Tubular dysfunction, one of the most common manifestations of renal dysfunction in this patient population, was first described in the literature approximately 20 years ago and has been reported in up to 60% of patients with TDT. It is believed to be related to iron overload, chronic anemia, and desferrioxamine toxicity, and has also been associated with undergoing a splenectomy. A cross-sectional, case-control study found that among 40 splenectomized and 26 nonsplenectomized children with beta thalassemia major, splenectomized patients reported increased levels of N-acetyl-beta-D-glucosaminidase (32 ± 14.3 µg/g creatinine vs 18.3 ± 15.2 µg/g creatinine; P <.01 for both compared with healthy individuals), alpha-1 microglobulin (27.5 ± 13.6 mg/g creatinine vs 13 ± 8.5 mg/g creatinine; P <.01 for both compared with healthy individuals), and serum ferritin (683 ± 160 ng/mL vs 483 ± 227 ng/mL; P <.01 for both compared with healthy individuals) more frequently.

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Changes in glomerular function have also been observed in patients who have undergone multiple transfusions. It is believed that chronic anemia decreases systemic vascular resistance, leading to hyperdynamic circulation and, subsequently, increased renal plasma flow and glomerular filtration rate. Theoretically, these changes could lead to a progressive decline in the glomerular filtration rate over time, through the typical pathway of hyperfiltration, albuminuria, and progressive renal damage.

In addition, renal tubular cells subjected to iron overload may induce injury in the interstitium by releasing cytokines and growth factors that result in tubulointerstitial scarring and glomerular sclerosis.

Nephrolithiasis, or the presence of crystalline stones (calculi) within the urinary system, can occur in as many as 59% of patients with TDT. This was shown in a study that found 69% of affected patients had multiple stones and 56% developed stones of variable composition. In a larger study with 166 participants who had TDT, nephrolithiasis was associated with reduced bone mineral density of the femoral neck (odds ratio, 5.59; 95% CI, 1.16-27.03) and an increased risk for fracture in male patients (odds ratio, 2.13).

Role of Chelating Agents

Although the introduction of iron chelators has led to improved survival in beta thalassemia, these treatment agents may be associated with their own set of complications. There are currently 3 such agents available to patients: deferiprone and deferasirox, which are taken orally, as well as parenteral deferoxamine mesylate. Renal complications related to chelating agents are rare, but this treatment approach has been linked to renal function deterioration.

There are currently no results from large randomized controlled trials that support the use of deferiprone. One study showed a modest, nonsignificant, and nonprogressive elevation in serum creatinine from a baseline mean of .33 ± .14 g/dL to .42 ± .11 mg/dL over a 6-month period in a cohort of 100 children with TDT who were less than 10 years old and had received 50 mg/kg to 100 mg/kg deferiprone. Deferiprone is not considered to be nephrotoxic, but it has a narrow therapeutic window and carries a risk for serious adverse effects such as agranulocytosis, neutropenia, and disabling arthropathy. Therefore, it is specifically approved for patients with TDT for whom treatment with other chelating agents is contraindicated or inadequate.

Deferasirox is well absorbed by the gastrointestinal tract and is generally well tolerated. However, because of its lipophilicity, deferasirox forms a highly charged triple negative complex with iron when it enters the tubular cells. As it is unable to easily penetrate membranes, it instead accumulates and may result in proximal tubulopathy and Fanconi syndrome, though Fanconi syndrome typically affects less than 1% of patients and primarily those treated for more than 6 months. Defersirox used at therapeutic doses has also been associated with hypercalciuria, which suggests a biological mechanism for both increased kidney stones and accelerated bone resorption.

The third agent, parenteral deferoxamine mesylate, chelates iron located in plasma and ferritin by forming a metabolically inactive complex that is excreted by the kidneys.  Acute renal failure requiring dialysis has been reported in patients who received an overdose of parenteral deferoxamine mesylate due to administration pump failure. In addition, as with deferasirox, increases in serum creatinine that are transient and lie within the normal range have been documented in 14% of patients receiving parenteral deferoxamine mesylate in one phase 3 trial. Of note, treatment with parenteral deferoxamine mesylate is associated with a risk of Yersinia, mucormycosis, and Vibrio vulnificus infections, as well as sepsis.

“More data are required to fully portray renal disease among patients with TDT and nontransfusion-dependent thalassemia, as well as the current prevalence of this comorbidity in the era of new guidelines concerning iron chelation and blood transfusion,” said Dr Demosthenous.

Reference

1.     Demosthenous C, Vlachaki E, Apostolou C, et al. Beta-thalassemia: renal complications and mechanisms: a narrative review. Hematol. 24:1;426-438. doi:10.1080/16078454.2019.1599096