Hereditary spherocytosis (HS) is a common type of hereditary haemolytic anaemia. It is clinically and genetically heterogeneous disorder, with spherocytosis, anaemia, jaundice and splenomegaly as typical clinical characteristics.1 Clinical severity is variable with most patients having a well-compensated haemolytic anaemia. Some individuals are asymptomatic, whereas others have severe haemolytic anaemia requiring erythrocyte transfusion. Patients are classified by clinical features as severe, moderate or mild using the criteria establish by Eber SW.2 The assessment should be issued when the patient is in a stable baseline state, as with the undercurrent illness the severity may be overestimated. Children with severe HS are rare (about 5%). They are constantly anaemic and may be transfusion dependent, especially in the first few years of life.

The primary causes of the disease are abnormalities of the red blood cell membrane structural proteins leading to the loss of membrane surface area, erythrocytes deformability and decrease of stability, finally resulting in haemolysis. The aetiology is related to the genes encoding proteins involved in the interaction between the erythrocyte membrane and the lipid bilayer, namely ankyrin (ANK1), α1-spectrin (SPTA1), βI-spectrin (SPTB), band 3 (SLC4A1) and protein 4.2 (EPB42).3 Variants in SPTB gene are causing HS type 2 (MIM#616649) and are inherited in an autosomal dominant manner. They are responsible for approximately 25% of HS cases in the United States of America and Europe presenting with mild to moderately severe disease where transfusion is usually not needed.1,3 Sporadically, large genomic deletions of SPTB gene were associated to psychomotor developmental delay and autism4,5 while SPTB gene substitution was associated to prenatal hydrops fetalis.6 Additionally, variants in SPTB gene were associated to hereditary elliptocytosis (MIM#617948). Among kidney disease, isolated cases of nephrotic syndrome due to membranoproliferative glomerulonephritis7 and macroscopic haematuria with proteinuria due to IgA nephropathy8 were reported in patients with HS. Here we present a three-generation family with seven patients with spherocytosis due to the novel variant in SPTB gene (NM_001024858; c.4796G>A; p.Trp1599Ter). Among the patients in the family, two adults had end-stage kidney disease and one chronic kidney disease (CKD) stage 4 with histopathologicaly unspecific findings of interstitial fibrosis and focal segmental glomerulosclerosis (FSGS) that was later on attributed to tubulo-interstitial kidney disease due to disease causing UMOD variant.

HS is a common type of hereditary haemolytic anaemia, rarely accompanied by renal manifestations.7 We present a family with seven members presenting with HS due to the novel SPTB variant p.Trp1599Ter suspected to cause βI-spectrin deficiency. In the same family, all three affected adult family members had CKD that was later on attributed to the known UMOD gene variant p.Trp184Cys.

Contrary to the HS in sickle cell disease (SCD), another type of haemolytic anaemia, numerous renal syndromes were described, including increased GFR, acute renal failure, renal tubular disease, chronic renal insufficiency, renal tubular acidosis and others as reviewed in Pham et al.11 Acute kidney injury during SCD pain crisis may be an important risk factor for developing CKD.12 Development of kidney disease in SCD is not fully elucidated. It is associated with oxidative stress caused by the vaso-occlusive episodes, ischaemia-reperfusion injury and the associated chronic inflammatory response, glomerular hyperfiltration and chronic exposure of renal tubular epithelium to high levels of filtered plasma proteins due to proteinuria, as reviewed by Wesson.13 Proximal tubule dysfunction, including tubular proteinuria, is a significant complication in SCD that can eventually lead to CKD. Haemoglobin dimers released from red blood cells upon haemolysis are filtered into the kidney and internalised by megalin/cubilin receptors into proximal tubule cells. Proximal tubule cells are especially sensitive to haem toxicity and tubular dysfunction in SCD is thought to result from prolonged exposure to filtered hemoglobine.14 The mechanism behind the development of kidney disease in HS is not clear and might be related to the mechanism in SCD, since haemolytic crisis are probably the initiators of its development in both cases. Involvement of renal cortex and medulla in the absence of other known causes of medullary tissue remodelling (diabetes, chronic infections, NSAIDS and congenital disorders) suggested haemolysis as one of the potentially pathogenic mechanism of tubular and/or vascular injury leading to interstitial fibrosis and secondary glomerulosclerosis.

In here presented family, we initially speculated that haem toxicity was the cause of the CKD, especially since it had an onset in the adulthood after many haemolytic crises. Nevertheless, to eliminate the less probable existence of additional genetic factors that could contribute to the co-occurrence of the renal disease, we have analysed genes associated to the inherited glomerular disorders and ADTKD. To our surprise, we have identified a variant p.Trp184Cys in UMOD gene in all three adult patients with kidney failure. It was previously reported in 3 members of a Caucasian family with ADTKD, but their clinical presentation was not individually described.15 In general, early onset hyperuricemia is a hallmark of the ADTKD due to UMOD deficiency, where renal survival and clinical characteristic are extremely variable even in patients in the same family. Disease causing UMOD variants are resulting in deficient production of functional uromodulin normally expressed in tubular cells and intracellular deposition of mutant uromodulin. This is leading to accelerated tubular damage and consequently end-stage renal kidney disease.16 Renal biopsy in two adult patients revealed rather unspecific histological changes including interstitial fibrosis, tubular atrophy, glomerulosclerosis and normal podocytes without foot process effacement even in advanced chronic tubulointerstitial changes, which pointed towards tubules/interstitium as primarily affected compartment and is in accordance with the UMOD deficiency. They presented with low proteinuria suggesting FSGS as secondary glomerular changes due to hyperfiltration in remaining overloaded glomeruli. Other risk factors (i.e.: low birth weight, renal asymmetry, obesity, drugs, inherited glomerular disorders) for FSGS development were not present. In addition, two paediatric patients, namely subjects III-3 and III-4, had the same UMOD disease-causing variant. Currently they have no reported haemolytic crises and normal kidney function, but both have high serum uric acid, low fractional excretion of urinary uric acid and low serum uromodulin level confirming deficient production of functional uromodulin.

NGS based genetic testing approach has proved useful as a first-line approach in identification of the genetic aetiology of inherited haemolytic anaemias where several genes can be candidates to be causative.17 Furthermore, in cases with complex clinical manifestations that cannot be directly attributed to one disorder NGS enables analysis of all genes associated to individual manifestation in the same experiment without the need of the strict preselection. This proofed to be extremely valuable in here reported family with co-occurrence of two rare inherited disorders with the clinical onset in different stages of life. Furthermore, the importance of the valid clinical evaluation of the index patients and their family members prior the NGS analysis is well recognised. In here presented family it was crucial since index patients had no kidney disease, but the genetic and clinical evaluation of the family enabled recognition of UMOD related ADTKD in their junior cousins with currently normal kidney function. Consequently, their renal function and serum uric acid level will be closely monitored in order to timely introduce hyperuricemia treatment.18,19 This is emphasising the importance of serum uric acid detection in routine laboratory screening of paediatric patients in order to identify early signs of tubular injury indicating possible ADTKD.

The co-occurrence of any two rare inherited disorders is extremely rare, while to our knowledge the co-occurrence of genetically confirmed HS and ADTKD has not been previously reported. It is not possibly to evaluate whether the haemolytic crises due to HS are influencing the progression of the UMOD related renal disease, especially, since the UMOD related kidney disease characteristics in general and in here presented family (Fig. 5) are extremely variable. Nevertheless, the observed kidney disease in the family is warranting the regular nephrological examinations in paediatric patients in the family in order to recognise elevated serum uric acid as the first signs of tubular dysfunction, since early onset of hyperuricemia treatment may slow the progression of subsequent kidney disease. The future clinical course in index patients with HS and their two cousins with co-occurrence of HS and UMOD disease-causing variant will highlight the potential role of UMOD related disease as well as HS on kidney function. Clinical data of five patients of different ages with the co-occurrence of two genetic disorders is extremely valuable and my shed a light on the complex pathophysiology of the genetically based co-morbidity.

The study was supported by the financial support from the Slovenian Research Agency (research core funding P3-0343 and P1-0170).

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