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Written by Priti Meena,MD; Rima Zahr, MD.
Infographics by Priti Meena, MD; Salar Bani Hani, MD
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
Sickle cell disease (SCD) is one of the most commonly encountered hereditary haematologic diseases worldwide. Sickle cell anemia (SCA) is the most severe and common form. Every year about 300,000 babies are born with SCA.SCD is caused by a homozygous (more common) or compound heterozygote inheritance of a mutation in the β-globin gene. A single base-pair point mutation (GAG to GTG) leads to the substitution of the amino acid glutamic acid (hydrophilic) to valine (hydrophobic) in the 6th position of the β-chain of hemoglobin. SCD is a multi-system disorder that results in both acute and chronic complications presenting when fetal hemoglobin (HbF) drops towards the adult level by five to six months of age. Unfortunately, in poor resource countries, more than 90 percent of children with SCD do not survive to see adulthood. Chronic anemia, asplenia/hyposplenia, sepsis, stroke, pulmonary hypertension, priapism, avascular necrosis of the hip, hemolysis, and recurrent acute vaso-occlusive crises are the frequently observed manifestations (figure 1).
Figure 1. Overview of sickle cell disease
Kidney disease in SCD remains an important cause of increased mortality and contributes to substantial morbidity. Here, we discuss kidney involvement in SCD with underlying pathogenetic mechanisms, manifestations, and potential therapeutic options.
Renal involvement in SCD
SCD gives rise to diverse renal manifestations (figure 2) with varying severity starting from impaired urinary concentrating ability to those that are rare and fatal such as renal medullary carcinoma. Sickle cell nephropathy (SCN) is more likely to be observed with more severe genotypes (homozygous HbSS and sickle-beta thalassemia) rather than with milder genotypes (HbSC disease or sickle-beta thalassemia).
Figure 2. Kidney manifestations of sickle cell disease
Pathogenesis of sickle cell nephropathy
The inner medulla environment is ideal for Hb S polymerization and subsequent RBC sickling and intravascular hemolysis, which is related to some inherent properties of the inner medulla such as lower blood flow and oxygen tension, acidosis, hyperosmolarity, and low blood flow. Sickled RBCs consequently cause microvascular occlusion of the vasa recta, which is the sole supply for renal papillae.
Furthermore, depletion of nitric oxide (NO), facilitated by intravascular hemolysis, vasoconstriction, and increased reactive oxygen species (due to elevated endothelin-1 concentration) causes disseminated vascular injury. This entire process sets up a vicious cycle for the development of chronic medullary ischemia. The injury from viscosity-vaso-occlusive damage leads to hemolysis-endothelial dysfunction which further contributes to systemic damage in SCD. Heme has a pro-inflammatory action and induces vasculopathic chemokines, such as monocyte chemoattractant protein-1 adding further to vascular injury. In addition, heme is nephrotoxic, specifically leading to tubular injury. Hemolysis alongside NO deficiency contributes to the occurrence of glomerulopathy in SCD.
Glomerular injury: Hemolysis and endothelial dysfunction mainly affect the renal cortex, causing hyperfiltration and glomerular injury. In SCD patients, the size of the glomerulus tends to expand with age, with glomerular congestion starting to appear at beyond the age of 2 years. Histopathology shows hypertrophy of the glomeruli and hemosiderin deposits in the tubular cells predominantly. The most common renal pathologies seen are focal segmental glomerulosclerosis (FSGS) followed by membranoproliferative glomerulonephritis (MPGN), and thrombotic microangiopathy (less common). The typical age for glomerular diseases is 7-18 months.
Figure 3. Manifestations of sickle cell nephropathy by age
Proteinuria: Loss of size and charge selectivity as sickled RBC induce endothelial activation and inflammation, leading to albuminuria. Some degree of tubular proteinuria could be due to tubular injury caused by hemolysis. The age of 7 years old is widely considered the typical age of onset of albuminuria. A higher level of albuminuria has a direct correlation with progression to ESRD in adulthood.
Renal tubular disorders: Damage to the vasa recta caused by sickled RBCs, leads to a loss of countercurrent multiplication and exchange system, produces hyposthenic urine. The patient often complains of nocturia and polyuria. Hypoxia and disturbance in the medullary blood flow lead to reduced hydrogen ions and electrochemical gradients along the collecting ducts. Impaired distal hydrogen and potassium secretion can result in a partial distal renal tubular acidosis as well.
Hematuria: Microscopic hematúria can be present in up to 30% of patients with SCD. The reason could be due to nutcracker syndrome, renal infarction, renal papillary necrosis. Macroscòpic hematuria can be present due to papillary necrosis as a consequence of vascular occlusion.
Electrolyte imbalance: Hyperuricemia and hyperkalemia are often observed.
AKI: AKI in SCN is mostly caused by the vaso-occlusive crisis and is common between the ages of 8-18 years. Other contributing factors to AKI could be dehydration, infection, rhabdomyolysis, concurrent use of nephrotoxic medications, renal vein thrombosis, or obstruction in the urinary tract.
Chronic kidney disease: Published studies revealed a high prevalence of CKD (in up to one-fourth to one-third of adults) amongst patients with sickle cell disease. Even the presence of sickle cell trait has been found to be associated with an increased risk of CKD, declining eGFR, and albuminuria.
Renal infarction and papillary necrosis are frequent in SCN and can be observed in as many as 23 to 40% of patients. Contributing factors are interstitial nephritis, acute pyelonephritis, diabetes mellitus, or analgesic use. Urinary tract obstruction and infection can further add to complications. Renal infarcts could present with nausea, vomiting, flank pain, fever, and rarely hypertension.
Renal medullary carcinoma (RMC): Though very rare, RMC is a very fatal complication of SCN with the typical age of onset being early adulthood. It is a non-clear-cell kidney cancer. RMC is predominantly found in individuals with sickle cell trait. It commonly presents with flank pain and hematuria or a palpable abdominal mass. RMC is characterized as highly aggressive, and often metastatic at presentation.
Patients with SCN often suffer from other comorbidities such as pulmonary hypertension, systemic hypertension, and central nervous system (CNS) injuries including stroke.
In SCD patients it can be challenging to correctly estimate GFR due to glomerular hyperfiltration, supranormal proximal tubule function, and hydroxyurea (causing interference in measurement platforms like i-stat Creatinine). The use of cystatin C might give a better correlation with eGFR in this population, however, this has not been validated.
Management Strategies
There is no one specific treatment for the management of SCN and treatment often requires multi-drug therapy. It is important to first address the primary disease, SCD, and work in concert with hematologists. Nephrologists can then focus on the development of novel therapies to address albuminuria, to slow the progress of kidney disease.
Hydroxyurea is the mainstay of therapy for SCD. Hydroxyurea increases HbF levels and inhibits the polymerization of HbS. Hydroxyurea prevents the onset and progression of albuminuria in children with sickle cell anemia. It is important to note that hydroxyurea is metabolized via kidneys and also removed by hemodialysis; thus dose adjustments may be required in individuals with impaired kidney function. A very rare adverse event is myelotoxicity. Furthermore, treating physicians must be aware of the possibility of waning effectiveness over time, and work with hematologist to monitor therapy.
Adequate hydration to maintain a urine output of 1.2 mL/kg/h is an essential part that reduces the chances of recurrent AKI in SCD (supported by a low grade of evidence). Concurrent use of nephrotoxic medications should be avoided. Recurrent blood transfusions can cause high panel reactivity, due to a high level of circulating induced plasma antibodies from foreign antigens, and can complicate finding a matching donor for renal transplantation. Usually, kidney damage occurs during the early part of childhood; thus early identification and treatment to limit damage is crucial.
ACEi and ARBs
As supported by a few trials, the initiation of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) for renal complications, regardless of blood pressure, has been suggested by current guidelines with very low certainty in the evidence about effects. Though RAAS inhibition had shown a decline in albuminuria with the greatest benefits seen in patients with macroalbuminuria, no significant reduction in the progression of CKD could be observed in published trials.
Endothelin receptor antagonists (Crizanlizumab) have shown potent reno-protective effects in mice studies, but human studies are currently ongoing.
Other disease-modifying drugs and therapies Voxelotor, an HbS polymerization inhibitor, is currently being used in patients with SCD. In a phase 3 randomized, placebo-controlled trial in SCD patients, Voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. Another, new agent is Crizanlizumab, a P-selectin inhibitor. It has been shown to decrease vaso-occlusive pain crises in individuals 16 years and older. Results from another multicenter study, assessing the effect of this drug on CKD, are pending.
Gene therapy with the use of LentiGlobin in SCD patients showed promising results in a recently published analysis. It led to reduced hemolysis and complete resolution of severe vaso-occlusive events.
Dialysis and transplantation As in non-SCD patients, the choice of dialysis modality between hemodialysis and peritoneal dialysis depends on clinical factors and patient preferences. Experience of transplantation in SCD patients is limited because they are less likely to be placed on a kidney transplant waiting list. In a recent analysis, kidney transplantation was found to be associated with a substantial decrease in mortality in the sickle cell group with a decrease in 10-year mortality of 20.3 percentage points when compared with their matched waitlisted candidates. (PMID: 33632759)
Take Home Message:
Renal Involvement begins early in the first decade of life and is commonly manifested as hyposthenuria
Albuminuria occurs in ~ 20% of children, and is a harbinger of kidney disease progression
Mean survival in patients with SCN is significantly decreased when a diagnosis of ESKD is made
Treatment of SCN should focus on the treatment of albuminuria, the use of ACEI and ARBs have been used in these patients
Screening for SCN should being in childhood with a yearly urinalysis (UACR and UPCR)
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.