Sickle cell nephropathy in Pediatrics.pptx
- 1. SICKLE CELL NEPHROPATHY Dr. Omondi Obudho Paediatrics Resident | 2025 Maseno University
- 2. Dr. Omondi Obudho | Paediatrics Resident 2025 VERVIEW Epidemiology Introduction Etiology Pathophysiology Histopathology Clinical Manifestation 02 Management Investigations Differential Diagnoses Complications What Next? Prognosis
- 3. • Sickle cell disease (SCD) is a debilitating genetic disorder that poses a significant global health burden, particularly in regions with limited healthcare resources • Renal complications, including acute and chronic kidney injury, are among the most severe manifestations of SCD, contributing substantially to morbidity and mortality • Globally, sickle cell nephropathy (SCN) is a major concern, as it often progresses silently, leading to end-stage renal disease (ESRD) if not detected and managed early INTRODUCTION 03 • Despite advancements in understanding SCD, the prevalence, risk factors, and clinical profile of SCN remain poorly characterized, especially in low-resource settings, underscoring the need for targeted research to address this gap • In Sub-Saharan Africa, the burden of SCD and its renal complications is particularly severe due to the high prevalence of the disease and limited access to comprehensive care. Dr. Omondi Obudho | Paediatrics Resident 2025
- 4. • In Kisumu County, Kenya, SCD represents a major public health challenge, with approximately 21% of children born with the sickle cell trait and around 1,500 new cases diagnosed annually • The high prevalence is attributed to the region's malaria endemicity, as the sickle cell trait offers partial protection against severe malaria • While comprehensive data on the prevalence of pediatric SCN in sub-Saharan Africa is limited, available studies indicate a significant burden. • A cross-sectional study conducted in northwestern Tanzania evaluated 153 children with SCD. At enrollment, 31.4% exhibited renal dysfunction, defined by the presence of albuminuria (>20 mg/L) or an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m². EPIDEMIOLOGY 04 Dr. Omondi Obudho | Paediatrics Resident 2025
- 5. • Another study from Dar es Salaam, Tanzania, reported that 14.7% of children with SCD had renal dysfunction, characterized by an eGFR below 60 mL/min/1.73 m². This study primarily involved children under 10 years of age. • These findings highlight a substantial prevalence of renal complications among children with SCD in sub-Saharan Africa. • The variability in reported rates underscores the need for more extensive, region-specific research to accurately determine the burden of pediatric sickle cell nephropathy across the continent. • Limited healthcare infrastructure and inconsistent implementation of renal monitoring further exacerbate the risk of undetected and untreated renal complications, highlighting the urgent need for localized research to inform clinical practice and policy EPIDEMIOLOGY 05 Dr. Omondi Obudho | Paediatrics Resident 2025
- 6. ETIOLOGY 06 The sickle hemoglobin mutation (hemoglobin S or HbS) results in the replacement of the glutamate for valine in the sixth amino acid position of the beta-globin chain, thereby changing the arrangement of the Hb tetramer molecule in the homozygous person from A2B2 to A2BS2. GENETICS SCD occurs in those homozygous for HbS (referred to as sickle cell anemia) or in heterozygotes when HbS coexists with another abnormal or missing beta- chain, for example, HbC (A2SC) or HbS beta thalassemia (A2SBthal). Sickle cell trait occurs in those heterozygous for HbS when the other Hb molecule is normal HbAS (A2SB). HbS Dr. Omondi Obudho | Paediatrics Resident 2025
- 7. ETIOLOGY 07 • Age: Older Children • Severity of Anemia: Early severe anemia • Hemolysis: Severe hemolysis • Genetic Factors: The Central African Republic sickle haplotype • Blood Pressure: Elevated blood Risk Factors for SCN 01 • Genetic variants of MYH9 and APOL1 • Infection with parvovirus B19 • Recurrent Acute chest syndrome • Vaso occlusive episodes • Nephrotic range proteinuria • Underlying hypertension • Severe anemia Progression to CKD 02 Dr. Omondi Obudho | Paediatrics Resident 2025
- 8. • HbS polymerization is the key pathophysiological event, and it occurs during cellular or tissue hypoxia, oxidative stress, or dehydration. • The mutated beta-globin chains of the HbS molecule tend to form a tetramer resulting in the change in the shape of red blood cell (RBC) to a crescent or sickle, with increased rigidity • Local oxygen tension, acidosis, and hyperosmolarity are some factors that influence the tetramerization. • Repeated cycles of tetramer formation make the sickle RBCs exhibit high adhesion to the activated endothelium resulting in increased microvascular transit time, leading to further sickling. • The whole process ultimately results in the early destruction of the RBCs (hemolysis) and frequent, widespread vaso-occlusive episodes with consequent acute and chronic organ damage. PATHOPHYSIOLOGY 08 Dr. Omondi Obudho | Paediatrics Resident 2025
- 9. The renal complications in SCD originate from the occluded vessels (vasa recta) in the renal medulla, given the low partial pressure of oxygen (10 to 35 mm Hg), acidosis, and high osmolarity, which predisposes to hemoglobin S tetramerization and subsequent sickling of the erythrocytes. PATHOPHYSIOLOGY 09 Vaso-occlusion with ischemia-reperfusion injury Repeated sickling & sludging lead to microinfarcts & ischemic injury gives rise to chronic microvascular disease seen in patients with SCN. The factors which promote the cycles of chronic medullary hypoxia include: • Hypoxia-inducible factor 1alpha (HIF1A) and its activation • Expression of endothelin-1 • Reduced nitric oxide promoting increased reactive oxygen species and vasoconstriction Hypoxia Dr. Omondi Obudho | Paediatrics Resident 2025
- 10. Injury from a paradoxical increase in the total RBF and GFR in renal medulla ultimately results in proteinuria and glomerulosclerosis, which together with tubulointerstitial fibrosis leads to progressive CKD. Polyuria, from the decreased concentrating ability, a consequence of tubular injury may be seen in childhood and adolescence. PATHOPHYSIOLOGY 10 Hyperfiltration Type IV RTA (hyperkalemia and mild hyperchloremic metabolic acidosis) can be observed in these patients before a significant loss of nephron mass and proteinuria from secondary FSGS (focal segmental glomerulosclerosis). Papillary necrosis may result from ischemia from the sickling of red cells Renal Tubular Acidosis Dr. Omondi Obudho | Paediatrics Resident 2025
- 11. • No pathognomonic lesion defines SCN, but glomerular hypertrophy, leading to hyperfiltration, is universal and is seen in children as young as 1 to 3 years of age. • Renal papillary necrosis can be seen with complete occlusion of vasa recta and can be complicated by superimposed infection and colic from clots. • An aggressive form of renal cell medullary carcinoma (due to chronic medullary hypoxia), affects • FSGS is the most common lesion in SCN and is associated with proteinuria. Collapsing pattern and expansive pattern of FSGS may be observed. patients with SCN. HISTOPATHOLOGY 11 Dr. Omondi Obudho | Paediatrics Resident 2025
- 12. • Hyperfiltration from glomerular hypertrophy with eGFR exceeding more than 200 ml/minute/1.73 mt2. • Self-limiting microhematuria, which can be painless to visible, painful gross hematuria, requiring transfusions. • Microalbuminuria and proteinuria which increases protein losses • Nephrogenic diabetes insipidus • Acute kidney injury CLINICALLY 12 • Nephrotic syndrome in up to 4% of patients • Hyposthenuria is almost universal in SCD • Renal infarction presenting with flank or abdominal pain, nausea, vomiting, and fevers • Hyperkalemia and mild hyperchloremic metabolic acidosis (type IV renal tubular acidosis) • Urinary tract infections and pyelonephritis • Progressive chronic kidney disease with age. Dr. Omondi Obudho | Paediatrics Resident 2025
- 13. Increased glomerular filtration rate (GFR), causing excessive filtration of plasma. Early adaptation to chronic anemia and increased cardiac output in SCD, leading to increased renal blood flow. Early onset albuminuria/proteinuria -Progression to glomerulosclerosis and CKD CLINICALLY 13 HYPERFILTRATION Inability of the kidneys to concentrate urine, leading to dilute urine (low urine osmolality). Papillary necrosis may result from ischemia from the sickling of red cells Damage to the renal medulla and vasa recta due to repeated sickling in the hypoxic environment of the renal papilla. Polyuria, Nocturia HYPOSTHENURIA Dr. Omondi Obudho | Paediatrics Resident 2025
- 14. INVESTIGATIONS 14 • Proteinuria/Albuminuria Early marker of → glomerular damage. • Microscopic Hematuria Indicates renal → papillary necrosis. • Low Urine Specific Gravity (<1.010) → Suggests hyposthenuria (inability to concentrate urine). Urinalysis • Serum Creatinine & Blood Urea Nitrogen (BUN) → Assess renal function; may be normal in early SCN but rise in advanced disease. • Estimated Glomerular Filtration Rate (eGFR) → Elevated in hyperfiltration stage but declines as kidney damage progresses. Kidney Function Tests Dr. Omondi Obudho | Paediatrics Resident 2025
- 15. INVESTIGATIONS 15 • Renal Ultrasound May → show increased kidney size (early SCN) or shrunken kidneys (advanced CKD). • Doppler Studies Assess → renal blood flow and vascular abnormalities. • CT scan to rule out medullary renal carcinoma especially in sickle cell trait patients Imaging • Performed when atypical features (e.g., rapidly worsening kidney function, nephrotic syndrome) are present. • Helps distinguish SCN from other glomerular diseases (e.g., focal segmental glomerulosclerosis, lupus nephritis). Biopsy Dr. Omondi Obudho | Paediatrics Resident 2025
- 16. • The conservative approach, with bed rest, oral hydration, remains the cornerstone in the management of gross hematuria. Severe cases need urine alkalinization, loop diuretics to increase urine flow, and blood transfusion. • Hydroxycarbamide or hydroxyurea is the only proven drug for the management of SCD. • In patients with hypertension, the goal of a patient with proteinuria is less than 130/80 mm Hg MANAGMENT 16 • Erythropoiesis-stimulating agents (ESA), in combination with hydroxyurea should be commenced when hemoglobin drops 10% to 15% below the normal reference range and no more than 10 to 10.5 g/dL • Intermittent intravenous iron supplementation might be warranted given prolonged subclinical gastrointestinal bleeding. Dr. Omondi Obudho | Paediatrics Resident 2025
- 17. • Aminocaproic acid, which inhibits fibrinolysis by inhibiting plasmin activity, or desmopressin acetate which improves clotting via the increase in plasma factor VIII and von Willebrand factor, can be used in patients with gross hematuria from papillary necrosis • High dose urea (up to 160 gm per day) can be used in patients with refractory cases as its shown to prevent the tetramerization of sickle hemoglobin. MANAGMENT 17 • Hemopoietic stem cell transplantation (HSCT) is potentially curative and is largely limited to children who remain resistant to hydroxyurea and with severe cerebrovascular complications, VOC episodes, and acute chest syndrome. • Renal transplantation offers the best survival outcomes in patients with SCN who require renal replacement therapy Dr. Omondi Obudho | Paediatrics Resident 2025
- 18. • SCN shares features with glomerular, tubulointerstitial, and vascular kidney diseases. • Diagnosis requires clinical correlation, urinalysis, kidney function tests, and renal biopsy (in uncertain cases) to rule out mimickers. • Other Causes of Glomerular Disease such as Focal Segmental Glomerulosclerosis (FSGS), Diabetic Nephropathy, and Hypertensive Nephropathy • Other Causes of Tubular Dysfunction such as Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD), Bartter and Gitelman Syndromes • Other Causes of Hematuria and Papillary Necrosis such as Lupus Nephritis, IgA Nephropathy (Berger’s Disease), Renal Papillary Necrosis (RPN) from other causes such as Diabetes mellitus, analgesic nephropathy, tuberculosis, or pyelonephritis DIFFERENTIAL DIAGNOSES 18 Dr. Omondi Obudho | Paediatrics Resident 2025
- 19. Microalbuminuria and Proteinuria: Early indicators of glomerular damage, with microalbuminuria occurring in 30–60% of SCD patients. Hematuria: Ranges from painless to severe; more frequent in individuals with sickle cell trait due to renal medullary infarctions. Hyposthenuria: Impaired urine concentration leading to polyuria and dehydration, resulting from ischemic injury to the renal medulla. Tubular Dysfunction: Includes incomplete distal renal tubular acidosis, leading to metabolic acidosis and hyperkalemia. COMPLICATIONS 19 Renal Papillary Necrosis: Ischemic injury causing necrosis of renal papillae Chronic Kidney Disease (CKD) and End- Stage Renal Disease (ESRD): Progressive decline in renal function Tubular Dysfunction: Includes incomplete distal renal tubular acidosis, leading to metabolic acidosis and hyperkalemia. Renal Medullary Carcinoma: A rare but aggressive cancer predominantly affecting individuals with sickle cell trait or disease. Dr. Omondi Obudho | Paediatrics Resident 2025
- 20. Sickle cell nephropathy (SCN) is a significant complication of sickle cell disease (SCD), leading to progressive kidney damage. In sub-Saharan Africa, the prognosis of SCN is influenced by several factors: High Prevalence and Mortality: • Approximately 66% of the 120 million people living with SCD worldwide reside in Africa, with around 1,000 new cases daily. Without intervention, 50-80% of infants born with SCD in Africa die before the age of five. Limited Access to Healthcare: • In sub-Saharan Africa, access to medical care and public health strategies to decrease mortality and morbidity associated with SCD is often limited. Challenges in Early Detection and Management: • The absence of widespread newborn screening and surveillance programs leads to unreliable data on SCD prevalence and impact, hindering early detection and management of SCN. PROGNOSIS 20 Dr. Omondi Obudho | Paediatrics Resident 2025
- 21. • Sickle cell nephropathy (SCN), a significant complication of sickle cell disease (SCD), poses substantial health challenges in sub-Saharan Africa. • Addressing SCN effectively requires a multifaceted approach encompassing early detection, comprehensive management, and capacity building. • Standardized new-born screening and early intervention for children was initiated in twelve Sub-Saharan countries: Benin, Burkina Faso, Cameroon, Democratic Republic of the Congo, Ghana, Kenya, Liberia, Mali, Nigeria, Senegal, United Republic of Tanzania, and Uganda. • Promote Comprehensive Management Strategies, including Hydroxyurea Therapy as well as regular Renal Function Monitoring • Research on SCN prevalence, predictors, and early asymptomatic nephropathy, along with patient outcome registries, is essential for targeted interventions and informed policy decisions. WHAT NEXT? 21 Dr. Omondi Obudho | Paediatrics Resident 2025
- 22. Dani Martinez | Engineering 2023 • Divers J, Naylor K, et al. APOL1, MYH9 and kidney disease in people of African ancestry. Nat Rev Nephrol. 2020. (pubmed.ncbi.nlm.nih.gov) • Nath KA, Kasinath BS. Sickle cell nephropathy: APOL1 takes center stage. Nat Rev Nephrol. 2015. (nature.com). • Renal Papillary Necrosis (RPN) in an African Population: Disease Patterns, Relevant Pathways, and Management by G. R. Gaudji et al • Early blood transfusions protect against microalbuminuria in children with sickle cell disease O.Alvarez MD et al • How I treat renal complications in sickle cell disease C. C. Sharpe et al https://doi.org/10.1182/blood-2014-02-557439 REFERENECES 22
- 23. THANK YOU Dr. Omondi Obudho Paediatrics Resident | 2025 Maseno University