Nephrology updates

Henoch-Schِnlein purpura

Patrick Niaudet, MD
Burton D Rose, MD
Gerald B Appel, MD
Gene G Hunder, MD


Henoch-Schِnlein purpura is a systemic vasculitis with a prominent cutaneous component that is also seen in two other disorders: mixed cryoglobulinemia; and hypersensitivity vasculitis (which includes what had been called serum sickness) . The presence of skin vasculitis with palpable petechiae or purpura is typically a major finding in these disorders (see below).

Henoch-Schِnlein purpura (HSP) is characterized by the tissue deposition of IgA-containing immune complexes . The pathogenesis of this disorder may be similar to that of IgA nephropathy, which is associated with identical histologic findings in the kidney. The observation of the simultaneous occurrence of HSP and IgA nephropathy in twins after an adenovirus infection is further evidence in support of a common pathogenesis .

IgA deposition is prominent in both HSP and IgA nephropathy, but the renal injury may be mediated at least in part by IgG autoantibodies directed against mesangial cell antigens . The course of the renal disease and circulating antibody titers are roughly parallel, and these autoantibodies do not appear to be present in those patients with HSP who do not have renal involvement .

CLINICAL MANIFESTATIONS – HSP occurs more often in children than in adults, and many cases follow an upper respiratory tract infection, suggesting that the precipitating antigen may be infectious. Half of affected children are under age 5, although renal involvement is more likely to be severe in older children . The disease may be more severe in the few adults who develop this disorder. One retrospective study examined the clinical course among children (less than 20 years of age) and adults (greater than 20 years of age) with Henoch-Schِnlein purpura . Compared to children, adults had more severe and frequent renal involvement, and required more aggressive treatment regimens, including corticosteroids and cytotoxic therapy.

The clinical manifestations include a classic tetrad that can occur in any order and at any time over a period of several days to several weeks: rash; arthralgias; abdominal pain; and renal disease . However, other organs, such as the central nervous system and lung, may also be involved. As an example, the combination of renal disease and hemoptysis can simulate the presentation of Wegener's granulomatosis or anti-GBM antibody disease.

The relative frequency of the major symptoms in children is as follows: purpura (100 percent); arthritis (82 percent); abdominal pain (63 percent); renal disease (40 percent); and gastrointestinal bleeding (33 percent) [8].

• The rash in HSP is typically purpuric (with normal clotting studies) and distributed symmetrically over the lower legs and arms . In children, however, the rash may initially be urticarial and associated with local edema .

• Arthralgias most commonly affect the knees and ankles. These symptoms are always transient and there is no permanent damage to the joints.

Gastrointestinal disease – Gastrointestinal symptoms are present in the majority of patients with HSP . Symptoms include colicky abdominal pain (presumably due to local vasculitis) that is frequently associated with vomiting. The pain typically develops within 8 days of the appearance of the rash, although much longer intervals (weeks to months) have been described . Gastrointestinal lesions without cutaneous purpura have also been described in case reports . Bleeding (melena or hematochezia) is seen in approximately 25 percent of patients while up to 50 percent have occult bleeding . Rare complications include intussusception (typically in the ileum), pancreatitis, cholecystitis, and a protein-losing enteropathy .

Purpuric lesions may be seen on endoscopy, commonly in the descending duodenum, stomach, and colon . The terminal ileum may also be involved. Submucosal edema, ulceration and spasm of the ileum and jejunum may be seen during a small bowel series.

Renal disease – Renal involvement is common in HSP and is not predictably related to the severity of extrarenal involvement. Studies in children have found that carefully measured red cell excretion is increased in almost all cases . However, clinically overt disease, as manifested by hematuria and/or proteinuria, occurs in 30 to 70 percent of patients. It is estimated that HSP nephritis accounts for approximately 15 percent of all glomerulopathies in childhood .

Renal disease is usually noted within a few days to four weeks after the onset of systemic symptoms . The urinalysis in affected patients reveals mild proteinuria with an active sediment characterized by microscopic (or macroscopic) hematuria with red cell and other cellular casts. Most patients have relatively mild disease characterized by asymptomatic hematuria and proteinuria with a normal or only slightly elevated plasma creatinine concentration. However, more marked findings may occur including the nephrotic syndrome, hypertension, and acute renal failure.

There is a general but not absolute correlation between the severity of the clinical manifestations and the findings on renal biopsy . Patients with only asymptomatic hematuria, for example, usually have only focal mesangial proliferation. The appearance of proteinuria is associated with more marked cellular proliferation and, if protein excretion is in the nephrotic range, frequent crescent formation . Exacerbation of renal symptoms and biopsy-confirmed worsening of glomerular lesions may be observed in patients with repeated attacks of purpura or macroscopic hematuria.

The percentage of glomeruli showing crescents seems to be the most important prognostic finding. In one study of 151 children referred to a major academic center and then followed for one to 18 years, the following observations were noted :

• Among patients with crescents involving more than 50 percent of glomeruli, 37 percent progressed to end-stage renal disease and another 18 percent had chronic renal disease.

• Similarly, 86 percent of children who developed end-stage renal disease had crescents affecting more than 50 percent of glomeruli.

• On the other hand, 70 percent patients who recovered or had only minimal urinary abnormalities at latest examination had few or no crescents on initial biopsy.

DIAGNOSIS – The characteristic tetrad is virtually pathognomonic of HSP in children, as clotting disorders and sepsis can be easily excluded. However, HSP must be distinguished in adults from other systemic autoimmune diseases (such as hypersensitivity vasculitis and systemic lupus erythematosus) that can produce similar symptoms. Confirmation of the diagnosis of HSP requires evidence of tissue deposition in the skin or kidney of IgA by immunofluorescence microscopy . Biopsy of the skin lesions reveals inflammation of the small blood vessels, called a leukocytoclastic vasculitis, that is most prominent in the postcapillary venules . This finding is relatively nonspecific (also being found in other forms of hypersensitivity vasculitis) unless accompanied by vascular IgA deposition which can, in some cases, also be seen in areas of seemingly uninvolved skin . Renal biopsy is another method to establish the diagnosis, but this invasive procedure is generally reserved for patients in whom the diagnosis is uncertain or in whom there is clinical evidence of more severe renal involvement.

There are also clinical criteria that can be used to distinguish between Henoch-Schِnlein purpura and hypersensitivity vasculitis. One report suggested that hypersensitivity vasculitis rather than Henoch-Schِnlein purpura is present with 74 percent accuracy if no more than two of the following criteria were present :

• Palpable purpura
• Bowel angina
• Gastrointestinal bleeding
• Hematuria
• Age at onset < or =20 years

PROGNOSIS – Our current understanding of the long-term outcome of the renal disease in HSP is primarily derived from studies in children. The overall outcome is good in most patients; as an example, complete recovery occurs in 94 and 89 percent of children and adults, respectively . All of the manifestations of active HSP usually resolve spontaneously, although recurrent episodes of purpura and glomerulonephritis may be seen (see Recurrent disease below) .

Among those with renal involvement, only a minority have persistent disease. This was illustrated by the results of a population-based retrospective study of 69 Spanish children followed for a median of seven years: 12 percent had continued hematuria and proteinuria and none developed renal failure . Persistent renal disease was closely associated with the presence of nephrotic syndrome at the time of diagnosis (odds ratio of 22.9, p<0.0001).

The renal prognosis is excellent in most patients, who tend to have focal glomerular involvement and transient hematuria and proteinuria that resolves within several months . Spontaneous recovery can also occur in patients with severe renal involvement as manifested by acute renal failure, nephrotic-range proteinuria, and crescents on renal biopsy. As noted above, however, many of these patients (and a much smaller percentage of those with mild urinary abnormalities at presentation) will have persistent proteinuria, hypertension, and renal insufficiency . It is estimated that HSP accounts for approximately three percent of cases of end-stage renal disease in children.

However, the long-term prognosis may not be benign in all patients who appear to recover from the acute episode. Consider these serial observations in a group of children with HSP and evidence of nephritis during the acute episode :

• At two years, one-half were in complete remission, while one-third had persistent urinary abnormalities with a normal plasma creatinine concentration.

• Of 88 children followed for 10 years, most of the children with asymptomatic urinary abnormalities had gone into remission, while some of those with renal insufficiency had progressed to end-stage renal disease .

• Of 78 children followed for 23 years, 17 (22 percent) had deteriorated clinically. Included in this group were seven children who had apparently completely recovered at 10 years . Furthermore, 36 percent of 44 pregnancies were complicated by hypertension and/or persistent proteinuria.

Patients with late progression generally have no signs of active renal (as manifested by hematuria and cellular casts) or extrarenal disease. The following sequence, which may apply to many different renal diseases, has therefore been proposed . There is a variable degree of irreversible nephron loss during the acute episode, leading to compensatory hyperfiltration (driven in part by intraglomerular hypertension) and hypertrophy in the remaining glomeruli. Over a period of years, these adaptive changes induce further glomerular injury that is independent of the primary disease. It is possible that modalities such as the administration of an angiotensin converting enzyme inhibitor might be beneficial in those patients with evidence of progressive renal failure.

Recurrent disease – Recurrences are common, occurring in approximately one-third of patients [8,22]. Recurrent symptoms and signs, which tend to mimic the original episode but are less severe, are normally observed within four months of resolution of the initial symptoms; recurrences are more likely in patients with nephritis .

TREATMENT – As mentioned above, complete recovery occurs in 94 and 89 percent of children and adults, respectively . Most patients receive no specific therapy. There is suggestive evidence that corticosteroids enhance the rate of resolution of the arthritis and abdominal pain; however, they do not appear to prevent recurrent disease .

Renal disease – A separate issue is treatment of the initial active renal disease. Specific treatment should be considered only in patients with marked proteinuria and/or impaired renal function during the acute episode. We recommend performance of renal biopsy in this setting, since the severity of the histologic lesions (particularly the degree of crescent formation) appears to be the best indicator of prognosis.

There is no evidence from controlled trials that therapy with conventional doses of corticosteroids or cyclophosphamide has a beneficial effect in patients with renal involvement . By comparison, more aggressive therapy may be beneficial in patients with advanced disease, which is usually defined as crescentic nephritis. In this setting, a regimen consisting of pulse intravenous methylprednisolone (250 to 1000 mg per day for three days) followed by oral prednisone (1 mg/kg per day for three months) may be beneficial . This regimen is primarily aimed at reversing the inflammatory process (such as macrophage infiltration), rather than the IgA deposition itself. One prospective, but uncontrolled, study used this regimen in 38 children presenting with the nephrotic syndrome and/or crescents affecting more than 50 percent of glomeruli . Only four (10 percent) progressed to end-stage renal disease, three of whom had been treated late in the course of their disease. Thus, early therapy may be important to prevent irreversible glomerular injury.

Other regimens that have been evaluated in children with crescentic nephritis include corticosteroids and azathioprine (19 of 21 children showed improvement in renal function in an uncontrolled study) and multidrug regimens such as corticosteroids, cyclophosphamide, and dipyridamole, or corticosteroids, cyclophosphamide, heparin/warfarin, and dipyridamole . However, since spontaneous recovery is often observed in patients with crescent formation, it remains unknown whether these regimens are superior to no or less aggressive therapy.

Plasmapheresis has also been used in a number of patients with severe disease . Its efficacy is uncertain (due in part to concurrent administration of corticosteroids and/or cytotoxic drugs) and there are potential side effects. However, limited data suggests that plasmapheresis alone may be curative in some patients. As an example, among nine children with crescentic nephritis, plasmapheresis constituted the sole therapy for renal involvement, with corticosteroids only being used for severe abdominal pain . At follow-up at nearly 10 years, four children had complete recovery and two had only microscopic hematuria. The remaining three children had recurrent proteinuria, with progression to end-stage renal failure in two.

A different regimen, intravenous immune globulin, has been tried in a small number of patients with heavy proteinuria and a progressive decline in glomerular filtration rate.

Renal transplantation – Renal transplantation can be performed in those patients who progress to end-stage renal disease, although recurrent disease can occur . Mesangial hypercellularity and IgA deposition in the graft are common, but many cases are subclinical. It has been suggested that clinically evident recurrence occurs in approximately 35 percent of patients at five years . Overall, approximately 10 percent of patients experience graft loss due to recurrent disease.

The diagnosis of recurrent renal disease is based upon the demonstration of mesangial IgA deposits. One possibility, however, is that asymptomatic IgA deposits may have been present in the donor kidney prior to transplantation. Several reports have documented this phenomenon, but the IgA deposits disappeared within weeks after transplantation due presumably to the lack of circulating IgA-containing immune complexes in the recipient . Thus, persistent deposits presumably reflect recurrent disease.

Recurrent glomerular disease, often in association with active extrarenal involvement, can lead to loss of the graft . This appears to be more likely in patients with aggressive initial disease who progressed to end-stage renal disease in less than three years after the onset of Henoch-Schِnlein purpura . As a result, it is recommended that transplantation be delayed for 12 to 24 months after the disappearance of purpura . However, this approach does not prevent recurrent disease in all patients .

Preliminary observations suggest that the risk of recurrent disease also may be higher in living-related donors, a finding similar to that seen in IgA nephropathy. In one study of 12 living-related donor transplants, for example, five had clinical recurrence and four had isolated histologic recurrence . Two of these patients did not have recurrent disease in a second cadaver graft.

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