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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2008  |  Volume : 19  |  Issue : 6  |  Page : 964-968
Renal tubular dysfunction with nephrocalcinosis in a patient with beta thalassemia minor


Department of Nephrology, Sri Ramachandra Medical College, Sri Ramachandra University, Chennai, Tamilnadu, India

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   Abstract 

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.

Keywords: Nephrocalcinosis, Thalassemia minor, Renal tubular dysfunction

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;19:964-8

How to cite this URL:
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 Nov 24];19:964-8. Available from: https://www.sjkdt.org/text.asp?2008/19/6/964/43473

   Introduction Top


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. [1] 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. [2]

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. [2] Studies of renal involve­ment in thalassemic syndromes have been varied and few. Renal tubular function abnor­malities are well described in beta thalassemia major, [3] alpha thalassemia [4] as well as in beta­thalassemia/Hb E disease. [5] 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. [6] 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. [6] We here in report a patient who was found to have thalassemia minor and nephrocalcinosis with evidence of renal tubular dysfunction.


   Case Report Top


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.


   Discussion Top


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. [7] 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, [6],[8],[9] although it is well reported in beta thalassemia major, [3] alpha thalassemia [4] as well as in beta­thalassemia/Hb E disease. [5] 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. [8] 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. [6]

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. [9]

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. [6],[10] In addition, increased iron turn over from low grade hemolysis of microcytic erythrocytes evident with increased LDH levels may be another factor. [6] 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.

 
   References Top

1.Rund D, Rachmilewitz E Beta thalassemia. N Engl J Med 2005;353(11):1135-46.  Back to cited text no. 1    
2.Forget BG. Thalassemia syndromes. In: Hematology: Basic principles and practice, 3 rd Edition, Hoffman, R, Benz, Jr EJ, Shattil, SJ, et al, (Eds), Churchill Livingstone, New York 2000.p.485.  Back to cited text no. 2    
3.Aldudak B, Karabay Bayazit A, Noyan A, et al. Renal function in pediatric patients with beta-thalassemia major. Pediatr Nephrol 2000; 15(1-2):109-12.  Back to cited text no. 3    
4.Sumboonnanonda A, Malasit P, Tanphaichitr VS, Ongajyooth S, Petrarat S, Vongjirad A. Renal tubular dysfunction in alpha-thalasse­mia. Pediatr Nephrol 2003;18(3):257-60.  Back to cited text no. 4    
5.Ongajyooth L, Malasit P, Ongajyooth S, et al. Renal function in adult beta-thalassemia / Hb E disease. Nephron 1998;78(2):156-61.  Back to cited text no. 5    
6.Cetin T, Oktenli C, Ozgurtas T, et al. Renal tubular dysfunction in beta-thalassemia minor. A J Kid Di 200342(6)11648  Back to cited text no. 6    
7.Nephrocalcinosis-Oliver Wrong in Oxford Text book of clinical nephrology 3rd edition. Edited by Davidson AM, Cameron JS, Grunfield JP, Ponticelli C, Ritz E. Oxford, University press pages 1257-1291, 2005.  Back to cited text no. 7    
8.Oktenli C, Bulucu F. Renal tubular dysfunction in a patient with beta-thalassemia minor. Nephron 2002;92(1):222-3.  Back to cited text no. 8    
9.Kalman S, Atay AA, Sakallioglu O, et al. Renal tubular function in children with beta­thalassemia minor. Nephrology (Carlton) 2005;10(5):427-9.  Back to cited text no. 9    
10.Koliakos G, Papachristou F, Koussi A, et al. Urine biochemical markers of early renal dysfunction are associated with iron overload in beta-thalassaemia. Clin Lab Haematol 2003; 25(2):105-9.  Back to cited text no. 10    

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Correspondence Address:
Murugesan Ram Prabahar
Department of Nephrology, Sri Ramachandra Medical College, Sri Ramachandra University, Chennai-116, Tamilnadu
India
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PMID: 18974585

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