Pediatrics

Henoch-Schonlein Purpura Nephritis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Henoch-Schönlein purpura nephritis? What are the typical findings for this disease?

Henoch-Schönlein purpura (HSP) is a relatively common problem in pediatrics. The exact incidence is unknown because of its variable clinical presentation and because children with the problem are evaluated by a wide range of pediatric care providers. Renal involvement occurs in more than 75% of cases and, in the vast majority, this manifests as hematuria alone or hematuria and low-grade proteinuria. In 10%-20% of cases, there may be significant proteinuria, nephrotic syndrome, or acute glomerulonephritis.

The long-term prognosis for children with HSP nephritis is determined by the severity of renal inflammation and the percentage of glomeruli with crescents in a kidney biopsy specimen. There is no proven therapy for HSP nephritis. Moderate cases may be treated with a prolonged course of oral corticosteroids and mycophenolate mofetil. More severe cases may be treated with intravenous pulse methylprednisolone and other immunosuppressive medication.

All patients with HSP nephritis require extended follow-up. Patients with HSP nephritis account for less than 5% of the pediatric population in whom end-stage kidney disease develops. These patients are candidates for kidney transplantation.

The diagnosis of HSP is based on the presence of any combination of the following four features: (1) purpuric rash on the buttocks and extensor surfaces of the hands and feet, (2) arthritis, (3) abdominal pain, and (4) renal involvement. The four features can occur in any sequence, which can complicate recognition of the disease. The cutaneous manifestations are the most characteristic finding that facilitates the diagnosis. The renal involvement of HSP is marked by hematura, proteinuria and, in severe cases, azotemia and hypertension. There is no routine laboratory test to identify HSP and it remains a clinical diagnosis. To confirm that a child has HSP nephritis requires measurement of blood pressure, microscopic examination of the urine, determination of urinary protein excretion, serum creatinine concentration, and calculation of glomerular filtration rate (GFR). A kidney biopsy specimen showing mesangial IgA deposition in a child with suggestive complaints and findings confirms the diagnosis.

The most common symptom is a purpuric rash that can begin as urticaria. The lesions are often seen first on the buttocks and then generally spread to the extensor surfaces of the arms, legs, and lateral malleoli. The lesions can regress and then recur over the first 2-4 weeks after the diagnosis is made. Patients with recurrent skin lesions may be at greater risk for HSP nephritis.

Arthritis and colicky abdominal pain are the next most common symptoms. The arthritis is not deforming. The abdominal pain usually subsides but can be caused by intussusception. The latter problem may require surgical intervention.

What other disease/condition shares some of these symptoms?

Patients with HSP nephritis usually have prominent purpura and can be confused with children with hematologic disorders like idiopathic thrombocytopenia purpura or acute lymphoblastic leukemia. The rash is palpable and painless. However, it can be confused with erythema multiforme or erythema nodosum.

The occurrence of arthritis can suggest the occurrence of rheumatologic disorders like juvenile inflammatory arthritis.

The abdominal pain is nonspecific and can suggest an anatomic abnormality, infectious enteritis, or inflammatory bowel disease.

The renal disease can mimic poststreptococcal acute glomerlonephritis or systemic lupus erythematosus (SLE) nephritis. However, the C3 level is normal in HSP nephritis.

HSP nephritis and pulmonary findings may be confused with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

The combination of more than one clinical feature helps confirm the diagnosis of HSP nephritis.

What caused this disease to develop at this time?

Thecause of HSP remains unknown. It has been linked to exposure to variousmedications or antecedent infections such as strepococcal pharyngitis.HSP nephritis and IgA nephropathy share an important feature, namely,mesangial deposition of IgA in the mesangial region of the glomerulus.There may be some relationship betwen the two entities and there arecases of identical twins in which HSP nephritis developed in one and IgAnephropathy simultaneously developed in the other.

Somenephrologists consider IgA nephropathy to be HSP nephritis without therash. However, HSP nephritis is less likely to recur, is more likely to affect younger children, and has prominent extrarenal features.

Causes of HSP:

Infections: parvovirus 19, hepatitis B, hepatitis C, streptococci

Medications:antibiotics, angiotensin-converting enzyme inhibitors,angiotensin-receptor blockers, nonsteroidal antiinflammatory drugs

Vaccination

Insect bites

Food allergies

No relationship to trauma

Physical examination: purpuric lesions, arthritis, abdominal tenderness

Epidemiology and genetics

AlthoughHSP is the most common vasculitis in childhood, the exact incidence isunknown.The incidence is higher in the first compared with the seconddecade of life. It occurs more commonly in boys than in girls, 2:1. Itis uncommon in African Americans.

There is nospecific genetic cause for HSP nephritis. However, patients withHSP nephritis have undergalactosylated IgA1 in the circulation, andthere are genetic abnormalities in galactosylating enzymes in childrenwith HSP nephritis and their first-order relatives.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Complete blood count, prothrombin time, partial thromboplastin time to exclude hematologic disease. The platelet count and coagulation studies should be normal.

Comprehensive metabolic profile to determine serum creatinine and albumin concentrations.

Calculated GFR.

Microscopic examination of the urine.

Urinary protein-creatinine ratio in a first-morning sample.

C3 level.

Antinuclear antibody test, double-stranded DNA, ANCA titer, cryoglobulin determination, rheumatoid factor determination in uncertain cases.

A skin biopsy showing leukocytoclastic vascultis is diagnostic.

Similarly, a kidney biopsy showing mesangial deposition of IgA is diagnostic. In addition, there can be focal or diffuse mesangial cell hypercellularity and a variable degree of crescent formation related to the severity of the disease. On electron microscopy there are deposits in the mesangial regions.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not required for assessment of HSP nephritis because the site of injury is the glomerulus.

An abdominal ultrasonogram with follow-up computed tomographic scan may be necessary to rule out an intussusception in a child with HSP nephritis and severe abdominal pain.

Chest radiography may be needed to assess for pulmonary edema in cases of severe HSP nephritis.

Confirming the diagnosis

Patients with HSP who do not have evidence of nephritis should have a urinalysis done weekly for 1 month and then monthly for 5 more months to monitor for the development of renal involvement. It is unlikely that a patient with HSP will manifest nephritis more than 6 months after the initial episode. Children with recurrent rash should be monitored more closely because they may be at higher risk of the development of significant renal disease.

Patients with HSP nephritis at the time of diagnosis can be put into three categories:

Class I, mild; hematuria and/or urine protein-creatinine ratio less than 0.5. These children should be followed monthly until the urinalysis resolves.

Class II, moderate: urine protein-creatinine ratio greater than 0.5. Follow monthly and if abnormality persists for more than 3-6 months, consider a kidney biopsy to guide therapy.

Class III, severe: nephrotic syndrome and/or acute glomerulonephritis. These children need to be hospitalized for close observation and clinical monitoring. They usually undergo a kidney biopsy to guide therapy.

If you are able to confirm that the patient has Henoch-Schönlein purpura nephritis, what treatment should be initiated?

Short-term immediate management should focus on analgesia and blood pressure control.

HSP without signs of nephritis: There is conflicting evidence whether a short tapering course of prednisone given for 5-7 days can prevent the occurrence of nephritis. The side effects are minimal but the efficacy is uncertain. The use of this treatment is at the discretion of the attending physician.

HSP with mild nephritis: These patients may benefit from oral corticosteroids to alleviate abdominal pain and arthritis. There is no need for any specfic therapy directed at the kidneys.

HSP with more severe nephritis: These patients need to be hospitalized for monitoring and treatment. Although there are no proven therapies for HSP nephritis based on findings of randomized clinical trials, many patients with clinically evident HSP nephritis will be treated with various immunosuppressive medications. The initial therapy is usually intravenous administration of three to five pulses of methylprednisolone, 30 mg/kg to a maximum of 1 g. The pulse steroids can be given daily or every other day depending on the blood pressure and general condition. Additional therapy may include cyclophosphamide or mycophenolate mofetil.

Plasmapheresis is not indicated for the treatment of HSP nephritis. Newer agents like cyclosporine, tacrolimus or rituximab have not been studied in large case series or randomized clinical trials.

Longer term treatment may include prolonged administration of prednisone and mycophenolate mofetil for 1-2 years.

Patients in whom end-stage kidney disease develops secondary to HSP nephritis are candidates for kidney transplantation. They can receive living related or deceased donor kidneys. However, the disease may recur even in the absence of symptoms and lead to allograft failure in 10%-30% of cases within 5 years of kidney transplantation.

What are the adverse effects associated with each treatment option?

Corticosterioids: hypertension, hyperglycemia, acne, mood changes, increased appetite and weight gain, cataracts, defective bone mineralization, impaired growth.

Mycophenolate mofetil: gastrointestinal complaints, hepatitis, leukopenia.

What are the possible outcomes of Henoch-Schönlein purpura nephritis?

Children with mild to moderate HSP nephritis generally achieve full recovery and have minimal risk of permanent kidney injury or progression to end-stage kidney disease. Children with more severe HSP nephritis are at significant risk for the development of hypertension, persistent proteinuria, reduced GFR, and progression to end-stage kidney disease.

There are cases of children with mild disease who experienced kidney failure many years after the initial episode and children with severe disease who make a complete recovery. Thus, all children with HSP nephritis require prolonged follow-up with serial monitoring of growth, blood pressure, urinary protein excretion, and kidney function.

The benefits of immunosuppressive therapy have never been conclusively proven in a long-term randomized controlled clinical trial of children with HSP nephritis. Therefore, the risk-benefit ratio of prednisone and other immunosuppressive medications is uncertain in this context

What causes this disease and how frequent is it?

The incidence of HSP nephritis is not well defined. It is most common in the first decade of life and occurs most often in the fall and winter months. It occurs throughout the world.

There is not a clear-cut infectious cause. HSP nephritis is not linked to to zoonotic exposures. It can occur after insect bites.

There is no single etiologic locus for the occurrence of HSP nephritis.

How do these pathogens/genes/exposures cause the disease?

The disease can occur after infections caused by streptococci, Staphylococcusaureus, Salmonella, Shigella, HIV, hepatitis B and C, and parvovirus 19.

Other clinical manifestations that might help with diagnosis and management

The most important thing to remember is that renal disease can occur before any other manifestation of HSP. If it occurs in association with arthritis alone or abdominal pain alone, it may be difficult to distinguish from other causes of acute glomerulonephritis in childhood such as poststreptococcal glomerulonephritis, IgA nephropathy, SLE nephritis, or ANCA-associated vasculitis. The occurrence of the rash greatly facilitates recognition of the disease.

HSP nephritis is among the causes of pulmonary-renal syndrome in children. The other considerations are SLE, Goodpasture disease, ANCA-associated vasculitis, and pneumococcal-associated hemolytic uremic syndrome.

What complications might you expect from the disease or treatment of the disease?

Hypertension

Chronic kidney disease

Are additional laboratory studies available; even some that are not widely available?

Other laboratory tests that are supportive of a diagnosis of HSP nephritis include the following:

Increased serum IgA1 concentration

Positive IgA rheumatoid factor

Circulating IgA1-containing immune complexes

How can Henoch-Schönlein purpura nephritis be prevented?

HSP nephritis may be prevented by a short course of oral corticosteroids. However, this is unproved and is not considered the standard of care in children with newly diagnosed HSP.

There are no behavioral factors that trigger the disease or that are consequences of HSP nephritis.

HSP nephritis is generally a sporadic disease and there is no role for genetic counseling.

There are no nutritional factors involved in the pathogenesis of HSP nephritis or in the treatment of routine cases.

What is the evidence?

Peru, H, Soylemezoglu, O, Bakkaloglu, SA. "Henoch Schonlein purpura in childhood: clinical analysis of 254 cases over a 3-year period". Clin Rheumatol. vol. 27. 2008. pp. 1087-92.

(Excellent report describing a large contemporaneous series.)

Davin, JC. "Henoch Schonlein purpura nephritis: pathophysiology, treatment, and future strategy". Clin J Am Soc Nephrol. vol. 6. 2011. pp. 679-89.

(Excellent review of renal disease in HSP.)

Weiss, PF, Feinstein, JA, Luan, X. "Effects of corticosteroids on Henoch Schonlein purpura: a systematic review". Pediatrics. vol. 120. 2007. pp. 1079-87.

(One side in the controversy.)

Chartapisak, W, Opastiraku, S, Willis, INS. "Prevention and treatment of renal disease in Henoch Schonlein purpura; a systematic review". Arch Dis Child. vol. 94. 2009. pp. 132-7.

(The other side in the controversy.)

Ongoing controversies regarding etiology, diagnosis, treatment

The key controversies in the area include the following:

The relationship of HSP nephritis and IgA nephropathy.

The prognosis in mild to moderate cases.

The role of corticosteroids in preventing nephritis in children with newly diagnosed HSP.

The optimal time to perform a kidney biopsy in mild to moderate cases.

Optimal treatment for the entire spectrum of HSP nephritides.

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