Nephrology Hypertension

Glomerular and Vascular Diseases: Sickle Cell Disease

Does this patient have sickle cell nephropathy?

  • Renal complications observed in patients with sickle cell disease (SCD) and/or sickle cell trait.

  • May range from mild tubular dysfunction to chronic kidney disease (CKD).

  • Renal abnormalities would include:

    • hematuria

    • renal papillary necrosis

    • tubular dysfunction

    • proteinuria

    • nephrotic syndrome

    • chronic kidney disease

    • renal medullary carcinoma

    • acute kidney injury

    • pyelonephritis

Hematuria and renal papillary necrosis in sickle cell nephropathy

  • Hematuria may be microscopic or macroscopic.

  • Usually painless, benign and self-limited. It may be hemorrhagic, prolonged and difficult to control resulting in severe blood loss.

  • It can occur at any age and is a common finding in patients with sickle cell trait and disease.

  • Gross hematuria is most often reported in patients with sickle cell trait because of higher frequency of this trait compared to that of sickle cell disease.

  • Bleeding is usually unilateral and occurs more commonly in the left kidney as a result of increased venous congestion in a longer left renal vein that is prone to kinking and compression by adjacent vessels.

  • Hematuria may signal presence of renal papillary necrosis, renal stone disease or renal carcinoma.

    • Renal papillary necrosis can be asymptomatic and may be an incidental finding in imaging studies.

    • It may be, but not always, associated with macroscopic hematuria.

    • Sloughing of renal papillae can occasionally cause acute kidney injury from obstruction.

    • Urinary tract infection has been associated with renal papillary necrosis and has been suspected to contribute to its development in SCD.

What are the the causes of hematuria and renal papillary necrosis?

  • Hypoxia, hyperosmolarity, acidity and hemoconcentration in the renal medulla provide a conducive environment for hemoglobin S polymerization and red blood cell (RBC) sickling.

  • Sickled RBCs cause vascular obstruction resulting in hematuria from medullary congestion, destruction of vasa recta, focal infarctions and renal papillary necrosis.

  • Renal medullary carcinoma is another cause of hematuria that should always be ruled out in sickle cell patients with gross hematuria.

    • Described almost exclusively in patients with sickle cell trait.

    • Medullary hypoxia is believed to promote growth of this aggressive tumor

Tubular dysfunction and hemodynamic changes in sickle cell nephropathy

  • Urinary concentrating defect is the most common tubular dysfunction in SCD.

    • Inability to concentrate urine leads to polyuria, nocturnal enuresis and increased risk for dehydration in children.

    • Patients can concentrate their urine only up to 400-450 mOSm/kg during episodes of dehydration.

    • Urine osmolality can be increased by multiple blood transfusions but renal concentrating ability is lost after the age of 15 reflecting chronic damage attributed to RBC sickling.

    • Higher fetal Hb in infants with SCD is associated with better concentrating ability.

  • There is deficiency of urinary acidification in the form of incomplete distal renal tubular acidosis (RTA).

    • RTA is usually manifest in the setting of decreased kidney function and additional acid load.

  • Abnormalities in K excretion have been demonstrated in patients with SCD.

    • Impaired potassium secretion in the setting of normal renin and aldosterone suggests primary tubular defect.

    • Hyperkalemia is not apparent under normal conditions.

    • Patients may maintain normal serum K through increased intracellular shift via beta-adrenergic stimulation during K load.

  • Excessive proximal tubular function

    • Increased re-absorption of Na, phosphate and beta-2 microglobulin

      • Increased proximal reabsoprtion of Na could provide reason for blunted response to loop diuretics.

      • Hyperphosphatemia occurs during active hemolysis because of increased phosphate load and decreased phosphate excretion.

    • Increased secretion of creatinine and uric acid.

      • Creatinine clearance overestimates GFR in sickle cell patients as a result of increased creatinine excretion.

  • Increased glomerular filtration rate and renal plasma flow ("hyperfiltration") have been demonstrated in early stages of SCD.

What are the causes of tubular dysfunction and hemodynamic changes?

  • Impairment in renal medullary blood flow as a result of RBC sickling leads to micro-infarcts and disruption of countercurrent multiplication and exchange system of the inner medulla.

  • Destruction of vasa recta in the renal medulla results in ischemic tubular damage that can explain defects such as RTA, impaired potassium excretion and decreased tubular response to aldosterone.

  • Increased GFR and hyperfiltration can be attributed to increased secretion of vasodilating prostaglandins and nitric oxide (NO) in response to sickling and chronic hypoxia.

Glomerulopathy and chronic kidney disease in sickle cell nephropathy

  • Patients with SCD develop proteinuria and renal impairment that over time would progress to CKD.

    • Renal dysfunction begins early in infancy in the form of glomerular hyperfiltration.

  • Microalbuminuria is an initial marker for renal damage that would progress to overt proteinuria with CKD progression.

    • Microalbuminuria incidence increases with age.

  • Nephrotic syndrome has been reported in patients with sickle cell nephropathy (SCN).

    • Proteinuria gradually develops.

    • Sudden onset of proteinuria requires evaluation for other forms of glomerulopathy.

  • Predictors for end stage renal disease (ESRD)

    • Increasing proteinuria

    • Worsening anemia

    • Development of hypertension.

  • 4-12% incidence of ESRD with median age of 35 years.

  • There is a low survival rate in patients with SCN treated by dialysis; 2-year survival rate is just 60%.

  • Patients with SCN are less likely to receive a kidney transplant. compared to patients with other causes of ESRD.

    • Possible reasons:

      • High sensitization because of frequent blood transfusions

      • Higher infection risk

      • Increased risk of avascular necrosis with steroids

      • Increased risk of vaso-occlusive crises post-transplant

      • Concern about SCN recurrence after transplant

  • There is no difference in 1-year transplant survival compared to other transplanted ESRD patients but there is lower graft survival at 3 years.

  • Survival is greater in transplanted sickle cell patients compared to those who remain on dialysis.

What are the causes of glomerulopathy and chronic kidney disease?

  • Focal segmental glomerulosclerosis (FSGS) is the most common histology in SCN.

    • Other histology - membranoproliferative glomerulonephritis (MPGN), thrombotic microangiopathy (TMA) and glomerulopathy specific to SCD

    • Glomerular hypertrophy

    • Focal tubulointerstitial changes with interstitial fibrosis and tubular atrophy adjacent to sclerotic glomeruli.

    • Negative deposits in immunofloresence (IF) and electron microscopy (EM)

  • Hyperfiltration associated with increased prostaglandins and NO; and changes in glomerular permeability and filtration coefficient would explain the early development of FSGS

  • Recent studies have implicated formation of reactive oxygen species and peroxynitrites accompanying increased NO synthesis in causing direct cellular injury and enhancement of apoptosis. Such evidence supports mechanisms other than glomerulat hyperfiltration alone for glomerular damage as well as tubulointerstitial inflammation and scarring seen in SCN.

What tests to perform?

Signs of hematuria

  • Diagnostic work up should exclude other causes of hematuria. This would include urinary tract infections, renal stone disease, tumors, vascular malformations, vasculitis, glomerulonephritis and coagulation disorders.

    Renal ultrasound is the initial imaging study to screen for stone, tumor and renal papillary necrosis.

    • Increased echogenicity in the medullary pyramids in the absence of hypercalciuria is characteristic radiologic finding in patients with SCD disease.

  • Helical CT is helpful in earlier detection of renal papillary necrosis.

  • Cystoscopy can be performed to help in identifying source and location of the bleeding.

Signs of tubular dysfunction

  • Close monitoring of electrolytes and acid base status, particularly in settings of decreased kidney function, dehydration, hemolysis and sickle cell crisis.

  • 24-hour creatinine clearance should not be used to estimate GFR since increased creatinine secretion overestimates renal function.

  • Alternative methods for GFR estimation include:

    • Cystatin-C measurement

    • Nuclear GFR studies

      • DTPA

      • Iothalamate

    • Inulin clearance (will not be practical or feasible in typical clinical practices).

Signs of glomerulopathy and CKD

  • Yearly evaluation of kidney function and urinary protein excretion (microalbuminuria or proteinuria) should be performed.

  • Consider other causes of proteinuria and evaluation with:

    • Antinuclear antibody (ANA)

    • Serum and urine immunoelectrophoresis

    • Antistreptolycin O (ASO) titers

    • C3 and C4 levels

    • Viral studies

      • Hepatitis B surface antigen and antibodies (c and S), hepatitis C antibody

      • HIV

      • Human parvovirus B19

  • Indications for renal biopsy:

    • Sudden onset of nephrotic syndrome

    • Clinical suspicion of acute glomerulonephritis (hematuria, decreased kidney function, edema and hypertension)

    • Rapid or unexplained deterioration in kidney function.

  • Consider using cystatin C or nuclear studies to assess glomerular filtration rate (GFR) in early stages of CKD (as above).

  • Staging CKD based on creatinine may not be informative until patient has advanced CKD (e.g. eGFR <30 ml/min/1.73m2) due to increased tubular creatinine secretion and over-estimation of eGFR .

How should patients with sickle cell nephropathy be managed?

General management

  • Blood transfusion

  • Early use of hydroxyrurea

  • Erythroyte stimulating agents

  • Adequate hydration

  • Treatment strategies that limit frequency of sickling may decrease renal complications.

  • Bone marrow transplant (BMT) is the only known cure for sickle cell disease, but that procedure is associated with significant complications. No studies have been done to show that BMT affects onset or progression of SCN.

Hematuria

  • Most of the episodes of gross hematuria subside spontaneously and would only require conservative and supportive management.

  • Conservative management

    • Increasing percentage of fetal hemoglobin by using hydoxyurea and erythrocyte stimulating agents

    • Bed rest to avoid dislodging clots

    • Increase fluid intake up to ~4 liters/1.73 m2/day

    • Maintenance of high urinary flow (urine volume of 2-4 liters per day) to prevent formation of clot in the bladder and reduce renal medullary osmolarity.

      • Loop diuretics

      • Hypotonic fluids should be considered because of increased Na absorption and tendency for Na retention in patients with sickle cell disease.

      • Urine alkalinization with 8-12 g/1.73 m2/day of NaHCO3.

  • Blood transfusion may be required in cases of severe blood loss.

    • Increases normal hemoglobin A which reduces medullary sickling.

  • In refractory cases, the following treatments have been done to control bleeding. Treatment recommendations are based on case reports and series.

    • Epsilon aminocaproic acid

      • Inhibits fibrinolysis

      • 1 g/1.73 m2 TID or 100-mg/kg PO q 6 hr until 2 days after cessation of bleeding.

      • May cause urinary tract obstruction because of clot formation.

    • Urea

    • Desmopressin

    • Arteriography with focal embolization

    • Balloon tamponade

    • Partial or total nephrectomy on rare occasion.

Tubular dysfunction

  • There are no specific treatments for tubular dysfunction in patients with SCD.

  • Normally it is not necessary to treat tubular dysfunction since it does not become a problem unless decreased kidney function, hemolysis or dehydration is present.

  • The following preventive measures can be done to prevent significant complications:

    • Increase fluid intake especially in situations when water loss could be excessive (exercise, hot environment, fever etc.).

    • Treat diarrhea and dehydration promptly.

    • Avoid IV fluids with standard Na content since proximal tubular sodium reabsoprtion is increased placing patient at risk of volume retention resulting in fluid overload.

    • Avoid thiazide diuretics that can aggravate hyperuricemia.

    • Avoid nonsteroidal antiinflammatory drugs (NSAIDS)

  • During hemolysis and sickle cell crisis, monitor serum K closely especially if patient has renal impairment and is on medications that can aggravate hyperkalemia (beta-blocker, Angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB) or K-sparing diuretics).

  • Edema may be difficult to treat because of poor response to diuretics.

  • Monitor creatinine over time and increasing trend from baseline. Even mild elevation of serum creatinine may be indicative of decreased kidney function because of enhanced proximal tubular secretion. Serum creatine should be closely monitored since even slight increases may reflect clinically relevant deterioration in kidney function .

Proteinuria, glomerulopathy and CKD

  • Reduction of proteinuria

  • ACE inhibitor

  • ARB

  • Hydroxyurea

  • Combined used of hydroxyurea and ACE inhibitor

  • Long-term studies are lacking but a recent study has shown decreased prevalence of CKD in patients on long-term use of hydroxyurea (17 year follow-up).

  • Monitor for hyperkalemia when using ACEI or ARB.

  • Dose of hydroxyurea should be adjusted based on kidney function.

  • Avoidance of potentially nephrotoxic medications such as NSAIDS , IV contrast and aminoglycosides.

Anemia of CKD should be treated with oral iron, hydroxyurea and erythrocyte stimulating agents

  • Target Hb is approximately 10 g/dl.

  • Hb above 10 g/dl and faster correction of anemia (>1-2% increase in Hct per week) can cause vaso-occlusive crises.

  • Treatment of hypertension.

    • There is low incidence of hypertension in patients with SCD but if present, elevated BP should be treated.

    • Consider treating patients with pre-hypertension, as occurrence of stroke, pulmonary hypertension and other signs of target organ damage are higher even in sickle cell patients with blood pressures that are within the normal range.

    • Drug of choice is ACE inhibitor or ARB.

    • Avoid diuretics

  • Renal replacement (dialysis) and transplant indications should be the same as in others with CKD stage 4 or 5.

  • Transplant should be strongly considred since it provides the best long-term outcomes.

    • Risks, benefits and complications of transplant should be carefully reviewed with each patient.

  • Rising hematocrit can cause sickle cell crises after transplantation. Complications such as renal vein thrombosis, renal infarction and recurrence of sickle cell nephropathy have been described.

    • Treatment with hydroxyurea and exchange transfusions have been used to prevent post-transplant complications.

What happens to patients with sickle cell nephropathy?

  • Development of CKD is the ultimate outcome of sickle cell nephropathy.

  • Renal dysfunction starts early in infancy and is manifested by glomerular hyperfiltration and decreased urinary concentrating ability.

  • Damage to renal microvasculature associated with chronic RBC sickling in the renal medulla leads to tubular defects, focal infarctions and scarring.

  • Glomerular hyperfiltration, excessively increased NO, oxidative stress, and inflammation contribute to glomerular hypertrophy and eventual development of FSGS.

  • Progressive kidney damage clinically manifests with hematuria, increasing proteinuria, hypertension and worsening anemia.

  • Sickle cell disease carries a 3-fold increase in mortality compared to patients with other causes of ESRD.

How to utilize team care?

A multidisciplinary approach in the management of patients with SCD decreases rates of complications and improves clinical outcomes.

Management is by a primary hematologist working in conjunction with multidisciplinary team that would include primary care physician, nephrologist, nurse, social worker, pscychologist, geneticist, dietitian, health educator, and pharmacist.

Patients are usually seen in a multidisciplinary sickle cell clinic that would coordinate comprehensive care with a primary care physician.

A knowlegeable primary care provider or other health professionals, in the setting of limited access to such clinic, would manage patients with periodic referral to SCD specialists for comprehensive evaluation and management of serious complications.

Nurses, nurse practitioners, and physician assistants are key team members in providing longitudinal care focused on health promotion and maintenance in patients with sicke cell disease.

Joint nephrology and hematology SCD clinics provides an ideal environment where "speedy" formulation of management plans involving CKD, dialysis and transplantation can be made.

Are there clinical practice guidelines to inform decision making?

  • There is a paucity of randomized controlled trial data to guide decision making.

  • Management of patients with SCN is mostly guided by level III evidence (opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees).

Other considerations

  • Not all renal disease in patients with SCD can be attributed to sickle cell nephropathy. Clinicians should rule out renal diseases that can cause hematuria, proteinuria and renal dysfunction (lupus nephritis, HIV, hepatitis B or C, etc.). Renal medullary carcinoma should be ruled out in patients with gross hematuria.

  • Acute kidney injury is not uncommon. Most common etiology would be volume depletion in setting of decreased urinary concentrating ability.

  • Sickle cell patients have higher risk of urinary tract infection that can be complicated by urosepsis.

  • Kidney damage may not be easily identifiable at early stages of sickle cell nephropathy using traditional biomarkers such as creatinine and creatinine clearance. Ongoing research on novel biomarkers predicting early renal injury may someday help clinicians diagnose sickle cell nephropathy early and institute appropriate early intervention.

  • Although with little supportive evidence at this time, early treatment of microalbuminuria in children with hydroxyurea and ACE inhibitor may be considered to decrease incidence of CKD.

What is the evidence?

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(Retrospective analysis on 3 cases showing effectiveness of enalapril combined with hydroxyurea in reducing proteinuria. Duration of treatment and follow up is around 3 years.)

Foucan, L, Bourhis, V, Bangou, J, Mérault, L, Etienne-Julan, M, Salmi, RL. "A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia". Am J Med. vol. 104. 1998. pp. 339-342.

(This is a small RCT demonstrating reduction in albumin excretion with captopril compared to placebo in 22 adult sickle cell patients. Duration of follow up is 6 months.)

Gabrovsky, A, Aderinto, A, Aderinto, A, Spevak, M, Vichinsky, E, Resar, LM. "Low dose, oral epsilon aminocaproic acid for renal papillary necrosis and massive hemorrhage in hemoglobin SC disease". Pediatr Blood Cancer. vol. 54. 2010. pp. 148-150.

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Ojo, AO, Govaerts, TC, Schmouder, RL, Leichtman, AB, Leavey, SF, Wolfe, RA, Held, PJ, Port, FA, Agodoa, LY. "Renal transplantation in end-stage sickle cell nephropathy". Transplantation. vol. 67. 1999. pp. 291-295.

(A seminal study supporting recommendations for transplantation in SCD patients with ESRD. Short term graft survival rates are comparable to other patients.

Osegbe, DN. "Haematuria and sickle cell disease. A report of 12 cases and review of the literature". Trop Geogr Med. vol. 42. 1990. pp. 22-27.

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Pham, PT, Pham, PC, Wilkinson, AH, Lew, SQ. "Renal abnormalities in sickle cell disease". Kidney Int. vol. 57. 2000. pp. 1-8.

Pitts, TO, Spero, JA, Bontempo, FA, Greenberg, A. "Acute renal failure due to high-grade obstruction following therapy with epsilon-aminocaproic acid". Am J Kidney Dis. vol. 8. 1986. pp. 441-444.

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(One of the largest and longitudinal observational studies on adult sickle cell disease.)

Powars, DR, Elliott-Mills, DD, Chan, L, Niland, J, Hiti, AL, Opas, LM, Johnson, C. "Chronic renal failure in sickle cell disease: Risk factors, clinical course, and mortality". Ann Intern Med. vol. 115. 1991. pp. 614-620.

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(This is a thorough review of the topic.)

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(Long term follow up study on the use of hydroxyurea demonstrating small number of patients with renal dysfunction. Study provides indirect evidence of the effect of a treatment preventing sickling on limiting renal complications.)

Sundaram, N, Bennett, M, Wilhelm, J, Kim, MO, Atweh, G, Devarajan, P, Malik, P. "Biomarkers for early detection of sickle nephropathy". Am J Hematol. vol. 86. 2011. pp. 559-566.

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(Demonstrates that renal dysfunction in the form of hyperfiltration manifests at an early age in SCD. DTPA was used to measure GFR.)

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