- Email: [email protected]
Urinary Hematin Calculi
0022-5347 /91/1455-1043$03.00/0 Vol. 145 1043-1044, Printed in
THE JOURNAL OF UROLOGY AMERICAN UROLOG!CAL ASSOClATlON, INC.
1
Copyright© 1991 by
URINARY HEMATIN CALCULI JEFFREY I. MILLER, ROBERT B. McBEATH
AND
GEORGE W. DRACH*
From the Department of Surgery, Section of Urology, University of Arizona, Tucson, Arizona
ABSTRACT
We report 2 cases of nephrolithiasis owing to hematin stones. One patient had no apparent explanation for this finding, while the other was receiving warfarin anticoagulation for a prosthetic aortic valve. The chemical nature, etiology and clinical features of hematin calculi are discussed. KEY WORDS:
urinary calculi, heme
Hematin is an extremely rare constituent of urinary calculi, occurring in only 135 of 10,000 calculi (1.35%) reported by Herring. 1 In only 26 of these instances (0.26%) hematin was found as a major component, and it occurred in its pure (100%) form in only 3 patients. The only underlying risk factor for hematin formation appears to be bleeding within the upper urinary tract. Indeed, theories regarding its organization into a calculus are based on the biochemical transformation of heme in an old blood clot. Hematin most often occurs in the form of small intercrystalline inclusions found within almost any other type of calculus that might have been the original stimulus for irritative bleeding. In addition, crystals of hematin may form the nucleus for other calculi or may develop into the pure form. We report 2 cases of predominantly hematin calculi. One patient had no identifiable risk factors predisposing to hematin stone formation. The chemical nature, etiology and clinical features of hematin calculi are discussed.
ulated with a prothrombin time of 17.6 seconds (control 11.5 seconds). She has remained stone-free at 2 years. DISCUSSION
Hematin stone formation occurs most often as a secondary component of other more common urinary calculi. In more than 90% of the patients a source of associated bleeding can be discovered. 1 Hematin stones may occur de novo as exemplified by our 2 patients with no history of nephrolithiasis. A bleeding diathesis may exist as in our case 2. The formation of hematin calculi begins with the presence of free heme within the renal collecting system. Heme is a metalloporphyrin consisting of a tetrapyrrole ring complexed with iron (fig. 2, A). In humans it serves as the prosthetic group of hemoglobin, which primarily mediates oxygen transport and storage. 3 Under alkaline conditions (pH greater than 7.0) heme
CASE REPORTS
Case 1. A 63-year-old woman presented to the emergency room with the acute onset of colicky left flank pain and tenderness associated with nausea and vomiting. She had no history of nephrolithiasis. Urinalysis revealed a pH of 8.5 and 2 red blood cells per high power field. Urine culture yielded no bacteria. An excretory urogram (IVP) showed left ureterovesical junction obstruction owing to an opaque calculus (fig. 1). After injection extravasation of contrast material was noted from a forniceal rupture. The patient was treated conservatively for several days until eventual spontaneous passage of the stone. The stone appeared in multiple fragments, the largest measuring 0.3 X 0.5 X 0.2 cm. It was dark reddish-brown. Chemical microscopy revealed hematin, which was confirmed by infrared spectroscopy according to the methods described by Swinehart and Porro. 2 The patient denied any history of urinary tract trauma, and she took no medications. There was no underlying bleeding diathesis, and platelet count, prothrombin time and partial thromboplastin time were all within normal limits. At 2-year followup there has been no new stone formation. Case 2. A 70-year-old woman presented with the acute onset of right flank pain and tenderness. There was no history of nephrolithiasis. She had been chronically anticoagulated with warfarin after an aortic prosthetic valve was placed 5 years earlier. Urinalysis revealed a pH of 5.0 with 25 red blood cells per high power field. An IVP showed high grade obstruction at the right ureterovesical junction. The patient was managed conservatively and passed a black, hard irregular stone measuring 0.4 X 0.3 x 0.1 cm. Analysis by chemical microscopy revealed pure hematin. There was no history of trauma. The patient had been adequately anticoagAccepted for publication September 19, 1990. * Requests for reprints: Department of Surgery, Section of Urology, University of Arizona Health Sciences Center, 1505 N. Campbell Ave., Tucson, Arizona 85724.
FIG. 1. Case 1. Pelvic plain radiograph reveals radiopaque calculus just above left pubic ramus. CH,
A.
CH,
B.
H,C
H,C
CH,
CH, I
HOOCCH,
CH 2 I
CH2 COOH
CH 2 I
HOOCCH 2
FIG. 2. A, molecular structure of heme. B, molecular structure of hematin with addition of hydroxyl group to iron moiety.
1043
1044
MILLER, MCBEATH AND DRACH
FIG. 3. Reference infrared spectograph of pure hematin stone. (Obtained from Louis G. Herring Co., Orlando, Florida.)
is oxidized to he matin (or hydroxyheme) by the addition of a hydroxyl group to its central iron molecule (fig. 2, B). Upon return to an acid environment (pH less than 7.0) the added hydroxyl group becomes protonated resulting in precipitation of solid hematin. Eventually polymerization occurs between the carboxylic acid group of 1 molecule and the coordinated OH2 group of another. 4 If conditions remain constant, a calculus can occur. Although the urinary pH in our 2 patients differed considerably, it is quite conceivable that only a brief period of alkalinity would be necessary for the initial oxidation of heme to occur. The subsequent protonization and precipitation of hematin would occur after a return to more usual acid conditions. The pK of this reaction is 7.6.'5 To our knowledge, no studies involving the formation of hematin from heme have been performed under environmental conditions similar to those of human urine. Therefore, further investigation is necessary to confirm the aforementioned in vitro observations. Stone analysis should be performed, since the clinical suspicion for hematin is usually low. In fact, the results of stone analysis were unexpected in both of our patients. Reference infrared spectophotometric and chemical microscopic patterns of hematin exist, and they are consulted by most stone analysis laboratories. 6 For specific reference hematin can be obtained in its pure form from major chemical companies. (Although found
in the body only under rare conditions, such as phosgene poisoning, hematin has been used clinically in the treatment of acute hepatic porphyria. 6 • 7 ) Because of the unique molecular bonding of the hematin porphyrin ring, it is highly amenable to infrared spectroscopy for identification. Figure 3 shows a reproduction of such a reference tracing. Although hematin is not a pure crystal, almost all chemical compounds (with the rare exception of fibrinous and bacterial calculi) become crystalline when they pass from a liquid or gas into the solid state. 8 When ground into a coarse powder hematin exhibits distinct optical properties including its refractive index, Hence, chemical microscopy also can be used for analysis. Because of its ring-like atomic arrangement and central iron molecule, hematin is suboptimally identified by x-ray crystallography, since it has indeterminate interplanar spacings. By virtue of chemical composition hematin calculi are radiolucent. In our case 1 the radiopacity of hematin was likely due to the inclusion of minute quantities of calcium salts that did not affect stone analysis. Therapy for hematin stones involves usual pain medication and relief of obstruction. There are no specific recommendations for metabolic treatment. In summary, hematin is a rare urinary calculus. Urinary tract bleeding (prior nephrolithiasis, trauma and so forth) appears to provide the source of heme for conversion to hematin within a specific pH range. Occasionally, as in our case 1, no underlying causative bleeding can be identified. REFERENCES 1. Herring, L. C.: Observations on the analysis of ten thousand urinary calculi. J. UroL, 88: 545, 1962. 2. Swinehart, J. S. and Porro, T. J.: Biomedical application. 1. The
3. 4. 5. 6. 7. 8.
clinical analysis of renal stones. In: Perkin-Elmer Series: Biomedical Applications, 1969. Instrument Division, PerkinElmer Corporation, Norwalk, Connecticut, 06852. Bottomley, S. S. and Muller-Eberhard, U.: Pathophysiology of heme synthesis. Sem. HematoL, 25: 282, 1988. Falk, J. E.: Porphyrins and metalloporphyrins. Their General, Physical and Coordination Chemistry, and Laboratory Methods. Amsterdam: Elsevier Publishing Co., p. 47, 1964. Arawak Laboratories, Los Angeles, California: Personal communication. The Merck Index, 10th ed. Rahway, New Jersey: Merck & Co., Inc., pp. 670-671, 1983. Bissell, D. M.: Treatment of acute hepatic porphyria with hematin. J. HepatoL, 6: 1, 1988. Prien, E. L. and Frondel, C.: Studies in urolithiasis: 1. The composition of urinary calculi. J. Urol., 57: 949, 1947.
THE JOURNAL OF UROLOGY AMERICAN UROLOG!CAL ASSOClATlON, INC.
1
Copyright© 1991 by
URINARY HEMATIN CALCULI JEFFREY I. MILLER, ROBERT B. McBEATH
AND
GEORGE W. DRACH*
From the Department of Surgery, Section of Urology, University of Arizona, Tucson, Arizona
ABSTRACT
We report 2 cases of nephrolithiasis owing to hematin stones. One patient had no apparent explanation for this finding, while the other was receiving warfarin anticoagulation for a prosthetic aortic valve. The chemical nature, etiology and clinical features of hematin calculi are discussed. KEY WORDS:
urinary calculi, heme
Hematin is an extremely rare constituent of urinary calculi, occurring in only 135 of 10,000 calculi (1.35%) reported by Herring. 1 In only 26 of these instances (0.26%) hematin was found as a major component, and it occurred in its pure (100%) form in only 3 patients. The only underlying risk factor for hematin formation appears to be bleeding within the upper urinary tract. Indeed, theories regarding its organization into a calculus are based on the biochemical transformation of heme in an old blood clot. Hematin most often occurs in the form of small intercrystalline inclusions found within almost any other type of calculus that might have been the original stimulus for irritative bleeding. In addition, crystals of hematin may form the nucleus for other calculi or may develop into the pure form. We report 2 cases of predominantly hematin calculi. One patient had no identifiable risk factors predisposing to hematin stone formation. The chemical nature, etiology and clinical features of hematin calculi are discussed.
ulated with a prothrombin time of 17.6 seconds (control 11.5 seconds). She has remained stone-free at 2 years. DISCUSSION
Hematin stone formation occurs most often as a secondary component of other more common urinary calculi. In more than 90% of the patients a source of associated bleeding can be discovered. 1 Hematin stones may occur de novo as exemplified by our 2 patients with no history of nephrolithiasis. A bleeding diathesis may exist as in our case 2. The formation of hematin calculi begins with the presence of free heme within the renal collecting system. Heme is a metalloporphyrin consisting of a tetrapyrrole ring complexed with iron (fig. 2, A). In humans it serves as the prosthetic group of hemoglobin, which primarily mediates oxygen transport and storage. 3 Under alkaline conditions (pH greater than 7.0) heme
CASE REPORTS
Case 1. A 63-year-old woman presented to the emergency room with the acute onset of colicky left flank pain and tenderness associated with nausea and vomiting. She had no history of nephrolithiasis. Urinalysis revealed a pH of 8.5 and 2 red blood cells per high power field. Urine culture yielded no bacteria. An excretory urogram (IVP) showed left ureterovesical junction obstruction owing to an opaque calculus (fig. 1). After injection extravasation of contrast material was noted from a forniceal rupture. The patient was treated conservatively for several days until eventual spontaneous passage of the stone. The stone appeared in multiple fragments, the largest measuring 0.3 X 0.5 X 0.2 cm. It was dark reddish-brown. Chemical microscopy revealed hematin, which was confirmed by infrared spectroscopy according to the methods described by Swinehart and Porro. 2 The patient denied any history of urinary tract trauma, and she took no medications. There was no underlying bleeding diathesis, and platelet count, prothrombin time and partial thromboplastin time were all within normal limits. At 2-year followup there has been no new stone formation. Case 2. A 70-year-old woman presented with the acute onset of right flank pain and tenderness. There was no history of nephrolithiasis. She had been chronically anticoagulated with warfarin after an aortic prosthetic valve was placed 5 years earlier. Urinalysis revealed a pH of 5.0 with 25 red blood cells per high power field. An IVP showed high grade obstruction at the right ureterovesical junction. The patient was managed conservatively and passed a black, hard irregular stone measuring 0.4 X 0.3 x 0.1 cm. Analysis by chemical microscopy revealed pure hematin. There was no history of trauma. The patient had been adequately anticoagAccepted for publication September 19, 1990. * Requests for reprints: Department of Surgery, Section of Urology, University of Arizona Health Sciences Center, 1505 N. Campbell Ave., Tucson, Arizona 85724.
FIG. 1. Case 1. Pelvic plain radiograph reveals radiopaque calculus just above left pubic ramus. CH,
A.
CH,
B.
H,C
H,C
CH,
CH, I
HOOCCH,
CH 2 I
CH2 COOH
CH 2 I
HOOCCH 2
FIG. 2. A, molecular structure of heme. B, molecular structure of hematin with addition of hydroxyl group to iron moiety.
1043
1044
MILLER, MCBEATH AND DRACH
FIG. 3. Reference infrared spectograph of pure hematin stone. (Obtained from Louis G. Herring Co., Orlando, Florida.)
is oxidized to he matin (or hydroxyheme) by the addition of a hydroxyl group to its central iron molecule (fig. 2, B). Upon return to an acid environment (pH less than 7.0) the added hydroxyl group becomes protonated resulting in precipitation of solid hematin. Eventually polymerization occurs between the carboxylic acid group of 1 molecule and the coordinated OH2 group of another. 4 If conditions remain constant, a calculus can occur. Although the urinary pH in our 2 patients differed considerably, it is quite conceivable that only a brief period of alkalinity would be necessary for the initial oxidation of heme to occur. The subsequent protonization and precipitation of hematin would occur after a return to more usual acid conditions. The pK of this reaction is 7.6.'5 To our knowledge, no studies involving the formation of hematin from heme have been performed under environmental conditions similar to those of human urine. Therefore, further investigation is necessary to confirm the aforementioned in vitro observations. Stone analysis should be performed, since the clinical suspicion for hematin is usually low. In fact, the results of stone analysis were unexpected in both of our patients. Reference infrared spectophotometric and chemical microscopic patterns of hematin exist, and they are consulted by most stone analysis laboratories. 6 For specific reference hematin can be obtained in its pure form from major chemical companies. (Although found
in the body only under rare conditions, such as phosgene poisoning, hematin has been used clinically in the treatment of acute hepatic porphyria. 6 • 7 ) Because of the unique molecular bonding of the hematin porphyrin ring, it is highly amenable to infrared spectroscopy for identification. Figure 3 shows a reproduction of such a reference tracing. Although hematin is not a pure crystal, almost all chemical compounds (with the rare exception of fibrinous and bacterial calculi) become crystalline when they pass from a liquid or gas into the solid state. 8 When ground into a coarse powder hematin exhibits distinct optical properties including its refractive index, Hence, chemical microscopy also can be used for analysis. Because of its ring-like atomic arrangement and central iron molecule, hematin is suboptimally identified by x-ray crystallography, since it has indeterminate interplanar spacings. By virtue of chemical composition hematin calculi are radiolucent. In our case 1 the radiopacity of hematin was likely due to the inclusion of minute quantities of calcium salts that did not affect stone analysis. Therapy for hematin stones involves usual pain medication and relief of obstruction. There are no specific recommendations for metabolic treatment. In summary, hematin is a rare urinary calculus. Urinary tract bleeding (prior nephrolithiasis, trauma and so forth) appears to provide the source of heme for conversion to hematin within a specific pH range. Occasionally, as in our case 1, no underlying causative bleeding can be identified. REFERENCES 1. Herring, L. C.: Observations on the analysis of ten thousand urinary calculi. J. UroL, 88: 545, 1962. 2. Swinehart, J. S. and Porro, T. J.: Biomedical application. 1. The
3. 4. 5. 6. 7. 8.
clinical analysis of renal stones. In: Perkin-Elmer Series: Biomedical Applications, 1969. Instrument Division, PerkinElmer Corporation, Norwalk, Connecticut, 06852. Bottomley, S. S. and Muller-Eberhard, U.: Pathophysiology of heme synthesis. Sem. HematoL, 25: 282, 1988. Falk, J. E.: Porphyrins and metalloporphyrins. Their General, Physical and Coordination Chemistry, and Laboratory Methods. Amsterdam: Elsevier Publishing Co., p. 47, 1964. Arawak Laboratories, Los Angeles, California: Personal communication. The Merck Index, 10th ed. Rahway, New Jersey: Merck & Co., Inc., pp. 670-671, 1983. Bissell, D. M.: Treatment of acute hepatic porphyria with hematin. J. HepatoL, 6: 1, 1988. Prien, E. L. and Frondel, C.: Studies in urolithiasis: 1. The composition of urinary calculi. J. Urol., 57: 949, 1947.