Renal Manifestations of Sickle Cell Disease

Background

Hemolysis, vaso-occlusion, and ischemia-reperfusion injury are the clinical hallmarks of sickle cell disease (SCD). The renal manifestations of SCD range from various tubular and glomerular functional abnormalities to gross anatomic alterations of the kidneys. ^[1]

The hypoxic, acidotic, and hyperosmolar environment of the inner medulla are known to promote sickling of red blood cells (RBCs) with resultant impairment in renal medullary blood flow, ischemia, microinfarction, and papillary necrosis. ^[2] Hematuria commonly occurs due to vascular obstruction and RBC extravasation into the collecting system or due to papillary necrosis.

The underlying mechanisms of renal injury or sickle cell nephropathy (SCN) relate mainly to hypoxia and ischemia. The clinical manifestations are determined by the predominant site of tubular involvement. RBC sickling and congestion in the vasa recta leads to ischemia and associated impairment of solute reabsorption by the ascending limb of the loop of Henle and impairs urinary concentrating ability. More distal tubular dysfunction may impair renal acidification and potassium secretion, leading to an incomplete form of distal renal tubular acidosis and hyperkalemia.  

Patients with SCD generally have lower blood pressure compared with their healthy unaffected counterparts, and hypertension is seen in only 2-6% of patients. ^[3] The low incidence of hypertension is attributed to reduced vascular reactivity, compensatory systemic vasodilatation associated with microvascular disturbances from sickling of RBCs and thrombotic complications, elevated levels of prostaglandins and nitric oxide, and possibly renal sodium and water wasting associated with suboptimal medullary concentrating activity.  Blood pressures in the range defined as normal for the general population may thus represent hypertension in patients with SCD.

In patients with SCD, supranormal renal hemodynamics—including increased renal blood flow, renal plasma flow, and glomerular filtration rate—occur as early as infancy, but decrease with age. Such alterations in renal hemodynamics lead to increased renal growth and glomerular enlargement. Grossly, the kidneys appear hypertrophied, with a characteristic smooth, capsular surface. ^[4] Kidney function is usually normal during adolescence but frequently becomes subnormal as chronic kidney disease progresses. The kidneys eventually shrink, and the capsular surface becomes grossly distorted and scarred. ^{[4, 5]}

Risk factors associated with progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) include the following ^[6] :

• Hypertension
• Nephrotic range proteinuria
• Severe anemia
• Vasoocclusive crisis
• Acute chest syndrome
• Stroke
• βS-gene haplotype
• Genetic variants of MYH9 and APOL1 ^[7]
• Pulmonary hypertension
• Parvovirus B19 infection

Protective factors include the following:

• Co-inheritance with α-thalassemia
• Higher fetal hemoglobin level ^[8]

Pathophysiology

The renal medulla contains the vasa recta—that is, the capillaries that are derived from the efferent arterioles of the juxtamedullary glomeruli. These capillaries have a hairpin configuration similar to that of the loops of Henle. The low oxygen tension or relatively hypoxic, hypertonic, and acidotic environment of the inner medulla predisposes RBCs in the vasa recta to sickle, particularly in the settings of severe intravascular volume depletion. The resulting increased blood viscosity contributes to ischemia and eventual infarction that involves the renal microcirculation.  

Medullary ischemia and infarction cause papillary necrosis. Sloughed papillae may obstruct urinary tract outflow, leading to obstructive uropathy. Nevertheless, current data suggest that hematuria and papillary necrosis do not portend greater risk for renal failure.

The primary management goals in sickle cell nephropathy (SCN) are the prevention of complications and the reduction of morbidity, primarily from progression to end-stage renal disease (ESRD). The diagnosis of chronic kidney disease (CKD) in patients with sickle cell disease (SCD) generally occurs between 30 and 40 years of age, with ESRD developing in approximately 11% of patients. SCD accounts for fewer than 1% of all new cases of ESRD, ^[9]   but 5%-18% of patients with SCD develop ESRD. ^[10] Of overall mortality in patients with SCD, 16%-18% is ascribed to kidney disease. ^[6]

In general, CKD in patients with SCD reduces life expectancy by 25 to 30 years. The median survival in patients with and without kidney failure is to age 29 and 51 years, respectively.  Survival is substantially worse in patients with SCD receiving any form of renal replacement therapy compared with their counterparts without SCD.

Patients with hypertension, nephrotic-range proteinuria, hematuria, and severe anemia are more likely to progress to overt kidney failure. ^{[11, 12, 13]} Two genetic modifiers of SCD, namely, the fetal hemoglobin (HbF) levels and α–globin genotype, may affect renal prognosis. Patients with the lowest HbF levels are more likely to develop kidney failure and vaso-occlusive complications. In one study, the β^S Central African Republic (CAR) haplotype was found at a significantly higher frequency in SCD patients who developed kidney failure than in those who did not, presumably due to the lower HbF levels associated with the β^S CAR haplotype. ^[11]

Studies suggest that co-inheritance of α-thalassemia has a protective effect against proteinuria and SCN. ^[14] The coincidence of SCD and α-thalassemia reduces intra-erythrocytic concentration of hemoglobin S and RBC volume, and reduces hemolysis.

In a large cohort study consisting of nearly 9909 Black patients, of whom 739 had sickle cell trait (SCT) and 243 had hemoglobin C trait, SCT was found to be associated with a twofold increased risk of developing kidney failure requiring dialysis compared with individuals without SCT. Furthermore, the risk for ESRD in SCT carriers was similar to that in APOL1 high-risk genotype carriers. In contrast to SCT, hemoglobin C trait was not associated with increased ESRD risk. ^[15]

The incidence of complications related to hemodialysis does not significantly differ from that observed in the general population. However, it is noteworthy that there is an increased risk of infection secondary to encapsulated organisms, such as Streptococcus pneumoniae, in patients who have undergone splenectomy as part of their SCD treatment regimen. ^[16]

A wide spectrum of glomerular lesions has been described in SCD patients. The most frequently identified morphologic lesion associated with SCD is perihilar focal segmental glomerulosclerosis (FSGS).

Glomerular ischemia leads to a compensatory increase in renal blood flow and glomerular filtration rate (GFR); such hyperfiltration, combined with glomerular hypertrophy, probably contributes to glomerulosclerosis. As glomerulosclerosis becomes more extensive, GFR starts to decrease. Nonselective proteinuria may result.

Classic FSGS is characterized by glomerular hypertrophy, glomerular capillary hypertension, podocyte damage, and mesangial destruction. Variable degrees of mesangial cell proliferation with matrix expansion may be seen, along with surrounding tubular atrophy and interstitial fibrosis. ^{[17, 18]}   Medullary fibrosis is prominent, suggesting that SCD-associated FSGS affects mainly the juxtamedullary nephrons supplied by the vasa recta. Both collapsing and expansive patterns of FSGS have been described. ^[19]

Other glomerular lesions associated with SCN include membranoproliferative glomerulonephritis (MPGN) with mesangial expansion and basement membrane duplication, SCD glomerulopathy (glomerular hypertrophy with or without mesangial hypercellularity), and thrombotic microangiopathy associated with retinitis. ^[19]   Unlike idiopathic MPGN, SCD-associated MPGN are devoid of immune complexes and electron-dense deposits. SCD patients with FSGS tend to progress to end-stage renal disease (ESRD) more rapidly than do patients with MPGN.

Asymptomatic hematuria is considered to be one of the most prevalent features of SCN. ^{[10, 20]} An additional pathologic process that may involve the glomeruli is chronic tubulointerstitial nephritis secondary to analgesic-abuse nephropathy, which is common in subjects with this condition. Although rare with modern screening for blood-borne pathogens, HIV nephropathy and hepatitis-associated glomerulonephropathies may be seen.

Red blood cell sickling and congestion in the vasa recta cause medullary ischemia and interfere with the countercurrent exchange mechanism in the inner medulla. The suboptimal maintenance of the high interstitial osmolality in the inner medulla reduces effective water reabsorption across the collecting tubules, and thus reduces kidney concentrating ability.

Isothenuria, or the impaired ability to concentrate urine (urine osmolality < 450 mOsm/kg), is the earliest manifestation of SCN. ^[21] In children, the concentrating defect can present as enuresis or nocturia. The higher-than-usual obligatory urine output or polyuria associated with isothenuria predisposes SCD patients to volume depletion, especially in warm environments. Intravascular volume depletion potentiates the occurrence of sickle cell crisis and should be managed with intravenous isotonic saline infusion.

In young children, maximal urine osmolality can be increased by multiple blood transfusions. However, the concentrating defect is commonly irreversible after the age of 15 years. Vasopressin synthesis and release is normal in SCD; hence, the concentrating defect is not responsive to vasopressin. 

Other processes that occur in the renal medulla include urinary acidification and potassium excretion. Ischemia involving the renal medulla leads to the inability to maintain a hydrogen ion gradient (causing an incomplete form of distal renal tubular acidosis) and an electrochemical gradient (which may lead to hyperkalemia) along the collecting ducts.

The suboptimal acid handling in patients with SCD is usually not clinically apparent under normal conditions, but can be unmasked in the setting of mild kidney insufficiency as hyperchloremic metabolic acidosis. As with the urinary acidification defect, SCD patients do not develop hyperkalemia unless kidney function impairment or stress (such as volume contraction) occurs during a sickle cell crisis. ^[19] Necrosis of the renal papillae can result in microscopic or macroscopic hematuria.

In contrast to distal tubule function, proximal tubular function is supranormal in patients with SCD. This is evidenced by increased reabsorption of sodium, phosphate, and β2 microglobulin and increased secretion of uric acid and creatinine.

Hence, assessment of kidney function in SCD patients based on serum creatinine or creatinine-based equations may overestimate true GFR. Although the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is thought to be the best equation, overestimation of as much as 45 mL/min has been observed. ^[22] Limited studies suggest that cystatin C–based equations may enable clinicians to more accurately assess kidney function in SCD patients. Further studies are needed. 

The supranormal proximal tubular function may not significantly affect the pharmacokinetics of certain medications that rely on tubular secretion for elimination, such as penicillin or cimetidine. ^[23]

Renal medullary carcinoma occurs almost exclusively in patients with sickle cell trait; it is seldom seen in those with sickle cell disease (SCD). Patients are typically males (the male-to-female ratio is 2.4:1) in their second decade of life. ^[24] Affected individuals may present with gross hematuria; abdominal or flank pain; and, less frequently, an abdominal mass and unexplained weight loss.

Metastatic disease is generally present at diagnosis and portends a poor prognosis, with a median survival of 3 months following diagnosis. Of 217 cases reported in the literature, tumor-related mortality was 95% despite various treatment strategies including nephrectomy, chemotherapy, radiation therapy, or a combination thereof. ^[24]

Early diagnosis may improve morbidity and mortality. Consequently, patients with sickle cell trait and hematuria should be evaluated extensively to exclude renal medullary carcinoma. In patients with the disease, computed tomography (CT) scanning or intravenous pyelography (IVP) usually demonstrates a centrally located, infiltrative lesion invading the renal sinus with pelvic caliectasis. For localized non-metastatic tumors, nephrectomy may be effective.    

Hematuria

Painless hematuria (microscopic, macroscopic, or gross) is common in sickle cell disease (SCD). Bleeding is usually mild and typically remits spontaneously within a few days.

The left kidney is affected four times more 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, the so-called nutcracker phenomenon. The increased venous pressure leads to increased relative hypoxia in the renal medulla, hence sickling. Hematuria originates bilaterally in approximately 10% of cases.

Although renal papillary necrosis typically presents as painless gross hematuria, it may be complicated by obstructive uropathy and urinary tract infections. Renal medullary carcinoma is an uncommon cause of gross hematuria.

Proteinuria

In individuals with SCD, the prevalence of albuminuria and proteinuria is 30% within the first 3 decades of life and increases up to 70% in older patients. A  study of 101 Yemeni children with SCD, aged 1–16 years, the overall prevalence of microalbuminuria was 30.7%, with male predominance (80.6%);  the mean age of children with microalbuminuria was 7.5 ± 3.2 years, and 10% of them were under 5 years of age. ^[25]  

Albuminuria or overt proteinuria often precedes the elevation of creatinine. The development of nephrotic syndrome has been linked to progression to kidney failure. ^[2] Proteinuria may be associated with defects in glomerular permselectivity, tubular injury, and/or specific single nucleotide polymorphisms in the MYH9 and APOL1 genes. ^{[7, 19]}

Prior to confirming a diagnosis of SCN, other causes of renal dysfunction should be ruled out, including the following:

• Recent or current use of nephrotoxic medications
• Acute tubular necrosis secondary to hemodynamic perturbations from other causes
• Hematuria secondary to nephrolithiasis, urinary tract tumors, or coagulopathies
• Acute edema or proteinuria secondary to other glomerular disease processes (active urine sediments suggest pathology other than SCN), membranoproliferative glomerulonephritis (MPGN) associated with hepatitis C virus infection, membranous glomerulopathy associated with chronic hepatitis B infection, or renal vein thrombosis
• Papillary necrosis from disorders such as diabetic nephropathy, analgesic-abuse nephropathy, or chronic tubulointerstitial nephritis
• Postrenal failure secondary to obstruction from papillary necrosis or nephrolithiasis

Laboratory studies

The diagnosis of SCN is based on the clinical signs and symptoms of the condition, as well as on laboratory test results. In patients with possible SCN, the following tests are recommended:

• Urinalysis with microscopic analysis and quantitation of degree of proteinuria, with either a spot urine protein-to-urine creatinine ratio or a 24-hour urine protein determination
• Estimation of kidney function using the Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, or a 24-hour urine creatinine clearance (however, it should be noted that estimated glomerular filtration rate [eGFR] based on serum creatinine may greatly overestimate true GFR)
• Fractional excretion of sodium and fractional excretion of urea tests – These are used to exclude prerenal causes of kidney failure.
• Hepatitis C virus and human immunodeficiency virus (HIV) tests – These are administered because of the increased risk of transfusion-related infectious diseases in patients with SCN, who may require multiple blood transfusions

Annual screening for albuminuria is recommended for patients with SCD, beginning at age 10 years, although earlier initiation is potentially beneficial. Albuminuria should be confirmed by either a first morning urine sample or 2 consecutive untimed urine samples. ^[26]  

Several biomarkers have emerged as potential early indicators of kidney dysfunction in children with SCD, including nephrin, kidney injury molecule 1 (KIM-1), vascular growth factors, chemokines, and renin-angiotensin system molecules (see Novel Biomarkers of Renal Function). ^[27] Percutaneous kidney biopsy is rarely required in the diagnosis of SCN and primarily serves to rule out other glomerular disease processes.

Imaging studies

Ultrasonography of the kidneys can be used to exclude other causes of postrenal or obstructive uropathy (eg, nephrolithiasis), while computed tomography (CT) scanning can be used to exclude renal medullary carcinoma in patients presenting with hematuria. The risk of radiocontrast nephropathy in patients with SCN is similar to that of the general population. ^[28]

Hematuria

Hematuria in SCD is typically self-limited and treatment consists of bed rest and maintenance of high urine flow rate. However, in cases of massive hematuria, the following measures may also be considered ^[29] :

• Urinary alkalinization to minimize hemoglobin precipitation
• Loop diuretic administration to prevent microtubular obstruction
• Blood transfusions to reduce HbS and sickling

Refractory cases of hematuria may require high doses of oral urea to achieve blood urea nitrogen levels greater than 100 mg/dL (for its presumed inhibitory effect on gelation of deoxygenated sickle hemoglobin), or treatment with vasopressin or epsilon-aminocaproic acid (EACA) to promote clotting. ^[30] EACA is generally given in a dosage of 2 to 3 g daily over several days, not to exceed 12 g daily due to risk of thrombosis. It is also noteworthy that blood clot formation within the collecting system from the use of EACA may lead to tubular obstruction. Angiographic embolization of the involved renal vessel or balloon tamponade for bleeding from papillary necrosis may be considered in cases of failed conservative medical therapies.

Proteinuria

The most recent Cochrane database review, in 2015, revealed a potential for reduction in microalbuminuria and proteinuria with the use of captopril in patients with SCD compared with those without the disease. ^[31] While evidence-based recommendations remain lacking, a trial of an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB) seems justifiable due to the well-established renoprotective effect of these drugs. ^[26] Improving nocturia has been reported to be an additional beneficial effect of ACEIs, presumably as a result of reduction in GFR. Hypotension and hyperkalemia, particularly in the presence of impaired kidney function, may limit the use of ACEI and ARB therapy.

American Society of Hematology (ASH) guidelines on treatment of albuminuria in patients with SCD advise that the initiation of ACEis and ARBs in these patients requires adequate follow-up and monitoring of adverse effects (eg, hyperkalemia, cough, hypotension). ^[26] In addition, the ASH guidelines endorse the following Kidney Disease Improving Global Outcomes recommendations for this setting:

• Start medication at a lower dose in patients with a GFR of < 45 mL/min/1.73 m ²
• Assess GFR and measure serum potassium within 1 week after starting the medication or escalating the dose
• Temporarily suspend the medication during interval illness, planned intravenous radiocontrast administration, or bowel preparation for colonoscopy or prior to major surgery.

The theoretical benefit of nonsteroidal anti-inflammatory drugs (NSAIDs) in any patient with glomerular hyperfiltration has not consistently been shown. NSAID use in patients with SCD should be avoided due to the potential for adverse hemodynamic-related kidney function deterioration, precipitation of papillary necrosis, and the development of NSAID-associated interstitial nephritis and glomerulonephropathies.

The use of hydroxyurea has been suggested to reduce proteinuria and hyperfiltration. One prospective study consisting of 26 patients with SCD suggested that hydroxycarbamide (hydroxyurea) has a renoprotective effect by decreasing proteinuria. However, no effect on microalbuminuria was found. ^[32] A cross-sectional study of 149 adult patients following up in a comprehensive sickle cell clinic showed that those using hydroxyurea were less than one-third as likely to exhibit albuminuria (defined as either urinary albumin-to-creatinine ratios ≥30 mg/g or ≥1+ proteinuria on two separate dipstick). ^[33]

A multicenter trial in infants (mean age 13.8 months) demonstrated that treatment with hydroxyurea for 24 months did not influence the GFR. However, it was associated with better urine-concentrating ability and less renal enlargement, suggesting a possible renoprotective effect. ^[34]

Since oxidant stress is also believed to be involved in progression of kidney disease, some authors have suggested giving supplemental vitamin E, because of its antioxidant properties. Anecdotal evidence supports its use. Dietary protein restriction is not recommended, because of the underlying growth failure and decreased energy state in most patients with SCD. ^[35]

Anemia in patients with SCD is managed differently from anemia due to chronic kidney disease. The recommended hemoglobin (Hb) target should be an Hb concentration of no greater than 10-10.5 g/dL (or a hematocrit of no greater than 30%). In addition, a rise in the hematocrit of greater than 1-2% per week should be avoided. ^{[20, 36]} Higher Hb levels and more rapid correction of anemia may precipitate a vasoocclusive crisis. 

In children and adults with SCD and worsening anemia associated with chronic kidney disease, American Society of Hematology guidelines suggest using combination therapy with hydroxyurea and erythrocyte-stimulating agents (ESAs), such as erythropoietin or darbepoetin alfa. This is a conditional recommendation, as there is very low certainty in the evidence about effects. For patients already on steady-state hydroxyurea, use of ESAs is appropriate in patients who experience a simultaneous drop in hemoglobin and absolute reticulocyte count. ^[26]

Blood transfusions may also be used to achieve the appropriate hemoglobin concentration. While blood transfusions provide a higher proportion of HbA compared with patients’ own blood, ESAs likely do not provide a similar benefit and may be associated with increased vaso-occlusive risk. ESA dosing may be higher in individuals receiving hydroxyurea due to its inherent bone marrow suppressive effect. However, it has also been suggested that the addition of an ESA may allow administration of higher doses of hydroxyurea and improved fetal hemoglobin levels. ^[37]

For patients presenting with severe anemia and/or hemolytic crisis, appropriate hematology consultation is recommended.

Patients with sickle cell disease (SCD) comprised only 410 of the 442,017 patients with end-stage renal disease (ESRD) who started hemodialysis from June 1, 2005 to May 31, 2009 in the US Centers for Medicare and Medicaid systems. ^[38] The relatively small size of the SCD-ESRD population has limited the development of optimal management strategies. Hemodialysis is reportedly the leading form of renal replacement therapy for SCD-ESRD patients, ^[39] but therapeutic options for these patients also include peritoneal dialysis and kidney transplantation.

Both hemodialysis and peritoneal dialysis may confer their own theoretical advantages. Hemodialysis may be used for urgent or emergent need for standard and exchange blood transfusions. In contrast, peritoneal dialysis and its inherent slow rate of ultrafiltration may minimize any acute rise in hematocrit and thus lower the risk of vaso-occlusive crisis. ^[40]

Of interest, only 6.8% of SCD patients began dialysis with a functioning arteriovenous fistula, despite similar rates of predialysis nephrology care. Mortality in SCD patients is approximately 26% during the first year of therapy for ESRD, which is nearly threefold higher than in ESRD patients without SCD. However, SCD patients who received pre-dialysis nephrology care had a lower death rate than those who did not receive such care. ^[38]

Kidney transplantation may offer survival advantage over remaining on dialysis for appropriately selected patients with ESRD due to SCN. ^[26] As in the general population, allograft survival for patients with SCN is greater in those with a living donor than in those with a deceased donor. In the current era of transplantation, desensitization protocols may allow highly sensitized patients (related to multiple blood transfusions) to undergo a successful kidney transplant; for discussion of this topic, see Kidney Transplantation.

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%. ^[41] Complications specific to the SCD population include higher infection risk due to autosplenectomy and precipitation of sickle cell crises with anemia correction following a successful transplant. Kidney transplant may be also complicated by allograft venous thrombosis, deep vein thrombosis, and vaso-occlusive crises. ^{[42, 43, 44]} Recurrent disease in the allograft 3.5 years post-transplant has been reported. ^{[42, 45]} However, SCN is not a contraindication for transplantation.

Suggested maneuvers to decrease the incidence of post-transplant complications in these patients include the following ^{[43, 44]} :

• Preoperative blood transfusions to decrease hemoglobin S levels
• Preoperative oxygen supplementation with 40% oxygen
• Pretransplantation warming of the kidney allograft using 37º C saline
• Intraoperative and postoperative dopamine infusion at 4 μg/kg/min

Fluid intake and output should be closely monitored. Compared with the general population, these patients have an increased risk of intravascular volume depletion, especially secondary to volume losses from diarrhea and vomiting, thus increasing the risk of an acute sickle cell crisis. Intravenous fluid and partial exchange transfusions may be considered in patients who develop sickle crises. However, management of the kidney transplant candidate and recipient with SCD should be individualized.