Sickling Cells, Cyclic Nucleotides, and Protein Kinases: The Pathophysiology of Urogenital Disorders in Sickle Cell Anemia

Abstract

<jats:p>Sickle cell anemia is one of the best studied inherited diseases, and despite being caused by a single point mutation in the<jats:italic>HBB</jats:italic>gene, multiple pleiotropic effects of the abnormal hemoglobin S production range from vaso-occlusive crisis, stroke, and pulmonary hypertension to osteonecrosis and leg ulcers. Urogenital function is not spared, and although priapism is most frequently remembered, other related clinical manifestations have been described, such as nocturia, enuresis, increased frequence of lower urinary tract infections, urinary incontinence, hypogonadism, and testicular infarction. Studies on sickle cell vaso-occlusion and priapism using both<jats:italic>in vitro</jats:italic>and<jats:italic>in vivo</jats:italic>models have shed light on the pathogenesis of some of these events. The authors review what is known about the deleterious effects of sickling on the genitourinary tract and how the role of cyclic nucleotides signaling and protein kinases may help understand the pathophysiology underlying these manifestations and develop novel therapies in the setting of urogenital disorders in sickle cell disease.</jats:p>

Urinary Bladder Dysfunction in Transgenic Sickle Cell Disease Mice

“…The multiple pleiotropic effects of the abnormal hemoglobin S production include vaso-occlusive crisis, stroke, pulmonary hypertension, osteonecrosis, leg ulcers and priapism [ 1 – 3 ]. SCD-associated urological complications have also been described, such as nocturia, enuresis, increased frequency of urinary infections and urinary incontinence [ 4 ]. Among the SCD patients presenting urinary tract infection, one to two thirds exhibit recurrent infection that may be accompanied by fever [ 5 ].…”

“…There is also an increased incidence of urinary tract infection during pregnancy in sickle cell trait and SCD [ 6 – 9 ]. As part of the renal complications of sickling, renal medullary infarcts lead to decreased ability to concentrate urine, yielding higher daily urinary volumes [ 10 ], compensatory polydipsia, and possibly the need for nocturnal bladder voiding [ 4 ]. Additionally, in SCD, there is a strong association between enuresis and overactive bladder symptoms such as daytime incontinence, urgency and frequency [ 11 – 15 ].…”

“…However, scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms (LUTS) in SCD patients is lacking. Some hypotheses to explain LUTS in these patients include inability of the kidneys to concentrate urine, social and genetic factors, delays in neurophysiological development, and urinary bladder dysfunction [ 16 , 17 ] [ 4 , 18 ].…”

Nocturnal Enuresis in Children and Adolescent with Sickle cell Anemia

“…This assumption was based on the fact that failure to concentrate urine is one of the earliest infarction-related renal complication of SCA [44]. Hyposthenuria, was therefore plausibly thought to manifest as polyuria and enuresis [45][46][47]. Subsequent studies did not support this assumption.…”

“…Strong association between NE and urinary bladder dysfunction (UBD) was reported in children and adults with SCA [6,14,19,47,48,51,52]. Enuresis and nocturia, as indicators of UBD, are common in individuals with sickle cell anemia [18,43,53,54].…”