Sickle cell nephropathy

CHAPTER 48

SICKLE CELL NEPHROPATHY Phuong-Chi T. Pham and Phuong-Thu T. Pham

1. What is the pathophysiology of sickle cell disease (SCD)? Hemolysis, vasoocclusion, and ischemia reperfusion are the clinical hallmarks of SCD. The substitution of glutamate for valine at position 6 of the hemoglobin b-chain is the mutation defining hemoglobin S (HbS). HbS polymerizes when the concentration of its deoxygenated form exceeds a critical threshold. Conditions that promote HbS polymerization and red blood cell sickling include low local oxygen tension, acidemia (reduces HbS affinity for oxygen), and hyperosmolality (dehydrates red blood cells and increases HbS concentration). Extensive HbS polymerization, red blood cell sickling, cell membrane injury, and associated cell membrane adhesive interactions with the endothelium contribute to vasoocclusion leading to multiorgan damage. 2. What is the pathophysiology of sickle cell nephropathy (SCN)? Increased blood viscosity and red blood cell sickling promoted by the renal medullary milieu of low oxygen tension, low pH, and high osmolality lead to vasoocclusion and hypoperfusion in the medullary microcirculatory beds, and result in local ischemia and infarction. Severe medullary hypoperfusion can lead to papillary necrosis, sloughing, and obstructive uropathy. In contrast to medullary hypoperfusion, glomerular ischemia appears to promote compensatory increase in kidney blood flow and the glomerular filtration rate (GFR). Glomerular hyperfiltration is mediated by glomerular hypertrophy and increased activity of vasodilatory factors including prostaglandins, kallikrein, carbon monoxide, and possibly nitric oxide (NO). Proximal tubular secretory and absorptive hyperfunctioning are characteristic of SCD. Tubular hyperfunctioning is thought to reflect glomerulotubular balance in the face of glomerular hyperfiltration, and is evidenced by increased proximal tubular secretion of uric acid and creatinine and increased tubular reabsorption of low-molecular-weight protein (b2-microglobulins) and phosphate. Hypersecretion of creatinine causes an overestimation of the true GFR when using serum creatinine-based estimated GFR equations. Chronic hemolysis and hemoglobinuria involving HbS can induce oxidant-mediated tubular injury, proliferation of mesangial cells, and upregulation of proinflammatory and profibrogenic responses to promote glomerulosclerosis and tubulointerstitial fibrosis. Progressive kidney failure occurs due to: • Increased glomerular growth • Heme-induced injury to mesangial cells with chronic hemolysis • Repetitive vascular congestion and vasoocclusion-induced endothelial injury • Capillary rarefaction (reduced capillary density) • Ischemia-reperfusion-induced proinflammatory and profibrogenic responses Contributing factors to kidney vascular congestion and dysfunction include: • Endothelin-1: increases kidney vascular congestion, inflammation, and vasoconstriction induced by hypoxia • Thrombospondin: induces shedding of microparticles from red blood cells that can lead to oxidantmediated endothelial injury, red blood cell adhesion to the endothelium, and worsening of kidney vasoocclusive disease • Adenosine: promotes red blood cell sickling by increasing levels of 2,3-diphosphoglycerate in red blood cells. 3. In addition to proximal tubular hyperfunctioning, what other tubular abnormalities may be seen in patients with SCD? • Diminished concentrating ability: Red blood cell sickling and congestion in the vasa recta leads to ischemia and associated impairment of solute reabsorption by the ascending limb of Henle loop and the vasa recta function as countercurrent exchangers. The suboptimal maintenance of the high interstitial osmolality in the inner medulla reduces effective water reabsorption across the

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SICKLE CELL NEPHROPATHY  337 collecting ducts, hence the reduced kidney concentrating ability. A diminished concentrating ability leads to hypo- or isosthenuria where urine osmolality typically does not exceed 450 mosm/Kg. Affected adults present with polyuria, nocturia, and volume depletion and children with enuresis. Blood transfusions of HbA-containing red blood cells can improve concentrating ability in children younger than age 15, but not thereafter due to permanent injury. • Renal tubular acidosis: Patients may develop incomplete distal renal tubular acidosis via reduced H1-ATPase activity due to hypoxemia, selective aldosterone deficiency, distal nephron resistance to aldosterone, reduced ammonium availability, or, in rare cases, hyporenin hypoaldosteronism. 4. What are the common abnormal urinary findings in SCD? • Hematuria: Both microscopic and macroscopic hematuria may be observed. The left kidney is affected four times greater than the right due to the increased venous pressure within the longer left vein that is compressed between the aorta and the superior mesenteric artery. This is known as the “nutcracker phenomenon.” The increased venous pressure leads to increased relative hypoxia in the renal medulla, hence sickling. In 10% of cases, hematuria occurs bilaterally. Hematuria may also indicate the presence of papillary necrosis and, in rare cases, renal medullary carcinoma. The latter is predominantly observed in sickle cell trait rather than SCD. • Proteinuria: The prevalence of albuminuria and proteinuria is 30% within the first three decades of life and increases up to 70% in older patients. Proteinuria may be associated with defects in glomerular permselectivity, tubular injury, and/or specific single nucleotide polymorphisms in the APOL1 genes. • Bacteriuria: Patients with SCD may be at increased risk for urinary tract infections from encapsulated organisms due to autosplenectomy, abnormally dilute and alkaline urine (more favorable for bacterial growth compared with hypertonic and acidic urine), and papillary necrosis. However, significant bacteriuria generally occurs in less than 10% of sickle cell patients, half of whom are asymptomatic. 5. What are the common causes of acute kidney injury (AKI) in patients with SCD? • AKI may occur more frequently among patients with acute chest syndrome than those with a painful crisis. Predisposing factors leading to AKI include volume depletion due to concentrating defects, sickling process, and hemolysis. Patients may present with acute tubular necrosis from volume depletion or sepsis, tubular injury from ischemia-induced rhabdomyolysis, hemosiderin accumulation, or chronic use of nonsteroidal antiinflamatory drugs, kidney vein thrombosis, or, in rare cases, hepatorenal syndrome due to liver failure associated with the sickling process per se or transfusion-associated complications. • Kidney infarction and papillary necrosis: Severe ischemia can lead to kidney infarction and papillary necrosis. Papillary necrosis typically presents as painless gross hematuria, but may be complicated by obstructive uropathy and urinary tract infections. Current data suggest that hematuria and papillary necrosis do not portend greater risk for kidney failure. Acute segmental or total kidney infarction may present with flank or abdominal pain, nausea, vomiting, fevers, and presumably renin-mediated hypertension. 6. How does SCD affect blood pressure? Patients with SCD generally have lower blood pressure compared with their healthy unaffected counterparts due to presumed reduced vascular reactivity, compensatory systemic vasodilatation associated with microvascular disturbances from the sickling of red blood cells and thrombotic complications, elevated levels of prostaglandins and nitric oxide, and possibly kidney sodium and water wasting associated with suboptimal medullary concentrating activity. Blood pressures in the “normal” range defined for the general population may thus represent hypertension in patients with SCD. Whether the lower blood pressure reduces long-term cardiovascular disease risks is not known as the median survival for patients with SCD is only 40 years. 7. How do SCD and sickle cell trait (SCT) differ with respect to common kidney manifestations? Kidney manifestations are generally more common and severe in SCD compared with those seen in sickle cell trait. However, one notable exception is the increased frequency of aggressive renal medullary carcinoma seen among patients with sickle cell trait. Renal medullary carcinoma occurs almost exclusively in patients with sickle cell trait (not SCD). Renal medullary carcinoma typically presents in young patients (20 to 30 years old) as an aggressive metastatic disease at the time of diagnosis. Median survival is 3 months following diagnosis. Affected individuals may present with hematuria, flank pain, and/or abdominal mass.

338  KIDNEY DISEASES IN SPECIAL POPULATIONS 8. What are the underlying pathogenesis of chronic kidney disease (CKD) and risk factors associated with CKD progression in patients with SCN? • Pathogenesis of CKD: Although glomerular filtration is increased in younger patients with SCD, it progressively declines after the age of 30. The development of CKD is thought to be due to early glomerular hypertrophy and hyperfiltration; tubular hyperfunctioning; endothelial injury with repeated sickling and vasoocclusive episodes; hemolysis and iron-induced proinflammatory and profibrotic changes in endothelial cells; and glomerular mesangium and tubulointerstitium. • Risk factors for CKD progression: underlying hypertension, nephrotic range proteinuria, severe anemia, vasoocclusive crisis, acute chest syndrome, stroke, bS-gene haplotype, genetic variants of MYH9 and APOL1, pulmonary hypertension, and infection with parvovirus B19. Of note, although studies have provided statistical evidence implicating APOL1 variation in nondiabetic nephropathies, MYH9 risk variants are still associated with CKD in non–African American populations and in SCD nephropathy. It has been hypothesized that MYH9 and APOL1 may be coregulated and interact under anemic stress to induce nephropathy risk. • Protective factors: coinheritance with a-thalassemia, higher fetal hemoglobin. 9. What tests are needed to diagnose SCN? The diagnosis of SCN is based on clinical manifestations and is primarily a diagnosis of exclusion. Routine evaluation for common causes of proteinuria (particularly when severe) and active urinary sediments, obstructive uropathy, and kidney biopsy should be performed as clinically indicated. • Routine proteinuria evaluation for both infectious (e.g. HIV, hepatitis B and C) and noninfectious serologies associated with glomerular diseases based on age, gender, and risks. • Imaging studies including kidney ultrasound to rule out obstructive uropathy, bladder scanning for postvoid retention or bladder neck obstruction, and possibly a computed tomography scan with or without contrast agent as clinically indicated. • Review of recent or current use of nephrotoxic medications. • Kidney biopsy as clinically indicated by active urinary sediment, significant proteinuria (e.g., urine protein to creatinine ratio .1 g/g) with predominant albuminuria, or unexplained rapid kidney function deterioration. 10. What are typical radiographic findings in SCN? • Increased echodensity and “garland” pattern of calcification in the medullary pyramids. • Calyceal clubbing on contrast computed tomogram urography seen with papillary necrosis (often described with “egg in a cup” or “golf ball and a club”). 11. Why do patients with SCN develop hyperphosphatemia? • Release of intracellular phosphate from acute hemolysis or rhabdomyolysis. • Proximal tubular hyperfunctioning with increased reabsorption of phosphate via sodium phosphate cotransporters in early disease. • Reduced filtration of phosphate in advanced kidney disease. 12. What glomerular disorders are commonly seen in patients with SCN? • Secondary focal segmental glomerulosclerosis (FSGS) and its variants are major glomerular lesions observed in SCD. Both collapsing and noncollapsing patterns of FSGS have been described. The development of FSGS is likely adaptive to the initial glomerular hyperfiltration followed by repeated episodes of ischemia and reperfusion injuries. Glomerular hypertrophy was found to be greater in HbS patients than in idiopathic FSGS. Medullary fibrosis is prominent, suggesting that SCDassociated FSGS mainly affects the juxtamedullary nephrons supplied by the vasa recta. • Membranoproliferative glomerulonephropathy and thrombotic microangiopathy may also occur, but at a lower frequency than FSGS. Membranoproliferative glomerulonephritis (MPGN) with mesangial expansion and basement membrane duplication may be seen either as an isolated finding or in association with FSGS. It has been suggested that this rare form of MPGN is caused by fragmented red blood cells lodged in isolated capillary loops and phagocytosed by mesangial cells, stimulating the expansion of the mesangium and new basement membrane deposition. Although MPGN was initially attributed to immune complex injury, subsequent studies demonstrated that MPGN commonly occurred without immune complex deposits. In essence, the absence of immune complexes and electron-dense deposits differentiates SCD-associated MPGN from other forms of MPGN that are associated with lymphoproliferative or autoimmune disorders, chronic infections, or dysregulation of the complement system. • Although rare with modern screening for blood borne pathogens, HIV nephropathy and hepatitisassociated glomerulonephropathies may be possible.

SICKLE CELL NEPHROPATHY  339 13. How is sickle cell anemia managed? • Goal hemoglobin for patients with sickle cell anemia and the correction rate of the anemia are recommended to be no more than 10 to 10.5 g/dL and less than 1% to 2% per week, respectively. Higher hemoglobin levels and more rapid correction of anemia may precipitate a vasoocclusive crisis. • Anemia correction may be achieved with blood transfusion or the use of erythropoietin stimulating agents (ESA). Blood transfusions provide a higher proportion of HbA compared with stimulating endogenous red blood cells with an ESA. Additionally, the use of ESA may be associated with increased vasoocclusive risk. ESA dosing may need to be higher in individuals receiving hydroxyurea due to the inherent bone marrow suppressive effect of the latter. However, it has also been suggested that the addition of ESA may allow administration of higher doses of hydroxyurea and improved fetal hemoglobin levels. Hydroxyurea is used in the treatment of SCD to increase the synthesis of fetal hemoglobin, which, unlike HbS, does not sickle. 14. How is hematuria managed? • Conservative measures, including bedrest and oral hydration, remain the cornerstone in the management gross hematuria. • In more severe cases, hydration with alkaline fluids may be used to correct volume depletion, acidemia, or both, to reduce sickling and minimize HbS precipitation. Other considerations include the use of loop diuretic to prevent microtubular obstruction, and blood transfusions to reduce HbS and sickling. • Alternative therapeutic options may be considered in refractory cases and include high-dose urea, vasopressin, or epsilon-aminocaproic acid (EACA). High doses of oral or intravenous urea (up to 160 g/day) to achieve blood urea nitrogen greater than 100 mg/dL has been shown to inhibit the polymerization of deoxygenated sickle hemoglobin and are reported to be effective in some refractory cases. Vasopressin is thought to improve clotting via the increase in plasma factor VIII and von Willebrand factor. Vasopressin may be given intravenously over 30 minutes at 0.3 mcg of DDAVP/kg body weight. EACA inhibits fibrinolysis by inhibiting plasmin activity. However, blood clot formation within the collecting system from the use of EACA may lead to tubular obstruction, leading to kidney injury. Note that these alternative therapeutic options lack data and are not without adverse effects. Their use should only be considered for refractory cases. Optimal EACA dosing is not known, but has been suggested to be 2 to 3 g daily (5 to 50 mg/kg every 8 to 12 hours) over several days, not to exceed 12 g daily due to risk of thrombosis. • Angiographic embolization of the involved kidney vessel or balloon tamponade for bleeding from papillary necrosis may be considered in cases of failed conservative medical therapies. • Unilateral nephrectomy is not recommended, because bleeding can recur in the contralateral kidney. 15. How are patients with CKD managed? • Progression of CKD: • Although angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are commonly used to reduce proteinuria in addition to slowing CKD progression and lowering blood pressures in non–sickle cell nephropathies, significant antiproteinuric benefits have not been proven in patients with SCD. Nonetheless, the most updated Cochrane database review (in 2015) revealed a potential for reduction in microalbuminuria and proteinuria with the use of captopril among patients with SCD compared with those without the disease. Confirmatory studies using other ACEi and ARB are lacking. • Hydroxyurea may have a role in reducing proteinuria and hyperfiltration. It has been suggested that the increase in fetal Hb with the use of hydroxyurea reduces sickling, which would lead to improved tissue oxygenation, decreased cardiac output, and reduced kidney blood flow, and therefore decreased hyperfiltration, glomerular injury, and proteinuria. • End-stage kidney disease (ESKD): All forms of kidney replacement may be beneficial to patients with ESKD from sickle cell anemia. • Dialysis: Both hemo and peritoneal dialytic therapies may be offered to patients reaching ESKD if there is no modality-specific contraindication. Both modalities confer their own theoretical advantages. • Hemodialysis: Readily available vascular access may be used for the urgent or emergent need for standard and exchange blood transfusions. • Peritoneal dialysis: The slow rate of ultrafiltration minimizes any acute rise in hematocrit, and therefore leads to a lower risk of vasoocclusive crisis. • Kidney transplantation: • Kidney transplantation may be hindered by high levels of panel reactive antibody due to numerous previous blood transfusions. There is also a higher infection risk due to autosplenectomy. Sickle

340  KIDNEY DISEASES IN SPECIAL POPULATIONS cell transplant patients have higher risks of avascular necrosis with chronic steroid use and precipitating sickle cell crises due to anemia correction following a successful transplant. • Kidney transplant may be also complicated by allograft venous thrombosis, deep vein thrombosis, and vasoocclusive crises. 16. What is the prognosis of patients with SCN • In general, patients with SCD have life expectancy reduced by 25 to 30 years. • Patients with SCD and kidney failure: Median survival among patients with and without kidney failure is 29 and 51 years, respectively. Survival is substantially worse among patients with SCD and ESKD compared with their counterpart without the disease. • Kidney transplant recipients: Although survival of transplant recipients with SCD is inferior to that of matched African American recipients without the disease, survival of SCD patients is comparable with that of matched diabetic patients. One-year graft survival exceeds 60% to 80%.

KEY PO I N T S 1. The clinical hallmarks of sickle cell disease are: • Hemolysis • Vasoocclusion • Ischemia reperfusion The underlying mechanisms of kidney injury or sickle cell nephropathy (SCN) primarily relate to hypoxia and ischemia. 2. SCN encompasses a wide range of kidney abnormalities indicating that all segments of the nephron can be affected. The clinical presentation of SCN includes: • Hyposthenuria • Isothenuria • Hematuria • Proteinuria • Hyperkalemia • Papillary necrosis • Rental tubular acidosis • Nephrogenic diabetes insipidus • Glomerulonephritis • Acute kidney injury • Progressive decline in glomerular filtration rate and eventual development of end-stage kidney disease (ESKD) 3. Goal hemoglobin and correction rate of anemia should be no more than 10 to 10.5 g/dL and less than 1% to 2% per week, respectively. Higher hemoglobin levels and more rapid correction of anemia may precipitate a vasoocclusive crisis. 4. All forms of renal replacement may be beneficial to patients with ESKD from sickle cell anemia. These include hemodialysis, peritoneal dialysis, and kidney transplantation.

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