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Familial microscopic hematuria caused by hypercalciuria and hyperuricosuria
Familial Microscopic Hematuria Caused by Hypercalciuria and Hyperuricosuria Manuel Praga, MD, Raquel Alegre, MD, Eduardo Herna´ndez, MD, Enrique Morales, MD, Beatriz Domı´nguez-Gil, MD, Agustı´n Carren˜o, MD, and Amado Andre´s, MD ● We report 12 patients belonging to five different families in whom persistent isolated microhematuria was associated with hypercalciuria and/or hyperuricosuria. Four patients had episodes of gross hematuria, three patients had passed renal stones, and a history of nephrolithiasis was obtained in four of the families (80%). Calcium oxalate and uric acid crystals were commonly observed in the urine sediments. Urinary erythrocytes had a normal appearance on phase-microscopic examination. Reduction of calciuria and uricosuria by thiazide diuretics, allopurinol, forced fluid intake, and dietetic measures led to a persistent normalization of urine sediment with complete disappearance of hematuria. Determination of calcium and uric acid urinary excretions should be included in the study of familial hematuria. 娀 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Familial hematuria; hypercalciuria (HC); hyperuricosuria (HU); nephrolithiasis; thiazides; allopurinol.
P
ERSISTENT MICROSCOPIC hematuria is a frequent diagnostic dilemma that, not uncommonly, has a familial presentation. Thin basement membrane nephropathy (TBMN) is the most frequent cause of familial microhematuria; in addition, several cases of familial immunoglobulin A (IgA) nephropathy have been reported.1-6 Here we report on 12 patients belonging to five different families in whom persistent microhematuria was associated with increased urinary excretions of calcium and/or uric acid. These metabolic abnormalities have not previously been described as a cause of familial microhematuria. METHODS Since 1980, we have followed a routine study protocol in every patient admitted to our department for persistent microhematuria. Persistent isolated microscopic hematuria is defined as the repeated presence of more than five erythrocytes per high-power field in the urine sediment, together with normal renal function and negative proteinuria in at least three consecutive determinations during a 6-month period. In addition to complete physical examination, general serum biochemistry, phase-microscopic examination of urine sediment, urine cultures, and renal ultrasonography, 24-hour urinary excretions of calcium and uric acid were routinely measured. Hypercalciuria (HC) is defined as a urinary calcium excretion of more than 4 mg/kg/24 h, and hyperuricosuria (HU) as a uric acid excretion of more than 800 mg/24 h in men and 750 mg/24 h in women in at least three consecutive determinations. In patients aged younger than 15 years, HU is defined as a uric acid excretion greater than 15 mg/kg/d. Patients with microhematuria associated with HC were treated with hydrochlorothiazide, 25 to 100 mg/d, and those with HU received allopurinol, 100 to 300 mg/d, to observe if microhematuria disappeared coinciding with the normalization of calcium and uric acid urinary excretions.
For patients who met the diagnostic criteria of persistent isolated microhematuria, as previously defined, it was generally asked to perform a urinary sediment examination in first-degree relatives (Fig 1). Following this policy, we have identified five families (including 12 patients) with persistent microhematuria in whom the correction of HC and HU with hydrochlorothiazide or allopurinol, respectively, led to the complete disappearance of microhematuria. Urinary calcium excretion was measured by absorption spectrophotometry, and urinary uric acid by a uricase enzymatic test.
RESULTS
The most important clinical data of the patients with microhematuria are listed in Table 1. All the patients showed persistent microscopic hematuria that had been discovered in routine analysis by general practitioners. HC was observed in four patients, HU in three patients, and the remaining five patients showed both HC and HU. In addition to microscopic hematuria, calcium oxalate and uric acid crystals were frequently observed in the urinary sediments (Table 1). On phase-microscopic examination, urinary erythrocytes had a normal appearance in every patient. Renal function was normal in every case, and proteinuria was negative. Urine cultures were From the Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain. Received May 6, 1999; accepted in revised form July 16, 1999. Address reprint requests to Manuel Praga, MD, Servicio de Nefrologı´a, Hospital 12 de Octubre, Carretera de Andalucı´a, Km 5,400, 28041 Madrid, Spain. E-mail: mpragat@ senefro.org
娀 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3501-0021$3.00/0
American Journal of Kidney Diseases, Vol 35, No 1 (January), 2000: pp 141-145
141
142
PRAGA ET AL
Fig. 1. Pedigrees of the five families. Numbers to the left of patients correspond with patient’s number in Tables 1 and 2. (ⴙ) Studied family members; (䊐) males; (䊊) females; (䊏, 䊉), males or females with microhematuria associated with HC and/or HU; HC, hypercalciuria; HU, hyperuricosuria; NL, nephrolithiasis.
repeatedly negative. Renal ultrasonographies, performed in all patients, and intravenous urographies, performed in five patients, had normal results; nephrolithiasis was not observed in any patient. As shown in Table 1, four patients had previously passed renal stones, and three patients had gross hematuria episodes, usually coinciding with physical exercise. Some of the studied family members showed HC, HU, or nephrolithiasis in the absence of microscopic hematuria (Fig 1). A familial history of nephrolithiasis was recorded in four of the families. As described in Methods, those patients with
HC were treated with thiazide diuretics, and those with HU with allopurinol for 2 months. Patients showing both HC and HU were treated simultaneously with both medications. After a few weeks of treatment, and coinciding with the normalization of calciuria and uricosuria, hematuria disappeared in every patient (Table 2). After 6 to 12 months of treatment, thiazide diuretics and allopurinol were gradually substituted by nonpharmacological measures (forced fluid intake, low-salt and low-purine diets). Throughout follow-up (7.4 ⫾ 2.5 years; range, 3 to 12 years), patients were examined yearly in our outpatient clinic. General serum biochemistry, urinary sedi-
FAMILIAL HEMATURIA DUE TO CRYSTALLURIA
143
Table 1. Characteristics of the Five Families With Microhematuria Associated With HC and HU Family
Patient
Age (y)
HC/HU
Urine Sediment
1
1 Mother 2 Daughter 3 Son 4 Mother 5 Daughter 6 Son 7 Mother 8 Son 9 Mother 10 Daughter 11 Sister 12 Brother
55 32 30 36 15 17 52 17 39 10 30 33
HC HC ⫹ HU HC HC ⫹ HU HU HU HC ⫹ HU HU HC ⫹ HU HC ⫹ HU HC HC
mh, CO crystals mh, CO crystals mh mh, CO crystals mh, UA crystals mh mh, CO ⫹ UA crystals mh, UA crystals mh, CO crystals mh mh mh, CO crystals
2
3 4 5
Previous NL/MH
NL NL, MH NL, MH
NL, MH
Abbreviations: HC, hypercalciuria; HU, hyperuricosuria; CO, calcium oxalate; UA, uric acid; NL, nephrolithiasis; mh, microhematuria; MH, gross hematuria.
more appropriate diagnostic workup of patients with microhematuria remains controversial.7-9 In this context, the demonstration of the familial character of the problem would be particularly interesting because only a few entities have been identified as causes of familial microhematuria. According to the results of several studies,1-4 the most common cause is TBMN. This entity, also known as benign familial hematuria, was reported the first time by Rogers et al10 in 1973; they described the distinctive histological characteristic of the disease, a diffuse thinning of the glomerular basement membrane.10-12 Clinically, it is characterized by a persistent microhe-
ment examination, and 24-hour urinary excretions of calcium and uric acid were examined at every visit. No patient had a new episode of gross hematuria or renal stone formation. Urinary sediment remained normal in every patient, and only two patients showed a transitory and short-duration reappearance of microhematuria coinciding with noncompliance with dietetic measures and prescribed forced water intake. DISCUSSION
The causes of persistent microhematuria are multiple, ranging from benign conditions to tumors of the urinary tract. As a consequence, the
Table 2. Evolution of Calciuria, Uricosuria, and Microhematuria After Hydrochlorothiazide and/or Allopurinol Treatment ⫹1 Month
Baseline Patient C No. (mg/kg/d)
1 2 3 4 5 6 7 8 9 10 11 12
5.9 5.5 4.5 4.7 1.4 1.5 5.4 2.5 4.4 4.9 5 4.9
UA (mg/d)
702 1,086 650 790 820 805 1,010 1,056 930 20.5* 520 495
⫹3 Months
mh C UA mh C UA mh (erythrocytes/hpf) Treatment (mg/kg/d) (mg/d) (erythrocytes/hpf) (mg/kg/d) (mg/d) (erythrocytes/hpf)
25 45 18 30 15 25 16 20 40 28 15 22
T T⫹A T T⫹A A A T⫹A A T⫹A T⫹A T T
3.2 3 2.8 3.7 2.1 1.6 3.8 2.2 3.1 3.3 3.9 3.6
639 625 620 414 510 467 645 730 670 12* 498 474
5 0 0 0 0 0 8 0 5 0 8 0
2.1 2.1 2.6 2.5 1.9 2 3.1 2.2 2.3 2.7 3 2.5
522 473 602 368 367 339 481 466 523 8* 516 433
Abbreviations: C, calciuria; UA, uricosuria; mh, microhematuria; hpf, high power field; T, thiazides; A, allopurinol. *In patient 10, uricosuria is expressed in mg/kg/d.
0 0 0 0 0 0 0 0 0 0 0 0
144
maturia without derangement of renal function, although a considerable proportion of patients develop proteinuria and hypertension on longterm follow-up.11-14 Patients with Alport’s syndrome can also show isolated persistent microhematuria during the earlier stages of the disease15; however, family screening usually uncovers proteinuria and renal failure in other members of the family, in addition to deafness.16 Finally, several families with IgA nephropathy have been reported,5,6,17 although the true incidence of familial IgA nephropathy is unknown. In this study, we report on a not previously described cause of familial microhematuria. Several studies described the association of HU and HC with persistent microhematuria,18-24 but the familial character of this association had not been recognized. The mechanisms through which these metabolic abnormalities cause hematuria are unknown, but it is suspected that persistent HC and HU can induce microcrystal formation in tubular lumen that in turn injure the tubular epithelium, resulting in microscopic bleeding. However, episodes of gross hematuria also have been described in patients with HC and HU, frequently related to physical exercise.18-24 To show the etiologic relationship between HC and/or HU and hematuria, it is necessary to observe a normal urinary sediment after the normalization of calcium and uric acid urinary excretions; thiazide diuretics and allopurinol are very effective treatments for HC and HU, respectively. In all our patients, we could show the definite disappearance of microhematuria after the start of these treatments. In a recent study, we described a high prevalence of HC, HU, and nephrolithiasis among patients with biopsy-proven TBMN.25 However, in these patients, the normalization of calciuria and uricosuria by means of thiazide diuretics and allopurinol treatment did not result in a disappearance of hematuria, which persisted throughout long-term follow-up. On phase-microscopic examination of urine sediment, most erythrocytes were dysmorphic. Conversely, in the present study, erythrocytes had a normal appearance in every patient, strongly suggesting their nonglomerular origin.7,26 Both HC and HU are known risk factors for the development of nephrolithiasis, and these metabolic disturbances show a familial aggregra-
PRAGA ET AL
tion.27,28 In accordance with this fact, three of our patients had passed renal stones, and four patients had episodes of gross hematuria. Moreover, a positive history of nephrolithiasis was obtained in four of the five studied families (80%). After the first 6 to 12 months of followup, thiazide diuretics and allopurinol were substituted by standard nonpharmacologic treatments for nephrolithiasis (forced fluid intake, dietary measures) in every patient. No patient had new episodes of gross hematuria or renal stone formation. In conclusion, we strongly recommend the measurement of calciuria and uricosuria in every family with hematuria, mainly in those with a history of nephrolithiasis and when crystals are observed in the urinary sediment. If HC or HU are detected, treatment with thiazides and/or allopurinol can normalize urinary sediment, avoiding further invasive diagnostic procedures. REFERENCES 1. Tiebosch AT, Wolters J, Frederik P, van der Wiel TW, Zeppenfeldt E, van Breda Vriesman PJ: Epidemiology of idiopathic glomerular diseases: A prospective study. Kidney Int 32:112-116, 1987 2. Topham PS, Harper SJ, Furness PN, Harris HPG, Walls J, Feehally J: Glomerular disease as a cause of isolated microscopic hematuria. Q J Med 87:329-335, 1994 3. Blumenthal SS, Fritsche C, Lemann J: Establishing the diagnosis of benign familial hematuria. The importance of examining the urine sediment of family members. JAMA 259:2263-2266, 1988 4. Praga M, Vara J, Alegre R, Morales JM, Andre´s A: Familial isolated microhematuria. Clinical characteristics and long-term follow-up. J Am Soc Nephrol 7:1620A, 1996 (abstr) 5. Julian BA, Quiggins PA, Thompson JS, Woodford SY, Gleason K, Wyatt RJ: Familial IgA nephropathy. Evidence of an inherited mechanism of disease. N Engl J Med 312:202208, 1985 6. Schena FP, Scivittaro V, Ranieri E, Sinico R, Benuzzi S, Di Cillo M, Aventaggiato L: Abnormalities of the IgA immune system in members of unrelated pedigrees from patients with IgA nephropathy. Clin Exp Immunol 92:139144, 1993 7. Fogazzi GB, Ponticelli C: Microscopic hematuria. Diagnosis and management. Nephron 72:125-134, 1996 8. Mariani AJ, Mariani MC, Macchioni C, Stams UK, Hariharan A, Moriera A: The significance of adult hematuria: 1000 Hematuria evaluations including a risk-benefit and cost-effectiveness analysis. J Urol 141:350-355, 1989 9. Messing EM, Young TB, Hunt VB, Wehbie JM, Rust P: Urinary tract cancers found by home screening with hematuria dipstick in healthy men over 50 years of age. Cancer 64:2361-2367, 1989 10. Rogers PW, Kurtzman NA, Bunn SM, White MG:
FAMILIAL HEMATURIA DUE TO CRYSTALLURIA
Familial benign essential hematuria. Arch Intern Med 131: 257-262, 1973 11. Tiebosch AT, Frederik P, van Breda Vriesman PJ, Mooy J, van Rie H, van de Wiel T, Wolters J, Zeppenfeldt E: Thin basement membrane nephropathy in adults with persistent hematuria. N Engl J Med 320:14-18, 1989 12. Goel S, Davenport A, Goode NP, Shires M, Hall CL, Harrison PR, Maciber AG: Clinical features and outcome of patients with thin and ultrathin glomerular membranes. Q J Med 88:785-793, 1995 13. Trachtman H, Weiss RA, Bennet B, Greifer I: Isolated hematuria in children: Indications for a renal biopsy. Kidney Int 25:94-99, 1984 14. Aarons I, Smith PS, Davies RA, Woodroffe AJ, Clarkson AR: Thin membrane nephropathy: A clinicopathological study. Clin Nephrol 32:151-158, 1989 15. Piqueras AI, White RH, Raafat R, Moghal N, Milford DV: Renal biopsy diagnosis in children presenting with hematuria. Pediatr Nephrol 12:386-391, 1998 16. Kashtan CE, Michael AF: Alport syndrome. Kidney Int 50:1445-1463, 1996 17. Schena FP: Immunogenetic aspects of primary IgA nephropathy. Kidney Int 48:1998-2013, 1995 18. Stapleton FB, Roy S, Noe NH, Jerkins G: Hypercalciuria in children with hematuria. N Engl J Med 310:13451348, 1984 19. Andre´s A, Praga M, Bello I, Dı´az-Rolo´n JA, Gutie´rrezMillet V, Morales JM, Rodicio JL: Hematuria due to hypercalciuria and hyperuricosuria in adult patients. Kidney Int 36:96-99, 1989
145
20. Bayle MS, Manchen˜o CR: Hyperuricosuria and microhematuria in childhood. Am J Dis Child 143:878-879, 1989 21. Perrone HC, Aizen H, Toporovski J, Schor N: Metabolic disturbances as a cause of recurrent hematuria in children. Kidney Int 39:707-710, 1991 22. Cervera A, Corral MJ, Go´mez-Campdera´ FJ, de Lecea AM. Luque A, Lo´pez-Go´mez JM: Idiopathic hypercalciuria in children: Classification, clinical manifestations and outcome. Acta Pediatr Scand 76:271-278, 1987 23. Garcı´a CD, Miller LA, Stapleton FB: Natural history of hematuria associated with hypercalciuria in children. Am J Dis Child 145:1204-1207, 1991 24. Perrone HC, Stapleton FB, Toporovsji J, Schor N: Hematuria due to hyperuricosuria in children: 36-Month follow-up. Clin Nephrol 48:288-291, 1997 25. Praga M, Martı´nez MA, Andre´s A, Alegre R, Vara J, Morales E, Herrero JC, Novo O, Rodicio JL: Association of thin basement membrane nephropathy with hypercalciuria, hyperuricosuria and nephrolithiasis. Kidney Int 54:915-920, 1998 26. Rizzoni G, Braggion F, Zacchello G: Evaluation of glomerular and nonglomerular hematuria by phase-contrast microscopy. J Pediatr 103:370-374, 1983 27. Asplin JR, Favus MJ, Coe FL: Nephrolithiasis, in Brenner BM (ed): The Kidney (ed 5). Philadelphia, PA, Saunders, 1996, pp 1893-1935 28. Favus MJ: Hypercalciuria: Lessons from studies of genetic hypercalciuric rats. J Am Soc Nephrol 5:S54-S58, 1994 (suppl 1)
P
ERSISTENT MICROSCOPIC hematuria is a frequent diagnostic dilemma that, not uncommonly, has a familial presentation. Thin basement membrane nephropathy (TBMN) is the most frequent cause of familial microhematuria; in addition, several cases of familial immunoglobulin A (IgA) nephropathy have been reported.1-6 Here we report on 12 patients belonging to five different families in whom persistent microhematuria was associated with increased urinary excretions of calcium and/or uric acid. These metabolic abnormalities have not previously been described as a cause of familial microhematuria. METHODS Since 1980, we have followed a routine study protocol in every patient admitted to our department for persistent microhematuria. Persistent isolated microscopic hematuria is defined as the repeated presence of more than five erythrocytes per high-power field in the urine sediment, together with normal renal function and negative proteinuria in at least three consecutive determinations during a 6-month period. In addition to complete physical examination, general serum biochemistry, phase-microscopic examination of urine sediment, urine cultures, and renal ultrasonography, 24-hour urinary excretions of calcium and uric acid were routinely measured. Hypercalciuria (HC) is defined as a urinary calcium excretion of more than 4 mg/kg/24 h, and hyperuricosuria (HU) as a uric acid excretion of more than 800 mg/24 h in men and 750 mg/24 h in women in at least three consecutive determinations. In patients aged younger than 15 years, HU is defined as a uric acid excretion greater than 15 mg/kg/d. Patients with microhematuria associated with HC were treated with hydrochlorothiazide, 25 to 100 mg/d, and those with HU received allopurinol, 100 to 300 mg/d, to observe if microhematuria disappeared coinciding with the normalization of calcium and uric acid urinary excretions.
For patients who met the diagnostic criteria of persistent isolated microhematuria, as previously defined, it was generally asked to perform a urinary sediment examination in first-degree relatives (Fig 1). Following this policy, we have identified five families (including 12 patients) with persistent microhematuria in whom the correction of HC and HU with hydrochlorothiazide or allopurinol, respectively, led to the complete disappearance of microhematuria. Urinary calcium excretion was measured by absorption spectrophotometry, and urinary uric acid by a uricase enzymatic test.
RESULTS
The most important clinical data of the patients with microhematuria are listed in Table 1. All the patients showed persistent microscopic hematuria that had been discovered in routine analysis by general practitioners. HC was observed in four patients, HU in three patients, and the remaining five patients showed both HC and HU. In addition to microscopic hematuria, calcium oxalate and uric acid crystals were frequently observed in the urinary sediments (Table 1). On phase-microscopic examination, urinary erythrocytes had a normal appearance in every patient. Renal function was normal in every case, and proteinuria was negative. Urine cultures were From the Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain. Received May 6, 1999; accepted in revised form July 16, 1999. Address reprint requests to Manuel Praga, MD, Servicio de Nefrologı´a, Hospital 12 de Octubre, Carretera de Andalucı´a, Km 5,400, 28041 Madrid, Spain. E-mail: mpragat@ senefro.org
娀 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3501-0021$3.00/0
American Journal of Kidney Diseases, Vol 35, No 1 (January), 2000: pp 141-145
141
142
PRAGA ET AL
Fig. 1. Pedigrees of the five families. Numbers to the left of patients correspond with patient’s number in Tables 1 and 2. (ⴙ) Studied family members; (䊐) males; (䊊) females; (䊏, 䊉), males or females with microhematuria associated with HC and/or HU; HC, hypercalciuria; HU, hyperuricosuria; NL, nephrolithiasis.
repeatedly negative. Renal ultrasonographies, performed in all patients, and intravenous urographies, performed in five patients, had normal results; nephrolithiasis was not observed in any patient. As shown in Table 1, four patients had previously passed renal stones, and three patients had gross hematuria episodes, usually coinciding with physical exercise. Some of the studied family members showed HC, HU, or nephrolithiasis in the absence of microscopic hematuria (Fig 1). A familial history of nephrolithiasis was recorded in four of the families. As described in Methods, those patients with
HC were treated with thiazide diuretics, and those with HU with allopurinol for 2 months. Patients showing both HC and HU were treated simultaneously with both medications. After a few weeks of treatment, and coinciding with the normalization of calciuria and uricosuria, hematuria disappeared in every patient (Table 2). After 6 to 12 months of treatment, thiazide diuretics and allopurinol were gradually substituted by nonpharmacological measures (forced fluid intake, low-salt and low-purine diets). Throughout follow-up (7.4 ⫾ 2.5 years; range, 3 to 12 years), patients were examined yearly in our outpatient clinic. General serum biochemistry, urinary sedi-
FAMILIAL HEMATURIA DUE TO CRYSTALLURIA
143
Table 1. Characteristics of the Five Families With Microhematuria Associated With HC and HU Family
Patient
Age (y)
HC/HU
Urine Sediment
1
1 Mother 2 Daughter 3 Son 4 Mother 5 Daughter 6 Son 7 Mother 8 Son 9 Mother 10 Daughter 11 Sister 12 Brother
55 32 30 36 15 17 52 17 39 10 30 33
HC HC ⫹ HU HC HC ⫹ HU HU HU HC ⫹ HU HU HC ⫹ HU HC ⫹ HU HC HC
mh, CO crystals mh, CO crystals mh mh, CO crystals mh, UA crystals mh mh, CO ⫹ UA crystals mh, UA crystals mh, CO crystals mh mh mh, CO crystals
2
3 4 5
Previous NL/MH
NL NL, MH NL, MH
NL, MH
Abbreviations: HC, hypercalciuria; HU, hyperuricosuria; CO, calcium oxalate; UA, uric acid; NL, nephrolithiasis; mh, microhematuria; MH, gross hematuria.
more appropriate diagnostic workup of patients with microhematuria remains controversial.7-9 In this context, the demonstration of the familial character of the problem would be particularly interesting because only a few entities have been identified as causes of familial microhematuria. According to the results of several studies,1-4 the most common cause is TBMN. This entity, also known as benign familial hematuria, was reported the first time by Rogers et al10 in 1973; they described the distinctive histological characteristic of the disease, a diffuse thinning of the glomerular basement membrane.10-12 Clinically, it is characterized by a persistent microhe-
ment examination, and 24-hour urinary excretions of calcium and uric acid were examined at every visit. No patient had a new episode of gross hematuria or renal stone formation. Urinary sediment remained normal in every patient, and only two patients showed a transitory and short-duration reappearance of microhematuria coinciding with noncompliance with dietetic measures and prescribed forced water intake. DISCUSSION
The causes of persistent microhematuria are multiple, ranging from benign conditions to tumors of the urinary tract. As a consequence, the
Table 2. Evolution of Calciuria, Uricosuria, and Microhematuria After Hydrochlorothiazide and/or Allopurinol Treatment ⫹1 Month
Baseline Patient C No. (mg/kg/d)
1 2 3 4 5 6 7 8 9 10 11 12
5.9 5.5 4.5 4.7 1.4 1.5 5.4 2.5 4.4 4.9 5 4.9
UA (mg/d)
702 1,086 650 790 820 805 1,010 1,056 930 20.5* 520 495
⫹3 Months
mh C UA mh C UA mh (erythrocytes/hpf) Treatment (mg/kg/d) (mg/d) (erythrocytes/hpf) (mg/kg/d) (mg/d) (erythrocytes/hpf)
25 45 18 30 15 25 16 20 40 28 15 22
T T⫹A T T⫹A A A T⫹A A T⫹A T⫹A T T
3.2 3 2.8 3.7 2.1 1.6 3.8 2.2 3.1 3.3 3.9 3.6
639 625 620 414 510 467 645 730 670 12* 498 474
5 0 0 0 0 0 8 0 5 0 8 0
2.1 2.1 2.6 2.5 1.9 2 3.1 2.2 2.3 2.7 3 2.5
522 473 602 368 367 339 481 466 523 8* 516 433
Abbreviations: C, calciuria; UA, uricosuria; mh, microhematuria; hpf, high power field; T, thiazides; A, allopurinol. *In patient 10, uricosuria is expressed in mg/kg/d.
0 0 0 0 0 0 0 0 0 0 0 0
144
maturia without derangement of renal function, although a considerable proportion of patients develop proteinuria and hypertension on longterm follow-up.11-14 Patients with Alport’s syndrome can also show isolated persistent microhematuria during the earlier stages of the disease15; however, family screening usually uncovers proteinuria and renal failure in other members of the family, in addition to deafness.16 Finally, several families with IgA nephropathy have been reported,5,6,17 although the true incidence of familial IgA nephropathy is unknown. In this study, we report on a not previously described cause of familial microhematuria. Several studies described the association of HU and HC with persistent microhematuria,18-24 but the familial character of this association had not been recognized. The mechanisms through which these metabolic abnormalities cause hematuria are unknown, but it is suspected that persistent HC and HU can induce microcrystal formation in tubular lumen that in turn injure the tubular epithelium, resulting in microscopic bleeding. However, episodes of gross hematuria also have been described in patients with HC and HU, frequently related to physical exercise.18-24 To show the etiologic relationship between HC and/or HU and hematuria, it is necessary to observe a normal urinary sediment after the normalization of calcium and uric acid urinary excretions; thiazide diuretics and allopurinol are very effective treatments for HC and HU, respectively. In all our patients, we could show the definite disappearance of microhematuria after the start of these treatments. In a recent study, we described a high prevalence of HC, HU, and nephrolithiasis among patients with biopsy-proven TBMN.25 However, in these patients, the normalization of calciuria and uricosuria by means of thiazide diuretics and allopurinol treatment did not result in a disappearance of hematuria, which persisted throughout long-term follow-up. On phase-microscopic examination of urine sediment, most erythrocytes were dysmorphic. Conversely, in the present study, erythrocytes had a normal appearance in every patient, strongly suggesting their nonglomerular origin.7,26 Both HC and HU are known risk factors for the development of nephrolithiasis, and these metabolic disturbances show a familial aggregra-
PRAGA ET AL
tion.27,28 In accordance with this fact, three of our patients had passed renal stones, and four patients had episodes of gross hematuria. Moreover, a positive history of nephrolithiasis was obtained in four of the five studied families (80%). After the first 6 to 12 months of followup, thiazide diuretics and allopurinol were substituted by standard nonpharmacologic treatments for nephrolithiasis (forced fluid intake, dietary measures) in every patient. No patient had new episodes of gross hematuria or renal stone formation. In conclusion, we strongly recommend the measurement of calciuria and uricosuria in every family with hematuria, mainly in those with a history of nephrolithiasis and when crystals are observed in the urinary sediment. If HC or HU are detected, treatment with thiazides and/or allopurinol can normalize urinary sediment, avoiding further invasive diagnostic procedures. REFERENCES 1. Tiebosch AT, Wolters J, Frederik P, van der Wiel TW, Zeppenfeldt E, van Breda Vriesman PJ: Epidemiology of idiopathic glomerular diseases: A prospective study. Kidney Int 32:112-116, 1987 2. Topham PS, Harper SJ, Furness PN, Harris HPG, Walls J, Feehally J: Glomerular disease as a cause of isolated microscopic hematuria. Q J Med 87:329-335, 1994 3. Blumenthal SS, Fritsche C, Lemann J: Establishing the diagnosis of benign familial hematuria. The importance of examining the urine sediment of family members. JAMA 259:2263-2266, 1988 4. Praga M, Vara J, Alegre R, Morales JM, Andre´s A: Familial isolated microhematuria. Clinical characteristics and long-term follow-up. J Am Soc Nephrol 7:1620A, 1996 (abstr) 5. Julian BA, Quiggins PA, Thompson JS, Woodford SY, Gleason K, Wyatt RJ: Familial IgA nephropathy. Evidence of an inherited mechanism of disease. N Engl J Med 312:202208, 1985 6. Schena FP, Scivittaro V, Ranieri E, Sinico R, Benuzzi S, Di Cillo M, Aventaggiato L: Abnormalities of the IgA immune system in members of unrelated pedigrees from patients with IgA nephropathy. Clin Exp Immunol 92:139144, 1993 7. Fogazzi GB, Ponticelli C: Microscopic hematuria. Diagnosis and management. Nephron 72:125-134, 1996 8. Mariani AJ, Mariani MC, Macchioni C, Stams UK, Hariharan A, Moriera A: The significance of adult hematuria: 1000 Hematuria evaluations including a risk-benefit and cost-effectiveness analysis. J Urol 141:350-355, 1989 9. Messing EM, Young TB, Hunt VB, Wehbie JM, Rust P: Urinary tract cancers found by home screening with hematuria dipstick in healthy men over 50 years of age. Cancer 64:2361-2367, 1989 10. Rogers PW, Kurtzman NA, Bunn SM, White MG:
FAMILIAL HEMATURIA DUE TO CRYSTALLURIA
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