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Renal Manifestations of Inflammatory Bowel Disease

Open AccessPublished:September 07, 2018DOI:https://doi.org/10.1016/j.rdc.2018.06.007

      Keywords

      Key points

      • Renal and urinary involvement has been reported to occur in 4% to 23% of inflammatory bowel disease (IBD) patients, manifested primarily as urinary calculi, fistulas, and obstruction. Parenchymal renal disease is rare but has been well documented and presents most commonly as glomerulonephritis or tubulointerstitial nephritis.
      • IgA nephropathy is the most frequent finding on renal biopsy in IBD and has a significantly higher diagnostic prevalence compared with all non-IBD renal biopsies. This may reflect a common pathogenic mechanism.
      • Although several cases of tubulointerstitial nephritis have been related to drug exposure, there is increasing evidence that this finding may represent a true extraintestinal manifestation of IBD itself.
      • A high index of clinical suspicion is needed for the early diagnosis and prevention of IBD-related renal manifestations and complications. Optimal screening and monitoring protocols, however, have yet to be established.

      Introduction

      Inflammatory bowel disease (IBD) is a condition characterized by chronic inflammation of the gastrointestinal tract with the 2 most common types Crohn disease (CD) and ulcerative colitis (UC). The inciting agent and exact underlying mechanism of IBD is not entirely known; however, there is convincing evidence that it is mediated by abnormal T-cell function in genetically susceptible individuals.
      • Marsal J.
      • Agace W.W.
      Targeting T-cell migration in inflammatory bowel disease.
      • Sartor R.B.
      Mechanisms of disease: pathogeneis of chrone's disease and ulcerative colitis.
      Despite these etiologic similarities, the 2 diseases are characterized by different T-cell responses with CD driven mainly by a T helper (Th)1/ Th17 cell response in which interleukin (IL)-12 and IL-23 cytokines play key roles, whereas UC is driven mainly by a Th2 cell-like response with natural killer T cells producing IL-13 and IL-5.
      • Strober W.
      • Fuss I.J.
      Pro-inflammatory cytokines in the pathogenesis of IBD.
      Epidemiologic studies have shown an overall greater incidence of CD among women compared with men, although this varies by geographic region and age, whereas no significant gender difference is seen in UC.
      • Brant S.R.
      • Nguyen G.C.
      Is there a gender difference in the prevalence of Crohn's disease or ulcerative colitis?.
      Involvement of other organs outside primary intestinal disease is seen in both CD and UC, although the reasons for this are not entirely clear.

      Extraintestinal manifestations

      Extraintestinal manifestations (EIMs) of IBD are common, occurring in 6% to 47% of patients, and can involve nearly every organ system.
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      • Blanchard J.F.
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      The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study.
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      • Lana R.
      • Taxonera C.
      • et al.
      Extraintestinal manifestations in inflammatory bowel disease: differences between Crohn's disease and ulcerative colitis.
      • Corica D.
      • Romano C.
      Renal involvement in inflammatory bowel diseases.
      Some EIMs may precede IBD, although the majority accompany the underlying intestinal disease and are influenced by its activity.
      • Das K.M.
      Relationship of extraintestinal involvements in inflammatory bowel disease: new insights into autoimmune pathogenesis.
      The development of one EIM seems to increase the susceptibility of developing others, and there is a high concordance of EIMs in siblings and first-degree relatives with IBD.
      • Sato H.
      • Umemura K.
      • Yamamoto T.
      • et al.
      Interstitial nephritis associated with ulcerative colitis in monozygotic twins.
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      The most common organs involved include the skin, eyes, joints, and hepatobiliary tract and their involvement is dependent on different mechanisms.
      • Danese S.
      • Semeraro S.
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      • et al.
      Extraintestinal manifestations in inflammatory bowel disease.
      These include
      • Systemic reactive manifestations often directly related to intestinal inflammation and disease activity, reflecting a common pathogenic mechanism
        • Danese S.
        • Semeraro S.
        • Papa A.
        • et al.
        Extraintestinal manifestations in inflammatory bowel disease.
      • Autoimmune diseases independent of IBD but reflecting an overall susceptibility to autoimmunity due to genetic risk factors and systemic immune dysregulation, such as aberrant self-recognition and generation of autoantibodies
        • Oikonomou K.
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        • Eleftheriadis T.
        • et al.
        Renal manifestations and complications of inflammatory bowel disease.
      • Deposition of circulating immune complexes or in situ formation of immune complexes leading to an increased risk of glomerulonephritis and perhaps tubulointerstitial nephritis (TIN)
        • Ambruzs J.M.
        • Walker P.D.
        • Larsen C.P.
        The histopathologic spectrum of kidney biopsies in patients with inflammatory bowel disease.
        • Waters A.M.
        • Zachos M.
        • Herzenberg A.M.
        • et al.
        Tubulointerstitial nephritis as an extraintestinal manifestation of Crohn's disease.
      • Manifestations secondary to the metabolic and anatomic derangements commonly present as a direct result of intestinal disease and/or its treatment, also referred to as complications rather than manifestations
        • Rothfuss K.S.
        • Stande E.F.
        • Herrlinger K.R.
        Extraintestinal manifestations and complications in inflammatory bowel diseases.
        • Oikonomou K.
        • Kapsoritakis A.
        • Eleftheriadis T.
        • et al.
        Renal manifestations and complications of inflammatory bowel disease.
      Renal and urinary involvement has been reported to occur in 4% to 23% of IBD patients manifested primarily as urinary calculi, fistulas, and ureteral obstruction.
      • Shield D.E.
      • Lytton B.
      • Weiss R.M.
      • et al.
      Urologic complications of inflammatory bowel disease.
      • Pardi D.S.
      • Tremaine W.J.
      • Sandborn W.J.
      • et al.
      Renal and urologic complications of inflammatory bowel disease.
      Parenchymal renal disease is rare but has been well documented in the worldwide literature. This has been in the form of case reports and small series describing glomerulonephritis,
      • Ridder R.M.
      • Kreth H.W.
      • Kiss E.
      • et al.
      Membranous nephropathy associated with familial chronic ulcerative colitis in a 12-year-old girl.
      • Shaer A.J.
      • Stewart L.R.
      • Cheek D.E.
      • et al.
      IgA antiglomerular basement membrane nephritis associated with Crohn's disease: a case report and review of glomerulonephritis in inflammatory bowel disease.
      • Plaisier E.
      • Borradori L.
      • Hellmark T.
      • et al.
      Anti-glomerular basement membrane nephritis and bullous pemphigoid caused by distinct anti-a3(IV)NC1 and anti-BP180 antibodies in a patient with Crohn's disease.
      • Peeters A.J.
      • van den Wall Bake A.W.
      • Daha M.R.
      • et al.
      Inflammatory bowel disease and ankylosing spondylitis associated with cutaneous vasculitis, glomerulonephritis, and circulating IgA immune complexes.
      • Schofield P.M.
      • Williams P.S.
      Proliferative glomerulonephritis associated with Crohn's disease.
      • Hellwege H.H.
      • Bläker F.
      • Gebbers J.O.
      Hypocomplementemic membranoproliferative glomerulonephritis in a child with ulcerative colitis.
      • Koçak E.
      • Köklü S.
      • Akbal E.
      • et al.
      Development of glomerulonephritis early in the course of Crohn's disease.
      minimal change disease,
      • Barbour V.M.
      • Williams P.F.
      Nephrotic syndrome associated with sulphasalazine.
      • Fornaciari G.
      • Maccari S.
      • Borgatti P.P.
      • et al.
      Nephrotic syndrome from 5-ASA for ulcerative colitis? Complicated by carcinoma of the colon and sclerosing cholangitis.
      • Skhiri H.
      • Knebelmann B.
      • Martin-Lefevre L.
      • et al.
      Nephrotic syndrome associated with inflammatory bowel disease treated by mesalazine.
      • Firwana B.M.
      • Hasan R.
      • Chalhoub W.
      • et al.
      Nephrotic syndrome after treatment of Crohn's disease with mesalamine: case report and literature review.
      • Molnár T.
      • Farkas K.
      • Nagy F.
      • et al.
      Sulfasalazine-induced nephrotic syndrome in a patient with ulcerative colitis.
      • Novis B.H.
      • Korzets Z.
      • Chen P.
      • et al.
      Nephrotic syndrome after treatment with 5-aminosalicylic acid.
      secondary amyloidosis,
      • Guardiola-Arévalo A.
      • Alcántara-Torres M.
      • Valle-Muñoz J.
      • et al.
      Amyloidosis and Crohńs disease.
      • Wester A.L.
      • Vatn M.H.
      • Fausa O.
      Secondary amyloidosis in inflammatory bowel disease: a study of 18 patients admitted to Rikshospitalet University Hospital, Oslo, from 1962 to 1998.
      • Greenstein A.J.
      • Sachar D.B.
      • Panday A.K.
      • et al.
      Amyloidosis and inflammatory bowel disease. A 50-year experience with 25 patients.
      and TIN
      • Tadic M.
      • Grgurevic I.
      • Scukanec-Spoljar M.
      • et al.
      Acute interstitial nephritis due to mesalazine.
      • Margetts P.J.
      • Churchill D.N.
      • Alexopoulou I.
      Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine.
      • Tokuyama H.
      • Wakino S.
      • Konishi K.
      • et al.
      Acute interstitial nephritis associated with ulcerative colitis.
      • Izzedine H.
      • Simon J.
      • Piette A.M.
      • et al.
      Primary chronic interstitial nephritis in Crohn's disease.
      (Box 1). The morbidity and even mortality associated with renal EIMs are significant, and a high index of clinical suspicion is often needed for early recognition, as is continued surveillance to minimize recurrences and complications.
      Renal manifestations of inflammatory bowel disease
      • Nephrolithiasis
        • Calcium oxalate
        • Uric acid
      • Glomerulopathy
        • IgAN
        • Membranoproliferative glomerulonephritis
        • Membranous glomerulopathy
        • Antiglomerular basement membrane glomerulonephritis
        • Minimal change disease
      • AA amyloidosis
      • Tubulointerstitial disease
        • Acute tubular injury
        • TIN
          • Acute
          • Chronic
          • Granulomatous

      Renal insufficiency in inflammatory bowel disease

      Renal EIMs and IBD-related therapy are potential risk factors for the development of renal insufficiency (both acute and chronic) in patients with CD and UC. There is a lack of large, population-based studies, however, looking at actual incidence and prevalence of renal insufficiency in IBD patients. Two retrospective studies examined the frequency of renal insufficiency and its associated risk factors in IBD patients admitted to a tertiary care center.
      • Lewis B.
      • Mukewar S.
      • Lopez R.
      • et al.
      Frequency and risk factors of renal insufficiency in inflammatory bowel disease inpatients.
      • Primas C.
      • Novacek G.
      • Schweiger K.
      • et al.
      Renal insufficiency in IBD–prevalence and possible pathogenetic aspects.
      In Primas and colleagues’ study,
      • Primas C.
      • Novacek G.
      • Schweiger K.
      • et al.
      Renal insufficiency in IBD–prevalence and possible pathogenetic aspects.
      775 patients with IBD were analyzed and only 11 (2%) had renal insufficiency, all patients with CD. Significant risk factors identified were duration of disease, length of resected small bowel, and recurrent nephrolithiasis and the number of interventions due to stones. They extrapolated that this suggests an annual prevalence of 1.63/100,000 IBD patients (per year). A separate study by Lewis and colleagues
      • Lewis B.
      • Mukewar S.
      • Lopez R.
      • et al.
      Frequency and risk factors of renal insufficiency in inflammatory bowel disease inpatients.
      also retrospectively examined 251 admitted patients with IBD and found a higher 15.9% frequency of renal insufficiency, two-thirds of them chronic. This frequency was not statistically different between patients with CD and UC. They also found, however, that risk factors for renal insufficiency included older age and duration of disease as well as history of nephrolithiasis. They determined that for every 5-year increase in age, the likelihood of having renal insufficiency increased by 30%. Despite multiple reports of 5-aminosalicylate (5-ASA)-related nephrotoxicity, neither of the studies found 5-ASA therapy a significant risk factor for renal insufficiency. Both studies conclude that renal function should be routinely monitored in patients with IBD, particularly in elderly patients.
      Renal biopsy is not frequently performed on patients with IBD, although it should be considered in patients presenting with renal insufficiency, proteinuria, or hematuria, particularly if other comorbid conditions are absent or renal insufficiency persists despite removal of nephrotoxic agents. In the largest case series of IBD patients referred for renal biopsy, the most common indication was acute and/or chronic renal insufficiency followed by proteinuria (Table 1).
      • Ambruzs J.M.
      • Walker P.D.
      • Larsen C.P.
      The histopathologic spectrum of kidney biopsies in patients with inflammatory bowel disease.
      A cross-sectional national survey conducted among private gastroenterologists found that only 59% screen for renal insufficiency before initiating treatment with 5-ASA, a potential nephrotoxic agent.
      • Zallot C.
      • Billioud V.
      • Frimat L.
      • et al.
      CREGG (Club de Reflexion des cabinets et Groupes d'Hépato-Gastroentérologie). 5-Aminosalicylates and renal function monitoring in inflammatory bowel disease: a nationwide survey.
      If impairment is found, however, 80% report consulting a nephrologist prior to commencing treatment.
      Table 1Demographic and clinical characteristics of patients with inflammatory bowel disease referred for renal biopsy
      Adapted from Ambruzs JM, Walker PD, Larsen CP. The histopathologic spectrum of kidney biopsies in patients with inflammatory bowel disease. Clin J Am Soc Nephrol 2014;9(2):266; with permission.
      CharacteristicData
      Patients (n)83
      Men, n (%)51 (61)
      Mean age ± SD (y)46 ± 18
      UC, n (%)38 (46)
      CD, n (%)45 (54)
      Median serum creatinine (mg/dL) (25th, 75th percentiles)2.7 (1.7, 4.3)
      Indications for renal biopsy, n (%)
       Acute kidney injury26 (31)
       Chronic kidney disease9 (11)
       Acute on chronic kidney disease17 (21)
       Nephrotic-range proteinuria13 (16)
       Subnephrotic proteinuria12 (14)
       Isolated hematuria6 (7)

      Nephrolithiasis

      Nephrolithiasis is the most common urinary complication in IBD patients, most often the result of metabolic and anatomic derangements directly related to intestinal disease. Although large epidemiologic studies are lacking, smaller studies have estimated a lifetime risk for nephrolithiasis of 9% to 18% in IBD patients, higher than in the general population.
      • Shield D.E.
      • Lytton B.
      • Weiss R.M.
      • et al.
      Urologic complications of inflammatory bowel disease.
      • Gkentzis A.
      • Kimuli M.
      • Cartledge J.
      • et al.
      Urolithiasis in inflammatory bowel disease and bariatric surgery.
      The risk has been found to be higher in adult patients than pediatric patients, higher in CD than UC, and higher in those patients who have had surgical bowel resection, particularly of the terminal ileum (up to 28%).
      • Shield D.E.
      • Lytton B.
      • Weiss R.M.
      • et al.
      Urologic complications of inflammatory bowel disease.
      • Pardi D.S.
      • Tremaine W.J.
      • Sandborn W.J.
      • et al.
      Renal and urologic complications of inflammatory bowel disease.
      • Gkentzis A.
      • Kimuli M.
      • Cartledge J.
      • et al.
      Urolithiasis in inflammatory bowel disease and bariatric surgery.
      • Andersson H.
      • Bosaeus I.
      • Fasth S.
      • et al.
      Cholelithiasis and urolithiasis in Crohn's disease.
      The overall morbidity is often significant secondary to repeated recurrences requiring medical and surgical interventions, obstruction and hydronephrosis, and infection. As discussed previously, it has also been shown that recurrent nephrolithiasis and the number of interventions for its treatment are 2 risk factors for the development of chronic kidney disease in IBD patients.
      • Primas C.
      • Novacek G.
      • Schweiger K.
      • et al.
      Renal insufficiency in IBD–prevalence and possible pathogenetic aspects.
      • Gkentzis A.
      • Kimuli M.
      • Cartledge J.
      • et al.
      Urolithiasis in inflammatory bowel disease and bariatric surgery.
      Kidney stones in IBD patients are composed primarily of calcium oxalate or uric acid. Calcium oxalate is more commonly seen in patients with CD, particularly as a result of ileocolonic disease with subsequent bile salt and fatty acid malabsorption. This malabsorption results in increased oxalate intestinal absorption, termed enteric hyperoxaluria. There is also increased permeability of the colonic mucosa and decreased numbers of colonic oxalate-metabolizing bacteria (Oxalobacter formingens).
      • Pardi D.S.
      • Tremaine W.J.
      • Sandborn W.J.
      • et al.
      Renal and urologic complications of inflammatory bowel disease.
      • Allison M.J.
      • Cook H.M.
      • Milne D.B.
      • et al.
      Oxalate degradation by gastrointestinal bacteria from humans.
      These factors, along with low urinary volume and low concentration of stone inhibitors (ie, magnesium and citrate), all likely promote lithogenesis in IBD patients.
      • Parks J.H.
      • Worcester E.M.
      • O'Connor R.C.
      • et al.
      Urine stone risk factors in nephrolithiasis patients with and without bowel disease.
      • McConnell N.
      • Campbell S.
      • Gillanders I.
      • et al.
      Risk factors for developing renal stones in inflammatory bowel disease.
      Uric acid stones often result from loss of volume and bicarbonate through frequent diarrhea or small bowel ostomies resulting in concentrated and acidic urine.
      • Pardi D.S.
      • Tremaine W.J.
      • Sandborn W.J.
      • et al.
      Renal and urologic complications of inflammatory bowel disease.
      Pediatric IBD patients may have predominantly calcium phosphate stones.
      • Pardi D.S.
      • Tremaine W.J.
      • Sandborn W.J.
      • et al.
      Renal and urologic complications of inflammatory bowel disease.
      • Clark J.H.
      • Fitzgerald J.F.
      • Bergstein J.M.
      Nephrolithiasis in childhood inflammatory bowel disease.
      Finally, sulfasalazine-induced crystalluria and nephrolithiasis resulting in obstructive uropathy has rarely been reported.
      • Russinko P.J.
      • Agarwal S.
      • Choi M.J.
      • et al.
      Obstructive nephropathy secondary to sulfasalazine calculi.
      • Durando M.
      • Tiu H.
      • Kim J.S.
      Sulfasalazine-induced crystalluria causing severe acute kidney injury.
      Early recognition and management of nephrolithiasis in IBD patients are imperative and often involve a dietary, medical, and surgical approach.
      • Gaspar S.R.
      • Mendonca T.
      • Oliveira P.
      • et al.
      Urolithiasis and Crohn's disease.
      This includes patient counseling regarding risks, increased hydration and control of fluid losses from diarrhea and ostomy output, reduction in dietary oxalate and fat, and urinary alkalization.
      • Gkentzis A.
      • Kimuli M.
      • Cartledge J.
      • et al.
      Urolithiasis in inflammatory bowel disease and bariatric surgery.
      Some investigators have also advocated for imaging of the upper urinary tract at regular intervals as well as early elective surgical intervention for detected stones.
      • Gkentzis A.
      • Kimuli M.
      • Cartledge J.
      • et al.
      Urolithiasis in inflammatory bowel disease and bariatric surgery.
      • Ishii G.
      • Nakajima K.
      • Tanaka N.
      • et al.
      Clinical evaluation of urolithiasis in Crohn's disease.
      • Varda B.K.
      • McNabb-Baltar J.
      • Sood A.
      • et al.
      Urolithiasis and urinary tract infection among patients with inflammatory bowel disease: a review of US emergency department visits between 2006 and 2009.

      Glomerulopathy

      Glomerular involvement in IBD is rare, although several morphologic patterns of glomerular injury have been described (Fig. 1). These include
      • IgA nephropathy (IgAN)
        • Peeters A.J.
        • van den Wall Bake A.W.
        • Daha M.R.
        • et al.
        Inflammatory bowel disease and ankylosing spondylitis associated with cutaneous vasculitis, glomerulonephritis, and circulating IgA immune complexes.
        • Hubert D.
        • Beaufils M.
        • Meyrier A.
        Immunoglobulin a glomerular nephropathy associated with inflammatory colitis. Apropos of 2 cases.
        • Filiopoulos V.
        • Trompouki S.
        • Hadjiyannakos D.
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        IgA nephropathy in association with Crohn's disease: a case report and brief review of the literature.
        • Pipili C.
        • Michopoulos S.
        • Sotiropoulou M.
        • et al.
        Is there any association between IgA nephropathy, Crohn's disease and Helicobacter pylori infection?.
        • Ku E.
        • Ananthapanyasut W.
        • Campese V.M.
        IgA nephropathy in a patient with ulcerative colitis, Graves' disease and positive myeloperoxidase ANCA.
        • Choi J.Y.
        • Yu C.H.
        • Jung H.Y.
        • et al.
        A case of rapidly progressive IgA nephropathy in a patient with exacerbation of Crohn's disease.
        • Lee J.M.
        • Lee K.M.
        • Kim H.W.
        • et al.
        Crohn's disease in association with IgA nephropathy.
        • Onime A.
        • Agaba E.I.
        • Sun Y.
        • et al.
        Immunoglobulin a nephropathy complicating ulcerative colitis.
        • Youm J.Y.
        • Lee O.Y.
        • Park M.H.
        • et al.
        Crohn's disease associated with IgA nephropathy.
        • de Moura C.G.
        • de Moura T.G.
        • de Souza S.P.
        • et al.
        Inflammatory bowel disease, ankylosing spondylitis, and IgA nephropathy.
        • Forshaw M.J.
        • Guirguis O.
        • Hennigan T.W.
        IgA nephropathy in association with Crohn's disease.
        • Takemura T.
        • Okada M.
        • Yagi K.
        • et al.
        An adolescent with IgA nephropathy and Crohn disease: pathogenetic implications.
        • Trimarchi H.M.
        • Lotti A.
        • Lotti R.
        • et al.
        Immunoglobulin a nephropathy and ulcerative colitis. a focus on their pathogenesis.
        • McCallum D.
        • Smith L.
        • Harley F.
        • et al.
        IgA nephropathy and thin basement membrane disease in association with Crohn disease.
        • Dabadie A.
        • Gié S.
        • Taque S.
        • et al.
        Glomerular nephropathy with IgA mesangium deposits and Crohn disease.
        • Hirsch D.J.
        • Jindal K.K.
        • Trillo A.
        • et al.
        Acute renal failure in Crohn's disease due to IgA nephropathy.
        • López Barbarín J.M.
        • Lafuente Martínez P.
        • García Campos F.
        • et al.
        Crohn's disease associated with Berger's disease. A rare complication.
        • Iida H.
        • Asaka M.
        • Izumino K.
        • et al.
        IgA nephropathy complicated by ulcerative colitis.
        • Soejima A.
        • Nakabayasi K.
        • Kitamoto K.
        Iga nephropathy in a patient with ulcerative colitis.
        • Kammerer J.
        • Genin I.
        • Michel P.
        • et al.
        Glomerulonephritis caused by mesangial deposits of immunoglobulins A associated with Crohn disease.
        • Terasaka T.
        • Uchida H.A.
        • Umebayashi R.
        • et al.
        The possible involvement of intestine-derived IgA1: a case of IgA nephropathy associated with Crohn's disease.
      • Membranoproliferative glomerulonephritis
        • Schofield P.M.
        • Williams P.S.
        Proliferative glomerulonephritis associated with Crohn's disease.
        • Hellwege H.H.
        • Bläker F.
        • Gebbers J.O.
        Hypocomplementemic membranoproliferative glomerulonephritis in a child with ulcerative colitis.
        • Moayyedi P.
        • Fletcher S.
        • Hamden P.
        • et al.
        Mesangiocapillary glomerulonephritis associated with ulcerative colitis: case reports of two patients.
      • Minimal change disease
        • Barbour V.M.
        • Williams P.F.
        Nephrotic syndrome associated with sulphasalazine.
        • Fornaciari G.
        • Maccari S.
        • Borgatti P.P.
        • et al.
        Nephrotic syndrome from 5-ASA for ulcerative colitis? Complicated by carcinoma of the colon and sclerosing cholangitis.
        • Skhiri H.
        • Knebelmann B.
        • Martin-Lefevre L.
        • et al.
        Nephrotic syndrome associated with inflammatory bowel disease treated by mesalazine.
        • Firwana B.M.
        • Hasan R.
        • Chalhoub W.
        • et al.
        Nephrotic syndrome after treatment of Crohn's disease with mesalamine: case report and literature review.
        • Molnár T.
        • Farkas K.
        • Nagy F.
        • et al.
        Sulfasalazine-induced nephrotic syndrome in a patient with ulcerative colitis.
        • Novis B.H.
        • Korzets Z.
        • Chen P.
        • et al.
        Nephrotic syndrome after treatment with 5-aminosalicylic acid.
      • Membranous glomerulopathy
        • Ridder R.M.
        • Kreth H.W.
        • Kiss E.
        • et al.
        Membranous nephropathy associated with familial chronic ulcerative colitis in a 12-year-old girl.
        • Casella G.
        • Perego D.
        • Baldini V.
        • et al.
        A rare association between ulcerative colitis (UC), celiac disease (CD), membranous glomerulonephritis, leg venous thrombosis, and heterozygosity for factor V Leiden.
        • Warling O.
        • Bovy C.
        • Co D.O.
        • et al.
        Overlap syndrome consisting of PSC-AIH with concomitant presence of a membranous glomerulonephritis and ulcerative colitis.
      • Antiglomerular basement membrane glomerulonephritis
        • Shaer A.J.
        • Stewart L.R.
        • Cheek D.E.
        • et al.
        IgA antiglomerular basement membrane nephritis associated with Crohn's disease: a case report and review of glomerulonephritis in inflammatory bowel disease.
        • Plaisier E.
        • Borradori L.
        • Hellmark T.
        • et al.
        Anti-glomerular basement membrane nephritis and bullous pemphigoid caused by distinct anti-a3(IV)NC1 and anti-BP180 antibodies in a patient with Crohn's disease.
        • Hibbs A.M.
        • Bznik-Cizman B.
        • Guttenberg M.
        • et al.
        Ulcerative colitis in a renal transplant patient with previous Goodpasture disease.
        • Nakamura T.
        • Suzuki Y.
        • Koide H.
        Granulocyte and monocyte adsorption apheresis in a patient with antiglomerular basement membrane glomerulonephritis and active ulcerative colitis.
      • C3 glomerulopathy
        • Marques da Costa P.
        • Correia L.
        • Correia L.A.
        The complexity of renal involvment in IBD-C3 glomerulopathy in ulcerative colitis.
      Figure thumbnail gr1
      Fig. 1Glomerular lesions associated with inflammatory bowel disease. (A) Glomerulus with mesangial matrix expansion and hypercellularity in a patient with IgAN and CD (periodic acid–Schiff; original magnification ×400). (B) Positive IgA staining of the glomerular mesangium by immunofluorescence (fluorescein conjugated antihuman IgA; original magnification ×400). (C) Glomerular and vascular amyloid deposits show positive staining for AA in this case of AA amyloidosis and CD (immunoperoxidase; original magnification ×200). (D) Transmission electron photomicrograph showing a glomerulus with numerous subepithelial electron dense deposits (arrows) from a case of membranous glomerulopathy and CD (original magnification ×2000). Tissue staining for the phospholipase A2 receptor (PLA2R) and thrombospondin (THSD7A) were both negative (not shown here).
      The etiology of glomerular involvement in IBD is not entirely understood and may involve a common pathogenic mechanism or genetic susceptibility, deposition of intestine derived immune complexes as a result of increased mucosal permeability and antigenic exposure, and finally an effect of drug therapy, particularly in the case of minimal change disease. The fact that many reports show presentation or exacerbation of glomerulonephritis coincident with bowel disease activity, as well as subsequent resolution after successful IBD treatment, bolsters the consideration of glomerular injury as an EIM of IBD.
      • Oikonomou K.
      • Kapsoritakis A.
      • Eleftheriadis T.
      • et al.
      Renal manifestations and complications of inflammatory bowel disease.
      The most common reported glomerulonephritis in patients with IBD, by a wide margin, is IgAN. The largest cases series of renal biopsy findings in IBD patients also showed that IgAN was the most common diagnosis, present in 43% of all biopsies.
      • Ambruzs J.M.
      • Walker P.D.
      • Larsen C.P.
      The histopathologic spectrum of kidney biopsies in patients with inflammatory bowel disease.
      Given the relative frequency of subclinical IgAN in otherwise healthy populations, it has been suggested that this high frequency of IgAN found in IBD patients is coincidental.
      • Filiopoulos V.
      • Trompouki S.
      • Hadjiyannakos D.
      • et al.
      IgA nephropathy in association with Crohn's disease: a case report and brief review of the literature.
      • Pouria S.
      • Barratt J.
      Secondary IgA nephropathy.
      When Ambruzs and colleagues
      • Ambruzs J.M.
      • Walker P.D.
      • Larsen C.P.
      The histopathologic spectrum of kidney biopsies in patients with inflammatory bowel disease.
      compared their IBD cohort to all native renal biopsies from patients without IBD, however, they found the prevalence of IgAN in patients with IBD significantly higher. Hubert and colleagues
      • Hubert D.
      • Beaufils M.
      • Meyrier A.
      Immunoglobulin a glomerular nephropathy associated with inflammatory colitis. Apropos of 2 cases.
      reported the first cases of IBD-associated IgAN in 1984. They described both clinical and pathologic remission of renal disease concomitant with the symptomatic treatment of intestinal disease. There have been numerous subsequent case reports in the literature of IgAN in IBD, as discussed previously. A majority of these patients had occurrence of IgAN during onset or exacerbation of IBD as well as clinical remission of renal disease in conjunction with successful treatment of bowel inflammation. Elevated serum IgA levels were not consistently measured but were reported to be elevated in several patients. Repeat renal biopsy confirming histologic remission of glomerulonephritis was rare. When a biopsy was repeated, however, it showed resolution of both mesangial proliferation and IgA deposits.
      • Hubert D.
      • Beaufils M.
      • Meyrier A.
      Immunoglobulin a glomerular nephropathy associated with inflammatory colitis. Apropos of 2 cases.
      Secondary forms of IgAN have been described most commonly in the setting of liver disease. There has been increasing literature, however, associating mucosal inflammation and/or infection with IgAN.
      • Pipili C.
      • Michopoulos S.
      • Sotiropoulou M.
      • et al.
      Is there any association between IgA nephropathy, Crohn's disease and Helicobacter pylori infection?.
      • Pouria S.
      • Barratt J.
      Secondary IgA nephropathy.
      This is perhaps not surprising given the important immunologic role IgA plays in the defense against environmental and microbial antigenic exposures occurring at mucosal sites, in particular the gastrointestinal tract. Antibodies to various dietary antigens have also been detected both in sera as well as in IgA immune complexes and renal eluates in patients with IgAN.
      • Coppo R.
      The pathogenetic potential of environmental antigens in IgA nephropathy.
      Secondary IgAN in IBD, therefore, is likely to represent a complex interplay of mucosal inflammation, loss of antigenic exclusion and tolerance, chronic immune stimulation, and dysregulated IgA production and transport.
      • Pouria S.
      • Barratt J.
      Secondary IgA nephropathy.
      Given that intestinal mucosal immune responses are highly dependent on costimulation, the role of T-cell dysfunction in this process has also been implicated.
      • Wang J.
      • Anders R.A.
      • Wu Q.
      • et al.
      Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy.
      In their study of transgenic mice, Wang and colleagues
      • Wang J.
      • Anders R.A.
      • Wu Q.
      • et al.
      Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy.
      showed that T-cell–mediated mucosal immunity was critical in intestinal inflammation and in the pathogenesis of IgAN. Localized gastrointestinal immunosuppression (ie, enteric budesonide) as a potential treatment of primary IgAN likewise alludes to a pathogenic role of gut immune responses in the development of glomerulonephritis.
      • Filiopoulos V.
      • Vlassopoulos D.
      Steroids with local enteric action in IgA nephropathy and the association between kidney and bowel disease.
      • Smerud H.K.
      • Barany P.
      • Lindstrom K.
      • et al.
      New treatment for IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria.
      Genetic susceptibility has also been investigated and an association with HLA-DR1 has been described in both IgAN and IBD.
      • Forshaw M.J.
      • Guirguis O.
      • Hennigan T.W.
      IgA nephropathy in association with Crohn's disease.
      • Takemura T.
      • Okada M.
      • Yagi K.
      • et al.
      An adolescent with IgA nephropathy and Crohn disease: pathogenetic implications.
      More recently, new risk loci for IgAN have been identified with most implicating genes either directly associated with risk of IBD or maintenance of the intestinal epithelial barrier and response to mucosal pathogens.
      • Corica D.
      • Romano C.
      Renal involvement in inflammatory bowel diseases.
      • Kiryluk K.
      • Li Y.
      • Scolari F.
      • et al.
      Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.
      Together, these findings support a pathogenic link between immune mechanisms operating in IBD and IgAN rather than the idea that IBD serves only to exacerbate primary IgAN as has been previously suggested.

      Amyloidosis

      Amyloid A (AA) amyloidosis, so-called secondary amyloidosis, is a rare but serious complication of IBD. It involves the deposition of amyloid fibrils derived from serum AA (SAA) protein, an acute-phase reactant protein resulting from chronic inflammatory or infectious diseases. CD is the fourth leading cause
      • Tosca Cuquerella J.
      • Bosca-Watts M.M.
      • Anton Ausejo R.
      • et al.
      Amyloidosis in inflammatory bowel disease: a systematic review of epidemiology, clinical features, and treatment.
      of AA amyloidosis worldwide. Early reports of amyloidosis associated with IBD were largely from autopsy series. The kidneys are frequently involved (up to 90% of cases) with deposits predominantly involving the glomerular tuft and vessels. This results in not only significant patient morbidity with progressive renal impairment, proteinuria, and often end-stage kidney disease but also mortality.
      • Efstratiadis G.
      • Mainas A.
      • Leontsini M.
      Renal amyloidosis complicating Crohn's disease. Case report and review of the literature.
      A recent systematic review of amyloidosis in IBD reported an overall estimated frequency of 0.53%; however, when stratified, prevalence of amyloidosis in patients with CD was significantly higher than UC (1.05% vs 0.08%).
      • Tosca Cuquerella J.
      • Bosca-Watts M.M.
      • Anton Ausejo R.
      • et al.
      Amyloidosis in inflammatory bowel disease: a systematic review of epidemiology, clinical features, and treatment.
      Several studies have shown a clear predilection of AA amyloidosis in men, and it more commonly presents in those with long-standing disease, in particular those with fistulizing-stenotic forms, suppurative complications, and ileocolonic involvement, although cases of early presentation have also been reported.
      • Oikonomou K.
      • Kapsoritakis A.
      • Eleftheriadis T.
      • et al.
      Renal manifestations and complications of inflammatory bowel disease.
      • Guardiola-Arévalo A.
      • Alcántara-Torres M.
      • Valle-Muñoz J.
      • et al.
      Amyloidosis and Crohńs disease.
      • Wester A.L.
      • Vatn M.H.
      • Fausa O.
      Secondary amyloidosis in inflammatory bowel disease: a study of 18 patients admitted to Rikshospitalet University Hospital, Oslo, from 1962 to 1998.
      • Greenstein A.J.
      • Sachar D.B.
      • Panday A.K.
      • et al.
      Amyloidosis and inflammatory bowel disease. A 50-year experience with 25 patients.
      • Pukitis A.
      • Zake T.
      • Groma V.
      • et al.
      Effect of infliximab induction therapy on secondary systemic amyloidosis associated with Crohn's disease: case report and review of the literature.
      Patients with IBD and amyloidosis also frequently have other EIMs.
      The most common clinical presentation of amyloidosis in IBD is that of renal insufficiency (up to 70%) and nephrotic range proteinuria.
      • Tosca Cuquerella J.
      • Bosca-Watts M.M.
      • Anton Ausejo R.
      • et al.
      Amyloidosis in inflammatory bowel disease: a systematic review of epidemiology, clinical features, and treatment.
      Up to 15.3% of cases, however, show no evidence of renal injury or proteinuria at diagnosis, although this likely represents an overestimation.
      • Tosca Cuquerella J.
      • Bosca-Watts M.M.
      • Anton Ausejo R.
      • et al.
      Amyloidosis in inflammatory bowel disease: a systematic review of epidemiology, clinical features, and treatment.
      In terms of outcome, one prospective series found progression to end-stage renal disease in 15 of 22 (68%) patients with CD and AA amyloidosis, 6 of whom subsequently underwent renal transplantation.
      • Sattianayagam P.T.
      • Gillmore J.D.
      • Pinney J.H.
      • et al.
      Inflammatory bowel disease and systemic AA amyloidosis.
      Recurrence of amyloidosis occurred in only 1 graft after 14.5 years in a patient with sustained chronic active disease. Diagnosis of amyloidosis is most commonly made through tissue biopsy of the affected organ, typically a renal biopsy. Specific amyloid typing can be performed by immunohistochemistry testing or mass spectrometry.
      Treatment of AA amyloidosis in IBD focuses on controlling the underlying inflammatory state, decreasing the formation and circulating levels of SAA protein, and potentially reversing the amyloid deposits already present in affected organs.
      • Corica D.
      • Romano C.
      Renal involvement in inflammatory bowel diseases.
      • Guardiola-Arévalo A.
      • Alcántara-Torres M.
      • Valle-Muñoz J.
      • et al.
      Amyloidosis and Crohńs disease.
      There are currently no prospective, randomized control trials on treatment of amyloidosis in IBD. Corticosteroids and other immunosuppressive drugs (such as azathioprine, methotrexate, and cyclosporine), colchicine, dimethylsulfoxide, and elemental diet have all been used, although their effectiveness has not been established.
      • Ebert E.C.
      • Nagar M.
      Gastrointestinal manifestations of amyloidosis.
      • Cucino C.
      • Sonnenberg A.
      The comorbid occurrence of other diagnoses in patients with ulcerative colitis and Crohn's disease.
      • Saitoh O.
      • Kojima K.
      • Teranishi T.
      • et al.
      Renal amyloidosis as a late complication of Crohn's disease: a case report and review of the literature from Japan.
      Several studies with infliximab, a tumor necrosis factor (TNF)-α inhibitor, have been more promising and have demonstrated a decrease in SAA circulating levels, decrease in proteinuria, and stabilization of renal function, although it is unclear if reversibility of established damage can be achieved.
      • Tosca Cuquerella J.
      • Bosca-Watts M.M.
      • Anton Ausejo R.
      • et al.
      Amyloidosis in inflammatory bowel disease: a systematic review of epidemiology, clinical features, and treatment.
      • Pukitis A.
      • Zake T.
      • Groma V.
      • et al.
      Effect of infliximab induction therapy on secondary systemic amyloidosis associated with Crohn's disease: case report and review of the literature.
      • Park Y.K.
      • Han D.S.
      • Eun C.S.
      Systemic amyloidosis with Crohn's disease treated with infliximab.
      • Said Y.
      • Debbeche R.
      • Hamzaoui L.
      • et al.
      Infiximab for treatment of systemic amyloidosis associated with Crohn's disease.
      • Iizuka M.
      • Sagara S.
      • Etou T.
      Efficacy of scheduled infliximab maintenance therapy on systemic amyloidosis associated with crohn's disease.
      Newer treatments, such as tocilizumab, a humanized monoclonal antibody to the IL-6 receptor, have also shown promising results.
      • Tosca Cuquerella J.
      • Bosca-Watts M.M.
      • Anton Ausejo R.
      • et al.
      Amyloidosis in inflammatory bowel disease: a systematic review of epidemiology, clinical features, and treatment.
      • Ito H.
      • Takazoe M.
      • Fukuda Y.
      • et al.
      A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.
      • Brulhart L.
      • Nissen M.J.
      • Chevallier P.
      • et al.
      Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists.
      The administration of the drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, followed by a fully humanized monoclonal IgG1 antiserum amyloid P antibody, has been shown to effectively clear amyloid deposits from target organs, including kidney.
      • Tosca Cuquerella J.
      • Bosca-Watts M.M.
      • Anton Ausejo R.
      • et al.
      Amyloidosis in inflammatory bowel disease: a systematic review of epidemiology, clinical features, and treatment.
      • Richards D.B.
      • Cookson L.M.
      • Berges A.C.
      • et al.
      Therapeutic clearance of amyloid by antibodies to serum amyloid P component.
      • Richards D.B.
      • Cookson L.M.
      • Barton S.V.
      • et al.
      Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis.
      Further prospective trials are needed.

      Acute Tubular Injury

      Renal tubular injury has been reported as both an EIM of IBD as well as a complication of IBD-related therapy.
      • Schreiber S.
      • Hämling J.
      • Zehnter E.
      • et al.
      Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate.
      Specifically, renal tubular injury, in the form of proteinuria and enzymuria, has been frequently observed in IBD and is more strongly correlated with disease activity than therapy.
      • Fraser J.S.
      • Muller A.F.
      • Smith D.J.
      • et al.
      Renal tubular injury is present in acute inflammatory bowel disease prior to the introduction of drug therapy.
      • Herrlinger K.R.
      • Noftz M.K.
      • Fellermann K.
      • et al.
      Minimal renal dysfunction in inflammatory bowel disease is related to disease activity but not to 5-ASA use.
      • Kreisel W.
      • Wolf L.M.
      • Grotz W.
      • et al.
      Renal tubular damage: an extraintestinal manifestation of chronic inflammatory bowel disease.
      Kreisel and colleagues
      • Kreisel W.
      • Wolf L.M.
      • Grotz W.
      • et al.
      Renal tubular damage: an extraintestinal manifestation of chronic inflammatory bowel disease.
      measured enzymuria as an early marker of renal tubular damage in 147 consecutive patients with IBD. They found that pathologic enzymuria occurred in 28% of patients with UC and 19% of patients with CD. In UC, elevated enzymes were present almost exclusively in patients with active disease, with the highest levels measured before the start of therapy, and there was subsequent normalization in a subset of patients during the course of treatment with 5-ASA or sulfasalazine. Two subsequent studies looking at tubular proteinuria in IBD patients with normal renal function found pathologic proteinuria in essentially half of the patients and this correlated with disease activity and not 5-ASA treatment.
      • Fraser J.S.
      • Muller A.F.
      • Smith D.J.
      • et al.
      Renal tubular injury is present in acute inflammatory bowel disease prior to the introduction of drug therapy.
      • Herrlinger K.R.
      • Noftz M.K.
      • Fellermann K.
      • et al.
      Minimal renal dysfunction in inflammatory bowel disease is related to disease activity but not to 5-ASA use.
      These reports suggest that renal tubular injury in IBD may often be subclinical and represent a true EIM of active disease rather than a toxic drug effect. More sensitive markers for kidney injury are needed given the shortcomings of serum creatinine as an indication of renal function.

      Tubulointerstitial nephritis

      There have been several case reports of both acute and chronic TIN occurring in CD and UC patients, particularly in the setting of 5-ASA drug therapy and its derivatives.
      • Tadic M.
      • Grgurevic I.
      • Scukanec-Spoljar M.
      • et al.
      Acute interstitial nephritis due to mesalazine.
      • Margetts P.J.
      • Churchill D.N.
      • Alexopoulou I.
      Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine.
      • Agharazii M.
      • Marcotte J.
      • Boucher D.
      • et al.
      Chronic interstitial nephritis due to 5-aminosalicylic acid.
      • De Broe M.E.
      • Stolear J.C.
      • Nouwen E.J.
      • et al.
      5-Aminosalicylic acid (5-ASA) and chronic tubulointerstitial nephritis in patients with chronic inflammatory bowel disease: is there a link?.
      • Manenti L.
      • De Rosa A.
      • Buzio C.
      Mesalazine-associated interstitial nephritis: twice in the same patient.
      • Witte T.
      • Olbricht C.J.
      • Koch K.M.
      Interstitial nephritis associated with 5-aminosalicylic acid.
      This perhaps represents a complication rather than true manifestation of IBD; however, there are increasing reports of TIN presenting concurrently with IBD diagnosis in drug-naïve patients.
      • Izzedine H.
      • Simon J.
      • Piette A.M.
      • et al.
      Primary chronic interstitial nephritis in Crohn's disease.
      • Marcus S.B.
      • Brown J.B.
      • Melin-Aldana H.
      • et al.
      Tubulointerstitial nephritis: an extraintestinal manifestation of Crohn disease in children.
      Both sulfasalazine and 5-ASA have proved efficacy in inducing and maintaining disease remission in IBD patients, particularly in UC, so frequent and long-term drug exposures are not uncommon.
      • Gisbert J.P.
      • Gonzalez-Lama Y.
      • Mate J.
      5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
      Epidemiologic studies have shown that 5-ASA–related nephrotoxicity among IBD patients is rare with a mean overall risk and incidence that seems less than 0.5%.
      • Gisbert J.P.
      • Gonzalez-Lama Y.
      • Mate J.
      5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
      • Elseviers M.M.
      • D'Haens G.
      • Lerebours E.
      • et al.
      Renal impairment in patients with inflammatory bowel disease: association with aminosalicylate therapy?.
      In their case series of renal biopsies in IBD patients, Ambruzs and colleagues
      • Ambruzs J.M.
      • Walker P.D.
      • Larsen C.P.
      The histopathologic spectrum of kidney biopsies in patients with inflammatory bowel disease.
      found TIN the second most common finding after IgAN (Fig. 2). This included cases of both acute and chronic TIN and it was more frequently seen in UC patients (69%, (Ambruzs et al, unpublished data ,2014)). In a subset of patients with granulomatous interstitial nephritis, all of them had current or recent past exposure to aminosalicylates.
      Figure thumbnail gr2
      Fig. 2Tubulointerstitial lesions associated with IBD. (A) Tubular profiles show simplification, reactive nuclei, and apical cytoplasmic blebbing in this case of acute tubular injury (hematoxylin-eosin; original magnification ×200). (B) Interstitial edema with an intense mixed inflammatory infiltrate and prominent tubulitis diagnostic of acute TIN in a patient with UC (hematoxylin-eosin; original magnification ×100). (C) Intense interstitial inflammation, including epithelioid histiocytes and multinucleated giant cells forming noncaseating granulomata (arrows) from a case of granulomatous TIN in a patient with CD (periodic acid–Schiff; original magnification ×200). (D) The renal interstitium is expanded by fibrosis and has an associated inflammatory infiltrate with severe tubular atrophy in this case of chronic TIN in a patient with UC (Masson trichrome; original magnification ×100).
      The pathogenesis of 5-ASA–related nephrotoxicity is unknown, although it is believed to represent a delayed-type hypersensitivity reaction that is dose independent.
      • Arend L.J.
      • Springate J.E.
      Interstitial nephritis from mesalazine: case report and literature review.
      • Corrigan G.
      • Stevens P.E.
      Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease.
      • World M.J.
      • Stevens P.E.
      • Ashton M.A.
      • et al.
      Mesalazine-associated interstitial nephritis.
      A strong predilection in men has previously been reported and a recent genome-wide association study identified a genetic predisposition in the HLA region.
      • Sato H.
      • Umemura K.
      • Yamamoto T.
      • et al.
      Interstitial nephritis associated with ulcerative colitis in monozygotic twins.
      • Heap G.A.
      • So K.
      • Weedon M.
      • et al.
      Clinical features and HLA association of 5-aminosalicylate (5-ASA)-induced nephrotoxicity in inflammatory bowel disease.
      Onset of renal injury is typically within the first 12 months of treatment but delayed onset after several years has also been reported.
      • Gisbert J.P.
      • Gonzalez-Lama Y.
      • Mate J.
      5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
      • Heap G.A.
      • So K.
      • Weedon M.
      • et al.
      Clinical features and HLA association of 5-aminosalicylate (5-ASA)-induced nephrotoxicity in inflammatory bowel disease.
      Unfortunately, the most frequent form of 5-ASA–related TIN is that of severe, chronic, and progressive renal injury, which often escapes early clinical detection.
      • Gisbert J.P.
      • Gonzalez-Lama Y.
      • Mate J.
      5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
      • Arend L.J.
      • Springate J.E.
      Interstitial nephritis from mesalazine: case report and literature review.
      • Corrigan G.
      • Stevens P.E.
      Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease.
      Complete recovery of renal function has been reported if TIN is diagnosed within 10 months from the start of treatment. If diagnosis is delayed beyond 18 months, only one-third of cases show recovery of renal function, and this is usually only partial.
      • Corica D.
      • Romano C.
      Renal involvement in inflammatory bowel diseases.
      • Corrigan G.
      • Stevens P.E.
      Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease.
      • World M.J.
      • Stevens P.E.
      • Ashton M.A.
      • et al.
      Mesalazine-associated interstitial nephritis.
      Steroid therapy, along with drug withdrawal, may help hasten renal recovery.
      • Margetts P.J.
      • Churchill D.N.
      • Alexopoulou I.
      Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine.
      • Arend L.J.
      • Springate J.E.
      Interstitial nephritis from mesalazine: case report and literature review.
      • World M.J.
      • Stevens P.E.
      • Ashton M.A.
      • et al.
      Mesalazine-associated interstitial nephritis.
      • Co M.L.
      • Gorospe E.C.
      Pediatric case of mesalazine-induced interstitial nephritis with literature review.
      • Calviño J.
      • Romero R.
      • Pintos E.
      • et al.
      Mesalazine-associated tubulo-interstitial nephritis in inflammatory bowel disease.
      Given the lack of sensitive markers for early detection of renal injury, a high index of clinical suspicion is needed and routine monitoring of renal function in IBD patients has been emphasized, particularly in those undergoing treatment with aminosalicylates. There are currently no standardized or optimal algorithms for monitoring IBD patients, and there is no evidence that such screening or monitoring improves patient outcomes.
      • Gisbert J.P.
      • Gonzalez-Lama Y.
      • Mate J.
      5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
      However, there appears to be general consensus that renal function should be assessed prior to initiation of drug therapy, with ongoing monitoring of renal function every 3 months to 6 months the first year, followed by annual to semiannual monitoring thereafter.
      • Corrigan G.
      • Stevens P.E.
      Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease.
      • World M.J.
      • Stevens P.E.
      • Ashton M.A.
      • et al.
      Mesalazine-associated interstitial nephritis.
      • Calviño J.
      • Romero R.
      • Pintos E.
      • et al.
      Mesalazine-associated tubulo-interstitial nephritis in inflammatory bowel disease.
      The association between TIN in IBD patients and drug therapy is bolstered by those reports demonstrating a strong temporal relationship to drug exposure, recovery of renal function after withdrawal of the drug, and recurrence of renal injury upon rechallenge.
      • Manenti L.
      • De Rosa A.
      • Buzio C.
      Mesalazine-associated interstitial nephritis: twice in the same patient.
      • Witte T.
      • Olbricht C.J.
      • Koch K.M.
      Interstitial nephritis associated with 5-aminosalicylic acid.
      • Bailly E.
      • Von Tokarski F.
      • Beau-Salinas F.
      • et al.
      Interstitial nephritis secondary to vedolizumab treatment in Crohn disease and safe rechallenge using steroids: a case report.
      There have been several reports, however, of acute and chronic TIN occurring simultaneously with the diagnosis of IBD or in patients with no known exposure to nephrotoxic agents.
      • Waters A.M.
      • Zachos M.
      • Herzenberg A.M.
      • et al.
      Tubulointerstitial nephritis as an extraintestinal manifestation of Crohn's disease.
      • Tokuyama H.
      • Wakino S.
      • Konishi K.
      • et al.
      Acute interstitial nephritis associated with ulcerative colitis.
      • Izzedine H.
      • Simon J.
      • Piette A.M.
      • et al.
      Primary chronic interstitial nephritis in Crohn's disease.
      • Semjén D.
      • Fábos Z.
      • Pakodi F.
      • et al.
      Renal involvement in Crohn's disease: granulomatous inflammation in the form of mass lesion.
      • Zeier M.
      • Schmidt R.
      • Andrassy K.
      • et al.
      Idiopathic interstitial nephritis complicating ulcerative colitis.
      • Shahrani Muhammad H.S.
      • Peters C.
      • Casserly L.F.
      • et al.
      Relapsing tubulointerstitial nephritis in an adolescent with inflammatory bowel disease without aminosalicylate exposure.
      • Khosroshahi H.T.
      • Shoja M.M.
      Tubulointerstitial disease and ulcerative colitis.
      • Tovbin D.
      • Kachko L.
      • Hilzenrat N.
      Severe interstitial nephritis in a patient with renal amyloidosis and exacerbation of Crohn's disease.
      This seems particularly true in cases of granulomatous interstitial nephritis and CD.
      • Marcus S.B.
      • Brown J.B.
      • Melin-Aldana H.
      • et al.
      Tubulointerstitial nephritis: an extraintestinal manifestation of Crohn disease in children.
      • Archimandritis A.J.
      • Weetch M.S.
      Kidney granuloma in Crohn's disease.
      • Unal A.
      • Sipahioglu M.H.
      • Akgun H.
      • et al.
      Crohn's disease complicated by granulomatous interstitial nephritis, choroidal neovascularization, and central retinal vein occlusion.
      • Colvin R.B.
      • Traum A.Z.
      • Taheri D.
      • et al.
      Granulomatous interstitial nephritis as a manifestation of Crohn disease.
      • Timmermans S.A.
      • Christiaans M.H.
      • Abdul-Hamid M.A.
      • et al.
      Granulomatous interstitial nephritis and Crohn's disease.
      Additionally, TIN was most commonly found during active intestinal disease. These findings strongly implicate TIN as a true EIM of IBD with potentially serious consequences because renal impairment has been reported to persist despite initial response to treatment of the underlying bowel disease, with most showing chronic kidney disease, to include end-stage renal disease, in 30% by 3 years.
      • Waters A.M.
      • Zachos M.
      • Herzenberg A.M.
      • et al.
      Tubulointerstitial nephritis as an extraintestinal manifestation of Crohn's disease.
      Possible mechanisms for nondrug-related TIN include systemic immune dysregulation and cytokine activation, immunopathogenetic autoantibodies and immune complexes against organ-specific epitopes shared by colon and extracolonic sites (such as the tubular basement membrane), and possibly molecular mimicry
      • Das K.M.
      Relationship of extraintestinal involvements in inflammatory bowel disease: new insights into autoimmune pathogenesis.
      • Waters A.M.
      • Zachos M.
      • Herzenberg A.M.
      • et al.
      Tubulointerstitial nephritis as an extraintestinal manifestation of Crohn's disease.
      Although well described in association with anti–TNF-α therapy, development of granulomatous TIN has also been reported in association with vedolizumab, a newer therapeutic monoclonal antibody that selectively binds to the α4/β7 integrin.
      • Bailly E.
      • Von Tokarski F.
      • Beau-Salinas F.
      • et al.
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      The exact mechanism is unknown, although likely involves a similar delayed-type hypersensitivity as seen in other drug classes rather than a specific biologic effect of the monoclonal antibody.
      • Bailly E.
      • Von Tokarski F.
      • Beau-Salinas F.
      • et al.
      Interstitial nephritis secondary to vedolizumab treatment in Crohn disease and safe rechallenge using steroids: a case report.

      Renal manifestations in pediatric inflammatory bowel disease patients

      EIMs also occur in the pediatric IBD population in 20% to 35% of children with CD and 15% of children with UC.
      • Corica D.
      • Romano C.
      Renal involvement in inflammatory bowel diseases.
      • Marcus S.B.
      • Brown J.B.
      • Melin-Aldana H.
      • et al.
      Tubulointerstitial nephritis: an extraintestinal manifestation of Crohn disease in children.
      • Mamula P.
      • Markowitz J.E.
      • Baldassano R.N.
      Inflammatory bowel disease in early childhood and adolescence: special considerations.
      They can also precede the onset of gastrointestinal symptoms in 25% to 35% of cases.
      • Marcus S.B.
      • Brown J.B.
      • Melin-Aldana H.
      • et al.
      Tubulointerstitial nephritis: an extraintestinal manifestation of Crohn disease in children.
      Although the actual frequency of renal involvement in pediatric IBD is not well described, there have been several reports of nephrolithiasis,
      • Hueppelshaeuser R.
      • von Unruh G.E.
      • Habbig S.
      • et al.
      Enteric hyperoxaluria, recurrent urolithiasis, and systemic oxalosis in patients with Crohn's disease.
      • Torio M.
      • Ishimura M.
      • Ohga S.
      • et al.
      Nephrolithiasis as an extra-intestinal presentation of pediatric inflammatory bowel disease unclassified.
      • Yamamoto Y.
      • Kurokawa Y.
      • Oka N.
      • et al.
      A pediatric case of ammonium acid urate lithiasis with ulcerative colitis.
      glomerulonephritis (in particular, IgAN),
      • Ridder R.M.
      • Kreth H.W.
      • Kiss E.
      • et al.
      Membranous nephropathy associated with familial chronic ulcerative colitis in a 12-year-old girl.
      • Takemura T.
      • Okada M.
      • Yagi K.
      • et al.
      An adolescent with IgA nephropathy and Crohn disease: pathogenetic implications.
      • McCallum D.
      • Smith L.
      • Harley F.
      • et al.
      IgA nephropathy and thin basement membrane disease in association with Crohn disease.
      • Dabadie A.
      • Gié S.
      • Taque S.
      • et al.
      Glomerular nephropathy with IgA mesangium deposits and Crohn disease.
      TIN,
      • Waters A.M.
      • Zachos M.
      • Herzenberg A.M.
      • et al.
      Tubulointerstitial nephritis as an extraintestinal manifestation of Crohn's disease.
      • Tokuyama H.
      • Wakino S.
      • Konishi K.
      • et al.
      Acute interstitial nephritis associated with ulcerative colitis.
      • Marcus S.B.
      • Brown J.B.
      • Melin-Aldana H.
      • et al.
      Tubulointerstitial nephritis: an extraintestinal manifestation of Crohn disease in children.
      • Arend L.J.
      • Springate J.E.
      Interstitial nephritis from mesalazine: case report and literature review.
      • Co M.L.
      • Gorospe E.C.
      Pediatric case of mesalazine-induced interstitial nephritis with literature review.
      • Shahrani Muhammad H.S.
      • Peters C.
      • Casserly L.F.
      • et al.
      Relapsing tubulointerstitial nephritis in an adolescent with inflammatory bowel disease without aminosalicylate exposure.
      • Frandsen N.E.
      • Saugmann S.
      • Marcussen N.
      Acute interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease.
      and rarely AA amyloidosis.
      • Kirschner B.S.
      • Samowitz W.S.
      Secondary amyloidosis in Crohn's disease of childhood.
      A recent literature review by Corica and Romano
      • Corica D.
      • Romano C.
      Renal involvement in inflammatory bowel diseases.
      identified 50 reported cases of renal involvement in the pediatric IBD population and found a strong predilection in boys (72%) as well as a majority occurring in patients with CD (80%). The most common occurrence was nephrolithiasis (58%) followed by TIN (30%), the latter occurring in two-thirds of all UC patients reported. Similar to adults, no standard guidelines for routine surveillance of renal function have been established, although screening and more frequent monitoring has been recommended.
      • Co M.L.
      • Gorospe E.C.
      Pediatric case of mesalazine-induced interstitial nephritis with literature review.

      Summary

      Although renal and urinary involvement in IBD is not uncommon, renal parenchymal disease is rare and most commonly affects the glomerular and tubulointerstitial compartments. The most common findings on renal biopsy of IBD patients are IGAN and TIN, and this occurrence may represent a common pathogenic mechanism. The overall morbidity of IBD-related renal manifestations is significant, and there is often only a short window of injury reversibility. This, along with an often subtle clinical presentation, requires a high index of suspicion and likely routine monitoring of renal function in patients, in particular the elderly and those with other comorbidities. There are currently no established guidelines for the optimal screening and routine monitoring of renal function in IBD patients.

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