Histopathological Features of Sickle Cell Nephropathy in the Arab-Indian Haplotype

BackgroundSickle cell disease (SCD) is an autosomal recessive disease resulting in hemolytic anemia and recurrent vaso-occlusive events. Consequently, it can result in a broad range of functional and structural renal and cardiac alterations. Chronic kidney disease (CKD), in SCD, is associated with proteinuria, microalbuminuria, and hemoglobinuria. Cardiac complications in SCD include pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, and sudden death. In patients with advancing age, cardio-renal dysfunction can have substantial effects on morbidity and mortality. Our primary aim was to compare the incidence of major adverse cardiac events (MACE) and all-cause mortality in sickle cell nephropathy (SCN).MethodsIn this retrospective study, we used International Classification of Diseases (ICD)-10 codes to identify admissions in 2019 with a diagnosis of MACE with a prior diagnosis of SCD and/or SCN. Our search of the HCA Healthcare Enterprise Data Warehouse for adult patients >18 years yielded 6,693 patients with SCD, of which 658 patients (9.8%) had SCN. Primary endpoints were incidence of MACE and all-cause mortality. Patients with MACE encompassed those with nonfatal stroke, nonfatal myocardial infarction, and congestive heart failure (CHF) exacerbations. A secondary endpoint was length of stay (LOS). Logistic regression analysis was used for MACE and all-cause mortality. LOS was analyzed using multiple linear regression analysis. Results were considered statistically significant for analyses showing p <0.05. All outcomes were adjusted for demographic variables and comorbidities.ResultsLogistic regression, after adjustment for comorbidities, demonstrated that SCN patients had significantly higher odds of all-cause mortality (odds ratio [OR] 2.343, p = 0.035, 95% confidence interval [CI] 1.063-5.166) compared to patients without SCN. Compared to those without SCN, those with SCN did not have a higher odds of MACE (OR 1.281, p = 0.265, 95% CI 0.828-1.982). Linear regression for LOS did not reveal a significant association with SCN (p = 0.169, 95% CI 0.157-0.899).ConclusionBased on the analysis of 6,693 patients with SCD, SCN was associated with significantly higher odds of all-cause mortality. SCN was not associated with significantly higher odds of MACE or prolonged LOS.

Comments on renal abnormalities of sickle cell disease

Acute splenic sequestration crisis in sickle cell disease: Early detection and treatment

Sickle cell nephropathy (SCN) is a significant complication of sickle cell disease (SCD) with an asymptomatic onset in childhood and potential progression to chronic kidney disease (CKD). The clinical findings of SCN include hyposthenuria, hematuria, proteinuria, hyperfiltration, and CKD. Data on renal manifestation among patients with SCD in Saudi Arabia is lacking. Therefore, this study aimed to evaluate renal outcomes in patients with SCD who visited a hematology clinic at the National Guard Hospital, Jeddah. We conducted a retrospective chart review of renal complications in patients with SCD who are within 0-14 years of age and on regular follow-ups at the pediatric hematology clinic in King Abdulaziz Medical City-Jeddah, Saudi Arabia. Among the 140 patients with SCD, 99 met the inclusion criteria. The median age at diagnosis was 18 (1-108) months. Two SCD phenotypes were observed, with 82 (83%) patients having sickle cell anemia (HbSS) and 17 (17%) having HbS/B+ thalassemia. Of the total patients, 92 (93%) were administered hydroxyurea (HU), with a median starting age of 48 (9-168) months. The most common renal complication observed during routine urinalysis was hematuria (38%), followed by proteinuria (11%). After stratifying the sample into four age groups (0-3 years old, 4-7 years old, 8-11 years old, and 12-14 years old), the mean glomerular filtration rate (GFR) values were 96.16, 101.36, 112.69, and 120.11 ml/min/1.73 m2 respectively. Renal imaging revealed abnormal findings in 27 (29%) patients. The most common abnormality observed on US was increased echogenicity (43%). SCN is a significant complication of SCD. In this study, we assessed the renal outcomes in pediatric patients with SCD. After analyzing the clinical findings of SCN, we concluded that the presence of renal complications in pediatric patients presented a progressive pattern.

Background: Sickle cell disease (SCD) include a group of genetic abnormalities in which there is inheritance of Hb S (sickle hemoglobin) from both parents, or Hb S from one parent and a gene for beta-thalassemia or an abnormal hemoglobin from the other parent.The most common and the most severe form is sickle cell anemia. Aim of Study:To evaluate the feasibility of MRI in early detection of musculoskeletal complications of pediatric sickle cell disease (SCD) aiming to discriminate osteomyelitis from infarction.Patients and Methods: This prospective study included 30 patients (21 boys, 9 girls) with a mean age of 5 years proved to have SCD and suspected to have osteomyelitis.All patients underwent X-ray and different sequences MRI.Results: Persistence of red marrow and multiple bone infarctions were the most common MRI findings followed by osteomyelitis in 8, chondritis in 7, myositis in 4, septic arthritis in 3, subperiosteal and soft tissue abscess each in 2. There was difficulty in discriminating infarction from osteomyelitis Conclusion: MRI is helpful in early identification of musculoskeletal abnormalities in SCD in pediatrics.Early detection is crucial to initiate treatment to avoid the complication.

Introduction: Hemolysis is a fundamental feature that contributes to hypercoagulability and thrombotic complications in sickle cell disease (SCD). Factor V Leiden (FVL) and prothrombin G20210A mutations are the most common genetic thrombophilia. Objectives: The aim of this meta-analysis is to determine the relationship between FVL or prothrombin G20210A and susceptibility of vaso-occlusive complications (VOC) in SCD. Patients and Methods: For this meta-analysis, eligible studies were retrieved via two systematic searches performed on PubMed, Web of Science and Google Scholar databases. The keywords used in the former search included ‘sickle cell anemia’, ‘SCD’, ‘Factor V Leiden’ and ‘G1691A (rs6025) mutation, the letter using the keywords ‘sickle cell anemia’, ‘SCD’, ‘prothrombin, and ‘G20210A (rs1799963). Results: The final number of studies included was 10 about SCD-VOC and FVL (total patients with VOC 1086 and without VOC 933), and 6 about SCD-VOC and prothrombin G20210A mutation (total patients with VOC 609 and without VOC 674). Meta-analysis in fixed effect model showed that mutant genotypes (GA+AA vs. GG) of the FVL mutation was found to be higher in SCD patients with VOC than in SCD patients without VOC (OR, 3.53; 95% CI, 2.24–5.08; P < 0.001). However, the distribution of prothrombin G20210A mutation in SCD patients with or without VOC is similar (OR, 0.900; 95% CI, 0.51–1.59; P = 0.717). Conclusion: Our meta-analysis establishes that the FVL mutation as a high-penetrant risk factor for VOC in SCD patients, whereas the prothrombin G20210A is not associated with the risk of VOC in SCD patients. To further validate the clinical utility of these prothrombotic mutations in SCD patient, large scale and prospective studies in diverse populations are warranted.

Hemolytic, Vaso-Occlusive and Renal Complications of SCD: Report from the Central Missouri Cohort

Prospective Study of Complement Activation with Functional and Genetic Assays in Sickle Cell Disease

Interventions for chronic kidney disease in people with sickle cell disease.

Sickle cell nephropathy (SCN) is a major complication of sickle cell disease (SCD). However, it is not fully understood what role immune cells play in SCN. Recent studies have implicated IL‐17A+CD4+(TH17) cells in mediating kidney disease outside of SCD. Furthermore, levels of circulating TH17 cells are elevated in SCD patients. We have previously reported that humanized sickle cell (HbSS) mice show progressive age‐dependent nephropathy with proteinuria, glomerulosclerosis, loss of GFR, and elevated CD3+cells compared to control (HbAA) mice. However, a role for renal TH17 cells in SCN has not yet been defined. We hypothesized that HbSS mice have elevated renal TH17 cells compared to HbAA mice. Thus, we phenotyped renal and splenic lymphocytes from 16–24 week‐old male HbAA and HbSS mice by flow cytometry. HbSS mice had increased renal TH17 cells compared to HbAA mice (18.3 ± 2.0% vs. 0.2 ± 0.1%, respectively; p&lt;0.001) but no difference in renal CD4+cells. No differences were observed in splenic TH17 cells between HbSS and HbAA mice, which correlated with similar frequencies of splenic CD4+cells. Interestingly, HbSS mice had a significant increase in renal CXCR3+CD4+(TH1) cells compared to HbAA mice (48.8 ± 2.3% vs. 10.9 ± 3.3%, respectively; p&lt;0.001) but no difference in splenic TH1 cells. Next, we measured changes in circulating proinflammatory mediators by Luminex multiplex technology. HbSS mice had elevated levels of soluble intercellular adhesion molecule 1 (sICAM‐1: 2937 ± 240 ng/mL vs. 2396 ± 57 ng/mL, respectively; p=0.04 ) and plasminogen activator inhibitor 1 (PAI‐1: 546.9 ± 120 ng/mL vs. 69.6 ± 4.5 ng/mL; p=0.001 ) compared to HbAA mice. We conducted a preliminary flow cytometric analysis of activated renal and splenic CD4+cells from aged (8–13 month‐old) mice and observed decreased splenic CD4+cells in aged HbSS mice compared to aged HbAA mice (5.1% vs. 32.5%, respectively; n = 2) but no differences in renal CD4+cells. Activated CD44hiCD4+cells from aged HbSS mice were increased in both the spleen (68.8% vs. 30.8%; n = 2) and the kidney (22.2% vs. 14.0%, respectively; n = 2) compared to aged HbAA mice. We propose that these findings and initial observations suggest an important role for renal T cells, especially TH17 and TH1 cells, in promoting and exacerbating kidney injury and dysfunction in SCD.Support or Funding InformationSupport provided by NIH T32 DK116672 to PAM, F30 DK107194 to BMF, NIH P01 HL136267 to CDM, JSP, DMP, NIH T32 AR069516 to RJM, NIH U01 HL117684 to JSP, DMP, and ASN Ben J. Lipps Research Fellowship to MK.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sickle cell nephropathy is a major complication of sickle cell disease. It manifests in different forms, including glomerulopathy, proteinuria, hematuria, and tubular defects, and frequently results in end-stage renal disease (ESRD). Different pathophysiologic mechanisms have been proposed to explain the development of nephropathy in SCD, where hemolysis and vascular occlusion are the main contributors in the manifestations of this disease. Markers of renal injury, such as proteinuria and tubular dysfunction, have been associated with outcomes among patients with sickle cell nephropathy and provide means for early detection of nephropathy and screening prior to progression to renal failure. In small-sized clinical trials, hydroxyurea has demonstrated to be effective in slowing the progression to ESRD. Dialysis and renal transplantation represent the last resort for patients with sickle cell nephropathy. Nevertheless, despite the availability of diagnostic and therapeutic strategies, sickle cell nephropathy remains a challenging and under-recognized complication for patients with sickle cell disease.

Disease Severity in Sickle Cell Disease: Understanding Impairment in Health-Related Quality of Life.

Glomerular Hypertrophy and Alterations in Renin-Angiotensin System Activation Are Associated with Diminished Systemic Blood Pressure in Aging Mice with Sickle Cell Anemia

A functional promoter polymorphism of the δ‐globin gene is a specific marker of the Arab‐Indian haplotype

Transgenic Sickle Mice Are Markedly Sensitive to Renal Ischemia-Reperfusion Injury