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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.
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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.
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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.
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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.
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.
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.
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.
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
Deposition of circulating immune complexes or in situ formation of immune complexes leading to an increased risk of glomerulonephritis and perhaps tubulointerstitial nephritis (TIN)
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
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.
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,
IgA antiglomerular basement membrane nephritis associated with Crohn's disease: a case report and review of glomerulonephritis in inflammatory bowel disease.
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.
(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 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.
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
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).
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.
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.
Characteristic
Data
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)
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.
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%).
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.
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).
These factors, along with low urinary volume and low concentration of stone inhibitors (ie, magnesium and citrate), all likely promote lithogenesis in IBD patients.
Uric acid stones often result from loss of volume and bicarbonate through frequent diarrhea or small bowel ostomies resulting in concentrated and acidic urine.
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.
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.
Urolithiasis and urinary tract infection among patients with inflammatory bowel disease: a review of US emergency department visits between 2006 and 2009.
A rare association between ulcerative colitis (UC), celiac disease (CD), membranous glomerulonephritis, leg venous thrombosis, and heterozygosity for factor V Leiden.
IgA antiglomerular basement membrane nephritis associated with Crohn's disease: a case report and review of glomerulonephritis in inflammatory bowel disease.
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.
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.
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.
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.
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
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.
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.
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.
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.
Given that intestinal mucosal immune responses are highly dependent on costimulation, the role of T-cell dysfunction in this process has also been implicated.
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.
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.
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
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.
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%).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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%.
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.
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.
A strong predilection in men has previously been reported and a recent genome-wide association study identified a genetic predisposition in the HLA region.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
References
Marsal J.
Agace W.W.
Targeting T-cell migration in inflammatory bowel disease.
IgA antiglomerular basement membrane nephritis associated with Crohn's disease: a case report and review of glomerulonephritis in inflammatory bowel disease.
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.
CREGG (Club de Reflexion des cabinets et Groupes d'Hépato-Gastroentérologie). 5-Aminosalicylates and renal function monitoring in inflammatory bowel disease: a nationwide survey.
Urolithiasis and urinary tract infection among patients with inflammatory bowel disease: a review of US emergency department visits between 2006 and 2009.
A rare association between ulcerative colitis (UC), celiac disease (CD), membranous glomerulonephritis, leg venous thrombosis, and heterozygosity for factor V Leiden.
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