Sickle cell anemia in sub-Saharan Africa: advancing the clinical paradigm through partnerships and research.

Although renal medullary carcinoma (RMC) is a rare subtype of kidney cancer, it is particularly devastating in that it is nearly uniformly lethal. No established guidelines exist for the diagnosis and management of RMC. In April 2016, a panel of experts developed clinical guidelines on the basis of a literature review and consensus statements. The goal was to propose recommendations for standardized diagnostic and management approaches and to establish an international clinical registry and biorepository for RMC. Published data are limited to case reports and small retrospective reviews. The RMC Working Group prepared recommendations to inform providers and patients faced with a low level of medical evidence. The diagnosis of RMC should be considered in all patients younger than 50 years with poorly differentiated carcinoma that arises from the renal medulla. These patients should be tested for sickle cell hemoglobinopathies, and if positive, SMARCB1/INI1 loss should be confirmed by immunohistochemistry. ...

https://ascopubs.org/doi/pdf/10.1200/JOP.2017.020909

Renal Medullary Carcinoma: Establishing Standards in Practice

Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1 Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age dependence and predilection of RMC toward the right kidney.Significance: This perspective proposes an integrated and testable model of renal medullary carcinoma pathogenesis. Insights provided by this model can additionally inform other malignancies arising from the renal medulla and/or associated with loss of the SMARCB1 tumor suppressor gene. Clin Cancer Res; 24(9); 2044-9. ©2018 AACR.

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A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma.

Objective: To summarize prevalence data on the neurologic complications of sickle cell disease (SCD) in Africa. Methods: We searched EMBASE, PubMed, and African Index Medicus to identify all relevant articles published from inception to May 31, 2016. Each study was reviewed for methodologic quality. A random-effects model was used to estimate the prevalence of neurologic complications of SCD across studies. Results: Thirty-one studies were included. Methodologic quality was high or moderate in 90% of studies. Stroke, conditional and abnormal cerebral blood flow, seizures, and headache were the complications most frequently reported, with overall prevalence rates of 4.2%, 10.6%, 6.1%, 4.4%, and 18.9%, respectively. Some complications, like silent brain infarcts, peripheral neuropathies, neurocognitive deficits, or moyamoya disease, have been rarely or not studied at all in the African setting. Incidence data were scarce and of poor quality. Conclusions: The burden of neurologic complications of SCD is important in Africa and most likely underestimated. A better evaluation of this burden requires larger prospective studies using standard up-to-date screening methods. Accessibility to diagnostic tools such as neuroimaging, transcranial Doppler, EEG, and neuropsychological evaluation, as well as to preventive and therapeutic interventions and trained health care providers, should be improved in routine clinical practice.

https://n.neurology.org/content/neurology/89/14/1516.full.pdf

Neurologic complications of sickle cell disease in Africa: A systematic review and meta-analysis.

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a mutation in the sixth amino acid of the β-globin gene (HBB). It is the most common serious genetic diseases in childhood, affecting approximately 1 in 2500 births and 100 000 individuals in the USA, in addition to 300 000 new cases globally each year. Central nervous system injury is the most debilitating frequent complication of SCD and includes stroke, silent cerebral infarct (SCI), and cognitive impairment. Among children with sickle cell anemia (HbSS), 11% had a stroke by age 18 years before the implementation of transcranial Doppler screening. SCI is identified in 27% of children with HbSS by their 5th birthday. Children who develop SCI have greater cognitive impairment compared with either children with HbSS without SCI or siblings without SCD. A recent study of adults demonstrated significant cognitive dysfunction, even in participants with apparently mild SCD.

Sickle cell disease

Background: Stroke is a life-changing, debilitating complication of sickle cell disease (SCD). Previous studies had recorded high stroke prevalence amongst this group of patients. Nigeria has a large population of people affected by this condition and this study aims to assess the stroke prevalence in this large population. Methodology: Stroke prevalence data from 14 physicians working in 11 tertiary health centres across the country was collated by doctors using the sickle cell registers and patient case notes. This data was then collated and used to obtain the overall stroke prevalence in adult and children. Results: The stroke prevalence in sickle cell disease patients in Nigeria was observed to be 12.4 per 1000 patients. Prevalence in the adult patients was 17.7 per 1000 patients and 7.4 per 1000 patients in children. Twenty three percent of the affected patients had more than stroke episode. Conclusion: The stroke prevalence in Nigeria is lower than previously recorded rates and further studies will be required to investigate other factors which may play a role.

/pdf/stroke-prevalence-amongst-sickle-cell-disease-patients-in-2pwuu66b60.pdf

Stroke prevalence amongst sickle cell disease patients in Nigeria: a multi-centre study

Introduction: Previous studies had enlisted renal medullary carcinoma (RMC) as the seventh nephropathy in sickle cell disease (SCD). Clinical experience has contradicted this claim and this study is targeted at refuting or supporting this assumption. Objective: To estimate the prevalence of RMC and describe other renal complications in SCD. Materials and methods: 14 physicians (haematologists and urologists) in 11 tertiary institutions across the country were collated from patients’ case notes and hospital SCD registers. Results: Of the 3,596 registered sickle patients, 2 (0.056%) had been diagnosed with RMC over a ten year period, thereby giving an estimated prevalence rate of 5.6 per 100,000. The most common renal complication reported by the attending physicians was chronic kidney disease (CKD). The frequency of routine renal screening for SCD patients varied widely between centres – most were done at diagnosis, annually or bi-annually. Conclusion: The ten year prevalence of RMC in Nigerian SCD patients was determined to be 5.6 (estimated incidence of 0.56). RMC is not more common in SCD patients and therefore cannot be regarded as a “Seventh Sickle nephropathy”. Most of the managing physicians reported that the commonest nephropathy observed in their SCD patients was chronic kidney disease. Keywords: Renal medullary carcinoma, seventh nephropathy, sickle cell disease, Nigerian survey

/pdf/is-renal-medullary-carcinoma-the-seventh-nephropathy-in-42tqep9jbl.pdf

Okpala Iheanyi

Papers

Stroke prevalence amongst sickle cell disease patients in Nigeria: a multi-centre study

Is renal medullary carcinoma the seventh nephropathy in sickle cell disease? A multi-center Nigerian survey.