Continuing Education Activity

Sickle cell disease (SCD), is an autosomal recessive hemoglobin disorder that results from the replacement of glutamate for valine at the sixth amino acid of the beta-globin chain. This replacement results in the formation of hemoglobin S (HbS) tetramers that accumulate during oxidative stress, tissue hypoxia, or dehydration. The consequence of this is red blood cell sickling, early destruction of erythrocytes, and widespread vaso-occlusive episodes (VOC), subsequently causing multiorgan damage. Sickle cell nephropathy (SCN) is a group of renal complications that include hematuria, proteinuria, hyposthenuria, renal papillary necrosis, renal tubular disorders, acute and chronic kidney injury, sickle cell glomerulopathy, and renal medullary carcinoma. This activity illustrates the evaluation and treatment of sickle cell nephropathy and explains the role of the interprofessional team in managing patients with this condition.

Objectives:

• Describe sickle cell disease.
• Describe the complications expected in sickle cell nephropathy.
• Outline the evaluation and treatment options available for a patient with sickle cell nephropathy.
• Outline the importance of improving care coordination among the interprofessional team to monitor the patient for progression to end-stage renal disease and provide early intervention, which can lead to better life expectancy.

Introduction

Sickle cell disease (SCD), first discovered in West Africa is an autosomal recessive hemoglobin disorder, predominantly affecting persons of African, Mediterranean, Indian, and Middle Eastern descent. It results from the replacement of glutamate for valine at the sixth amino acid of the beta-globin chain. The mutation results in hemoglobin S (HbS) tetramers that accumulate during tissue hypoxia, oxidative stress or dehydration. The accumulation leads to red blood cell sickling, early destruction of erythrocytes, and widespread vaso-occlusive episodes (VOC), subsequently resulting in multiorgan damage. Some of the renal complications, collectively known as sickle cell nephropathy (SCN), include hematuria, hyposthenuria, renal papillary necrosis, proteinuria, renal tubular disorders, acute and chronic kidney injury, sickle cell glomerulopathy, and renal medullary carcinoma. Clinically significant renal involvement occurs more frequently in sickle cell disease than in sickle cell trait or in combined hemoglobinopathies, except renal medullary carcinoma, which appears to be more common among sickle cell trait patients. [1]

Natural history of SCD is highly variable with reduced life expectancy with multiorgan damage in symptomatic patients. In general, all patients have a reduced lifespan. Median survival in the United States and Jamaica is 45 to 55 years. [2]

Natural history by age in SCD is as follows:

• Newborn babies are asymptomatic for an initial couple of months, given fetal Hb (HbF) predominance.
• Early childhood is characterized by episodes of dactylitis, acute chest syndrome (ACS), sepsis, splenic sequestration, and stroke. Human parvovirus B19 infection can lead to severe and sudden anemia in children and adolescents with SCD as the virus destroys precursors of the red blood cells.
• After age 5: Classic painful vaso-occlusive crisis (VOC), which increases in frequency with age
• Adolescence is associated with nocturnal enuresis, avascular necrosis of the hip, leg ulcerations, delayed puberty, and priapism.[2]
• After age 25 to 30, the frequency of VOC tends to reduce and is replaced with signs and symptoms of chronic organ damage, including heart failure, pulmonary hypertension, sickle hepatopathy, and sickle cell nephropathy (SCN).[2]

The primary cause of death in younger patients is usually infection; whereas, in older patients, the primary cause of death is mostly irreversible organ damage.[3]

Etiology

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. 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). [4],[2]

Some of the risk factors associated with progression of chronic kidney disease (CKD) in SCN include:

• Genetic variants of MYH9 and APOL1
• Infection with parvovirus B19
• Recurrent Acute chest syndrome
• Vaso occlusive episodes
• Nephrotic range proteinuria
• Underlying hypertension
• Severe anemia

Coinheritance with alpha-thalassemia apart from higher fetal hemoglobin is protective factors.

Epidemiology

The high prevalence of SCD in West Africa and parts of Asia represents a probable survival advantage because the presence of the sickle cell gene protects against malaria. SCD is now a worldwide health problem because the carrier state has spread throughout Africa, Mediterranean, Middle East and South Asia, the Caribbean, North America, and Northern Europe.[5] SCD affects anywhere from 70,000 to 100,000 people in the United States and accounts for less than 1% of all new cases of end-stage renal disease (ESRD).[6] In a 25-year observational study of 725 SCD patients, 4% developed CKD at a median age of 23 years, most of them requiring dialysis within a few years.[7] When the study was extended by 15 years, the incidence was 12% (median age of 37 years).[3] Proteinuria is common in SCD, occurring in about 30% of patients. Sickle cell gene prevalence is about 8% in African Americans and about 25% in adult Nigerians.[5]

Pathophysiology

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 and frequent, widespread vaso-occlusive episodes with consequent acute and chronic organ damage.

The main 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[8],[9]

The renal complications in sickle cell disease 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. Repeated cycles of sickling and sludging lead to microinfarcts and ischemic injury giving rise to chronic microvascular disease which is seen in patients with SCN.[10] The factors which promote the cycles of chronic medullary hypoxia include[11]:

• Hypoxia-inducible factor 1alpha (HIF1A) and its activation
• Expression of endothelin-1  
• Reduced nitric oxide promoting increased reactive oxygen species and vasoconstriction

Hyperfiltration 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,[12]. Polyuria, from the decreased concentrating ability, a consequence of tubular injury may be seen in childhood and adolescence. 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 and manifest with gross hematuria and ureteric obstruction from sloughed ischemic papillae.

Possible mechanisms for glomerular abnormalities in HbSS patients include:

• The fragmented RBCs in glomerular capillaries activate the mesangial cells, which promote matrix proteins synthesis and migration into the peripheral capillary wall, resulting in GBM reduplication[13]
• Glomerular deposition of immune complexes comprising renal tubular epithelial antigen and specific antibody to renal tubular epithelial antigen, which mediate the glomerulonephritis[14]

Histopathology

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.[15] Given the glomerular hypertrophy, the GFR continues to rise throughout childhood and early adulthood, often exceeding 200 ml/min/1.73 m, but in comparison to diabetic nephropathy, the hyperfiltration is not associated with hypertension, as patients with SCN have lower systemic vascular resistance.[16] Nephrotic syndrome, though 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 collapsing variant of focal segmental glomerulosclerosis (FSGS).[17] Renal papillary necrosis can be seen with complete occlusion of vasa recta and can be complicated by superimposed infection and colic from clots.[18] An aggressive form of renal cell carcinoma, renal medullary carcinoma affects patients with sickle cell hemoglobinopathies, more so in teenagers and young adults. Chronic medullary hypoxia is thought to contribute to its pathogenesis.[19]. Patients with SCN 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 and on renal pathology, it is manifested as FSGS and interstitial fibrosis and tubular atrophy. FSGS is the most common lesion in SCN and is associated with proteinuria. Collapsing pattern and expansive pattern of FSGS may be observed.[20] Other renal biopsy lesions that have been reported in SCD comprise thrombotic microangiopathy and membranoproliferative glomerulonephritis, though neither are limited to SCN. The only characteristic interstitial lesion is abundant hemosiderin granules in proximal tubular epithelial cells.[21]

History and Physical

Some of the common findings in patients with sickle cell nephropathy include:

• Hyperfiltration from glomerular hypertrophy with eGFR exceeding more than 200 ml/minute/1.73 mt2. Hyperfiltration is seen in 51% of patients with HbSS with contribution from hemolysis mediated vasculopathy[22]
• Self-limiting microhematuria, which can be painless to visible, painful gross hematuria, requiring transfusions.
• Microalbuminuria and proteinuria which increases with age, reaching more than 60% of patients with SCD by age 45 years[23]
• 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
• Nephrogenic diabetes insipidus
• Acute kidney injury
• Progressive chronic kidney disease

Evaluation

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

The initial investigations in a patient with SCD, who presents with hematuria or proteinuria include:

• Basic metabolic panel
• Urine analysis and urine microalbumin to creatinine ratio
• Renal imaging with a renal ultrasound
• Intravenous pyelogram for papillary necrosis.
• CT scan to rule out medullary renal carcinoma especially in sickle cell trait patients.
• Serum albumin levels
• Autoantibodies and complement levels
• HIV, hepatitis B, and hepatitis C serologies
• Serum electrophoresis
• Renal biopsy when clinically indicated
• Review of the current and previous medication history

In a patient with eGFR less than 60 ml/mt/1.73mt2 with a rapid decline in eGFR by greater than 5mls/mt/1.73mt2 or with persistent proteinuria needs a nephrologist referral and evaluation. Especially, SCD patients with urinary protein to creatinine ratio (UPCR) greater than 300 mg/gm should be evaluated for other causes of CKD.

Treatment / Management

The conservative approach, with bed rest, oral hydration, remains the cornerstone in the management gross hematuria.

• Severe cases of hematuria 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. It acts primarily by increasing the levels of HbF diluting the levels of HbS and reduce the risk of tetramerization. No randomized adult trial is available, but it is proven to help with hyperfiltration and microalbuminuria in observational studies in children and adolescents and should be considered in patients with early signs of renal disease.
• Though a recent systematic review has concluded that available evidence is not sufficient to conclude use of renin-angiotensin system (RAS) blockade in SCN[24], it is a well-recognized practice based on its effects on the other proteinuric kidney diseases to initiate the RAS blockade, when the UPCR is greater than 300 mg/gms. Caution is warranted as many patients with SCN has normal or low normal blood pressures and "sick day" instructions to hold the medications during acute illness should be given.
• In patients with hypertension, the goal of a patient with proteinuria is less than 130/80 mm Hg.
• Evidence on chronic transfusions is mixed with one retrospective analysis showed protection against the development of microalbuminuria in children younger than 9 years of age. Prolonged courses of transfusions can lead to iron overload which poses challenges to treating clinicians.
• Erythropoiesis-stimulating agents (ESA), can be useful in combination with hydroxyurea. ESA should be commenced when hemoglobin(Hg) drops 10% to 15% below the normal reference range. Hg target should be lower in patients with SCD given the risk of vaso-occlusive episodes.
• Hg goal for patients with SCN is recommended to be no more than 10 to 10.5 g/dL, and the rate of correction rate of the anemia is less than 1% to 2% per week, given the risk of precipitating a vaso-occlusive crisis.
• Intermittent intravenous iron supplementation might be warranted given prolonged subclinical gastrointestinal bleeding.
• 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.
• 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.[25]

Differential Diagnosis

• Lupus nephritis
• Various glomerulonephritis
• Multiple myelomas
• Renal cell carcinoma
• Nephrolithiasis
• Viral nephropathy

Prognosis

• SCN accounts for less than 1% of ESRD patients in the United States, with higher mortality compared to other causes of ESRD[6]
• Median survival among patients with and without kidney failure is 29 and 51 years, respectively. 
• In a US study, the average age of patients with SCN, who reached end-stage renal disease (ESRD) requiring dialysis, is 23.1 years (with HbSS), with a mean time of death from the beginning of dialysis being 4 years.[7]
• United States renal data system (1992 through 1997) showed that SCN is an independent risk factor for the death in hemodialysis patients and are less likely to receive a renal transplant.[6]
• A French study of dialysis patients with ESRD from SCN compared the five years mortality, with patients of ESRD from other causes and it was 46.3% versus 6.4%. Moreover, these patients were much less likely to receive a renal transplant (26% versus 53.5%).[26]
• Recurrence of SCN has been reported in the literature.[27]
• The latest literature points toward improved outcomes in SN transplant recipients when compared to diabetic kidney disease.[28]

Consultations

• Nephrology
• Hematology
• Urology

Pearls and Other Issues

• The major underlying pathophysiological mechanism in kidney injury in SCN is from hypoxia, ischemia, and hemolysis.
• Early detection is key as the goal of treatment is to delay the progression of renal failure. 
• CKD development is from early glomerular hypertrophy and hyperfiltration; tubular hyperfunctioning; endothelial injury with sickling and vaso-occlusive episodes
• Diagnosis of SCN is primarily based on clinical manifestations and is essentially a diagnosis of exclusion.
• FSGS is the most common glomerular disorder in SCN.
• Hydroxyurea should be used in all patients with SCD and RAS blockade should be considered in SCN patients with proteinuria.
• Renal manifestations are generally more common and severe in SCD compared with those seen in sickle cell trait, except medullary renal cell carcinoma.
• All forms of renal replacement therapy are beneficial in ESRD patients from SCN, with renal transplantation giving a demonstrated advantage in survival benefit
• Physicians should be vigilant in SCD patients for any early signs of renal complications.

Enhancing Healthcare Team Outcomes

Patients with sickle cell are commonly followed by the primary care provider, nurse practitioner, hematologist and the internist. The renal function in these patients needs to be monitored by an interprofessional team because it can lead to end-stage renal disease and a shortened life expectancy. As soon as the renal function starts to decline, a nephrology consult should be made. Many of these patients do require dialysis and some may benefit from a kidney transplant. Without any treatment, the life span is severely limited.[29]