Renal Manifestations of Sickle Cell Disease

Updated: Jan 18, 2017
  • Author: Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Overview

Background

The renal manifestations of sickle cell disease (SCD) range from various functional abnormalities to gross anatomic alterations of the kidneys. The inner medulla’s relatively hypoxic, hypertonic, and acidotic environment is known to predispose to sickling of red blood cells (RBCs), which significantly decreases renal medullary blood flow through vaso-occlusion.

At the same time, hematuria, which is commonly seen in patients with sickle cell nephropathy, increases venous pressure, which further worsens ischemia of the renal medulla and predisposes the patient to further RBC sickling.

Depending on the predominant site of tubule involvement, clinical manifestations vary. Proximal tubule dysfunction generally impairs urinary concentration, while more distal tubule dysfunction may impair potassium excretion, leading to hyperkalemia (as seen in various forms of renal tubular acidosis).

Of note, hypertension is seen in only 2-6% of patients with SCD. [1] This has been attributed to several factors, including sodium and water wasting secondary to pathology involving the renal medulla, compensatory systemic vasodilatation due to significant reductions in the microcirculation, and increased levels of prostaglandins and nitric oxide.

Young people with SCD usually have normal renal function. Grossly, the kidneys tend to be hypertrophied, with a characteristic smooth, capsular surface. [2] As people with SCD grow older, the kidneys progress to end-stage renal disease (ESRD). The kidneys eventually shrink, and the capsular surface becomes grossly distorted and scarred. [2, 3]

Several factors have been associated with progression to chronic renal failure, including the following [4] :

  • Worsening anemia
  • Hypertension
  • Degree of proteinuria
  • Microscopic hematuria

Renal dysfunction is relatively more common and more severe in patients with HbSS and HbSβ0 thalassemia genotypes than in patients with HbSC or HbSβ+ thalassemia. [5, 6]

Pathophysiology

The renal medulla contains the vasa rectae, that is, the renal tubules and blood vessels located therein. Low oxygen tension, low pH, and high osmolality characterize the normal renal medullar environment. All of these conditions predispose to RBC sickling, especially with 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 renal failure. [7]

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Prognosis

The primary management goals in sickle cell nephropathy are the prevention of complications and the reduction of morbidity, primarily from progression to end-stage renal disease (ESRD). Sickle cell disease (SCD) accounts for fewer than 1% of all new cases of ESRD, [8] but 5-18% of patients with SCD develop ESRD. [9] Of overall mortality in patients with SCD, 16–18% is ascribed to kidney disease. [6]

The median age of renal failure in patients with SCD is 23 years, and the median survival time in patients with SCD after the diagnosis of ESRD is about 4 years. Thus, in patients who progress to ESRD, the median age of death after diagnosis is 27 years, despite dialysis treatment. [10]

Patients with hypertension, nephrotic-range proteinuria, hematuria, severe anemia, and a Central African Republic heritage are more likely to progress to overt renal failure. [4, 11, 12] However, the incidence of complications related to hemodialysis does not significantly differ from that observed in the general population.

Rrenal disease appears to behave differently in SCD patients with hemoglobin SS (HbSS) than in those with HbSC. Drawz et al reported that albuminuria or proteinuria was more prevalent in HbSS more than in HbSC, that proteinuria was associated with mortality in patients with HbSS, and that a lower than expected estimated glomerular filtration rate (eGFR) in elderly individuals was more prominent in those with HbSS. [13]

Note 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. [14]

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Glomerular Abnormalities

Glomerular enlargement, perihilar focal segmental glomerulosclerosis (FSGS), and hemosiderosis are commonly seen in patients with sickle cell nephropathy. [15, 16]

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

Lesions resembling those found in membranoproliferative glomerulonephritis (MPGN), with mesangial expansion and basement membrane duplication, [19] have been described, either as an isolated finding or in association with focal sclerosis. [20] However, unlike in idiopathic MPGN, these lesions are devoid of immune complexes and electron-dense deposits. Sickle cell disease (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 sickle cell nephropathy. [9, 21] Additional pathologic processes that may involve the glomeruli include chronic tubulointerstitial nephritis secondary to analgesic-abuse nephropathy, which is common in persons with this condition.

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Distal Tubule Abnormalities

Red blood cell (RBC) sickling in the vasa rectae is believed to interfere with the countercurrent exchange mechanism in the inner medulla. The resulting impairment of free water resorption manifests clinically as nocturia or polyuria.

The impaired ability to concentrate urine, termed isosthenuria, is the earliest manifestation of sickle cell nephropathy. [22] The ability to dilute urine remains intact and antidiuretic hormone (ADH) secretion remains normal in sickle cell nephropathy patients with isosthenuria, [9] because the vaso-occlusive process spares the superficial loops of the loop of Henle (which are supplied by peritubular capillaries rather than by the vasa rectae).

In patients aged 10-15 years, urinary concentrating capacity may be restored with multiple transfusions of normal RBCs. Conversely, in patients older than 15 years, the concentration defect is often irreversible. [10]

An impaired ability to concentrate urine readily leads to volume depletion, especially in warm environments. Intravascular volume depletion potentiates the occurrence of sickle cell crisis and is treated with intravenous fluid hydration, using isotonic saline.

Other processes that occur in the renal medulla include urinary acidification and the excretion of potassium. 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 (leading to hyperkalemia) along the collecting ducts. Gross hematuria can be secondary to papillary necrosis.

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Proximal Tubule Abnormalities

Increased resorption of phosphate and beta2 microglobulin, as well as increased secretion of ureic acid and creatinine, reflects excessive proximal tubule functioning. This excessive functioning accounts for the overestimation of the true glomerular filtration rate as measured with creatinine clearance in patients with sickle cell nephropathy. However, excessive proximal tubule functioning may not significantly affect the pharmacokinetics of certain medications that rely on tubular secretion for elimination (eg, penicillin, cimetidine). [7]

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Renal Medullary Carcinoma

Renal medullary carcinoma is usually seen in patients with sickle cell trait but is much less common in patients with sickle cell disease (SCD). [23] Affected patients are usually black males in the second decade of life who have macroscopic or gross hematuria and flank pain. Infrequently, these patients present with unexplained weight loss and an abdominal mass.

Renal medullary carcinoma is an aggressive malignancy, and immunotherapy and chemotherapy cannot modify its course. At the time of presentation, metastatic disease is usually found.

Therefore, patients with SCD or the sickle cell trait who present with hematuria should be evaluated extensively to exclude renal medullary carcinoma. When this form of cancer occurs, computed tomography (CT) scanning or intravenous pyelography (IVP) usually demonstrates a centrally located, infiltrative lesion invading the renal sinus with pelvic caliectasis.

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Hematuria and Proteinuria

Hematuria

Painless hematuria (microscopic, macroscopic, or gross) is a common symptom of sickle cell disease (SCD). Typically, the hematuria is mild and self-limited. As a rule, the hematuria originates from the left kidney; this has been attributed to the greater length of the left renal vein and compression of the left renal vein between the aorta and superior mesenteric artery (ie, the nutcracker phenomenon). [24] Hematuria can also be secondary to papillary necrosis. Renal medullary carcinoma is an uncommon cause of gross hematuria.

Hematuria increases venous pressure, which further worsens ischemia of the renal medulla, thus predisposing the patient to further red blood cell (RBC) sickling.

Proteinuria

Proteinuria in patients with SCD can progress to nephrotic syndrome, which has been linked to progression to renal failure. [25] Proteinuria has been attributed to glomerular capillary hypertension.

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Differential Diagnosis

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

  • 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, membranoproliferative glomerulonephritis (MPGN) from hepatitis C virus (HCV) 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
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Laboratory and Imaging Studies

Laboratory studies

The diagnosis of sickle cell nephropathy is based on the clinical signs and symptoms of the condition, as well as on laboratory test results. In patients with possible sickle cell nephropathy, 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 renal function with the Modification of Diet in Renal Disease or Cockcroft-Gault formula or a 24-hour urine creatinine clearance
  • Fractional excretion of sodium and fractional excretion of urea tests - These are used to exclude prerenal causes of renal failure.
  • Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) tests - These are administered because of the increased risk of transfusion-related infectious diseases in patients with sickle cell nephropathy, who may require multiple blood transfusions

Percutaneous renal biopsy is rarely required in the diagnosis of sickle cell nephropathy 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 sickle cell nephropathy is similar to that of the general population. [26]

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Treatment of Hematuria and Proteinuria

Hematuria

In sickle cell disease (SCD), treatment of hematuria consists of bed rest and maintenance of high urine flow rate. In cases of massive hematuria, one should consider iron replacement and/or blood transfusions. In the majority of cases, however, hematuria is self-limited.

Proteinuria

Although no specific treatment slows or prevents the progression of sickle cell nephropathy to end-stage renal disease (ESRD), evidence suggests that the reduction of proteinuria may be beneficial. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has been shown to reduce proteinuria and to be particularly renoprotective. This effect is perhaps explained by the ability of these compounds to lower intraglomerular pressure. [16, 27, 28] ACE inhibitors are recommended even in the absence of hypertension. [16, 27]

Since oxidant stress is also believed to be involved in renal disease progression, some authors have suggested giving supplemental vitamin E, because of its antioxidant properties. Some anecdotal evidence supports this practice.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to prevent glomerular hyperfiltration, these agents are not recommended because of their concomitant adverse effects on renal function. Dietary protein restriction is not recommended because of the underlying growth failure and decreased energy state in most patients with SCD. [29]

One prospective study in 26 patients with SCD found that treatment with hydroxyurea may have some renoprotective function by decreasing proteinuria, but no effect on microalbuminuria was shown. [30] 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. [31]

A multicenter trial in infants (mean age 13.8 months) demonstrated that treatment with hydroxyurea for 24 months did not influence the glomerular filtration rate. However, it was associated with better urine-concentrating ability and less renal enlargement, again supporting a renoprotective effect. [32]

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Treatment of Anemia

Anemia in patients with sickle cell disease (SCD) is managed differently from anemia due to chronic kidney disease. The recommended goal is for a hemoglobin concentration of no greater than 10g/dL or a hematocrit of no greater than 30%, because red blood cell (RBC) sickling (vaso-occlusive crisis) is more likely to occur with higher hemoglobin levels. A rise in the hematocrit of greater than 1-2% per week should be avoided. [21, 33]

Blood transfusions or erythrocyte-stimulating agents, such as erythropoietin or darbepoetin alfa, may be used to achieve the appropriate hemoglobin concentration. Interestingly, one study showed that addition of erythropoietin allows usage of higher doses of hydroxyurea (see above for discussion regarding beneficial effects of hydroxyurea), leading to higher fetal hemoglobin levels. [34]

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

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Treatment of End-Stage Renal Disease

Of the 400,000 patients with end-stage renal disease (ESRD) comprising the 2009 US Centers for Medicare and Medicaid systems, only 410 had sickle cell disease (SCD). The relatively small size of the SCD-ESRD population has limited the development of optimal management strategies. Nevertheless, hemodialysis is the leading form of renal replacement therapy for SCD-ESRD patients, but peritoneal dialysis is also an acceptable modality. [35] Interestingly, 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. Among SCD patients, however, those who received pre-dialysis nephrology care had a lower death rate than those who did not receive such care. [36]

Improved survival has been described in SCD patients with ESRD who have received kidney transplants, compared with SCD patients on chronic maintenance renal replacement therapy. As in the general population, allograft survival for patients with sickle cell nephropathy is greater in individuals with living, related donors than in patients with cadaveric donors.

For patients with sickle cell nephropathy, the waiting list for renal transplantation may be slightly longer than it is for the general population. This has been attributed to higher levels of panel-reactive antibodies stemming from multiple blood transfusions. In addition, the inherent immunocompromised status of patients with sickle cell nephropathy due to autosplenectomy predisposes them to higher rates of infection.

Because of underlying risk of vaso-occlusive crises, transplant recipients with SCD are at increased risk for renal allograft venous thrombosis and deep venous thrombosis. [37, 38, 39] Recurrent disease in the kidney transplant has been shown to occur within 3.5 years post-transplant. [40] However, sickle cell nephropathy is not a contraindication for transplantation.

Novel interventions are being investigated to try to decrease the incidence of post-transplant complications in these patients, including the following [38, 39] :

Preoperative blood transfusions to decrease levels of hemoglobin S

Preoperative supplementation with 40% oxygen

Pretransplantation warming of the renal allograft, using 37 º saline

Fluid intake and output should be closely monitored in kidney transplant recipients. 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.

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