M Zaidi 1, N Singh 2, M Kamran 2, N Ansari 2, SH Nasr 3 and A Acharya 2. the renal consult

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1 & 2008 International Society of Nephrology the renal consult Acute onset of hematuria and proteinuria associated with multiorgan involvement of the heart, liver, pancreas, kidneys, and skin in a patient with Henoch Schönlein purpura M Zaidi 1, N Singh 2, M Kamran 2, N Ansari 2, SH Nasr 3 and A Acharya 2 1 Department of Medicine, Bronx VA Medical Center, Mount Sinai School of Medicine, North Central Bronx Hospital, Bronx, New York, USA; 2 Renal Division, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA and 3 Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA CASE PRESENTATION A 17-year-old boy presented to the Emergency Room with abdominal pain, which began 7 days prior to his admission. The pain was accompanied by nausea, vomiting, and diarrhea, which he attributed to food poisoning. He began experiencing pain in both wrists 3 days prior to his visit. He denied history of fevers, chills, shortness of breath, dysuria, or rash. He admitted to experiencing a low level of energy after an upper respiratory tract infection 10 days prior to admission. His only medications at home were sertraline, resperidone, and methylphenidate for depression, which he was taking for 1 year prior to admission. Patient had been in foster care all his life. On physical examination, he was a well-developed, well-nourished boy, with body temperature of 981F, heart rate of 122 beats per min 1, blood pressure of 156/ 83 mm Hg, respiratory rate of 20 min 1, and a nonpruritic, nonpetechial, maculopapular rash on his left elbow and both lower extremities. He had swelling over both eyelids. He had diffuse abdominal tenderness and guaiac-positive stool, which turned to melena by hospital day 7. His laboratory workup is shown in Table 1. To summarize, on presentation, blood urea nitrogen was 17 mg per 100 ml (6.1 mmol l 1 )(normalrange: mg per 100 ml or mmol l 1 ) and serum creatinine was 0.8 mg per 100 ml (60 mmol l 1 ) with a GFR estimated at 160 ml min 1 by Schwartz formula. Liver function tests, amylase and lipase levels were normal. Amylase (normal range: U l 1 ) and lipase levels (normal range: 7 60 U l 1 ) rose to 165 and 79 U l 1, respectively on day 14 with aspartate aminotransferase (normal range: 1 40 U l 1 ), alanine aminotransferase (normal range: 1 45 U l 1 ), and g-glutamyltransferase (normal range: 9 54 U l 1 ) of 53, 75, and 211 U l 1, respectively, on day 16. Initial urinalysis was normal. Urinalysis on day 9 showed moderate blood and 2 þ protein on dipstick with microscopic examination showing red blood cells (RBCs) per high-power field. Proteinuria steadily increased from 0.6 g per day on day 9 to 3.5 g per day on day 16. Serologic test results were negative for antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, syphilis, Epstein Barr virus IgM, HIV antibody, hepatitis B surface antigen, and hepatitis C antibody. Antistreptolysin O antibody titer was 400 IU l 1 on admission rising to 800 IU l 1 on day 14. Complement 3 (C3) and complement 4 (C4) levels are given in the table. Computer tomography of the abdomen showed edema and thickening of the jejunum with other viscera reported as normal (Figure 1a). Skin biopsy showed evidence of leukocytoclastic vasculitis (Figure 1b). Echocardiography performed during his hospital stay for the complaints of shortness of breath and chest pain showed evidence of left ventricle dilatation with low normal ejection fraction and prominent coronary arteries. Renal biopsy was performed. Correspondence: A Acharya, Renal Division, 6E-23 B, Jacobi Medical Center, Building 1, Bronx, New York 10461, USA. anjali.acharya@nbhn.net Kidney International (2008) 73, ; doi: /sj.ki ; published online 21 November 2007 Received 23 May 2006; revised 18 August 2007; accepted 28 August 2007; published online 21 November 2007 RENAL BIOPSY FINDINGS Light microscopy evaluation revealed two cores of renal cortex containing 10 glomeruli, none of which were globally sclerotic. Glomeruli displayed mild diffuse and segmental mesangial hypercellularity. Superimposed on these mesangial proliferative features, three glomeruli displayed segmental endocapillary proliferation with focal infiltrating monocytes Kidney International (2008) 73,

2 Table 1 Laboratory data a. Blood count values On presentation Normal range White blood cell count l l 1 Polymorphonuclear 84.80% 48 82% cells Platelet count l l 1 b. Serum chemistry values On presentation Day 14 Day 16 Normal range Serum creatinine 0.8 mg per 100 ml (60 ìmol l 1 ) 0.6 mg per 100 ml (46 ìmol l 1 ) 0.4 mg per 100 ml (31 ìmol l 1 ) mg per 100 ml (9 88 ìmol l 1 ) Blood urea nitrogen 17 mg per 100 ml (6.1 mmol l 1 ) 19 mg per 100 ml ( 6.8 mmol l 1 ) 23 mg per 100 ml (8.2 mmol l 1 ) 3 25 mg per 100 ml ( mmol l 1 ) Amylase 81 U l U l U l U l 1 Lipase 17.2 U l U l U l U l 1 Aspartate 22 U l 1 31 U l 1 53 U l U l 1 aminotransferase Alanine 11 U l 1 38 U l 1 75 U l U l 1 aminotransferase g-glutamyltransferase N/A 110 U l U l U l 1 Antistreptolysin O 400 IU l IU l IU l 1 p200 IU l 1 antibody titer Complement 3 89 mg per 100 ml 70 mg per 100 ml 92 mg per 100 ml mg per 100 ml Complement mg per 100 ml 22.5 mg per 100 ml 25.3 mg per 100 ml mg per 100 ml c. On presentation Day 9 Day 16 Urinalysis Normal Moderate blood and 2+ protein, microscopic examination showing red blood cells per high-power field Proteinuria g per 100 ml per day 3.5 g per 100 ml per day N/A, not available. and neutrophils. Two glomeruli contained small cellular crescents associated with fibrin extravasation in Bowman s space (Figure 1c). There was no tubular atrophy, interstitial fibrosis, or inflammation. No red blood cell casts were identified. Vessels appeared unremarkable. No vasculitis was seen. Immunofluorescence revealed 3 þ granular to semilinear global glomerular mesangial staining for IgA (Figure 1d), with 1 to 2 þ C3, negative IgG, negative IgM, negative C1q, 2 þ k, and 3 þ l. No vascular staining was seen. By electron microscopy, the mesangial areas were globally expanded by mild increase in mesangial cell number and matrix containing abundant small- to medium-sized mesangial electron dense deposits. There was segmental endocapillary hypercellularity including a few infiltrating neutrophils. No electron-dense deposits involving the peripheral capillaries were identified. No endothelial tubuloreticular inclusions were seen. There was mild-to-moderate effacement of foot processes involving approximately 30% of the glomerular capillary surface area. No tubulointerstitial or vascular electron-dense deposits were identified. PATHOLOGIC DIAGNOSIS Diffuse mesangial and focal endocapillary proliferative glomerulonephritis with focal cellular crescents, consistent with Henoch Schönlein purpura (HSP) nephritis. CLINICAL FOLLOW-UP Treatment was started with pulse intravenous methylprednisolone 1000 mg per day for 3 days. The patient was then started on prednisone 60 mg orally once a day and 10 mg of fosinopril orally once daily with a decrease in proteinuria to less than a gram per day at follow-up after 2 months. Renal function remained normal at 3 months follow-up. DISCUSSION Henoch Schönlein purpura is the most common systemic small vessel vasculitis in children generally between 2 and 15 years of age with 50% of the cases manifesting before the age of 5 years. Renal disease is more likely to occur and be more severe in older children. It has a slight male preponderance. From the limited epidemiologic data, HSP seems to be far less common in adults. There may be seasonal variations with most cases in the fall and winter. It is seen infrequently in African-American individuals. It is characterized by the tissue deposition of IgA-containing immune complexes. 1 The etiology of HSP remains unknown though infections and drugs have been implicated as triggers in over half of the patients. The pathogenesis of this disorder may be similar to that of IgA nephropathy, that is, secondary to defective glycosylation and decreased clearance of IgA1, and increased binding and deposition of mesangial IgA with co-deposition 504 Kidney International (2008) 73,

3 a b c d Figure 1 CT scan of the abdomen and biopsy of skin and kidney. (a) Computer tomography scan of the abdomen shows significant thickening and edema of jejunum (arrow) (60 60 mm ( DPI)). (b) The skin biopsy shows leukocytoclastic vasculitis. The dermal small vessels display endothelial cell swelling (arrowhead) and are infiltrated and surrounded by neutrophils, many of which show fragmentation of nuclei (karyorrhexis) (arrows) (hematoxylin eosin (H&E), original magnification 600). (c) A glomerulus shows compression of the tuft by a segmental cellular crescent (arrow) admixed with fibrin (arrowhead). The underlying tuft exhibits mild segmental mesangial hypercellularity (H&E, original magnification 600). (d) On immunofluorescence, there is intense positivity for IgA in a global mesangial distribution (original magnification 400). of C3 in some cases, which may result in low serum C3 levels. A low C3 level is, however, very rare in HSP. HSP is characterized by the following tetrad of symptoms, which may occur in any order: rash, arthralgias, abdominal pain, and renal disease (Table 2), with other organ involvement being uncommon. Renal manifestations of HSP Renal involvement is one of the serious manifestations of HSP. Common renal manifestations are hematuria and proteinuria, which may be in the nephrotic range. Persistent disease is uncommon, especially in children. A retrospective analysis of an unselected population of patients with HSP including 46 adults and 116 children showed that the disease is more severe in adults with higher frequency of Table 2 Major clinical manifestations of HSP seen during the course of the disease Symptoms Percentage of patients Purpura 100 Abdominal pain 63 Gastrointestinal bleeding 33 Arthritis 82 Nephritis 40 HSP, Henoch Schönlein purpura. Saulsbury FT. Medicine (Baltimore) 1999; 78:395. renal involvement. 2 However, the authors found that the final outcome was good in both groups. 2 A retrospective analysis of a cohort of 250 adults with HSP diagnosed on renal biopsy with a follow-up of 15 years showed that roughly Kidney International (2008) 73,

4 10% became dialysis dependent at the end of the follow-up. 3 It is estimated that 3% of end-stage renal disease in children is due to HSP. Poor prognostic determinants include hypertension, heavy proteinuria, renal insufficiency, older age, persistent purpura, crescents in greater than 50% of glomeruli on biopsy, and low levels of factor XIII. 4 Nonrenal manifestations of HSP Dermatologic features. Purpura is one of the presenting manifestations in roughly 50% of patients and develops in % of cases during the course of the disease and is considered to be a mandatory criterion by many. It begins as erythematous macules, which turn into purpuric petechiae. The eruption is symmetric and affects the extensor surfaces of the lower legs, forearms, and buttocks, and spares the trunk. Unusual sites to be affected are earlobes, nose, and external genitalia. Erythema nodosum and blistering lesions are some of the other skin lesions that may be seen. Arthritis. Arthralgias and periarticular edema are seen in 60 85% of patients during the course of the disease. Knees, ankles, elbows, and wrists are commonly affected. Joint manifestations may precede the skin findings in 25% of the patients. Intra-abdominal manifestations Intra-abdominal manifestations are very common in HSP. About two-thirds of the patients manifest abdominal pain (likely owing to local vasculitis), and one-third have occult or gross gastrointestinal bleeding. The most common surgical complication of HSP is intussusception. 5 In contrast to idiopathic intussusception, which is ileocolic in more than 80% of children, it is confined to the small bowel in most cases of HSP. 6 8 Other abdominal complications include acute appendicitis, bowel obstruction secondary to ileus, bowel ischemia and infarction, perforation of the bowel, and pancreatitis. 5 The correct diagnosis may be difficult to make when the abdominal complaints precede the onset of rash or renal involvement, as in this case. Acute pancreatitis is a rare presentation of HSP. 5 It is presumed to be caused by vasculitic involvement of the pancreas. 9 Most cases of HSP-associated pancreatitis reported were mild in nature. However, hemorrhagic pancreatitis with intraperitoneal bleeding has been described. 10 Rash usually precedes the development of pancreatitis. Pancreatitis when present, develops in the first week of the disease but has been reported to occur a few weeks to a few months after the initial presentation. 9,11,12 Making the correct diagnosis is important to avoid unnecessary laparotomy. The diagnosis can be confirmed by amylasemia and ultrasonography. Pancreatic pseudocysts are seen in 20% of children with acute pancreatitis. 13 However, they have been reported in only one case of HSP-associated pancreatitis. 14 This may be due to the fact that HSP-associated pancreatitis is usually mild. In the absence of renal involvement, the long-term prognosis is excellent. 15 However, if renal impairment is present, the long-term prognosis depends on the severity of the glomerular involvement. 15 All cases of hepatitis in association with HSP reported thus far have been in conjunction with viral infections secondary to hepatitis A, B, and sometimes C. 10,12,13 A case of hepatitis was reported by Cheung et al. 14 in 2003 after vaccination for hepatitis B. In our patient, serologic tests for hepatitis B and C were negative. HSP associated with hepatitis A is extremely rare, with only five cases reported so far. Unfortunately, hepatitis A serology was not performed on our patient. Myocarditis in HSP Cardiac involvement, while common in Kawasaki s disease, is rare in HSP. Acute rheumatic carditis has been reported in HSP. 15 The clinical symptoms and echocardiographic features support the diagnosis of carditis in our patient. In all the cases described in the literature, the diagnosis of rheumatic carditis was made based on clinical features, EKG, echocardiography, and rising antistreptolysin O titers. In most cases, patients have been reported to recover completely, except for two who developed valvular lesions. This patient s presentation started with an upper respiratory tract infection with documented serologic evidence of group A b-hemolytic streptococcal infection. Whether the carditis seen here is independent from rheumatic carditis is debatable, and it is possible that the infection may have played a role in the pathogenesis of his carditis. Previous reports of poststreptococcal glomerulonephritis and rheumatic carditis in HSP patients support such a possibility Follow-up of cardiac findings may help in differentiating the two conditions. Treatment of HSP As mentioned above, complete recovery is seen in approximately 90% of patients. However, relapse is known to occur in about 30% of patients. Moderate-dose steroid therapy has been used for arthritis and gastrointestinal symptoms such as bleeding and ascites. Treatment of rapidly progressive or crescentic HSPN. The outcome of Henoch Schönlein purpura nephritis (HSPN) is difficult to determine due to selection bias in treatment. From unselected series, it appears that the risk of progression to end-stage renal disease in all children with HSPN is about 3%. Data on treatment of moderately severe HSPN are limited by the fact that they are from case series using historical controls. The evidence available in support of treatment of rapidly progressive or crescentic HSPN is from case series with N values of 8 38 patients. There has been no randomized controlled trial looking at treatment options in this group. Features suggestive of progression in these studies are heavy proteinuria and/or nephrotic syndrome and/or crescentic involvement of 450% of glomeruli. This evidence is described in detail by Wyatt and Hogg 19 and is paraphrased in Table 3. This article provides the most detailed information on evidence-based treatment options in IgA and HSP. There are no controlled data on the use of angiotensinconverting enzyme inhibitors and angiotensin receptor 506 Kidney International (2008) 73,

5 Table 3 Evidence available for treatment of rapidly progressive HSPN Treatment Follow-up Results Source 12 patients: i.v. M-P (3 days), PRED (3 months), oral CYC-P (2 months), DIPYR (6 months) 9 39 months Normal renal function in 11/12 patients; Complete remission in 7 patients Öner patients: i.v. M-P (3 days), oral PRED (3.5 months), CYC-P in 7 patients 1 16 years 27/36 recovered; 4 progressed to ESRD Niaudet patients: oral PRED, CYC-P, H/W, DIPYR 7.5±0.9 years 13/14 had good results; no cases of ESRD, 1 with persistent heavy proteinuria Iijima 23 9 patients: P-Exch three times per week for 2 weeks, then weekly for 6 weeks 9.6±4.3 years Good initial response in all; 2 progressed to ESRD, 4 with total remission Hattori 24 8 patients: P-Exch three times per week within 16 weeks of HSP Up to 13 years Transient benefit in all 8 patients; 4 developed ESRD, 3 had CRI, and 1 had good outcome Schärer 25 CRC, chronic renal insufficiency; CYC-P, cyclophosphamide; DIPYR, dipyridamole; ESRD, end-stage renal disease; HSP, Henoch Schönlein purpura; HSPN, Henoch Schönlein purpura nephritis; H/W, heparin/warfarin; i.v. M-P, intravenous methyl prednisolone; P-Exch, plasma exchange; PRED, prednisone. Data from Wyatt and Hogg. 19 Table 4 Classification criteria for Henoch Schonlein purpura Palpable purpura (mandatory criterion) in the presence of at least one of the following four features: (a) Diffuse abdominal pain (b) Any biopsy showing predominant IgA deposition (c)arthritis a or arthralgia (d) Renal involvement (any hematuria and/or proteinuria) Reference: Ozen et al. 26 a Acute, any joint. blockers, but it can be tried early on as a nonspecific intervention to slow progression of proteinuric renal disease. The disease can recur in transplanted kidneys in up to 35% of patients at 5 years. 20 However, graft loss is rare and occurs in less than 10% of cases. 20 In summary, this case demonstrates the myriad clinical manifestations of HSP in a single patient. In children, there is a consensus that it is inappropriate to apply the adult classification criteria. The working groups of the Pediatric Rheumatology European Society (PreS), American College of Rheumatology (ACR), and the European Society of Paediatric Nephrology (ESPN) have developed consensus criteria for the childhood vasculitis. According to this, palpable purpura qualifies for the diagnosis of HSP in the presence of at least one of the following four features: diffuse abdominal pain, any biopsy showing predominant IgA deposition, arthritis or arthralgia, and any renal involvement (see Table 4). Awareness of the abdominal manifestations of HSP is important for proper management and avoidance of unnecessary laparotomy. It is important to remember that the early outcome depends on the severity of the various organ involvements. But the long-term outcome is excellent in the absence of renal involvement. 3 Patients need long-term follow-up as the disease may recur. REFERENCES 1. Kauffmann RH, Herrmann WA, Meyer CJ et al. 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