FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2092118820> ?p ?o ?g. }

• W2092118820 endingPage "341" @default.
• W2092118820 startingPage "338" @default.
• W2092118820 abstract "Extraintestinal manifestations and complications occur in up to 35% of pediatric patients with inflammatory bowel disease (IBD) and can involve almost any organ system (1). The association of renal and urinary complications with Crohn disease (CD) has been well described (2,3). Although the most common manifestations are nephrolithiasis and ureteric obstruction, both glomerulonephritis and tubulointerstitial nephritis (TIN) have been reported in patients with CD (4–6). However, most of these patients were adults with long-standing IBD, and nearly all of them had previous exposure to 5-aminosalicylates, suggesting that 5-aminosalicylates had contributed to the development of chronic nephropathy (7–10). Recently, Izzedine et al (11) reported 4 adults with CD and TIN in the absence of 5-aminosalicylate exposure and proposed that their renal diseases were extraintestinal manifestations of IBD. Although there have been reports of biopsy-proven TIN in children receiving 5-aminosalicylate therapy for IBD (12,13), to our knowledge, there have been no reports of TIN in the absence of 5-aminosalicylate exposure. We report here 2 cases of children with biopsy-proven TIN as extraintestinal manifestations of CD. CASE 1 A 16-year-old previously healthy African American girl presented to Children's Memorial Hospital with a 6-month history of diarrhea, hematochezia, malaise, and a 40-lb weight loss. There was no family history of IBD, autoimmune disease, or renal disease. There was no history of medication use, including treatment with nonsteroidal anti-inflammatory drugs or antibiotics, before presentation. Physical examination revealed left upper quadrant abdominal tenderness and mild digital clubbing. The remainder of the examination was otherwise normal. Hypertension was noted, with a blood pressure of 140/83 mmHg. Laboratory studies demonstrated a microcytic anemia (hemoglobin 9.9 g/dL), thrombocytosis (platelet count 690,000 K/μL), and elevated erythrocyte sedimentation rate (115 mm/h) and C-reactive protein (3.78 mg/dL). Chemistry studies showed a serum creatinine of 2.5 mg/dL, and further evaluation demonstrated a random urine protein of 100 mg/dL and urine protein-creatinine ratio of 0.65 (normal <0.2). The results of an upper gastrointestinal series and small intestinal follow-through were normal. Histopathological examination from an esophagogastroduodenoscopy and colonoscopy revealed granulomatous gastritis and ileocolitis consistent with CD. Treatment with prednisone and later 6-mercaptopurine was initiated. Subsequent evaluation of her renal insufficiency and hypertension revealed elevated antinuclear antibodies (1:80, speckled pattern) and normal C3 and C4 levels. Anti–double-stranded DNA antibodies were not detected. Renal ultrasonography with Doppler showed no evidence of obstruction, structural abnormalities, or renal artery stenosis. Histopathological examination of a percutaneous renal biopsy specimen (Figure 1) showed prominent, patchy interstitial inflammation, predominantly composed of mononuclear cells with small foci of scattered eosinophils. Variable degrees of interstitial fibrosis were present in some areas. Occasional nonnecrotizing interstitial granulomas were present, predominantly in areas of inflammation. The renal tubules showed variable mild to moderate atrophy. Mild fibrosis in the periphery of the glomeruli was observed, with no other significant changes. These findings were consistent with granulomatous TIN. Rapid control of the hypertension was obtained with enalapril.FIG. 1: Biopsy specimen from patient in case 1, showing a well-formed, nonnecrotizing interstitial granuloma (arrow). A glomerulus, which does not show significant changes, is present in the lower left corner. Renal tubules have wrinkled and thickened basement membranes. There is a prominent interstitial mononuclear infiltrate, which produces significant increase in the distance between renal tubules (Jones silver stain; original magnification ×100).Six months later, the patient was dependent on high-dose steroid therapy to control her intestinal symptoms, and still no improvement was seen in her serum creatinine; therefore, infliximab therapy was initiated. Although her intestinal symptoms responded well to infliximab, the serum creatinine failed to improve. One year after diagnosis with CD, she was in clinical remission, but the serum creatinine remained persistently elevated at 2.1 mg/dL with an estimated creatinine clearance of 35 mL/min/1.73 m2 (normal, 120 mL/min/1.73 m2). CASE 2 An 11-year old previously healthy Hispanic girl presented to Children's Memorial Hospital with a 6-month history of hematochezia, tenesmus, abdominal pain, and a 12-lb weight loss. There was no family history of IBD, autoimmune disease, or renal disease. There was no history of medication use, including treatment with nonsteroidal anti-inflammatory drugs or antibiotics, before presentation. Physical examination revealed bilateral lower abdominal tenderness; the remainder of the examination was otherwise normal. Hypertension was noted, with a blood pressure of 143/87 mmHg. Laboratory studies showed a microcytic anemia (hemoglobin 9.3 g/dL), thrombocytosis (platelet count 679,000 K/μL), and an elevated erythrocyte sedimentation rate (94 mm/h) and C-reactive protein (2.68 mg/dL). Routine chemistry study demonstrated renal insufficiency, with a serum creatinine of 1.9 mg/dL that did not correct after fluid resuscitation. Further evaluation showed a random urine protein of 100 mg/dL and a urine protein-creatinine ratio of 0.78 (normal <0.2). The results of an upper gastrointestinal series and small intestinal follow-through were normal. Histopathological examination from an esophagogastroduodenoscopy and colonoscopy revealed granulomatous gastroduodenitis and ileocolitis consistent with CD. Treatment with prednisone was initiated and when the patient was discharged, low-dose mesalamine was begun. Subsequent evaluation of the patient's renal insufficiency and hypertension revealed normal C3, C4, and antinuclear antibodies. Anti–double-stranded DNA antibodies were not detected. Renal ultrasonography with Doppler showed no evidence of obstruction, structural abnormalities, or renal artery stenosis. Histopathological examination of a percutaneous renal biopsy specimen (Figure 2) showed a marked mononuclear interstitial infiltrate composed mostly of lymphocytes and few plasma cells, with occasional areas of interstitial fibrosis. Renal tubules in the areas of inflammation showed a variable degree of injury, such as dilation, epithelial degeneration, hyaline casts, epithelial inflammation, and/or atrophy. Glomeruli in the areas of inflammation and fibrosis showed mild secondary changes. These findings were consistent with TIN. Rapid control of the hypertension was obtained with lisinopril. After 2 weeks of therapy, the mesalamine was discontinued, and 6-mercaptopurine was initiated later.FIG. 2: Biopsy specimen from patient in case 2, showing a prominent mononuclear inflammatory infiltrate throughout the interstitium. Renal tubules are barely discernible because of the density of the infiltrate. A glomerulus, which shows mild nonspecific changes, is present in the upper left corner of the image (periodic acid–Schiff stain; original magnification ×100).Clinical remission was achieved with combined prednisone and 6-mercaptopurine therapy, and there was a decrease in the serum creatinine level from 1.9 to 0.9 mg/dL. Three months after tapering off prednisone therapy, the patient experienced her first relapse, evidenced by diarrhea, nocturnal urgency, abdominal pain, and increases in erythrocyte sedimentation rate (71 mm/h) and serum creatinine (1.9 mg/dL). She was unresponsive to a second course of prednisone therapy, and infliximab infusions were initiated. With infliximab, there was a marked response in her symptoms, and the serum creatinine improved to 0.6 mg/dL. She remained in clinical remission, receiving standard infliximab therapy for 4 months, but thereafter experienced relapses of her intestinal symptoms associated with a peak erythrocyte sedimentation rate of 92 mm/h and creatinine level of 2.2 mg/dL. Not responding to escalating prednisone and infliximab therapy, she was found to have low titer human anti-chimeric antibodies and was transitioned to adalimumab. At this writing, her intestinal symptoms are well controlled, and she has been able to taper steroid therapy, but the creatinine remains elevated at 2.1 mg/dL, with an estimated glomerular filtration rate of 39 mL/min/1.73 m2 (normal 120 mL/min/1.73 m2). DISCUSSION Extraintestinal manifestations of IBD occur in 20% to 35% of children with CD and in 15% of those with ulcerative colitis (14). Although our understanding of the pathogenesis of IBD has improved considerably during the past decade, the etiology of extraintestinal manifestations remains less clear. Proposed mechanisms include genetic factors, infectious agents, circulating bacterial endotoxins, and immune-complex deposition (5,15–18). Overall, the common denominator of proposed theories is based on an immunological response influenced by genetic factors. This centers on the idea of molecular mimicry with shared epitopes between intestinal bacterial proteins and host self antigens, which may include the interstitium of the kidney (15,19,20). Renal manifestations of CD are rare and include glomerulonephritis, amyloidosis, and nephrolithiasis (3). Tubulointerstitial nephritis has also been reported in patients with IBD, albeit most cases have been associated with 5-aminosalicylate exposure. Other pathogenetic possibilities for chronic TIN include a relationship to drugs or heavy metals; hereditary diseases; metabolic disturbances; immune-mediated, hematological, and oncological disturbances; obstructive uropathies; and a variety of infections (19). 5-Aminosalicylate drugs are known to be nephrotoxic, and it has been reported that 1 in 100 patients treated with this medication will experience some renal impairment and fewer than 1 in 500 will experience serious renal damage (21). Accordingly, the exposure to these medications may confound the etiology of Crohn-related renal disease. In our 2 patients, the renal lesions were similar to those described with mesalamine exposure. However, in both cases, there was evidence of renal insufficiency simultaneous with the diagnosis of CD. Although 1 of our patients subsequently received 5-aminosalicylate therapy, there was evidence of renal impairment before this treatment was begun, thus excluding the possible responsibility of mesalamine. In addition, neither patient had any known exposure to nonsteroidal anti-inflammatory drugs or any other nephrotoxic medication. Neither had evidence of primary renal or systemic infection previous to or concomitant with the diagnosis of TIN, and neither had evidence of other local or systemic autoimmune processes. We propose that both cases of TIN were not caused by mesalamine toxicity, nor by any other offending agent, infection, or inflammatory process, but rather were extraintestinal manifestations of CD. Our patients demonstrated many similarities in the natural course and severity of their intestinal disease and in their response to therapy. In both patients the intestinal disease proved steroid dependent, whereas the renal disease was shown to be steroid resistant. Ultimately, escalation to infliximab therapy resulted in control of the intestinal disease, but the TIN remained refractory. Furthermore, the renal disease in 1 patient also seemed to be unresponsive to adalimumab. This is contrary to previous reports of therapeutic efficacy of anti-TNF-α therapy for extraintestinal and metastatic CD of the liver, lung (17), and skin (22,23). Given this lack of response in our 2 patients, we propose that TNF-α may not be an integral part of the pathophysiology behind their TIN. In 1 of our patients, granulomas were identified in the kidney, redefining her disease as metastatic CD. Given that granulomas are aggregates of activated epithelioid macrophages, and understanding that activated macrophages secrete TNF-α, we may have expected a granulomatous interstitial nephropathy to be highly responsive to anti-TNF-α therapy. Although granulomas have been reported in a variety of organ systems in children with IBD and have been reported in an adult kidney (4), to our knowledge, this is the first report of renal metastatic CD in children. Depending on its cause, TIN can have a variable prognosis. When TIN is associated with mesalamine exposure, early discontinuation of mesalamine has led to improvement in kidney function in 78% of patients (12), but after a mean 10-month follow-up, 61% were left with chronic renal insufficiency and 13% with end-stage renal disease. In the absence of 5-aminosalicylate exposure, the limited reports available are even less optimistic. Of the 9 previous reports in adults, 50% experienced end-stage renal disease within 3 years of diagnosis, and 1 patient underwent renal transplantation (11). For renal metastatic CD, Archimandritis and Weetch (4) reported improvement in renal histopathology and creatinine clearance only after proctocolectomy. Although larger numbers and longer follow-up are needed to enable accurate comment on the prognosis of the Crohn-related kidney disease, the available data suggest that TIN, with or without exposure to 5-aminosalicylates, is a rare but serious complication. On the basis of the previous reports of TIN in adult patients with CD and with our 2 pediatric cases, we propose that TIN be added to the list of extraintestinal complications of pediatric CD. Furthermore, these cases raise questions about the potential benefit of monitoring for renal disease in patients with CD regardless of their exposure to 5-aminosalicylate therapy. Although there are several unanswered questions concerning the prevalence and prognosis of TIN in CD, we are hopeful that with future collaboration among gastroenterologists and nephrologists, many of these questions will be answered." @default.
• W2092118820 created "2016-06-24" @default.
• W2092118820 creator A5002029087 @default.
• W2092118820 creator A5011675701 @default.
• W2092118820 creator A5039089267 @default.
• W2092118820 creator A5042551999 @default.
• W2092118820 date "2008-03-01" @default.
• W2092118820 modified "2023-10-15" @default.
• W2092118820 title "Tubulointerstitial Nephritis: An Extraintestinal Manifestation of Crohn Disease in Children" @default.
• W2092118820 cites W1605395656 @default.
• W2092118820 cites W1782151952 @default.
• W2092118820 cites W1979665146 @default.
• W2092118820 cites W1981026734 @default.
• W2092118820 cites W1988173708 @default.
• W2092118820 cites W1991957588 @default.
• W2092118820 cites W2000415574 @default.
• W2092118820 cites W2002518345 @default.
• W2092118820 cites W2003590264 @default.
• W2092118820 cites W2006564212 @default.
• W2092118820 cites W2017358952 @default.
• W2092118820 cites W2018597175 @default.
• W2092118820 cites W2029791051 @default.
• W2092118820 cites W2040514248 @default.
• W2092118820 cites W2041426354 @default.
• W2092118820 cites W2055330537 @default.
• W2092118820 cites W2060561658 @default.
• W2092118820 cites W2062745584 @default.
• W2092118820 cites W2098570768 @default.
• W2092118820 cites W2114301460 @default.
• W2092118820 cites W2142496413 @default.
• W2092118820 cites W2170485499 @default.
• W2092118820 doi "https://doi.org/10.1097/mpg.0b013e31806dc2c4" @default.
• W2092118820 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18376255" @default.
• W2092118820 hasPublicationYear "2008" @default.
• W2092118820 type Work @default.
• W2092118820 sameAs 2092118820 @default.
• W2092118820 citedByCount "31" @default.
• W2092118820 countsByYear W20921188202012 @default.
• W2092118820 countsByYear W20921188202014 @default.
• W2092118820 countsByYear W20921188202015 @default.
• W2092118820 countsByYear W20921188202016 @default.
• W2092118820 countsByYear W20921188202017 @default.
• W2092118820 countsByYear W20921188202018 @default.
• W2092118820 countsByYear W20921188202019 @default.
• W2092118820 countsByYear W20921188202020 @default.
• W2092118820 countsByYear W20921188202021 @default.
• W2092118820 countsByYear W20921188202022 @default.
• W2092118820 countsByYear W20921188202023 @default.
• W2092118820 crossrefType "journal-article" @default.
• W2092118820 hasAuthorship W2092118820A5002029087 @default.
• W2092118820 hasAuthorship W2092118820A5011675701 @default.
• W2092118820 hasAuthorship W2092118820A5039089267 @default.
• W2092118820 hasAuthorship W2092118820A5042551999 @default.
• W2092118820 hasBestOaLocation W20921188201 @default.
• W2092118820 hasConcept C126322002 @default.
• W2092118820 hasConcept C203014093 @default.
• W2092118820 hasConcept C2777058396 @default.
• W2092118820 hasConcept C2779134260 @default.
• W2092118820 hasConcept C2779280984 @default.
• W2092118820 hasConcept C2992200296 @default.
• W2092118820 hasConcept C71924100 @default.
• W2092118820 hasConceptScore W2092118820C126322002 @default.
• W2092118820 hasConceptScore W2092118820C203014093 @default.
• W2092118820 hasConceptScore W2092118820C2777058396 @default.
• W2092118820 hasConceptScore W2092118820C2779134260 @default.
• W2092118820 hasConceptScore W2092118820C2779280984 @default.
• W2092118820 hasConceptScore W2092118820C2992200296 @default.
• W2092118820 hasConceptScore W2092118820C71924100 @default.
• W2092118820 hasIssue "3" @default.
• W2092118820 hasLocation W20921188201 @default.
• W2092118820 hasLocation W20921188202 @default.
• W2092118820 hasLocation W20921188203 @default.
• W2092118820 hasOpenAccess W2092118820 @default.
• W2092118820 hasPrimaryLocation W20921188201 @default.
• W2092118820 hasRelatedWork W2019430989 @default.
• W2092118820 hasRelatedWork W2025062623 @default.
• W2092118820 hasRelatedWork W2085446880 @default.
• W2092118820 hasRelatedWork W2094862489 @default.
• W2092118820 hasRelatedWork W2147907790 @default.
• W2092118820 hasRelatedWork W2383105242 @default.
• W2092118820 hasRelatedWork W2436073988 @default.
• W2092118820 hasRelatedWork W4380486554 @default.
• W2092118820 hasRelatedWork W4381193501 @default.
• W2092118820 hasRelatedWork W4383420693 @default.
• W2092118820 hasVolume "46" @default.
• W2092118820 isParatext "false" @default.
• W2092118820 isRetracted "false" @default.
• W2092118820 magId "2092118820" @default.
• W2092118820 workType "article" @default.