Pathophysiological Relevance of Renal Medullary Conditions on the Behaviour of Red Cells From Patients With Sickle Cell Anaemia.

David C.-Y Lu,John N Brewin,Anke Hannemann,David C Rees,John Stanley Gibson,Rasiqh Wadud

doi:10.3389/fphys.2021.653545

David C.-Y Lu, John N Brewin + Show 4 more

Open Access

https://doi.org/10.3389/fphys.2021.653545

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Abstract

Red cells from patients with sickle cell anaemia (SCA) contain the abnormal haemoglobin HbS. Under hypoxic conditions, HbS polymerises and causes red cell sickling, a rise in intracellular Ca2+ and exposure of phosphatidylserine (PS). These changes make sickle cells sticky and liable to lodge in the microvasculature, and so reduce their lifespan. The aim of the present work was to investigate how the peculiar conditions found in the renal medulla – hypoxia, acidosis, lactate, hypertonicity and high levels of urea – affect red cell behaviour. Results show that the first four conditions all increased sickling and PS exposure. The presence of urea at levels found in a healthy medulla during antidiuresis, however, markedly reduced sickling and PS exposure and would therefore protect against red cell adherence. Loss of the ability to concentrate urine, which occurs in sickle cell nephropathy would obviate this protective effect and may therefore contribute to pathogenesis.

Highlights

Red cells from patients with sickle cell anaemia (SCA; HbSS genotype) contain a mutated haemoglobin, HbS, which replaces the normal adult HbA (Bunn and Forget, 1986)
Lang’s group showed a protective effect of urea on PS exposure in normal red cells and platelets (Lang et al, 2004; Gatidis et al, 2010), probably via inhibition of sphingomyelinase. We investigated how these factors – hypoxia, low pH, lactate, hypertonicity, and urea – alter red cell sickling and PS exposure, and affect the lifespan of these cells
Our study has controlled oxygen tension using levels appropriate to those found in the renal medulla. As expected, these conditions are associated with increased sickling and PS exposure

Summary

Introduction

Red cells from patients with sickle cell anaemia (SCA; HbSS genotype) contain a mutated haemoglobin, HbS, which replaces the normal adult HbA (Bunn and Forget, 1986). HbS results from a point mutation of the DNA causing replacement of glutamic acid with valine at the sixth residue of the Hb β chain. This substitution allows neighbouring molecules of HbS to polymerise upon deoxygenation, forming long, rigid concatenations of Hb, which distort the normal red cell shape from biconcave disc to the distinctive sickle shapes together with other bizarre forms. Reduced red cell life span results in anaemia and ischaemic problems including pain, osteonecrosis, stroke, acute chest syndrome, proliferative retinopathy and others, one of which is nephropathy

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