_CCMBM 3_2016.qxp_- 23/01/17 09:40 Pagina 247
Case report
Malabsorption syndrome as a rare cause of nephrocalcinosis
Rui Abreu Cláudia Bento Luís Oliveira Teresa Morgado
Department of Nephrology, Centro Hospitalar Trás-os-Montes e Alto Douro, Vila Real, Portugal
Address for correspondence: Rui Miguel Guimarães Abreu Department of Nephrology Centro Hospitalar Trás-os-Montes e Alto Douro 5000-508 Vila Real, Portugal E-mail: [email protected]
increased intestinal absorption of oxalate and includes conditions like high-oxalate diet, fat malabsorption syndrome, changes in intestinal oxalate-degrading bacteria and genetic variations of intestinal oxalate transporters (4). The mechanism of increased intestinal oxalate absortion in hyperoxaluria due to fat malabsortion seems to be the formation of fatty acids-calcium complexes increasing the amount of soluble oxalate and also increase colonic oxalate permeability by bile and fatty acids (6). Daily urinary oxalate excretion is mildly elevated and normally does not reach the severe hyperoxaluria levels seen in PH patients (4). Nephrocalcinosis is, in most cases, asymptomatic and may be discovered as an incidental finding during a radiographic imaging. Urinalysis varies from benign to mild hematuria and proteinuria is usually less than 0,5 g/day (1). The diagnosis of this entity can be made by imaging or, less often, renal biopsy. Treatment of nephrocalcinosis is directed at the underlying cause, like reducing the oxalate urinary concentration in hyperoxaluria. Once treated secondary hyperoxaluria, nephrocalcinosis is unlikely to progress to end-stage renal disease (1). Lack of information exists about this last entity (7).
Summary Nephrocalcinosis is characterized by calcification of kidney parenchyma and can be caused by an increased amount of calcium, phosphate or oxalate in urinary excretion. We report a 35-year-old female with nephrocalcinosis. She had fitful steatorrhea since last year. Physical examination was normal. Analytic exams found normal renal function and ionogram. Primary hyperparathyroidism, renal tubular acidosis and sarcoidosis were excluded. Urinalysis showed mild hematuria, without proteinuria and 24-hour urine collection exhibited hyperoxaluria. Patient was submitted to an endoscopy and duodenal biopsy whose histology sustained the diagnosis of celiac disease. Fluid intake increase and gluten and oxalate free diet were initiated. KEY WORDS: celiac disease; hyperoxaluria; malabsorption syndrome; nephrocalcinosis.
Background Nephrocalcinosis is a disease characterized by diffuse deposition of calcium in the kidney parenchyma and tubules (1). Nephrocalcinosis usually affects the renal medulla (1). However, cortical involvement can coexist in cases of renal cortical necrosis, chronic glomerulonephritis, renal allograft rejection and in primary or secondary hyperoxaluria (2). Nephrocalcinosis is caused by an increased amount of calcium, phosphate or oxalate in urinary excretion, when their concentration exceeds the saturation limit (3). Clinical hyperoxaluria is considered when oxalate concentration exceeds the normal range of 10-40 mg/day (0,1-0,45 mmol/day) (4). Hyperoxaluria can be divided into two categories: primary hyperoxaluria (PH) and secondary hyperoxaluria (5). The former results from an increased endogenous oxalate synthesis due to inherited enzyme deficiencies (4). Secondary hyperoxaluria is due to Clinical Cases in Mineral and Bone Metabolism 2016; 13(3):247-248
Case report We describe a case of a 35-year-old female patient followed in nephrology consultation since February 2013 for nephrocalcinosis. She was previously healthy, except a moderate anxiety not treated and a fitful idiopathic edema but loop diuretics have never been taken. Her mother died from a breast cancer and her father died from a gastric cancer. She referred sporadic vomiting, diarrhea and steatorrhea since one year ago, occasionally medicated with domperidone. The chronic diarrhea was not associated with abdominal pain, weight loss, fever or bloody stools. She denied travel history and promiscuous sexual activity. Other genito-urinary and respiratory symptoms were absent. At physical examination, we didn’t find skin rash, mouth ulcers, lymphadenopathies or abdominal masses. Palpation of the thyroid was normal and no peripheral edema was noted at consults. She had normal arterial blood pressure (100/60 mmHg), she was normocardic (76 bpm) and weighted 55 Kg (body mass index of 22 Kg/m2). Laboratorial exams were described in Tables 1 and 2. We found normal renal function, serum phosphate, calcium and magnesium values of 3,0, 9,7 and 2,0 mg/dL, respectively and normal parathormone level of 56,4 pg/mL. Hypokalemia or metabolic acidosis were absent (K+: 3,7mEq/L and HCO3–: 24,6 mmol/L). Thyroid function was normal and angiotensin converting enzyme (ACE) was mildly elevated (43 U/L). Viric serologies and auto-imunity tests were negative. Urinalysis showed normal pH (6,5), erythrocytes (1+), and no proteins or glucose. Urinary sediment demonstrated mild hematuria (3-5 erythrocytes) and absence of leucocytes. Proteins in 24h-urine were normal (118 mg/day), and urinary phosphate too (809 mg/day). Urinary calcium was slightly low (92 mg/day), whereas oxaluria was of 460 μmol/24h (normal range: 40 - 320 μmol/day). Kidney ultrasound confirmed calcifications involving cortex and renal medulla, without nephrolithiasis. Thoracic compu-
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Table 1 - Laboratory findings. Serum analyzes Hemoglobin (g/dL) Leukocytes (103/uL) Platelets (103/uL) Glucose (mg/dL) Urea (mg/dL) Creatinine (mg/dL) Sodium (mEq/L) Potassium (mEq/L) Calcium (mg/dL) Phosphorus (mg/dL) Magnesium (mg/dL) Acid uric (mg/dL) Proteins (g/dL) Albumin (g/dL) PTH (pg/mL) TSH (mIU/L) T4 (pmol/L) ECA (U/L) pH HCO3- (mmol/L) Atc Anti-TTG (IgA) (U/mL) Atc Anti-TTG (IgG) (U/mL)
Values
Normal range
11,8 6,8 313 81 35 0,4 140 3,7 9,7 3,0 2,0 4,6 6,0 3,9 56,4 1,31 14,8 43 7,44 24,6 0,5 0,3
12,0 – 16,0 4,0 – 11,0 150 – 400 74 – 106 < 50 0,6 – 1,1 135 – 147 3,7 – 5,1 8,6 – 10,0 2,7 – 4,5 1,58 – 2,55 2,3 – 5,7 6,6 – 8,7 3,4 – 4,8 10,0 – 65,0 0,27 – 4,20 12,9 – 23,0 19 – 40 7,35 – 7,45 22 – 29 60 100 – 300 400 – 1300 40 – 320 < 150
Table 2 - 24-hour urine collection. 24-h Urine ClCr (mL/min) Calcium (mg/day) Phosphorus (mg/day) Oxalate (μmol/day) Proteins (mg/day)
terized tomography imaging excluded sarcoidosis and scintigraphy of parathyroids was normal. She was submitted to endoscopic evaluation which showed a 5 mm-polyp sessil in rectum. It was performed a duodenal biopsy and histology results sustained the diagnosis of celiac disease. Anti-transglutaminase (IgG and IgA) antibodies were both negative. Patient was referred to gastroenterology and nutrition consultation. She increased her daily fluid intake and initiated a gluten and oxalate free diet. She maintains follow-up with a nephrologist.
hypercalcemia and hypercalciuria were excluded, like primary hyperparathyroidism, sarcoidosis, hypothyroidism and calcium or vitamin D therapy. Hypercalciuric conditions without hypercalcemia were also rejected as distal renal tubular acidosis, medullary sponge kidney and others tubulopathies. Chronic hypokalemia and use of loop diuretics were absent. Phosphate nephropathy or neoplasia was unlikely due to lack of hyperphosphaturia. In this patient’s case with preserved renal function, oxalate level could be easily analyzed in 24h urine collection (6). Once hyperoxaluria is found, prompt evaluation for an underlying disorder is recommended. Chronic diarrhea and steatorrhea directed us to a fat malabsorption syndrome. Duodenal histology sustained the diagnosis of celiac disease, although anti-transglutaminase (IgG and IgA) antibodies were negative. This may happen in individuals already on a low gluten diet, with selective IgA deficiency or may be a false negative result (8). The mild elevation of urinary oxalate level and the presence of enteric symptoms with a probable diagnosis of celiac disease justifies a secondary type of hyperoxaluria, and not primary oxaluria. Treatment should be initiated as the underlying cause of hyperoxaluria is identified (4). In this case, increase of daily fluid intake was promptly done before diagnosis of malabsorption syndrome. Then, oxalate and gluten dietary restriction were performed with improvement of steatorrhea. In addition, oral administration of calcium supplements to bind oxalate in the gut can be a complementary strategy to lower oxalate absorption (4). Manipulation of gastrointestinal flora, with use of oxalate-degrading bacteria such O.formigenes can also be a therapy choice in this case to reduce intestinal oxalate concentration and thus absorption and urinary oxalate excretion (9).
Conflicts of interest None to declare.
References 1.
2. 3. 4. 5.
Discussion 6.
Nephrocalcinosis is associated with increased urinary excretion of calcium, phosphate or oxalate (3). Hypercalcemia or hyperphosphatemia can also be present. In the present case, a nephrocalcinosis patient with unestablished cause is referred to a nephrology consultation. Urinary and plasmatic calcium levels were normal. However, conditions that usually cause nephrocalcinosis with
248
7. 8. 9.
Wrong O. Nephrocalcinosis. In: Oxford Textbook of Clinical Nephrology, Davison AM, Cameron JS, Grünfeld J, et al (Eds), Oxford University Press, Oxford 2005. p.1375. Schepens D, et al. Images in Nephrology. Renal cortical nephrocalcinosis. Nephrol Dial Transplant. 2000;15(7):1080-1082. Sayer JA, Carr G, Simmons NL. Nephrocalcinosis: molecular insights into calcium precipitation within the kidney. Clin Sci (Lond). 2004;106(6):549. Robijn S, et al. Hyperoxaluria: a gut-kidney axis? Kidney Int. 2011;80(11): 1146-1158. Bhasin B, et al. Primary and secondary hyperoxaluria: Understanding the enigma. World J Nephrol. 2015;4(2):235-244. Lorenz EC, et al. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013;15(7):340. Evenepoel P, et al. Microscopic nephrocalcinosis in chronic kidney disease patients. Nephrol Dial Transplant. 2015;30(5):843-848. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656. Lieske JC, Goldfarb DS, De Simone C, Regnier C. Use of a probiotic to decrease enteric hyperoxaluria. Kidney Int. 2005;68:1244.
Clinical Cases in Mineral and Bone Metabolism 2016; 13(3):247-248
Case report
Malabsorption syndrome as a rare cause of nephrocalcinosis
Rui Abreu Cláudia Bento Luís Oliveira Teresa Morgado
Department of Nephrology, Centro Hospitalar Trás-os-Montes e Alto Douro, Vila Real, Portugal
Address for correspondence: Rui Miguel Guimarães Abreu Department of Nephrology Centro Hospitalar Trás-os-Montes e Alto Douro 5000-508 Vila Real, Portugal E-mail: [email protected]
increased intestinal absorption of oxalate and includes conditions like high-oxalate diet, fat malabsorption syndrome, changes in intestinal oxalate-degrading bacteria and genetic variations of intestinal oxalate transporters (4). The mechanism of increased intestinal oxalate absortion in hyperoxaluria due to fat malabsortion seems to be the formation of fatty acids-calcium complexes increasing the amount of soluble oxalate and also increase colonic oxalate permeability by bile and fatty acids (6). Daily urinary oxalate excretion is mildly elevated and normally does not reach the severe hyperoxaluria levels seen in PH patients (4). Nephrocalcinosis is, in most cases, asymptomatic and may be discovered as an incidental finding during a radiographic imaging. Urinalysis varies from benign to mild hematuria and proteinuria is usually less than 0,5 g/day (1). The diagnosis of this entity can be made by imaging or, less often, renal biopsy. Treatment of nephrocalcinosis is directed at the underlying cause, like reducing the oxalate urinary concentration in hyperoxaluria. Once treated secondary hyperoxaluria, nephrocalcinosis is unlikely to progress to end-stage renal disease (1). Lack of information exists about this last entity (7).
Summary Nephrocalcinosis is characterized by calcification of kidney parenchyma and can be caused by an increased amount of calcium, phosphate or oxalate in urinary excretion. We report a 35-year-old female with nephrocalcinosis. She had fitful steatorrhea since last year. Physical examination was normal. Analytic exams found normal renal function and ionogram. Primary hyperparathyroidism, renal tubular acidosis and sarcoidosis were excluded. Urinalysis showed mild hematuria, without proteinuria and 24-hour urine collection exhibited hyperoxaluria. Patient was submitted to an endoscopy and duodenal biopsy whose histology sustained the diagnosis of celiac disease. Fluid intake increase and gluten and oxalate free diet were initiated. KEY WORDS: celiac disease; hyperoxaluria; malabsorption syndrome; nephrocalcinosis.
Background Nephrocalcinosis is a disease characterized by diffuse deposition of calcium in the kidney parenchyma and tubules (1). Nephrocalcinosis usually affects the renal medulla (1). However, cortical involvement can coexist in cases of renal cortical necrosis, chronic glomerulonephritis, renal allograft rejection and in primary or secondary hyperoxaluria (2). Nephrocalcinosis is caused by an increased amount of calcium, phosphate or oxalate in urinary excretion, when their concentration exceeds the saturation limit (3). Clinical hyperoxaluria is considered when oxalate concentration exceeds the normal range of 10-40 mg/day (0,1-0,45 mmol/day) (4). Hyperoxaluria can be divided into two categories: primary hyperoxaluria (PH) and secondary hyperoxaluria (5). The former results from an increased endogenous oxalate synthesis due to inherited enzyme deficiencies (4). Secondary hyperoxaluria is due to Clinical Cases in Mineral and Bone Metabolism 2016; 13(3):247-248
Case report We describe a case of a 35-year-old female patient followed in nephrology consultation since February 2013 for nephrocalcinosis. She was previously healthy, except a moderate anxiety not treated and a fitful idiopathic edema but loop diuretics have never been taken. Her mother died from a breast cancer and her father died from a gastric cancer. She referred sporadic vomiting, diarrhea and steatorrhea since one year ago, occasionally medicated with domperidone. The chronic diarrhea was not associated with abdominal pain, weight loss, fever or bloody stools. She denied travel history and promiscuous sexual activity. Other genito-urinary and respiratory symptoms were absent. At physical examination, we didn’t find skin rash, mouth ulcers, lymphadenopathies or abdominal masses. Palpation of the thyroid was normal and no peripheral edema was noted at consults. She had normal arterial blood pressure (100/60 mmHg), she was normocardic (76 bpm) and weighted 55 Kg (body mass index of 22 Kg/m2). Laboratorial exams were described in Tables 1 and 2. We found normal renal function, serum phosphate, calcium and magnesium values of 3,0, 9,7 and 2,0 mg/dL, respectively and normal parathormone level of 56,4 pg/mL. Hypokalemia or metabolic acidosis were absent (K+: 3,7mEq/L and HCO3–: 24,6 mmol/L). Thyroid function was normal and angiotensin converting enzyme (ACE) was mildly elevated (43 U/L). Viric serologies and auto-imunity tests were negative. Urinalysis showed normal pH (6,5), erythrocytes (1+), and no proteins or glucose. Urinary sediment demonstrated mild hematuria (3-5 erythrocytes) and absence of leucocytes. Proteins in 24h-urine were normal (118 mg/day), and urinary phosphate too (809 mg/day). Urinary calcium was slightly low (92 mg/day), whereas oxaluria was of 460 μmol/24h (normal range: 40 - 320 μmol/day). Kidney ultrasound confirmed calcifications involving cortex and renal medulla, without nephrolithiasis. Thoracic compu-
247
_CCMBM 3_2016.qxp_- 23/01/17 09:40 Pagina 248
R. Abreu et al.
Table 1 - Laboratory findings. Serum analyzes Hemoglobin (g/dL) Leukocytes (103/uL) Platelets (103/uL) Glucose (mg/dL) Urea (mg/dL) Creatinine (mg/dL) Sodium (mEq/L) Potassium (mEq/L) Calcium (mg/dL) Phosphorus (mg/dL) Magnesium (mg/dL) Acid uric (mg/dL) Proteins (g/dL) Albumin (g/dL) PTH (pg/mL) TSH (mIU/L) T4 (pmol/L) ECA (U/L) pH HCO3- (mmol/L) Atc Anti-TTG (IgA) (U/mL) Atc Anti-TTG (IgG) (U/mL)
Values
Normal range
11,8 6,8 313 81 35 0,4 140 3,7 9,7 3,0 2,0 4,6 6,0 3,9 56,4 1,31 14,8 43 7,44 24,6 0,5 0,3
12,0 – 16,0 4,0 – 11,0 150 – 400 74 – 106 < 50 0,6 – 1,1 135 – 147 3,7 – 5,1 8,6 – 10,0 2,7 – 4,5 1,58 – 2,55 2,3 – 5,7 6,6 – 8,7 3,4 – 4,8 10,0 – 65,0 0,27 – 4,20 12,9 – 23,0 19 – 40 7,35 – 7,45 22 – 29 60 100 – 300 400 – 1300 40 – 320 < 150
Table 2 - 24-hour urine collection. 24-h Urine ClCr (mL/min) Calcium (mg/day) Phosphorus (mg/day) Oxalate (μmol/day) Proteins (mg/day)
terized tomography imaging excluded sarcoidosis and scintigraphy of parathyroids was normal. She was submitted to endoscopic evaluation which showed a 5 mm-polyp sessil in rectum. It was performed a duodenal biopsy and histology results sustained the diagnosis of celiac disease. Anti-transglutaminase (IgG and IgA) antibodies were both negative. Patient was referred to gastroenterology and nutrition consultation. She increased her daily fluid intake and initiated a gluten and oxalate free diet. She maintains follow-up with a nephrologist.
hypercalcemia and hypercalciuria were excluded, like primary hyperparathyroidism, sarcoidosis, hypothyroidism and calcium or vitamin D therapy. Hypercalciuric conditions without hypercalcemia were also rejected as distal renal tubular acidosis, medullary sponge kidney and others tubulopathies. Chronic hypokalemia and use of loop diuretics were absent. Phosphate nephropathy or neoplasia was unlikely due to lack of hyperphosphaturia. In this patient’s case with preserved renal function, oxalate level could be easily analyzed in 24h urine collection (6). Once hyperoxaluria is found, prompt evaluation for an underlying disorder is recommended. Chronic diarrhea and steatorrhea directed us to a fat malabsorption syndrome. Duodenal histology sustained the diagnosis of celiac disease, although anti-transglutaminase (IgG and IgA) antibodies were negative. This may happen in individuals already on a low gluten diet, with selective IgA deficiency or may be a false negative result (8). The mild elevation of urinary oxalate level and the presence of enteric symptoms with a probable diagnosis of celiac disease justifies a secondary type of hyperoxaluria, and not primary oxaluria. Treatment should be initiated as the underlying cause of hyperoxaluria is identified (4). In this case, increase of daily fluid intake was promptly done before diagnosis of malabsorption syndrome. Then, oxalate and gluten dietary restriction were performed with improvement of steatorrhea. In addition, oral administration of calcium supplements to bind oxalate in the gut can be a complementary strategy to lower oxalate absorption (4). Manipulation of gastrointestinal flora, with use of oxalate-degrading bacteria such O.formigenes can also be a therapy choice in this case to reduce intestinal oxalate concentration and thus absorption and urinary oxalate excretion (9).
Conflicts of interest None to declare.
References 1.
2. 3. 4. 5.
Discussion 6.
Nephrocalcinosis is associated with increased urinary excretion of calcium, phosphate or oxalate (3). Hypercalcemia or hyperphosphatemia can also be present. In the present case, a nephrocalcinosis patient with unestablished cause is referred to a nephrology consultation. Urinary and plasmatic calcium levels were normal. However, conditions that usually cause nephrocalcinosis with
248
7. 8. 9.
Wrong O. Nephrocalcinosis. In: Oxford Textbook of Clinical Nephrology, Davison AM, Cameron JS, Grünfeld J, et al (Eds), Oxford University Press, Oxford 2005. p.1375. Schepens D, et al. Images in Nephrology. Renal cortical nephrocalcinosis. Nephrol Dial Transplant. 2000;15(7):1080-1082. Sayer JA, Carr G, Simmons NL. Nephrocalcinosis: molecular insights into calcium precipitation within the kidney. Clin Sci (Lond). 2004;106(6):549. Robijn S, et al. Hyperoxaluria: a gut-kidney axis? Kidney Int. 2011;80(11): 1146-1158. Bhasin B, et al. Primary and secondary hyperoxaluria: Understanding the enigma. World J Nephrol. 2015;4(2):235-244. Lorenz EC, et al. Update on oxalate crystal disease. Curr Rheumatol Rep. 2013;15(7):340. Evenepoel P, et al. Microscopic nephrocalcinosis in chronic kidney disease patients. Nephrol Dial Transplant. 2015;30(5):843-848. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656. Lieske JC, Goldfarb DS, De Simone C, Regnier C. Use of a probiotic to decrease enteric hyperoxaluria. Kidney Int. 2005;68:1244.
Clinical Cases in Mineral and Bone Metabolism 2016; 13(3):247-248
