Year : 2008 | Volume
: 19 | Issue : 6 | Page : 964--968
Renal tubular dysfunction with nephrocalcinosis in a patient with beta thalassemia minor
Murugesan Ram Prabahar, Manish Jain, Venkatraman Chandrasekaran, Elayaperumal Indhumathi, Periasamy Soundararajan
Department of Nephrology, Sri Ramachandra Medical College, Sri Ramachandra University, Chennai, Tamilnadu, India
Murugesan Ram Prabahar
Department of Nephrology, Sri Ramachandra Medical College, Sri Ramachandra University, Chennai-116, Tamilnadu
Thalassemia is a hereditary anemia resulting from defect in hemoglobin production. Beta thalassemia is due to impaired production of beta globin chains, leading to a relative excess of alpha globin chains. The term beta thalassemia minor is used to describe heterozygotes, who carry one normal beta globin allele and one beta thalassemic allele. The vast majority of these patients are asymptomatic. However, a variety of renal tubular abnormalities including hypercalciuria, hypomagnesemia with renal magnesium wasting, decreased tubular absorption of phosphorus, hypouricemia with renal uric acid wasting, renal glycosuria and tubular proteinuria have been described even in patients with beta thalassemia minor. We here in report a 24-year old female patient who was found to have thalassemia minor and nephrocalcinosis with evidence of renal tubular dysfunction. Investigations revealed normal renal function, hypercalciuria, reduced tubular reabsorption of phosphorus, hypomagnesemia and renal magnesium wasting. Screening for aminoaciduria was found to be negative. An acid loading test revealed normal urinary acidification. Ultrasonogram of the abdomen revealed nephrocalcinosis and splenomegaly. Detailed work up for anemia showed normal white cell and platelet count while peripheral smear showed microcytic hypochromic anemia with few target cells. Hemoglobin electrophoresis revealed hemoglobin A of 92%, hemoglobin A2 of 6.2% and hemoglobin F of 1.8% consistent with beta thalassemia minor. Her parental screening was normal. A diagnosis of beta thalassemia minor with renal tubular dysfunction was made and the patient was started on thiazide diuretics to reduce hypercalciuria and advised regular follow-up.
|How to cite this article:|
Prabahar MR, Jain M, Chandrasekaran V, Indhumathi E, Soundararajan P. Renal tubular dysfunction with nephrocalcinosis in a patient with beta thalassemia minor.Saudi J Kidney Dis Transpl 2008;19:964-968
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Prabahar MR, Jain M, Chandrasekaran V, Indhumathi E, Soundararajan P. Renal tubular dysfunction with nephrocalcinosis in a patient with beta thalassemia minor. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2020 Dec 3 ];19:964-968
Available from: https://www.sjkdt.org/text.asp?2008/19/6/964/43473
Thalassemia is a hereditary anemia resulting from defect in hemoglobin production. Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of one or more globin chains.  In normal subjects, globin chain synthesis is very tightly controlled such that the ratio of production of alpha to non-alpha chains is 1.00 ± 0.05. Beta thalassemia is due to impaired production of beta globin chains, leading to a relative excess of alpha globin chains, thus disrupting this ratio. Excess alpha globin chains are unstable, incapable of forming soluble tetramers on their own, and precipitate within the cell, leading to a variety of clinical manifestations. The degree of alpha globin chain excess determines the severity of subsequent clinical manifestations, which are profound in patients homozygous for impaired beta globin synthesis and much less pronounced in heterozygotes, who generally have minimal or mild anemia and no symptoms. 
The terms beta thalassemia minor or beta thalassemia trait are used to describe heterozygotes, who carry one normal beta globin allele and one beta thalassemic allele. The vast majority of these patients are entirely asymptomatic, but do present an abnormal blood picture that is sometimes erroneously diagnosed as iron deficiency anemia. However, as a rule, the microcytosis is much more profound, and the anemia much milder, than that seen in iron deficiency anemia.  Studies of renal involvement in thalassemic syndromes have been varied and few. Renal tubular function abnormalities are well described in beta thalassemia major,  alpha thalassemia  as well as in betathalassemia/Hb E disease.  It has been postulated that low-grade hemolysis, tubular iron deposition and toxins derived from erythrocytes might cause renal tubular damage in adult patients with beta thalassemia minor.  A variety of renal tubular abnormalities have been occasionally described in patients with beta thalassemia minor; they include hypercalciuria, hypomagnesemia with renal magnesium wasting, decreased tubular absorption of phosphorus, hypouricemia with renal uric acid wasting, renal glycosuria and tubular proteinuria.  We here in report a patient who was found to have thalassemia minor and nephrocalcinosis with evidence of renal tubular dysfunction.
A twenty-four-year-old lady, an engineering graduate, was referred to us for evaluation of nephrocalcinosis detected during pre-employment screening. Physical examination revealed anemia. Her blood pressure was normal. She was evaluated for anemia earlier elsewhere and treated as iron deficiency anemia with intravenous iron injections. She was on oral iron supplementation thereafter till recently. The remainder of her physical examination and family history were unremarkable. She was investigated for nephrocalcinosis. Her renal function was normal. The serum calcium was normal, but she had hypophosphatemia. The i PTH (paratharmone) was 34 pg/mL and arterial blood gases were normal. Metabolic work up was done using twenty-four hour urine sample which revealed hypercalciuria, hyperuricosuria, and reduced tubular reabsorption of phosphorus. The details are shown in [Table 1]. Screening for aminoaciduria was found to be negative. Oral glucose tolerance test was with in normal limits. The 24-hour urine protein was 278 mg. Her urine culture was sterile. Acid loading test, which was done using ammonium chloride to rule out renal tubular acidosis, revealed normal urinary acidification. Computerized tomographic scan of the abdomen revealed nephrocalcinosis and splenomegaly [Figure 1]. She had normal liver function tests, upper gastrointestinal endoscopy was normal, stool testing for occult blood was negative and ophthalmological evaluation and slit lamp examination were normal.
Detailed work up for anemia was initiated because of associated splenomegaly and nephrocalcinosis. Investigations revealed anemia (hemoglobin 9.2 gm/dL, packed cell volume (PCV) 28%) with normal white cell and platelet counts. Peripheral smear showed microcytic hypochromic anemia with few target cells. Her red cell indices revealed mean corpuscular volume (MCV) of 64.2 fl, mean corpuscular hemoglobin (MCH) of 15.9 pg and mean corpuscular hemoglobin concentration (MCHC) of 24.8. The lactate dehydrogenase (LDH) was 554 IU/L, reticulocyte count was 2.0% and sickling test was negative. Serum vitamin B 12, folate, 25-OH vitamin D3, and 1, 25-OH vitamin D3 levels were normal. Serological tests including ANA, ANCA, anti ds DNA, anti RO, anti LA and anti u1 RNP were negative. Bone marrow was suggestive of erythroid hyperplasia. The direct and indirect coombs tests were negative. Her iron profile showed serum iron of 96 µg/dL, total iron binding capacity of 236 µg/dL, transferrin saturation of 40.6% and serum ferritin of 280 ng/mL. Hemoglobin electrophoresis, which was done to rule out hereditary anemia showed hemoglobin A of 92%, hemoglobin A2 of 6.2% and hemoglobin F of 1.8%. Her parental screening was normal.
A diagnosis of beta thalassemia minor with renal tubular dysfunction was made based on above clinical picture and investigations. She was advised to stop oral iron and was started on hydrochlorothiazide to reduce hypercalciuria, and advised regular follow-up. At last follow-up six months later, her renal function remains stable and she continues to have persistent asymptomatic anemia.
Nephrocalcinosis is defined as generalized increase in calcium content of the kidney. This is often detected as an incidental finding. Depending on the location of calcification, nephrocalcinosis can be classified as cortical and medullary. Cortical nephrocalcinosis is rare.
Medullary nephrocalcinosis is the typical pattern seen in 98% of human nephrocalcinosis. The common causes are hyperparathyroidism, distal tubular acidosis, idiopathic hypercalciuria and hyperoxaluria.  To our knowledge, nephrocalcinosis has not been reported in beta thalassemia minor, although other tubular abnormalities and renal stones have been reported previously.
In a search of English literature, we could find only three previous reports on renal tubular dysfunction in beta thalassemia minor, ,, although it is well reported in beta thalassemia major,  alpha thalassemia  as well as in betathalassemia/Hb E disease.  Persons with betathalassemia minor usually are asymptomatic. Beta-thalassemia minor is characterized by both microcytosis and hypochromia. It requires no treatment. Oktenli C et al first reported renal tubular dysfunction in a 20-year-old patient with beta-thalassemia minor.  The same group later prospectively investigated forty-one subjects with beta thalassemia minor and found that six of them (14.6%) showed evidence of tubulopathy such as hypercalciuria, decreased tubular reabsorption of phosphorus with hypophosphatemia, hypomagnesemia with renal magnesium wasting, hypouricemia with renal uric acid wasting, and tubular proteinuria. Among these forty-one patients, anemic patients had increased urinary zinc excretion, fractional excretion of sodium and uric acid compared with both controls and patients without anemia. The hemoglobin levels correlated significantly in a negative manner with urinary zinc, fractional excretion of sodium, and fractional excretion of uric acid in patients with beta-thalassemia minor. Serum lactate dehydrogenase levels correlated significantly in a positive manner with the same parameters. This study concluded that proximal renal tubular dysfunction is not rare in patients with beta-thalassemia minor. 
On the contrary, Kalman S et al, investigated thirty-two children with beta-thalassemia minor. The patients were classified as anemic (hemoglobin (Hb) 11 g/dL) and non-anemic (Hb > 11 g/dL). A control group was formed with eighteen healthy children whose ages and sexes matched those in the other groups. Fractional excretion of sodium, fractional excretion of magnesium, fractional excretion of uric acid, and tubular phosphorus reabsorption were calculated. Urinary excretion of calcium and zinc, glucosuria, beta-2 microglobulin and N-acetyl-beta-D-glycosaminidase were measured. There was no statistically significant difference among the three groups in terms of the results of any one of the above mentioned measurements. 
It has been postulated that low-grade hemolysis, shortened red cell life span, tubular iron deposition, oxidative lipid peroxidation and toxins derived from erythrocytes might cause renal tubular damage in adult patients with beta-thalassemia minor. , In addition, increased iron turn over from low grade hemolysis of microcytic erythrocytes evident with increased LDH levels may be another factor.  Our patient had anemia and subtle hemolysis as evidenced by elevated LDH, which could have contributed to renal tubular damage. We could not identify any other known cause of renal tubular dysfunction in our patient despite exhaustive investigations.
Our report has some potential limitations. We have not done genetic testing to confirm thalassemia trait and our diagnosis of thalassemia minor is based on hemoglobin electrophoresis. On electrophoresis in patients with beta thalassemia minor, over 90% of the hemoglobin will be hemoglobin-A along with an elevation in the hemoglobin-A2 value, sometimes to levels as high as 7 to 8%. We have not performed specific tests for tubular dysfunction like N-acetyl beta glycosaminidase measurement or urine electrophoresis.
Regarding management, this patient was put on hydrochlorothiazide for hypercalciuria and advised regular follow-up. She has been on regular follow-up with us for six months now. Her renal function remains stable and she continues to have asymptomatic persistent anemia and nephrocalcinosis. Beta thalassemia minor per se requires no specific therapy. It is important that the condition be diagnosed properly so that inappropriate use of iron is avoided. Transfusions are occasionally required in pregnant women who may develop a more severe "physiologic" anemia of pregnancy. However, patients with thalassemia minor share the same general risk as normal individuals for development of iron deficiency anemia from other causes. They should not be denied iron when true iron deficiency exists.
To conclude, renal tubular dysfunction is not rare in patients with beta thalassemia minor. However, large scale studies are needed to reveal whether there is an association between these two distinct disorders.
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