increased tubular secretion of urate in sickle hemoglobinopathies may protect against further injury due to cell anemia. Am J Med 59: 796-802, 1975 sickling. 18. Richie JP, Kerr WS: Sickle cell trait: Forgotten cause of hema- In summary, we have presented a case of papillary necrosis tuna in white patients. J Urol 122: 134-135, 1979 due to sickle cell trait that presented as gross hematuria. Sickle 19. Eckert DE, Jonitlis AJ, Davidson AJ: The incidence and mani- cell trait should be included in the differential diagnosis of any festations of urographic papillary abnormalities in patients with S patient who presents with unexplained hematuria. hemoglobinopathies. I 13: 59-63, 1974 20. Pandya KK, Koshy M, Brown N, Pressman D: Renal papillary References necrosis in sickle cell hemoglobinopathies. J Urol 1 15: 497-501,

1. Vaamonde CA, Oster JR. Strauss J: The kidney in sickle cell 1976 disease. In: The Kiclne in , edited by Suki WN, 2 1 . Mapp E, Karasick S. Pollack H, Wechsler Ri, Karasick D: Eknoyan 0, New York, Wiley, 1981, pp 159-195 Uroradiological manifestations of S-hemoglobinopathy. Seinin 2. De Jong PE. Van Eps LWS: Sickle cell nephropathy: New Roentgenol 22: 186-194, 1987 insights into its pathophysiology. Kidney Jut 27: 71 1-717, 1985 22. Vaamonde CA: Renal papillary necrosis in sickle cell hemoglo- 3. Allon M: Renal abnormalities in sickle cell disease. Arc/i Intern binopathies. Setnin Nephro/ 4: 48-64, 1984 Med 150: 501-504, 1990 23. Whalley PJ. Martin FG, Pritchard JA: Sickle cell trait and urinary 4. Falk Ri. Jennette SC: Sickle cell nephropathy. Adv Nephro/ 23: tract infection during pregnancy. J Am Med Assoc 189: 903-906, 133-147, 1994 I 964 5. Sears DA: The morbidity of sickle cell trait. Aiti J Med 64: 24. Maryniek SP, Ramsey EJ, Knochel JP: The effect of bicarbonate 1021-1036, 1978 and distilled water on sickle trait hematuria and in vitro studies 6. Lange RD. Minnich V. Moore CV: Effect of oxygen tension and on the interaction of osmolality and pH on erythroeyte sickling in pH on the sickling and mechanical fragility of erythrocytes from sickle cell trait. J Urol I 18: 793-796, 1977 patients with sickle cell anemia and sickle cell trait. J Lab C/in 25. Melnnes BK: The management of hematuria associated with Med 37: 789-801. 1957 sickle hemoglobinopathies. J Urol 124: 171-174. 1980 7. Van Eps LW, Pinedo-Veels C, DeVries OH, DeKoning J: Nature 26. Meyerfeld SA, Morganstern SL, Seery W, Cole AT: Medical of concentrating defect in sickle-cell nephropathy: Microangio- management of refractory hematuria in sickle-cell trait. graphic studies. Laticet I : 450-45 1, 1970 8: 112-113, 1976 8. Mostofi FK, Under Brueggs C, Diggs LW: Lesions in kidneys 27. Nilsson IM, Andersson L, Bjorkman SE: Epsilonamino-eaproic removed for unilateral hematuria in sickle cell disease. Arch acid (E-ACA) as a therapeutic agent based on 5 years clinical Pat/wlLabMed63: 336-351, 1957 experience. Acta Med Scand Suppi 448: 10-15, 1966 9. Van Eps LW, Schouten H. Romeny-Wachter C, LaPorte-Wijs- 28. Pariser S. Katz A: Treatment of sickle cell trait with oral urea. man L: The relationship between age and renal concentrating J Urol 151: 401-403, 1994 capacity in sickle cell disease and hemoglobin C disease. C/in 29. Gong MB. Davidson AJ: Development and progression of renal Chi,n Aeta 27: 501-51 1, 1970 papillary necrosis in SA hemoglobinopathy. Urol Radiol 2: 55- 10. Oster JR. Lespier LE. Lee SM, Pellegnni EL, Vaamonde CA: 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 affiliated with the : 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 modalities, renal transplantation, and continuous renal replacement therapy. The nephrol- ogy fellows are also trained in procedures such as percutaneous renal 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, 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.