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Hypercalciuria in children with juvenile rheumatoid arthritis: Association with hematuria
Hypercalciuria in children with juvenile rheumatoid arthritis." Association with hematuria After discovering juvenile rheumatoid arthritis (JRA), hematuria, and urolithiasis associated with hypercalciuria in two children, urinary calcium excretion was examined in 38 patients with JRA. Fasting urine caleium/creatinine (mg/mg) (UCa/UCr) ratios were increased (>0.21) in 12 patients, who had a mean UCa/UCr ratio of 0.34 + 0.14, compared with 0.09 + 0.06 in 26 normoealeiuric patients with JRA. Increased UCa/UCr ratios were found more frequently in patients with systemic JRA (P <0.05); however, no relationship between UCa/UCr ratios and either functional classification or drug therapy was observed, Four children with increased urine calcium to creatinine ratios were examined more extensively. Twenty-four-hour urine calcium excretion ranged from 4.0 to 7.2 mg/kg/24 hours. An orally administered calcium loading test demonstrated fasting hypercalciuria after dietary calcium restriction in these four patients. Serum calcium, bicarbonate, phosphorus, and parathyroid hormone values were normal. Hematuria was found in six o f 12 hypercalciuric patients with JRA but in only three o f 26 normocalciuric patients (P <0.016). We conclude that urinary calcium excretion is frequently increased in patients with JRA and that hypercalciuria may be related to the pathogenesis o f hematuria in some o f them. (J Pt~DIATR 1985;107:235-239)
F. Bruder Stapleton, M.D., Aram S. Hanissian, M.D., and Leslie A. Miller, B.S.
Memphis, Tennessee
BONE DEMINERALIZATION and hematuria, two apparently unrelated disease manifestations, have long been recognized to complicate juvenile rheumatoid arthritis2 -3 Because of periarticular osseous demineralization, serum calcium, parathyroid hormone, and vitamin D concentrations have been examined and found to be normal in adults with rheumatoid arthritis; however, to our knowledge, urinary calcium excretion has not been measured in adults or children with rheumatoid arthritis?,5 After seeing two patients with systemic J R A and hematuria who developed urinary calculi associated with hypercalciuria, we assessed urinary calcium excretion in children with J R A . In addition, because hypercalciuria without urolithiasis has been associated with childhood hematuria, 6 we questioned whether hypercalciuria might be related to the pathogeneFrom Pediatric Research Laboratory. Supported by the General Clinical Research Center Clinical Associate Physician Award R R O0211-19 from the U.S. Public Health Service (F.B.S,). Submitted for publication Oct. 9, 1984; accepted Jan. 24, 1985. Reprint requests: F. Bruder Stapleton, M.D., Pediatric Research Laboratory, 956 Court Ave., Rm. 3B09, Memphis, TN 38163.
sis of the hematuria that is sometimes observed in children with J R A . CASE REPORTS Patient 1. This 3-year-old white girl was diagnosed as having systemic JRA with hectic fevers, polyarthritis, and lymphadenopathy. Before therapy with salicylates, microscopic hematuria was noted. At 4V2 years of age she developed episodes of urinary incontinence, severe dysuria, and gross hematuria concomitant
JRA UCa/UCr
Juvenile rheumatoid arthritis Ratio of urinary calcium to urinary creatinine concentration
with fever and increased joint symptoms. Evaluation of the urinary tract at the onset of urinary symptoms yielded negative urine cultures and normal findings on intravenous pyelogram and voiding cystourethrogram. The serum antinuclear antibody and IgM rheumatoid factor tests yielded negative results. Cystoscopic evaluation at 4V2 years and at 5 years of age failed to reveal the source of hematuria. She was then referred for nephrologic consultation because of increasing episodes of dysuria and hematuria. At the time of evaluation, the patient was receiving tolectin sodium 200 mg three times daily for joint pain. There was no
The Journal o f P E D I A T R l C S
235
236
Stapleton, Hanissian, and Miller
Table
I. Clinical data
The Journal of Pediatrics August 1985
in 38 children with juvenile
rheumatoid arthritis
UCa/UCr (mg/mg) Age (yr) Sex (M/F) Disease type:t: Systemic Polyarticular Pauciarticular Functional classification
UCa/UCr <0.21 (n = 26)
UCa/UCr >0.21 (n = 12)
0.09 + 0.06 10.1 _+ 3.6 9/15
0.34 _+ 0.14" 6.1 _+ 3.8~ 5/7
5 11 10
7 2 3
6
6
13 7 0 3
2 4 0 6
1
I1 III IV Hematuriaw
UCa/UCr indicates the mg/mg ratio of fasting urine calcium to urine creatinine concentration. Values are mean + SD. *P <0.00l. "~P <0.01. SP <0.05. w <0.016.
T a b l e II. N u m b e r of patients receiving antiarthritic drug
therapy when urinary calcium was assessed
Therapy
UCa/UCr <0.21
UCa/UCr >0.21
None Salicylate Gold Prednisone Other
0 21 (3) 7 (t) 1 5
1 (1) 10 (3) 5 (1) 1 (I) 2 (2)
UCa/UCr is ratio of fasting urine calcium to urine creatinine concentration. Numbers in parentheses represent number of children with hematuria while receiving each therapy.
family history of renal disease or urolithiasis, physical examination revealed fusiform swelling of the interphalangeal joints of the hand and contractures of both elbows and knees. The urinalysis revealed a large reaction to hemoglobin, red blood cells "too numerous to count," proteinuria (1 +), and many calcium oxalate crystals. At 5V2 years of age the child spontaneously passed a calcium oxalate urinary calculus during an episode of dysuria and hematuria. Metabolic evaluation found creatinine clearance to be 110 ml/min/l.73 m s, normal uric acid and oxalate excretion, and increased urinary calcium excretion of 4.6 mg/kg/day. The serum calcium concentration was 9.5 mg/dl. No evidence of inflammatory bowel disease was found with barium enema studies. Patient 2. This 22-month-old white girl was diagnosed as having JRA after a 3-month history Of fever, polyarthritis, and increased erythrocyte sedimentation rate. Microscopic hematuria was noted on urinalysis. Urine cultures were negative, and findings on intravenous pyelogram were normal except for a radiopaque calculus in the bladder. A urinary calcium/creatinine ratio was
0.32 (normal <0.21). The patient was discharged for observation, but never returned for further evaluation. METHODS
Thirty-eight children who fulfilled the A m e r i c a n R h e u m a t i s m Association criteria 7 for the diagnosis of juvenile r h e u m a t o i d arthritis were the subject of this study. All m e t the exclusion criteria for other causes of childhood arthritis, including systemic lupus erythematosus. T h e patients ranged in age from 22 m o n t h s to 17 years, and h a d pauciarticular, polyarticular, or systemic J R A according to s t a n d a r d criteria. 7,8 E a c h patient was assigned a functional class from I to IV (IV being most debilitated) 9 by a pediatric rheumatologist (A.S.H.) who was unfamiliar with the patient's urinary calcium excretion. T h e r a p e u t i c agents being administered at the time of study were recorded. Each patient was instructed to collect and refrigerate a fasting second morning voided urine sample on the day of a clinic visit. A urinalysis was performed, a n d the urine calcium concentration was determined by atomic absorption and was measured with an a u t o m a t i c analyzer. H e m a t u r i a was determined by a positive hemoglobin reaction by dipstick and the presence of > 5 red blood cells per high-power field. A U C a / U C r ratio <0.21 was considered normal. 1~ ~ A n orally administered calcium loading test was performed in the Clinical Research Center in four patients, as previously described. ~~ In brief, after discontinuing all medications, the children ingested a 300 mg calcium, 2 g m sodium diet for 5 days before the study. Compliance was assessed by dietary records. O n the day of study, a fasting urine collection was obtained from 7:00 to 9:00 AM. Blood for determination of serum calcium, electrolyte, parathyroid hormone, and creatinine concentration was obtained at 9:00 AM and 1:00 PM. A standardized breakfast was eaten at 9:00 AM, and 1 g m / 1 . 7 3 m 2 body surface area of elemental calcium as calcium glubionate syrup was given. A second urine sample was collected from 9:00 AM to 1:00 PM. U r i n e samples were assayed for calcium and creatinine. This protocol was approved by the University of Tennessee C e n t e r for the H e a l t h Sciences C o m m i t t e e for biomedical research in h u m a n subjects. D a t a were analyzed using the C L I N F O computer system in the Clinical Research Center. Statistical significance was determined with the S t u d e n t t test for u n p a i r e d data, Fisher E x a c t test, and chi-square analysis where appropriate. RESULTS Fasting U C a / U C r were increased in 12 (32%) of 3 8 patients with J R A (Table I). T h e m e a n U C a / U C r ratio was 0.34 +_ 0.14 in hyl3ercalciuric children, compared with
Volume 107 Number 2
Hypercaleiuria and hematuria in J R A
237
Table III. Calcium studies in four children with J R A previously found to have increased fasting U C a / U C r ratios during clinic screening studies Serum Patient 1
2 3 4
Calcium (mg/dl)
9.5 9.1 9.9 9.3
Bicarbonate (mEq/L)
Urine
Phosphorus (mg/dl)
Creatinine (mg/dl)
PTH* (pmol/L)
CalciumS" (mg/kg/aay)
~4.4 4.2 4.4 4.5
0.6 0.5 0.4 0.5
68 57 62 58
7.2 4.0 5.0 4.6
23 25 23 22
*Normal, 60.4 • 20.0 pmol/L. ]'Normal, <4 mg/kg/day. 0.09 _+ 0.06 in the normocalciuric patients (P < 0.001). Normal fasting U C a / U C r ratios for children in our community are 0.09 +_ 0.06J ~ Hypercalciuric patients with JRA were younger (P < 0.01) than patients with normal calcium excretion, and hypercalciuria occurred more frequently in patients with systemic JRA: seven of 12 hypercalciuric patients had systemic JRA, compared with only five of 26 normocalciuric patients (P < 0.05). Polyarticular and pauciarticular JRA was found with equal frequency in hypercalciuric and normocalciuric groups. No statistical relationship between the functional classification of JRA and urinary calcium excretion was observed. All but one of the patients were receiving drug therapy for arthritis (Table II). One patient with systemic JRA had hypercalciuria ( U C a / C r 0.32) and was taking no medications. No statistical relationship between drug therapy and urinary calcium excretion was found. Four patients with hypercalciuria were studied more extensively while receiving no medications (Table III). Serum calcium, bicarbonate, phosphorus, parathyroid hormone, and creatinine concentrations were normal, and 24-hour urinary calcium excretion was >--4.0 m g / k g / d a y in each patient. Serum 25(OH) vitamin D and 1,25(OH)2 vitamin D concentration were normal in patient 3. Three of these children had hematuria at the time of evaluation; none had a history of urolithiasis. Results of an orally administered calcium loading test are shown in the Figure. The mean fasting U C a / U C r ratio was 0.44. A variable response to the calcium challenge was noted. Calcium excretion increased in two, decreased in one, and remained essentially unchanged in the other patient. None of the patients had a family history of urolithiasis. Fasting U C a / U C r ratios and 24-hour urinary calcium excretion were determined in family members of three of the four children, and were normal in each instance. Hematuria was discovered in 6 of 12 patients with J R A with increased U C a / U C r ; hematuria was macroscopic in two and microscopic in four patients. In each hypercalciuric patient, hematuria was confirmed at a later office or hospital visit. Only three of 26 patients with normal
U C a / U C r ratios had hematuria. Hematuria was microscopic in each and was reconfirmed in two patients in whom a second urine specimen was available. In one patient with normal U C a / U C r ratios and hematuria, the 24-hour urinary calcium excretion was 2.8 m g / k g / d a y (normal <4 mg/kg/day). Four of the hematuric patients had systemic JRA, two had polyarticular and three had pauciartieular disease. Proteinuria was not observed, and red blood cell casts were found in one urinalysis. Two children with hematuria were receiving gold therapy (Table II); one had an elevated and the other a normal U C a / U C r ratio. One patient with J R A with hematuria and hypercalciuria was receiving no antiarthritic medications. A percutaneous renal biopsy was performed in one patient with systemic J R A (patient 3, Table III) in whom microscopic and intermittent gross hematuria had been present for 2 years. No abnormalities were identified by light or electron microscopy, and no immunoreactants were found by immunofluorescence. After all diagnostic studies, this child received hydrochlorothiazide therapy 2 mg/kg/day. The 24-hour urinary calcium excretion decreased to 1.4 m g / k g / d a y and hematuria resolved. DISCUSSION Juxtaarticular demineralization is an early radiographic finding in children with JRA? Furthermore, generalized osteoporosis has been observed in children with JRA and in adults with rheumatoid arthritis, occasionally resulting in pathologic fractures of the long bones and in vertebral compression fractures?, ~z-~4In adults, osteoporosis is greatest in elderly and in immobilized patients and during corticosteroid therapy? 4 Growth failure in children with JRA has, in part, been attributed to diminished bone mineralization? The pathogenesis of osteopenia is uncertain; however, serum concentrations of parathyroid hormone and vitamin D metabolites are normal in adults with rheumatoid arthritis. 4'5 It is surprising that no studies examining urinary calcium excretion in either childhood or adult rheumatoid arthritis have been reported.
238
Stapleton, Hanissian, and Miller
1.0
0.9 0.8
E E L L)
0.7 O.6
-~ o u
Q5
>n-
0.4
n..
0.3
< _z
0.2 0.1
0
FASTING
POST CALCIUM LOAD
Figure. Oral calcium loading tests were performed after 1 week of dietary calcium restriction in four children with JRA in whom initial fasting UCa/UCr ratios were elevated. Fasting UCa/UCr ratios were increased in each patient. Dotted lines represent +2 SD for normal children in community.
Our data indicate that urinary calcium excretion is often increased in patients with J R A and that the increased urinary calcium excretion is not related to hypercalcemia, hyperparathyroidism, acidosis, or hypophosphatemia. Unfortunately, our study does not clarify the pathogenesis of hypercalciuria in these children with JRA because we did not assess bone mineralization. Recently, proximal renal tubule dysfunction with increased urinary excretion of B2-microglobulin has been reported in "rheumatic diseases. ''~5 Renal calcium wasting cannot be excluded entirely, because multiple measures of proximal tubule function were not examined in our patients; however, glycosuria, proteinuria, and hypophosphatemia were not present. The role of immobilization in hypercalciuria associated with J R A is also uncertain. No significant relationship between urinary calcium excretion and functional disability in our patients was noted, and none of our patients was consid-
The Journal of Pediatrics August 1985
ered to be severely disabled (class IV). Nonetheless, immobilization of even a single limb may be associated with increased urinary calcium excretion in children? 6 The calciuric response to an orally administered loading test in children with hypercalciuri~t and JRA differed somewhat from the response observed in children with hematuria 6 or calcium oxalate urolithiasis. ~7 These previous studies in children with idiopathic hypercalciuria have demonstrated a significant increase in urinary calcium excretion following an oral calcium challenge. The absence of a calciuric response in the hypercalciuric patients with JRA, along with the absence of evidence to support familial hypercalciuria, indicates that the pathogenesis of hypercalciuria in J R A may differ from idiopathic hypercalciuria. The association of hypercalciuria with systemic J R A may lend support to the hypothesis that local inflammatory mediators produce bone resorption (and secondarily cause hypercalciuria)? 8 Synovial inflammation in JRA might produce local demineralization by the production of the lymphokine, osteoclast activating factor, through monocyte-derived mediators, or by local prostaglandin E2 production. 18-20 Our two children with JRA, hypercalciuria, hematuria, and urolithiasis suggests that increased urinary calcium excretion may have adverse effects on the genitourinary system. Lorenz and Schneider 2~ have previously reported kidney stone formation in six of 89 German children with JRA. These authors did not measure urinary calcium excretion, but speculated that hypercalciuria might occur from immobilization and cortisone therapy. Urolithiasis in children is more common in our referral area and is often familial; therefore, it is possible that urolithiasis in our two patients was unrelated to JRA. 22 However, neither of the two children with urolithiasis had a family history of urinary calculi, and the incidence of hypercalciuria in our patients with JRA was more than 8 times greater than in the general population, and also greater than in children with hematuria. 6 Hypercalciuria without urolithiasis recently has been associated with hematuria in children. The 67% incidence of hypercalciuria in patients with both hematuria and J R A is nearly twice the incidence of hypercalciuria in children with unexplained hematuria at our center. 6 In one hypercalciuric child with systemic J R A and chronic hematuria, no glomerular disease was identified in renal biopsy specimens, and hematuria abated when urinary calcium was reduced during hydrochlorothiazide therapy. Hematuria has been noted previously in 28% to 38% of children with JRA, 2,2t and has many potential causes related to the disease or to the many antiarthritic drugs used to treat these patients. Such causes include papillary necrosis,
Volume t07 Number 2
interstitial nephritis, glomerulonephritis, vasculitis, amyloidosis, and urolithiasis. 22:6 This study suggests t h a t hypercaleiuria should also be considered in the evaluation of children with J R A and hematuria. S u c h children m a y be at risk for developing urolithiasis, particularly during periods of immobilization or during corticosteroid therapy. REFERENCES l. Brewer E J, Giannini EH, Peron DA: Juvenile rheumatoid arthritis. In Major problems in clinical pediatrics. Philadelphia, 1970, W. B. Saunders Co., pp 32. 2. Antilla R: Renal involvement in juvenile rheumatoid arthritis. Acta Paediatr Scand [Suppl] 227:1, 1972. 3. Cassidy JT, Martel W: Juvenile rheumatoid arthritis: Clinicoradiologic correlations. Arthritis Rheum 20:207, 1977. 4. Bird HA, Wright V, Henries U, et al: Comparison of serum 1,25-dihydroxycholecalciferol concentrations in rheumatoid arthritis and osteoarthrosis. Annals Rheum Dis 41:257, 1982. 5. Dunham J, Bourke BE, Bitensky L, et al: Circulating levels of biologically active parathyroid hormone in rheumatic diseases. Ann Rheum Dis 41:567, 1982. 6. Stapleton FB, Roy S, Noe HN, et al: Hypercalciuria in children with hematuria. N Engl J Med 310"1345, 1984. 7. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association: Current proposed revisions of the JRA criteria. Arthritis Rheum [Suppl] 20:195, 1977. 8. Schaller J, Wedgwood R J: Juvenile rheumatoid arthritis: A review. Pediatrics 50:940, 1972. 9. Steinbrocker O, Traeger CH, Batterman RC: Therapeutic criteria in rheumatoid arthritis. JAMA 140:659, 1949. 10. Stapleton FB, Noe HN, Jerkins G, et al: Urinary excretion of calcium following an oral calcium loading test in healthy children. Pediatrics 69:594, 1982. 11. Moore ES, Coe FL, McMann BJ, et al: Idiopathic hypercalciuria in children: Prevalence and metabolic characteristics. J PEDIATR 92:906, 1978.
Hypercalciuria a n d hernaturia in J R A
239
12. Maddison P J, Bacon PA: Vitamin D deficiency, spontaneous fractures and osteopenia in rheumatoid arthritis. Br Med J 2:433, 1974. 13. Duncan H, Frost HM, Villaneuva AR, et al: The osteoporosis of rheumatoid arthritis. Arthritis Rheum 8:943, 1965. 14. Saville PD, Kharmosh O: Osteoporosis of rheumatoid arthritis: Influence of age, sex and corticosteroids. Arthritis Rheum 10:423, 1967. 15. Bird HA, Yu H, Cooper EH: Renal proximal dysfunction in patients with rheumatic diseases. Br Med J 288:1044, 1984. 16. Rosen JF, Wolin DA, Finberg L: Immobilization hypercalcemia after single limb fractures in children and adolescents. Am J Dis Child 132:560, 1978. 17. Stapleton FB, Noe HN, Roy S I I l , et al: Hypercalciuria in children with urolithiasis. Am J Dis Child 136:675, 1982. 18. Oppenheim JJ, Ruscetti FW, Steeg PS: Interleukins and interferons. In Stobo JD, Fudenberg HH, Wells JV, editors: Basic and clinical immunology. Los Altos, Calif., 1978, Lange Medical Publications, pp 70-71. 19. Raisz LG, Luben RA, Mundy GR, et al: Effect of osteoclast activating factor from human leukocytes on bone metabolism. J Clin Invest 56:408, 1975. 20. Robinson DR, Tashjian AH Jr, Levine L: Prostaglandinstimulated bone resorption by rheumatoid syn0via: A possible mechanism for bone destruction in rheumatoid arthritis. J Clin Invest 56:1181, 1975. 21. Lorenz VK, Schneider F: Nephrolithiasis bei juveniler Rheumatoid-arthritis. Kinderartzl Prax 43:450, 1975. 22. Wortmann DW, Kelsch RC, Kuhns L, et al: Renal papillary necrosis in juvenile rheumatoid arthritis. J PED1ATR 97:37, 1980. 23. Salomon MI, Gallo G, Poon TP, et al: The kidney in rheumatoid arthritis. Nephron 12:297, 1974. 24. Davis JA, Cohen AH, Wersbart R, et al: Glomerulonephritis in rheumatoid arthritis. Arthritis Rheum 22:1018, 1979. 25. Pollak VE, Pirani CL, Steck IE, et al: The kidney in rheumatoid arthritis: Studies by renal biopsy. Arthritis Rheum 5:1, 1962. 26. Resnick J, Michael AF: Renal manifestations in connective tissue disease. In Edelmann CM Jr, editor. Pediatric kidney disease. Boston, 1978, Little, Brown & Co., pp 768-771.
F. Bruder Stapleton, M.D., Aram S. Hanissian, M.D., and Leslie A. Miller, B.S.
Memphis, Tennessee
BONE DEMINERALIZATION and hematuria, two apparently unrelated disease manifestations, have long been recognized to complicate juvenile rheumatoid arthritis2 -3 Because of periarticular osseous demineralization, serum calcium, parathyroid hormone, and vitamin D concentrations have been examined and found to be normal in adults with rheumatoid arthritis; however, to our knowledge, urinary calcium excretion has not been measured in adults or children with rheumatoid arthritis?,5 After seeing two patients with systemic J R A and hematuria who developed urinary calculi associated with hypercalciuria, we assessed urinary calcium excretion in children with J R A . In addition, because hypercalciuria without urolithiasis has been associated with childhood hematuria, 6 we questioned whether hypercalciuria might be related to the pathogeneFrom Pediatric Research Laboratory. Supported by the General Clinical Research Center Clinical Associate Physician Award R R O0211-19 from the U.S. Public Health Service (F.B.S,). Submitted for publication Oct. 9, 1984; accepted Jan. 24, 1985. Reprint requests: F. Bruder Stapleton, M.D., Pediatric Research Laboratory, 956 Court Ave., Rm. 3B09, Memphis, TN 38163.
sis of the hematuria that is sometimes observed in children with J R A . CASE REPORTS Patient 1. This 3-year-old white girl was diagnosed as having systemic JRA with hectic fevers, polyarthritis, and lymphadenopathy. Before therapy with salicylates, microscopic hematuria was noted. At 4V2 years of age she developed episodes of urinary incontinence, severe dysuria, and gross hematuria concomitant
JRA UCa/UCr
Juvenile rheumatoid arthritis Ratio of urinary calcium to urinary creatinine concentration
with fever and increased joint symptoms. Evaluation of the urinary tract at the onset of urinary symptoms yielded negative urine cultures and normal findings on intravenous pyelogram and voiding cystourethrogram. The serum antinuclear antibody and IgM rheumatoid factor tests yielded negative results. Cystoscopic evaluation at 4V2 years and at 5 years of age failed to reveal the source of hematuria. She was then referred for nephrologic consultation because of increasing episodes of dysuria and hematuria. At the time of evaluation, the patient was receiving tolectin sodium 200 mg three times daily for joint pain. There was no
The Journal o f P E D I A T R l C S
235
236
Stapleton, Hanissian, and Miller
Table
I. Clinical data
The Journal of Pediatrics August 1985
in 38 children with juvenile
rheumatoid arthritis
UCa/UCr (mg/mg) Age (yr) Sex (M/F) Disease type:t: Systemic Polyarticular Pauciarticular Functional classification
UCa/UCr <0.21 (n = 26)
UCa/UCr >0.21 (n = 12)
0.09 + 0.06 10.1 _+ 3.6 9/15
0.34 _+ 0.14" 6.1 _+ 3.8~ 5/7
5 11 10
7 2 3
6
6
13 7 0 3
2 4 0 6
1
I1 III IV Hematuriaw
UCa/UCr indicates the mg/mg ratio of fasting urine calcium to urine creatinine concentration. Values are mean + SD. *P <0.00l. "~P <0.01. SP <0.05. w <0.016.
T a b l e II. N u m b e r of patients receiving antiarthritic drug
therapy when urinary calcium was assessed
Therapy
UCa/UCr <0.21
UCa/UCr >0.21
None Salicylate Gold Prednisone Other
0 21 (3) 7 (t) 1 5
1 (1) 10 (3) 5 (1) 1 (I) 2 (2)
UCa/UCr is ratio of fasting urine calcium to urine creatinine concentration. Numbers in parentheses represent number of children with hematuria while receiving each therapy.
family history of renal disease or urolithiasis, physical examination revealed fusiform swelling of the interphalangeal joints of the hand and contractures of both elbows and knees. The urinalysis revealed a large reaction to hemoglobin, red blood cells "too numerous to count," proteinuria (1 +), and many calcium oxalate crystals. At 5V2 years of age the child spontaneously passed a calcium oxalate urinary calculus during an episode of dysuria and hematuria. Metabolic evaluation found creatinine clearance to be 110 ml/min/l.73 m s, normal uric acid and oxalate excretion, and increased urinary calcium excretion of 4.6 mg/kg/day. The serum calcium concentration was 9.5 mg/dl. No evidence of inflammatory bowel disease was found with barium enema studies. Patient 2. This 22-month-old white girl was diagnosed as having JRA after a 3-month history Of fever, polyarthritis, and increased erythrocyte sedimentation rate. Microscopic hematuria was noted on urinalysis. Urine cultures were negative, and findings on intravenous pyelogram were normal except for a radiopaque calculus in the bladder. A urinary calcium/creatinine ratio was
0.32 (normal <0.21). The patient was discharged for observation, but never returned for further evaluation. METHODS
Thirty-eight children who fulfilled the A m e r i c a n R h e u m a t i s m Association criteria 7 for the diagnosis of juvenile r h e u m a t o i d arthritis were the subject of this study. All m e t the exclusion criteria for other causes of childhood arthritis, including systemic lupus erythematosus. T h e patients ranged in age from 22 m o n t h s to 17 years, and h a d pauciarticular, polyarticular, or systemic J R A according to s t a n d a r d criteria. 7,8 E a c h patient was assigned a functional class from I to IV (IV being most debilitated) 9 by a pediatric rheumatologist (A.S.H.) who was unfamiliar with the patient's urinary calcium excretion. T h e r a p e u t i c agents being administered at the time of study were recorded. Each patient was instructed to collect and refrigerate a fasting second morning voided urine sample on the day of a clinic visit. A urinalysis was performed, a n d the urine calcium concentration was determined by atomic absorption and was measured with an a u t o m a t i c analyzer. H e m a t u r i a was determined by a positive hemoglobin reaction by dipstick and the presence of > 5 red blood cells per high-power field. A U C a / U C r ratio <0.21 was considered normal. 1~ ~ A n orally administered calcium loading test was performed in the Clinical Research Center in four patients, as previously described. ~~ In brief, after discontinuing all medications, the children ingested a 300 mg calcium, 2 g m sodium diet for 5 days before the study. Compliance was assessed by dietary records. O n the day of study, a fasting urine collection was obtained from 7:00 to 9:00 AM. Blood for determination of serum calcium, electrolyte, parathyroid hormone, and creatinine concentration was obtained at 9:00 AM and 1:00 PM. A standardized breakfast was eaten at 9:00 AM, and 1 g m / 1 . 7 3 m 2 body surface area of elemental calcium as calcium glubionate syrup was given. A second urine sample was collected from 9:00 AM to 1:00 PM. U r i n e samples were assayed for calcium and creatinine. This protocol was approved by the University of Tennessee C e n t e r for the H e a l t h Sciences C o m m i t t e e for biomedical research in h u m a n subjects. D a t a were analyzed using the C L I N F O computer system in the Clinical Research Center. Statistical significance was determined with the S t u d e n t t test for u n p a i r e d data, Fisher E x a c t test, and chi-square analysis where appropriate. RESULTS Fasting U C a / U C r were increased in 12 (32%) of 3 8 patients with J R A (Table I). T h e m e a n U C a / U C r ratio was 0.34 +_ 0.14 in hyl3ercalciuric children, compared with
Volume 107 Number 2
Hypercaleiuria and hematuria in J R A
237
Table III. Calcium studies in four children with J R A previously found to have increased fasting U C a / U C r ratios during clinic screening studies Serum Patient 1
2 3 4
Calcium (mg/dl)
9.5 9.1 9.9 9.3
Bicarbonate (mEq/L)
Urine
Phosphorus (mg/dl)
Creatinine (mg/dl)
PTH* (pmol/L)
CalciumS" (mg/kg/aay)
~4.4 4.2 4.4 4.5
0.6 0.5 0.4 0.5
68 57 62 58
7.2 4.0 5.0 4.6
23 25 23 22
*Normal, 60.4 • 20.0 pmol/L. ]'Normal, <4 mg/kg/day. 0.09 _+ 0.06 in the normocalciuric patients (P < 0.001). Normal fasting U C a / U C r ratios for children in our community are 0.09 +_ 0.06J ~ Hypercalciuric patients with JRA were younger (P < 0.01) than patients with normal calcium excretion, and hypercalciuria occurred more frequently in patients with systemic JRA: seven of 12 hypercalciuric patients had systemic JRA, compared with only five of 26 normocalciuric patients (P < 0.05). Polyarticular and pauciarticular JRA was found with equal frequency in hypercalciuric and normocalciuric groups. No statistical relationship between the functional classification of JRA and urinary calcium excretion was observed. All but one of the patients were receiving drug therapy for arthritis (Table II). One patient with systemic JRA had hypercalciuria ( U C a / C r 0.32) and was taking no medications. No statistical relationship between drug therapy and urinary calcium excretion was found. Four patients with hypercalciuria were studied more extensively while receiving no medications (Table III). Serum calcium, bicarbonate, phosphorus, parathyroid hormone, and creatinine concentrations were normal, and 24-hour urinary calcium excretion was >--4.0 m g / k g / d a y in each patient. Serum 25(OH) vitamin D and 1,25(OH)2 vitamin D concentration were normal in patient 3. Three of these children had hematuria at the time of evaluation; none had a history of urolithiasis. Results of an orally administered calcium loading test are shown in the Figure. The mean fasting U C a / U C r ratio was 0.44. A variable response to the calcium challenge was noted. Calcium excretion increased in two, decreased in one, and remained essentially unchanged in the other patient. None of the patients had a family history of urolithiasis. Fasting U C a / U C r ratios and 24-hour urinary calcium excretion were determined in family members of three of the four children, and were normal in each instance. Hematuria was discovered in 6 of 12 patients with J R A with increased U C a / U C r ; hematuria was macroscopic in two and microscopic in four patients. In each hypercalciuric patient, hematuria was confirmed at a later office or hospital visit. Only three of 26 patients with normal
U C a / U C r ratios had hematuria. Hematuria was microscopic in each and was reconfirmed in two patients in whom a second urine specimen was available. In one patient with normal U C a / U C r ratios and hematuria, the 24-hour urinary calcium excretion was 2.8 m g / k g / d a y (normal <4 mg/kg/day). Four of the hematuric patients had systemic JRA, two had polyarticular and three had pauciartieular disease. Proteinuria was not observed, and red blood cell casts were found in one urinalysis. Two children with hematuria were receiving gold therapy (Table II); one had an elevated and the other a normal U C a / U C r ratio. One patient with J R A with hematuria and hypercalciuria was receiving no antiarthritic medications. A percutaneous renal biopsy was performed in one patient with systemic J R A (patient 3, Table III) in whom microscopic and intermittent gross hematuria had been present for 2 years. No abnormalities were identified by light or electron microscopy, and no immunoreactants were found by immunofluorescence. After all diagnostic studies, this child received hydrochlorothiazide therapy 2 mg/kg/day. The 24-hour urinary calcium excretion decreased to 1.4 m g / k g / d a y and hematuria resolved. DISCUSSION Juxtaarticular demineralization is an early radiographic finding in children with JRA? Furthermore, generalized osteoporosis has been observed in children with JRA and in adults with rheumatoid arthritis, occasionally resulting in pathologic fractures of the long bones and in vertebral compression fractures?, ~z-~4In adults, osteoporosis is greatest in elderly and in immobilized patients and during corticosteroid therapy? 4 Growth failure in children with JRA has, in part, been attributed to diminished bone mineralization? The pathogenesis of osteopenia is uncertain; however, serum concentrations of parathyroid hormone and vitamin D metabolites are normal in adults with rheumatoid arthritis. 4'5 It is surprising that no studies examining urinary calcium excretion in either childhood or adult rheumatoid arthritis have been reported.
238
Stapleton, Hanissian, and Miller
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FASTING
POST CALCIUM LOAD
Figure. Oral calcium loading tests were performed after 1 week of dietary calcium restriction in four children with JRA in whom initial fasting UCa/UCr ratios were elevated. Fasting UCa/UCr ratios were increased in each patient. Dotted lines represent +2 SD for normal children in community.
Our data indicate that urinary calcium excretion is often increased in patients with J R A and that the increased urinary calcium excretion is not related to hypercalcemia, hyperparathyroidism, acidosis, or hypophosphatemia. Unfortunately, our study does not clarify the pathogenesis of hypercalciuria in these children with JRA because we did not assess bone mineralization. Recently, proximal renal tubule dysfunction with increased urinary excretion of B2-microglobulin has been reported in "rheumatic diseases. ''~5 Renal calcium wasting cannot be excluded entirely, because multiple measures of proximal tubule function were not examined in our patients; however, glycosuria, proteinuria, and hypophosphatemia were not present. The role of immobilization in hypercalciuria associated with J R A is also uncertain. No significant relationship between urinary calcium excretion and functional disability in our patients was noted, and none of our patients was consid-
The Journal of Pediatrics August 1985
ered to be severely disabled (class IV). Nonetheless, immobilization of even a single limb may be associated with increased urinary calcium excretion in children? 6 The calciuric response to an orally administered loading test in children with hypercalciuri~t and JRA differed somewhat from the response observed in children with hematuria 6 or calcium oxalate urolithiasis. ~7 These previous studies in children with idiopathic hypercalciuria have demonstrated a significant increase in urinary calcium excretion following an oral calcium challenge. The absence of a calciuric response in the hypercalciuric patients with JRA, along with the absence of evidence to support familial hypercalciuria, indicates that the pathogenesis of hypercalciuria in J R A may differ from idiopathic hypercalciuria. The association of hypercalciuria with systemic J R A may lend support to the hypothesis that local inflammatory mediators produce bone resorption (and secondarily cause hypercalciuria)? 8 Synovial inflammation in JRA might produce local demineralization by the production of the lymphokine, osteoclast activating factor, through monocyte-derived mediators, or by local prostaglandin E2 production. 18-20 Our two children with JRA, hypercalciuria, hematuria, and urolithiasis suggests that increased urinary calcium excretion may have adverse effects on the genitourinary system. Lorenz and Schneider 2~ have previously reported kidney stone formation in six of 89 German children with JRA. These authors did not measure urinary calcium excretion, but speculated that hypercalciuria might occur from immobilization and cortisone therapy. Urolithiasis in children is more common in our referral area and is often familial; therefore, it is possible that urolithiasis in our two patients was unrelated to JRA. 22 However, neither of the two children with urolithiasis had a family history of urinary calculi, and the incidence of hypercalciuria in our patients with JRA was more than 8 times greater than in the general population, and also greater than in children with hematuria. 6 Hypercalciuria without urolithiasis recently has been associated with hematuria in children. The 67% incidence of hypercalciuria in patients with both hematuria and J R A is nearly twice the incidence of hypercalciuria in children with unexplained hematuria at our center. 6 In one hypercalciuric child with systemic J R A and chronic hematuria, no glomerular disease was identified in renal biopsy specimens, and hematuria abated when urinary calcium was reduced during hydrochlorothiazide therapy. Hematuria has been noted previously in 28% to 38% of children with JRA, 2,2t and has many potential causes related to the disease or to the many antiarthritic drugs used to treat these patients. Such causes include papillary necrosis,
Volume t07 Number 2
interstitial nephritis, glomerulonephritis, vasculitis, amyloidosis, and urolithiasis. 22:6 This study suggests t h a t hypercaleiuria should also be considered in the evaluation of children with J R A and hematuria. S u c h children m a y be at risk for developing urolithiasis, particularly during periods of immobilization or during corticosteroid therapy. REFERENCES l. Brewer E J, Giannini EH, Peron DA: Juvenile rheumatoid arthritis. In Major problems in clinical pediatrics. Philadelphia, 1970, W. B. Saunders Co., pp 32. 2. Antilla R: Renal involvement in juvenile rheumatoid arthritis. Acta Paediatr Scand [Suppl] 227:1, 1972. 3. Cassidy JT, Martel W: Juvenile rheumatoid arthritis: Clinicoradiologic correlations. Arthritis Rheum 20:207, 1977. 4. Bird HA, Wright V, Henries U, et al: Comparison of serum 1,25-dihydroxycholecalciferol concentrations in rheumatoid arthritis and osteoarthrosis. Annals Rheum Dis 41:257, 1982. 5. Dunham J, Bourke BE, Bitensky L, et al: Circulating levels of biologically active parathyroid hormone in rheumatic diseases. Ann Rheum Dis 41:567, 1982. 6. Stapleton FB, Roy S, Noe HN, et al: Hypercalciuria in children with hematuria. N Engl J Med 310"1345, 1984. 7. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association: Current proposed revisions of the JRA criteria. Arthritis Rheum [Suppl] 20:195, 1977. 8. Schaller J, Wedgwood R J: Juvenile rheumatoid arthritis: A review. Pediatrics 50:940, 1972. 9. Steinbrocker O, Traeger CH, Batterman RC: Therapeutic criteria in rheumatoid arthritis. JAMA 140:659, 1949. 10. Stapleton FB, Noe HN, Jerkins G, et al: Urinary excretion of calcium following an oral calcium loading test in healthy children. Pediatrics 69:594, 1982. 11. Moore ES, Coe FL, McMann BJ, et al: Idiopathic hypercalciuria in children: Prevalence and metabolic characteristics. J PEDIATR 92:906, 1978.
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12. Maddison P J, Bacon PA: Vitamin D deficiency, spontaneous fractures and osteopenia in rheumatoid arthritis. Br Med J 2:433, 1974. 13. Duncan H, Frost HM, Villaneuva AR, et al: The osteoporosis of rheumatoid arthritis. Arthritis Rheum 8:943, 1965. 14. Saville PD, Kharmosh O: Osteoporosis of rheumatoid arthritis: Influence of age, sex and corticosteroids. Arthritis Rheum 10:423, 1967. 15. Bird HA, Yu H, Cooper EH: Renal proximal dysfunction in patients with rheumatic diseases. Br Med J 288:1044, 1984. 16. Rosen JF, Wolin DA, Finberg L: Immobilization hypercalcemia after single limb fractures in children and adolescents. Am J Dis Child 132:560, 1978. 17. Stapleton FB, Noe HN, Roy S I I l , et al: Hypercalciuria in children with urolithiasis. Am J Dis Child 136:675, 1982. 18. Oppenheim JJ, Ruscetti FW, Steeg PS: Interleukins and interferons. In Stobo JD, Fudenberg HH, Wells JV, editors: Basic and clinical immunology. Los Altos, Calif., 1978, Lange Medical Publications, pp 70-71. 19. Raisz LG, Luben RA, Mundy GR, et al: Effect of osteoclast activating factor from human leukocytes on bone metabolism. J Clin Invest 56:408, 1975. 20. Robinson DR, Tashjian AH Jr, Levine L: Prostaglandinstimulated bone resorption by rheumatoid syn0via: A possible mechanism for bone destruction in rheumatoid arthritis. J Clin Invest 56:1181, 1975. 21. Lorenz VK, Schneider F: Nephrolithiasis bei juveniler Rheumatoid-arthritis. Kinderartzl Prax 43:450, 1975. 22. Wortmann DW, Kelsch RC, Kuhns L, et al: Renal papillary necrosis in juvenile rheumatoid arthritis. J PED1ATR 97:37, 1980. 23. Salomon MI, Gallo G, Poon TP, et al: The kidney in rheumatoid arthritis. Nephron 12:297, 1974. 24. Davis JA, Cohen AH, Wersbart R, et al: Glomerulonephritis in rheumatoid arthritis. Arthritis Rheum 22:1018, 1979. 25. Pollak VE, Pirani CL, Steck IE, et al: The kidney in rheumatoid arthritis: Studies by renal biopsy. Arthritis Rheum 5:1, 1962. 26. Resnick J, Michael AF: Renal manifestations in connective tissue disease. In Edelmann CM Jr, editor. Pediatric kidney disease. Boston, 1978, Little, Brown & Co., pp 768-771.