ATYPICAL HUS encountered in neuhpoly ward

Nephrology

1. DISCUSSION ATYPICAL HEMOLYTIC UREMIC SYNDROME

2. Hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia , thrombocytopenia, and acute renal failure. It is the most common cause of acute renal failure in the pediatric population . The clinical course of hemolytic -uremic syndrome can vary from subclinical to life threatening.

3. Studies have revealed distinct subgroups of hemolytic -uremic syndrome and have identified several etiologies for the disease. STEC-HUS is used to describe hemolytic -uremic syndrome mediated by Shiga toxin ( Stx )–producing  Escherichia coli . This is also called classic, typical, Stx , diarrhea -positive, or D  +   hemolytic -uremic syndrome.

4. Pneumococcal-associated HUS is a subtype of atypical hemolytic -uremic syndrome, mediated by neuraminidase in the presence of infection with Streptococcus pneumoniae .   This is also called neuraminidase-associated hemolytic -uremic syndrome.

5. ATYPICAL HEMOLYTIC UREMIC SYNDROME Atypical HUS ( aHUS ) is used to describe hemolytic -uremic syndrome not mediated by Shiga toxin . This is also called diarrhea -negative, non– diarrhea -associated, or D  -   hemolytic -uremic syndrome . This disease is usually mediated by abnormalities of the complement system or other heritable factors .

6. CAUSES Causes of aHUS include the following: Inherited ( eg , mutations in the gene for factor H, a complement regulatory protein) S pneumoniae  (neuraminidase-associated) Portillo virus Coxsackie virus Influenza virus Epstein-Barr virus

7. Drugs ( eg , chemotherapy, cyclosporine) Bone marrow  or  hematopoietic stem cell transplantation Malignancy Idiopathic Systemic lupus erythematosus (SLE) Glomerulonephritis , especially membranoproliferative glomerulonephritis

8. SIGN AND SYMPTOMS Clinical signs and symptoms of aHUS can include abdominal pain,  confusion ,   fatigue, edema (swelling ),   nausea/vomiting  and diarrhea .   aHUS often presents with malaise and fatigue, as well as microangiopathic anemia .  However, severe abdominal pain and bloody diarrhea are unusual .

9. LABORATORY FINDINGS Classic findings in hemolytic -uremic syndrome (HUS) include anemia and thrombocytopenia, with fragmented RBCs ( eg , schistocytes , helmet cells, burr cells ). Testing for ADAMTS13 activity may help distinguish between atypical hemolytic -uremic syndrome ( aHUS ) and thrombotic thrombocytopenic purpura (TTP ).

10. WBC differential  may reveal a left shift ( ie , immature WBCs, including bands, myelocytes , metamyelocytes ) Coombs test results are negative, except with  S pneumoniae  –associated hemolytic -uremic syndrome. Reticulocyte count  is elevated. levels of serum  haptoglobin , which binds hemoglobin , are decreased.

11. Prothrombin time  (PT) and  activated partial thromboplastin time  ( aPTT ) are normal. Fibrin degradation products  are increased. Fibrinogen  levels are increased or within reference range. BUN  and  creatinine  levels are elevated.

12. Various electrolyte and ion derangements may be present because of vomiting, diarrhea , dehydration, and renal failure; these may include hyponatremia , hyperkalemia , hyperphosphatemia , hypocalcemia , and acidosis.  Phosphorus concentration is elevated. Patients with hyperkalemia may require ECG monitoring

13. IMAGING STUDIES Consider performing chest radiography to evaluate for pulmonary congestion or edema , if clinically indicated. Renal ultrasound typically reveals nonspecific findings ( eg , increased echogenicity ) and is of little use. Ultrasonography may be helpful if the diagnosis is uncertain or if one needs evaluation of blood flow in the large renal vessels.

14. Abdominal ultrasonography or CT scanning may help if clinical findings raise suspicion of intestinal obstruction or perforation. Noncontrast CT scanning or MRI of the head is indicated in patients with CNS symptoms or acute mental status changes .   Avoid iodinated contrast or gadolinium in patients with decreased renal function.

15. HISTOLOGICAL FINDINGS Renal biopsy is not usually necessary for diagnosis and may be contraindicated due to thrombocytopenia. Histologic analysis of kidney specimens reveals thrombotic microangiopathy , with swollen glomerular endothelial cells and red cells and platelets in the capillaries .

16. Accumulation of fibrinlike material in the subendothelial space creates a thickened appearance to the capillary walls. Thrombi may be observed in the glomerular capillaries and arterioles. These findings can progress to acute cortical necrosis involving both glomeruli and convoluted tubules.

17. Tissue section of the gut shows microangiopathy , with endothelial cell injury, and thrombosis, with submucosal edema and hemorrhage . Microthrombi may be observed in other organs, including the lungs, liver, heart, adrenal glands, brain, thyroid, pancreas, thymus, lymph nodes, and ovaries.

18. FLUID THERAPY Use potassium-free fluids until renal function has stabilized. Mild hypokalemia is tolerable and much less critical than hyperkalemia . Treat severe or symptomatic hypokalemia with very cautious potassium replacement . Once fluid deficits have been replaced, restrict fluid replacement to insensible losses plus actual output.

19. Monitor hydration status closely and frequently. This includes serial and frequent measurements of body weight, fluid intake and output, heart rate, and blood pressure.  Patients may develop fluid overload or hyperkalemia if not carefully managed.

20. Management of aHUS is very difficult and remains incompletely understood . Clinicians caring for patients with aHUS should search recent literature and confer with physicians with expertise in this disorder . Discontinue the offending agent if a drug-associated cause is identified.

21. Treat bacterial infections ( eg ,  S pneumoniae ) promptly and aggressively. Prior to the development of eculizumab , plasma therapies formed the mainstay of treatment for most forms of aHUS . These therapies use donor plasma products to replace the deficient or abnormal von Willebrand factor ( vWF ) metalloproteinase or complement factors.

22. THERAPEUTIC PLASMA EXCHANGE Therapeutic plasma exchange (TPE), which is also called plasmapheresis , was previously the preferred plasma therapy for aHUS , although its efficacy was never confirmed in controlled clinical trials . TPE removes the patient's plasma and replaces it with fresh frozen plasma (FFP) or a similar product .

23. Albumin should not be used for replacement because it does not contain the vWF metalloproteinase or complement factors, except in the case of pneumococcal-associated hemolytic -uremic syndrome or neuraminidase mediated hemolytic -uremic syndrome .

24. The role of plasma therapy in pneumococcal-associated hemolytic -uremic syndrome is controversial . Donor plasma may contain antibodies to the T antigen, which, in theory, could worsen the hemolytic process. Alternately , plasma exchange may remove neuraminidase and decrease the amount of circulating anti–T antibody. 

25. PLASMA INFUSION Plasma infusion consists of simply infusing donor plasma, such as FFP or cryoprecipitate-reduced plasma . this delivers the absent or abnormal vWF metalloproteinase or complement factors. Plasma infusion does not remove the abnormal factors, as TPE does.

26. The sole advantage of plasma infusion over TPE is its simplicity, because it can be performed in almost any medical facility and does not require specialized equipment, central venous access, or specially trained staff. Studies comparing TPE to plasma infusion have found superior outcomes with TPE.

27. ECULIZUMAB Eculizumab ( Soliris ) is the only treatment approved by the US Food and Drug Administration (FDA) (September, 2011) for adults and children with aHUS . Approval was based on data from adults and children who were resistant or intolerant to, or receiving, long-term plasma exchange/infusion. 

28. Data also included children (aged 2 mo to 17 y) who received eculizumab with or without prior plasma exchange/infusion . Eculizumab demonstrated significant improvement in platelet count from baseline ( P  = .0001). Thrombotic microangiopathy events were reduced, and maintained or improved kidney function was also reported.

29. Eculizumab is a humanized monoclonal antibody against C5, inhibiting progression of the complement cascade and blocking terminal complement activation . Specifically, eculizumab prevents cleavage of C5 into C5a and C5b, the latter being an essential component of the membrane attack complex.

30. Eculizumab is the treatment of choice for patients with aHUS .   Its advantages over plasma exchange include the following: Efficacy proven in controlled clinical trials FDA approval for indication of aHUS Simple intravenous administration No requirement for specialized equipment and specially trained personnel No need for donor plasma products

31. Eculizumab therapy should be started immediately upon diagnosis of aHUS . Treatment is given weekly initially and then tapered to every 2 weeks (except for patients weighing < 10 kg, who receive it every 3 wk ). Eculizumab may be used in place of plasma exchange. If patients are receiving concomitant plasma exchange, supplemental eculizumab dosing should be given after plasma exchange.

32. Inhibition of complement activation increases susceptibility to infection, especially with encapsulated organisms. Patients should receive vaccine for  Neisseria meningitidis  immediately prior to eculizumab treatment if they have not been immunized or if their immunization status is unknown . Patients should receive antibiotic prophylaxis for  N meningitidis  for at least 2 weeks following vaccination to allow time for development of immunity.

33. The optimal duration of eculizumab therapy is unknown and may be life-long. No clear data or guidelines exist to determine criteria for discontinuance . If treatment is discontinued, patients should be monitored carefully for signs of relapse.

34. RENAL TRANSPLANTATION Renal transplantation in patients with aHUS is more difficult because of the high risk of recurrence and allograft loss . The risk of recurrence varies with the complement mutation identified; such testing is essential, as is planning and counselling patients about transplantation options.

35. Note the following mutations and recurrence rates  Factor H mutation: 80-100% recurrence Factor I mutation: 80% recurrence Membrane cofactor protein mutation: 10-20% recurrence No (known) mutation identified: 30% recurrence

36. OTHER MEDICATION Corticosteroids may be of value in aHUS if the patient has an autoimmune-produced inhibitor of ADAMTS13. Clinical testing for inhibitors is available but has a long turnaround time. Limited case reports describe using intravenous immune globulin (IVIG) in patients with aHUS associated with organ transplantation. IVIG does not have a role in hereditary aHUS nor in STEC-HUS.

37. COMPLICATIONS Renal system complications are as follows: Renal insufficiency Renal failure Hypertension

38. CNS complications are as follows: Mental retardation Seizures Focal motor deficit Optic atrophy Cortical blindness Learning disability

39. Endocrine system complications are as follows: Diabetes mellitus Pancreatic exocrine insufficiency

40. GI system complications can include intestinal necrosis. Cardiac system complications can include congestive heart failure.

41. PROGNOSIS Patients with aHUS are at risk for relapses and a higher risk of progression to end-stage renal disease (ESRD). Ongoing treatment with eculizumab reduces this risk.

42. PATIENT EDUCATION Diet concerns are as follows: Low-salt diet to decrease risk of hypertension Diet high in iron and folic acid content to help recover from anemia High-energy diet to help patient regain lost weight Social worker or psychologist consultation can help the family cope with the illness.

43. REFERENCES http://emedicine.medscape.com/article/982025-followup#e7 http://ghr.nlm.nih.gov/condition/atypical-hemolytic-uremic-syndrome https://en.wikipedia.org/wiki/Atypical_hemolytic_uremic_syndrome https://rarediseases.org/rare-diseases/atypical-hemolytic-uremic-syndrome/