Macroscopic Hematuria Secondary to Hypercalciuria and Hyperuricosuria

Macroscopic Hematuria Secondary to Hypercalciuria and Hyperuricosuria Freda L. Levy, MD, R. David Kemp, MD, and Julia A. Breyer, MD • An adult presenting with asymptomatic gross hematuria attributable to hypercalciuria and hyperuricosuria is described. Extensive evaluations for other causes of hematuria were negative, and the gross hematuria resolved with treatment of the hypercalciuria and hyperuricosuria. Hematuria commonly attributable to these metabolic causes in children may also occur in adults. A 24-hour urine collection for the measurement of calcium and uric acid excretion in adults without nephrolithiasis may play an important role in the evaluation of hematuria. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Hematuriaj hypercalciuriaj hyperuricosuria.

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EMA TURIA is a common clinical condition that requires evaluation to identify the underlying etiology. 1,2 Patients often undergo a number of invasive procedures to locate an extrarenal, glomerular, or nonglomerular cause of hematuria. The differential diagnosis of hematuria is extensive and the common causes vary with age. 3-8 In children, the most common cause of hematuria is hypercalciuria, and in adults the most common causes are related to abnormalities of the genitourinary (GU) system.3A,9 Noninvasive tests to evaluate adults with hematuria currently include a complete history and physical examination, urinalysis, urine culture and cytology, and laboratory and radiologic tests. Invasive tests, including cystoscopy, renal arteriography, and renal biopsy, are often performed. An evaluation of hypercalciuria and hyperuricosuria currently is not recommended in adults, but it is in children. 4 - '6 This case report of an adult with gross hematuria due to hypercaIciuria and hyperuricosuria in the absence of renal calculi suggests that this noninvasive evaluation should be performed in adults as well. CASE REPORT A 36-year-old white man was well until August 1991 , at which time he noted the sudden onset of painless gross hematuria. Episodes of gross hematuria lasting I to 2 days occurred every I to 3 weeks for 4 months. Hematuria had not been not present on previous urinalyses. Initial evaluation of this patient included mUltiple urinalyses that revealed too numerous to count red blood cells (RBCs) per high-powered field (HPF), 0 to 3 white blood cells (WBCs)/HPF, and no casts; urine cultures that demonstrated no growth; urine cytologies that demonstrated no malignant cells; and an intravenous pyelogram. Two cystoscopies with retrograde pyelograms were performed that revealed no anatomic abnormalities and clear efflux from both ureters. No bleeding was seen from either ureteral orifice, although ureteral samples were not examined microscopically. A renal arteriogram demonstrated normal renal vasculature. The patient denied

any associated symptoms, such as flank pain, dysuria, voiding difficulties, arthralgias, hemoptysis, cough, fever, or the passage of gravel or stones. No gravel or stones were retrieved by straining the urine. Because the urologist was unable to demonstrate an anatomic abnormality or a site of bleeding, he referred the patient for an evaluation for intrinsic renal disease. The patient was taking no medications. Family history was negative for hematuria, renal disease, nephrolithiasis, and hearing disorders. The patient has three children, all of whom had normal urinalyses. Physical examination revealed a normotensive, afebrile, 76-kg white man in no discomfort. His heart and lung examination were unremarkable. Abdominal examination demonstrated active bowel sounds without palpable masses or bruits. Examination of the GU tract revealed normal external male genitalia and a normal-sized and nontender prostate. Neither peripheral edema nor rashes were noted. Laboratory values were as follows: blood urea nitrogen,. 19 mg/dL; creatinine, 1.0 mg/dL; sodium 143 mEq/L; potassium, 4.8 mEq/L; chloride, 105 mEq/L: HC0 3 , 28 mmolfL; albumin , 4.5 gjdL; calcium, 9.3 mgjdL; po. , 2.5 mgjdL; uric acid, 5.2 mgjdL; alkaline phosphatase, 61 IU/L; parathyroid hormone by immunoradiometric assay, 40 pgjmL (Allegro kits; Nichols Institute, San Juan Capistrano, CAl; cholesterol. 252 mg/dL; triglycerides, 67 mg/dL; lactic dehydrogenase, 126 IU/L; WBCs, 4,100 with a normal differential; hemoglobin, 16. 1 g/dL; hematocrit, 49%; mean corpuscular volume, 87 1L3; and platelet count, 236,000/mm 3. Urinalysis by dipstick (Multistix, Ames Reagent Strips; Miles, Inc, Elkhart, IN) demonstrated a specific gravity of 1.021, pH 7.0, trace albumin, and large blood. Microscopic examination of the urine revealed too numerous to count RBCs per HPF, 3 to 4 WBCs/HPF, no casts. and no crystals. The RBCs in the urine were isomorphic. The urine specimen used for culture and determination of sensitivity demonstrated no growth. The urine specimen used for cytology was also negative.

From the Division of Nephrology. Vanderbilt University Medical Center, Nashville, TN. Received September 30, 1993; accepted in revised form March 22, 1994. Address reprint requests to Freda L. L evy, MD, Dallas Nephrology Associates. 1150 North Bishop, Dallas. TX 75208. © 1994 by the Nat ional Kidney Foundation, Inc. 0272-6386/ 94/ 2403-0016$3.00/0

American Journal of Kidney Diseases, Vol 24, No 3 (September), 1994: pp 515-518

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516 Serologic evaluation revealed negativity for antinuclear antibody; normal C3 , C4 , and CHso; rheumatoid factor less than 1:20; nonreactive rapid plasma reagin; and an immunoglobulin A (IgA)-fibronectin level of6.0 U (nondiagnostic for the presence ofJgA nephropathy). Examination ofa 24-hour urine collection performed with the patient on a random diet revealed the following data: total volume, 1,220 mL/24 hr; total creatinine, 1,525 mg/24 hr (20 mg/kg); calculated creatinine clearance, 82 mL/min; total protein, 131 mg/d; and total calcium, 508 mg/d. Following the discovery of the hypercalciuria, the patient collected a 24-hour urine specimen after a sodium-, calcium-, and oxalate-restricted diet of 1 week's duration and underwent a "fast and calcium load" test to determine his intestinal absorption of calcium. 17 A urine amino acid screen was negative. Hypercalciuria was defined as 24-hour urinary calcium excretion greater than 4 mg/kg body wt/d on a random diet and greater than 200 mg/d following the restricted diet. Hyperuricosuria was defined as 24-hour urinary calcium excretion greater than 600 mg/d. IS . 19 Results of the 24-hour urine specimen on the restricted diet demonstrated the following values: total volume, 1,120 mL/ d; pH, 6.72; calcium, 246 mg/d; creatinine, 1,680 mg/d (22 mg/kg); sodium, 193 mEq/d; phosphorus, 885 mg/d; magnesium, 80 mg/d; uric acid, 896 mg/d; oxalate, 21 mg/d; and citrate, 1,098 mg/d. The fast and calcium load test demonstrated findings consistent with increased intestinal absorption of calcium but no evidence of fasting hypercalciuria. The 2hour fasting urinary collection revealed a ratio of 0.08 mg calcium/mg creatinine (factored for glomerular filtration rate) and the 4-hour postload urinary collection revealed a ratio of 0.31 mg calcium/mg creatinine. IS The metabolic evaluation demonstrated that the patient had absorptive hypercalciuria type I, hyperuricosuria, excessive dietary sodium intake, and high urinary citrate excretion. The patient's dietary sodium intake may have contributed in part to the observed high urinary calcium excretion. That sodium and calcium are handled at similar sites along the nephron is well established, and factors that increase renal sodium delivery increase urinary calcium excretion. However, the formulation of the 1-g calcium load contains less than 600 mg of sodium, and intestinal hyperabsorption of calcium was clearly demonstrated. Whether this patient is among a subset of patients with hypercalciuria whose urinary calcium excretion demonstrates an increased sensitivity to dietary sodium intake was not established. 20 A renal biopsy was initially considered. However, with two known metabolic derangements associated with hematuria in a normotensive individual with a normal creatinine clearance and in the absence of significant proteinuria, medical therapy was initially recommended. In the event that the hematuria did not respond to medical intervention, a biopsy would have been performed. Following metabolic evaluation, the patient was prescribed indapamide 2.5 mg/d to decrease urinary calcium and allopurinol 300 mg/d to decrease urinary uric acid. The patient was also instructed to decrease his dietary sodium and purine intake and to increase his daily fluid intake to maintain a urine volume greater than 2 L/d. Following the initiation of this therapy, the patient had no episodes of gross hematuria for 12 months. Laboratory evaluation on medical therapy revealed the following values: 24hour urine volume, 2,440 mL/d; pH, 6.30; calcium, 259 mg/

LEVY, KEMP, AND BREYER d; creatinine, 1,562 mg/d (20 mg/kg); sodium, 371 mEq/d; uric acid, 512 mg/d; oxalate, 26 mg/d; and citrate, 793 mg/ d. Microscopic examination of the urine showed 5 to 10 RBCs/ HPF, 0 to 3 WBCs/HPF, and no casts. The patient continued taking indapamide and allopurinol, and was instructed to continue his efforts to increase fluid intake and decrease purine and sodium intake. In November 1992, medical therapy was discontinued. Subsequently, in August 1993, the patient began to complain of low back spasms and had recurrent gross hematuria. A plain film of the abdomen demonstrated a columnization of small calcifications in the distal right ureter.

DISCUSSION

Hematuria (microscopic or macroscopic) occurs in up to 13% of the population. 21 Gross hematuria occurs less commonly than microscopic hematuria. The evaluation of hematuria in children includes a fasting spot urine collection to determine the urine calcium to urine creatinine ratio and/or a 24-hour urine collection to measure urinary calcium excretion. Hypercalciuria is the most common cause of asymptomatic hematuria in children, and hypercalciuria and hyperuricosuria are both well-described causes of isolated hematuria in children. 13-16 Perrone et al described a population of 250 children aged 8 months to 14 years who had recurrent hematuria, in whom 31 % of the cases were due to metabolic disturbances. 13 This study, along with others, illustrates that routine measurement of urinary calcium and uric acid excretion should be performed during evaluation of hematuria in children. Despite the literature illustrating hypercalciuria and hyperuricosuria as causes of hematuria in pediatric patients, a metabolic evaluation has received little attention in the adult hematuric patient. 22 ,23 In adults, the most common causes of hematuria are abnormalities of the GU system, such as urinary tract infection, prostatic disease, and GU malignancy.2-7 Our patient, despite repeated evaluations, had no evidence of a GU tract or renovascular abnormality. Primary renal disease less commonly causes hematuria. 1,2,4,5 In 80 adults with hematuria (26 recurrent macroscopic and 54 persistent microscopic) and a negative GU evaluation who underwent renal biopsy, 19A nephropathy was found in 27 patients, a normal kidney was found in 24 patients, and thin basement membrane nephropathy was found in 18 patients. In the remaining 11 patients, renal biopsy specimens

METABOLIC· EVALUATION OF HEMATURIA

demonstrated mesangioproliferative glomerulonephritis in five, interstitial nephritis in three, and focal global glomerulosclerosis in three. 24 Evaluation for 24-hour urinary excretion of calcium and uric acid was not performed in any of these patients, particularly those who were found to have normal kidneys on biopsy. The patient described in this report had no systemic signs or symptoms to suggest underlying renal disease, as indicated by normal renal function (normal serum creatinine and creatinine clearance) and normal protein excretion in the urine. Serologic evaluation including an IgA-fibronectin level was nondiagnostic. Circulating aggregates containing IgA and fibronectin in patients with IgA nephropathy provide a diagnostic marker for IgA nephropathy.25.26 The findings of hypercalciuria and hyperuricosuria in this patient and the temporal relationship of treating these with the resolution of his gross hematuria suggest that these metabolic abnormalities were etiologic. Hypercalciuria and hyperuricosuria have been postulated in a single study to account for microscopic hematuria in 37 adults in whom a GU evaluation was negative, although no renal biopsy was performed. 22 These patients were treated with thiazide diuretics and/ or allopurinol. Treatment resulted in the resolution of hematuria in 22 patients (59.4%) once the urine calcium and uric acid concentrations normalized. Six of the 15 nonresponders (patients with persistent microscopic hematuria despite normalization of urine calcium and uric acid concentrations after therapy) underwent renal biopsy, which revealed IgA nephropathy in three patients, membranoproliferative glomerulonephritis in two patients, and benign familial hematuria in one patient. It is unknown why these patients with hematuria, hypercalciuria, and hyperuricosuria did not have nephrolithiasis. In the patient described here, high urinary citrate excretion, an inhibitor of calcium oxalate and calcium phosphate stone formation, may have offered protection against crystallization and, therefore, stone formation. The mechanism of hematuria in this setting may be crystal damage to the GU epithelium. Crystal retention by the urothelium is required for the development of nephrolithiasis. Crystalluria itself may cause tubular injury, giving rise to crystal retention and stone growth, or crystals may adhere to a pre-

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existing side of epithelial damage and basement membrane disruption. 27 In evaluating patients with hypcrcalciuria, one must first make a distinction based on the presence or absence of hypercalcemia. The differential for hypercalcemic states and hypercalciuria includes primary hyperparathyroidism, sarcoidosis, and, rarely, other granulomatous conditions, vitamin D intoxication, and hyperthyroidism. Although the term "idiopathic hypercalciuria" has been used to refer to the syndrome of calcium oxalate nephrolithiasis, normocalcemia, and hypercalciuria, a group of specific disorders has been identified in patients using metabolic evaluations. A classification has been proposed by Pak that uses a 24-hour urine collection while the patient is on a random diet a 24-hour urine collection while the patient is on a diet restricted in calcium, sodium, and oxalate; and an indirect assessment of intestinal calcium absorption known as the "fast and calcium load" test. 17 Patients with hypercalciuria are divided into groups based on a primary increase in intestinal absorption of calcium or a decrease in renal tubular calcium reabsorption. Those individuals who have a renal tubular abnormality (which may be simply increased urinary calcium based on increased sensitivity to dietary sodium intake) have increased urinary calcium both in the fasting state and following a I-g oral load of calcium. Pak refers to these patients as having "absorptive hypercalciuria" or "renal hypercalciuria," respectively. Patients with renal hypercalciuria have increased intestinal absorption of calcium on the basis of secondary hyperparathyroidism. 17.28 Metabolic studies as well as population studies have provided evidence that high dietary protein intake, and especially animal protein intake, is a risk factor for nephrolithiasis. Increased dietary protein intake has been demonstrated to increase urinary excretion of urate and calcium, to increase net acid excretion, and to decrease urinary excretion of citrate. While a clear relationship between animal protein intake and increased calcium excretion is well established, the mechanism remains incompletely explained. 29 - 31 In the patient described, the restricted diet followed by the patient for the I week prior to the "fast and calcium load" test is a diet with a moderate protein recommendation.

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We report a patient with gross hematuria secondary to hypercalciuria and hyperuricosuria successfully treated by decreasing the urinary excretion of calcium and uric acid. In adults with isolated gross or microscopic hematuria, a 24hour urine collection to quantitate the excretion of calcium, uric acid, and possibly citrate is recommended. This may avoid the necessity of more invasive, costly procedures.

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17. Pak CYC: A physiologic basis for absorptive and renal hypercalciurias. Am J Physiol 237:F415-F423, 1979 18. Pak CYC, Kaplan RA. Bone H, Townsend 1, Waters 0: A simple test for the diagnosis of absorptive. resorptive and renal hypercalciurias. N Engl J Med 292:497-500. 1975 19. Pak CYC, Britton F, Peterson R, Ward D, Northcutt C, Breslau NA. McGuire J, Sakhaee K, Bush S. Nicar M. Norman DA. Peters P: Ambulatory evaluation of nephrolithiasis: Classification. clinical presentation and diagnostic criteria. Am J Med 69: 19-30, 1980 20. Wasserstein AG. Stolley PD. Soper KA. Goldfarb S. Agus ZS: Case-control study of risk factors for idiopathic calcium nephrolithiasis. Miner Electrolyte Metab 13:85-95. 1987 21. Mohr DN. Offord KP. Owen RA. Melton LJ III: Asymptomatic micro hematuria and urologic disease: A population-based study. JAMA 256:224-229, 1986 22. Andres A. Praga M. Bello I, Diaz-Rolon JA, GutierrezMillet V. Morales JM, Rodicio JL: Hematuria due to hypercalciuria and hyperuricosuria in adult patients. Kidney Int 36:96-99. 1989 23. Andres A. Praga M. Morales JM. Rodicio JL: Resolution of hypercalciuria-associated hematuria with thiazide diuretics in adult patients. in Puschett JB. Greenberg A (eds): Diuretics III: Chemistry. Pharmacology. and Clinical Applications. Elsevier. New York, NY. 1990. pp 44-45 24. Tiebosch ATMG. Frederik PM. van Breda Vriesman PJC, Mooy JMV. van Rie H. van de Wiel TWM. Wolters J. Zeppenfeldt E: Thin-basement-membrane nephropathy with persistent hematuria. N Engl J Med 320: 14-18. 1989 25. Peter JB, Hollingsworth PN. Dawkins RL. Delaney C, Thomas M. Jennette JC: Serologic diagnosis ofigA nephropathy: Clinical utility of assay for IgA-fibronectin aggregates. J Am Soc Nephrol 1:565. 1990 (abstr) 26. Jennette JC, Wieslander J. Tuttle R. Falk RJ: Serum IgA-fibronectin aggregates in patients with 19A nephropathy and Henoch-Schonlein purpura: Diagnostic value and pathogenic implications. Am J Kidney Dis 18:466-471. 1991 27. Mandel N. Riese N: Crystal-cell interactions: Crystal binding to rat renal papillary tip collecting duct cells in culture. Am J Kidney Dis 17:402-406. 1991 28. Coe FL. Parks JH. Asplin JR: The pathogenesis and treatment of kidney stones. N Engl J Med 327:1141-1152. 1993 29. Wilson D: Clinical and laboratory approaches forevaluation of nephrolithiasis. J UroI141:770-774. 1989 30. Breslau NA. Brinkley L. Hill KD. Pak CYC: Relationship of animal-rich diet to kidney stone formation and calcium metabolism. J Clin Endocrinol Metab 66: 140-146. 1988 31. Kok DJ. Iestra JA. Doorenbos CJ, Papapoulos SE: The effects of dietary excesses in animal protein and in sodium on the composition and the crystallization kinetics of calcium oxalate monohydrate in urines of healthy men. J Clin Endocrinol Metab 71:861-867.1990