Sickle Cell Nephropathy

Etiology

Sickle cell nephropathy is caused by a complex, multifactorial etiology involving genetic, molecular, and cellular mechanisms:

• HbS polymerization [6]
• Hemolysis-induced endothelial dysfunction
• Endothelial activation and inflammation
• Several genetic modifiers, including variants in APOL1, MYH9, HMOX1, HBA1, and HBA2, have been implicated in the development and progression of nephropathy in patients with sickle cell disease [7][8]
• Medullary ischemia: Sickling in the renal medulla, which is naturally hypoxic and hypertonic, exacerbates ischemic injury and tubulointerstitial damage
• Initiation of glomerular hyperfiltration: Early glomerular hypertrophy and hyperfiltration stress the nephron, setting the stage for progressive dysfunction

These initiating factors establish the pathologic groundwork for proteinuria, glomerulosclerosis, and long-term renal decline in patients with sickle cell disease.

Epidemiology

Sickle cell disease, a group of inherited hemoglobinopathies caused by mutations in the beta-globin chain of hemoglobin, affects approximately 100,000 individuals in the United States and over 3 million people worldwide. In the United States, the disease predominantly affects individuals of African descent, with 1 in 365 Black or African American births affected. However, sickle cell disease also occurs in individuals of Hispanic, Middle Eastern, Indian, and Mediterranean ancestry, reflecting a broader global genetic burden.[9][10]

Sickle cell nephropathy is a common and severe renal complication of sickle cell disease, with a high prevalence across all age groups and a propensity to progress rapidly to end-stage kidney disease. A United States–based Medicaid database analysis reported chronic kidney disease in 0.1% of children, 5% of adults, and 15.9% of adults older than 40 with sickle cell disease. Incidence rates of acute renal failure and chronic kidney disease in patients with sickle cell disease were 1.4% and 1.3%, respectively—2 to 3 times higher than in those without sickle cell disease. A 13.2% increase in chronic kidney disease prevalence was noted over 5 years, indicating steady disease progression despite interventions.[11] In addition, macroalbuminuria prevalence was shown to increase with age and longer disease duration.

Among adults globally, the prevalence of chronic kidney disease in patients with sickle cell disease ranges from 27.1% to 44.6%. For instance, one study reported chronic kidney disease in 38.9% of adult patients with sickle cell disease in Nigeria.[12], whereas another found chronic kidney disease in 27.1% and proteinuria in 26.5% of adult patients in Saudi Arabia.[13] A separate investigation reported a 44.6% prevalence of kidney disease among adults with sickle cell disease.[12] In a longitudinal cohort, baseline chronic kidney disease was present in 28.6% of patients, increasing to 41.8% over 5 years.[14] Macroalbuminuria affects up to 40% of patients with Hb SS by 40.[15]

In the pediatric population, early kidney dysfunction is notable. Proteinuria prevalence ranges from 3.2% to 6.2%, with abnormal albuminuria observed in 20.7% and chronic kidney disease in 26.5% of children with sickle cell disease.[16][17] Although less frequent than in adults, these early findings suggest a progressive disease trajectory beginning in childhood.

Notably, 30% of adults with sickle cell disease developed chronic kidney disease by 31, and 42% of those progressed to end-stage kidney disease within 5 years. A 2022 retrospective analysis of 2.19 million patients in the United States Renal Data System showed that 20% of individuals with sickle cell disease progressed to end-stage kidney disease before 30, with a 2.7-fold higher mortality rate and significantly lower kidney transplant rates than in patients with sickle cell disease, underscoring the ethnic and clinical disparities in outcomes.[18]

Pathophysiology

HbS polymerization is the key pathophysiological event in sickle cell nephropathy, occurring during cellular or tissue hypoxia, oxidative stress, or dehydration. The mutated beta-globin chains of the HbS molecule form tetramers, altering RBCs into crescent or sickled shapes with increased rigidity. Local oxygen tension, acidosis, and hyperosmolarity influence tetramerization. Repeated cycles of this transformation lead to high adhesion of sickled RBCs to activated endothelium, resulting in prolonged microvascular transit time and further sickling. This process leads to early RBC destruction and widespread vaso-occlusive episodes with acute and chronic organ damage.[19]

The leading cause of disease severity is the rate and degree of HbS tetramerization, which leads to 2 major pathophysiologic events:

• Vaso-occlusion with ischemia-reperfusion injury 
• Hemolytic anemia [20][21]

The renal medulla is the primary site of injury in sickle cell nephropathy, where the vasa recta are exposed to a uniquely hypoxic, acidic, and hypertonic environment. These factors promote sickling, leading to vascular congestion, ischemia, infarction, and chronic loss of glomerular and tubular function. Sickling in the vasa recta also impairs countercurrent exchange, causing reduced urine-concentrating ability (hyposthenuria), which can present as polyuria and nocturia, even in childhood.[22]

Additional contributing mechanisms include the following:

• Activation of hypoxia-inducible factor 1-alpha
• Upregulation of endothelin-1, a potent vasoconstrictor
• Decreased nitric oxide availability due to hemolysis, enhancing vasoconstriction and oxidative stress.[23]

These changes contribute to a paradoxical increase in renal blood flow and glomerular filtration rate (GFR), particularly in juxtamedullary nephrons, leading to hyperfiltration injury, proteinuria, and glomerulosclerosis. The concurrent development of tubulointerstitial fibrosis further accelerates the progression of chronic kidney disease.[24]

Possible mechanisms for glomerular abnormalities in HbSS patients include the following:

• The fragmented RBCs in glomerular capillaries activate the mesangial cells, which promote matrix protein synthesis and migration into the peripheral capillary wall, resulting in glomerular basement membrane reduplication.[25]
• Glomerular deposition of immune complexes comprising renal tubular epithelial antigen and their corresponding antibodies mediates the development of glomerulonephritis.[26]

Proximal tubular hyperfunction can lead to increased phosphate reabsorption, hyperuricemia, and falsely elevated creatinine clearance. In contrast, distal tubular dysfunction contributes to type IV renal tubular acidosis, characterized by hyperkalemia and metabolic acidosis.[27]

Moreover, free heme release during hemolysis induces oxidative stress through reactive oxygen species generation, lipid peroxidation, and depletion of antioxidants such as glutathione, affecting HMOX1 and SOD2 activity. Inflammatory pathways play a significant role, involving leukocyte adhesion through VCAM-1 and ICAM-1; activation of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6; and complement system activation.[28]

Histopathology

No pathognomonic lesion defines sickle cell nephropathy, but glomerular hypertrophy, leading to hyperfiltration, is universal and is observed in children as young as 1 to 3 years of age.[29] Given the glomerular hypertrophy, the GFR continues to rise throughout childhood and early adulthood, often exceeding 200 mL/min/1.73 m². However, unlike in diabetic nephropathy, the hyperfiltration is not associated with hypertension, as patients with sickle cell nephropathy have lower systemic vascular resistance.[30] Nephrotic syndrome, although uncommon (up to 4% of patients with proteinuria), is associated with a very poor renal prognosis. An infection with human parvovirus B19 (HPV B19) is a rare cause of acute nephrotic syndrome with severe hemolysis and life-threatening anemia. The biopsy in such patients shows a collapsing variant of focal segmental glomerulosclerosis.[31] Renal papillary necrosis can be observed with complete occlusion of vasa recta and can be complicated by superimposed infection and colic from clots.[32] Renal medullary carcinoma, an aggressive form of renal cell carcinoma, primarily affects patients with sickle cell hemoglobinopathies, with a higher incidence in teenagers and young adults. Chronic medullary hypoxia is believed to contribute to its pathogenesis.[33] Patients with sickle cell nephropathy advance through stages of tubular dysfunction and hyperfiltration, microalbuminuria through heavy proteinuria, and ultimately loss of GFR. Single-nephron GFR increases with the loss of other nephrons, leading to progressive damage to the glomeruli. On renal pathology, this damage manifests as focal segmental glomerulosclerosis, interstitial fibrosis, and tubular atrophy.

Focal segmental glomerulosclerosis is the most common lesion in sickle cell nephropathy and is associated with proteinuria. Collapsing pattern and expansive pattern of focal segmental glomerulosclerosis may be observed.[34] Other renal biopsy lesions that have been reported in sickle cell disease comprise thrombotic microangiopathy and membranoproliferative glomerulonephritis, though neither is limited to sickle cell nephropathy. The only characteristic interstitial lesion is abundant hemosiderin granules in proximal tubular epithelial cells.[35]

Kidney tissue in sickle cell nephropathy shows a sequence of histopathological changes that vary with disease stage.

Early Stage

• Glomerular hypertrophy
• Mesangial proliferation
• Early basement membrane reduplication
• Focal segmental glomerulosclerosis
• Hemosiderin deposition
• Minimal tubular and interstitial changes
• Vascular congestion

Middle Stage

• Progressive mesangial matrix accumulation
• Expansion or collapsing pattern of focal segmental glomerulosclerosis
• Tubular atrophy onset
• Interstitial fibrosis begins
• Progressive vascular congestion

Late Stage

• Global glomerulosclerosis
• Extensive basement membrane thickening
• Advanced tubular atrophy and fibrosis
• Chronic medullary ischemia with potential for renal medullary carcinoma
• Persistent hemosiderin accumulation
• Occasional thrombotic microangiopathy or MPGN-like patterns

History and Physical

Sickle cell nephropathy can present with a range of clinical findings, often progressing silently until significant renal damage has occurred.[36][37] 

History

• Patients often report polyuria and nocturia beginning in early childhood, due to hyposthenuria from impaired urine-concentrating ability.
• Hematuria, both microscopic and gross, may occur, often related to papillary necrosis from medullary ischemia. This condition is observed in 6.3% to 38% of pediatric patients.
• Growth retardation is frequently noted in pediatric patients as renal dysfunction progresses.
• Fatigue and pallor are common complaints reflecting chronic anemia.
• Elevated blood pressure may be noted by patients or outpatient providers during routine checks as the disease progresses.
• Pulmonary symptoms may arise from associated pulmonary hypertension and cardiac changes.
• In more advanced stages, patients may report facial or peripheral swelling suggestive of developing nephrotic syndrome.

Physical Examination

• Hypertension is present in up to 16.7% of pediatric cases and may become more prevalent in adults as sickle cell nephropathy progresses.
• Edema, both periorbital and peripheral, is observed in cases with significant proteinuria or nephrotic syndrome.
• Signs of anemia, such as pallor and tachycardia, may be evident on examination.
• In some cases, signs of volume depletion may be noted due to chronic polyuria.

Evaluation

The initial diagnosis of sickle cell nephropathy is based on the clinical manifestations and is primarily a diagnosis of exclusion. 

Chronic kidney disease in sickle cell disease often develops gradually. Therefore, regular monitoring is essential for all patients.[38] There is limited high-quality evidence to guide the choice and frequency of diagnostic tests. In general, evaluations begin between the ages of 3 and 5, and no later than 10. Children are typically assessed 2 to 3 times a year, whereas adults are assessed 4 to 6 times.

Monitoring and Diagnostic Testing

• Blood pressure is checked at each visit.
• Urinalysis and urine sediment analysis are performed annually to detect microscopic hematuria and proteinuria.
• A spot urine albumin-to-creatinine ratio is also obtained. If it exceeds 300 mg/g, a 24-hour urine protein test is performed, and nephrology referral is recommended.[39]
• The estimated GFR (eGFR) is calculated using serum creatinine. The Schwartz formula is often used in children, whereas the Chronic Kidney Disease Epidemiology Collaboration equation is used in adults.
• Hydroxyurea may falsely elevate creatinine when measured with i-STAT devices. In such cases, alternative confirmatory methods should be used.
• Patients on deferasirox should have monthly checks for creatinine, albumin, and urine protein. For deferoxamine, every 3 months is sufficient. Dose adjustments may be needed if creatinine rises.
• Cystatin C is a valuable alternative to creatinine, as it is not influenced by muscle mass or diet and may indicate kidney damage related to hemolysis.[8]
• Patients with sickle cell disease may also develop renal tubular acidosis, with features such as low CO₂, abnormal potassium, and sometimes high chloride.[40]
• If eGFR drops more than 10% in 1 year or falls below 60 mL/min/1.73 m², urine sediment analysis and kidney imaging are indicated.[41]
• Technetium-DTPA scans can be used to measure GFR in research settings; however, they may underestimate actual values due to protein binding.
• Kidney ultrasound is part of the routine evaluation for patients with declining kidney function, persistent proteinuria or hematuria, or symptoms of urinary blockage. However, ultrasound cannot reliably detect renal medullary carcinoma. If symptoms persist, a computed tomography scan is preferred.
• Kidney biopsy is not commonly used in sickle cell disease. When needed, decisions are made case by case, similar to general chronic kidney disease care.
• Several biomarkers are under investigation but are not yet used in routine clinical care. These biomarkers include urinary KIM-1, NAG, beta2-microglobulin, BMPR1B, MYH9, APOL1, and urinary kallikrein.[42]

Treatment / Management

Management of sickle cell nephropathy focuses on slowing the progression of renal damage, improving quality of life, and addressing associated complications. Therapeutic strategies include both conventional treatments and emerging interventions currently under investigation.

Conventional Therapies

• Hydroxyurea: A well-established agent in sickle cell disease management that improves urine-concentrating ability (mean difference: 42.23 mOsm/kg). However, it has shown no significant effect on GFR (mean difference: 0.58 mL/min/1.73m²). Hydroxyurea may help reduce albuminuria and is frequently used as a first-line therapy.[43]
• Angiotensin-converting enzyme inhibitors (captopril and lisinopril): Commonly used to reduce proteinuria in chronic kidney disease, although studies in sickle cell disease populations did not demonstrate a statistically significant benefit (mean difference:49 mg/d less).[43]
• RBC transfusions and chronic transfusion therapy: Used to reduce hemolysis and sickling; however, their impact on renal outcomes remains inadequately quantified in available trials.
• Erythropoiesis-stimulating agents: Sometimes combined with hydroxyurea in select cases, although more robust evidence on kidney-specific outcomes is needed.[44]
(A1)

Novel Therapies

• L-glutamine: A Food and Drug Administration–approved antioxidant for sickle cell disease that reduces oxidative stress. The effects of L-glutamine on renal outcomes are currently under investigation.[45]
• Crizanlizumab: A P-selectin inhibitor that reduces vaso-occlusive crises and is under evaluation for potential renal protection in sickle cell disease.[45]
• Voxelotor: A hemoglobin S polymerization inhibitor that may provide indirect renal protection through improved anemia and decreased hemolysis.[45]
• Gene Therapies: Recently approved curative therapies for sickle cell disease show promise, but their impact on kidney disease progression has yet to be established.[46]
(B3)

Renal Replacement Therapies

• Dialysis: A necessary intervention for end-stage kidney disease, which may develop early in patients with sickle cell disease. Compared to individuals without sickle cell disease, patients with sickle cell disease on dialysis have a 2.7-fold higher mortality rate and reduced access to kidney transplantation.
• Kidney transplantation: An established treatment for advanced chronic kidney disease/end-stage kidney disease. Although historically associated with poor outcomes in sickle cell disease, newer data suggest improved post-transplant survival. However, access remains limited due to prior biases in transplant eligibility criteria.[47]
(B3)

Combination Therapy Approach

• Combining hydroxyurea with chronic kidney disease–targeted therapies, such as RAAS blockers, shows promise. This approach necessitates careful monitoring due to complex drug interactions and the need for renal dose adjustments.[48]
(B3)

Supportive Management of Complications

• Conservative measures, including bed rest and oral hydration, remain the cornerstone of managing gross hematuria.
• Severe hematuria may require urine alkalinization, loop diuretics to increase urine flow, and blood transfusions.
• In refractory cases, additional interventions, such as desmopressin (DDAVP); antifibrinolytic agents, including tranexamic acid and epsilon-aminocaproic acid; vascular embolization; or balloon tamponade, have been described in case reports.
• The target blood pressure is 130/80 mm Hg in patients with hypertension and proteinuria.
• Intermittent intravenous iron supplementation may be necessary due to ongoing subclinical gastrointestinal blood loss.

Medications with known nephrotoxicity, including nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, radiocontrast agents, and certain iron chelators, should be avoided.

Differential Diagnosis

The following conditions should be considered and systematically ruled out when evaluating patients with sickle cell nephropathy, as they can present with similar renal manifestations:

• Lupus nephritis
• Multiple myeloma
• Renal cell carcinoma
• Nephrolithiasis
• Viral nephropathy
• Hypertensive nephrosclerosis
• Diabetic nephropathy
• Analgesic nephropathy
• HIV-associated nephropathy
• Amyloidosis
• Post-infectious glomerulonephritis
• Membranoproliferative glomerulonephritis
• IgA nephropathy
• Hemolytic uremic syndrome
• Thrombotic microangiopathy

Prognosis

Sickle cell nephropathy significantly contributes to morbidity and mortality in patients with sickle cell disease. End-stage kidney disease accounts for approximately 16% to 18% of sickle cell disease–related deaths.[6] In a historical cohort, chronic kidney disease developed in approximately 4% of individuals with HbSS disease, with death typically occurring around 4 years after the onset of kidney failure, at a median age of 27 years. Median survival among patients with and without kidney failure was 29 and 51 years, respectively, and the mortality risk among individuals with kidney failure was comparable to those with a history of stroke.[49] Survival is substantially decreased among patients with kidney failure and sickle cell disease compared to those with kidney failure but without sickle cell disease. The unadjusted 5-year mortality risk in patients with sickle cell disease and end-stage kidney disease was significantly elevated (hazard ratio 2.00, 95% CI: 1.66–2.40).[50] However, adjusted analyses suggest that this difference may be largely attributed to lower kidney transplantation rates among patients with sickle cell disease.[51] Post-transplantation survival has improved, with 1-year survival rates reaching approximately 88%.[52]

Additional data from cohort studies show genotype-specific progression, with eGFR declining faster in individuals with HbSS (2.05 mL/min/1.73 m²/year) compared to those with HbSC (1.16 mL/min/1.73 m²/year), and even faster in some cases (up to 3.2 mL/min/1.73 m²/year).[53] Patients with nephrotic syndrome demonstrate particularly poor outcomes, with 44% mortality reported within 24 months. A separate study found the hazard ratio for death in patients with sickle cell nephropathy compared to those without renal disease was 1.52 (95% CI: 1.27–1.82), reinforcing the long-term risk associated with renal involvement in sickle cell disease.[51] These findings highlight the critical importance of early detection and management of sickle cell nephropathy to improve survival outcomes.

Complications

Sickle cell nephropathy is associated with a broad spectrum of renal complications as follows:

• Hematuria
• Proteinuria and nephrotic syndrome
• Acute kidney injury
• Chronic kidney disease
• End-stage kidney disease
• Renal papillary necrosis
• Hyposthenuria 
• Renal tubular acidosis (type IV)
• Hypertension
• Electrolyte imbalances, such as hyperkalemia and metabolic acidosis
• Progressive glomerulosclerosis
• Tubulointerstitial fibrosis
• Reduced GFR
• Increased cardiovascular morbidity
• Increased mortality in patients with end-stage kidney disease
• Increased risk of renal medullary carcinoma
• Poor outcomes post-dialysis and transplantation