Common Kindling: Inflammatory Bowel Disease Associated with Kidney Disease

Written by:

AAmir Saeed MD, PGY-2 Internal Medicine, Merit Health Wesley, Hattiesburg MS

S Sabarinath MD DM FASN, Consultant Nephrologist and Renal Transplant Physician RMC Superspeciality hospital, Tiruppur, India

Infographics by Corina Teodosiu MD

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Overview of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a group of chronic immune-mediated disorders of the gastrointestinal tract, which include Crohn’s disease and ulcerative colitis (UC). The exact pathophysiology of IBD is still as yet unknown, however, current literature suggests that IBD is primarily driven by dysregulation of intestinal T-cells in genetically susceptible individuals, idiosyncratic reactions to medications, environmental factors, infectious agents and gut microbiota dysbiosis. IBD is also associated with numerous extraintestinal manifestations. The prevalence of these varies from 5 to 50%, and can affect various organ systems (Figure 1). The most frequently involved organs are joints (peripheral arthritis, sacroiliitis, ankylosing spondylitis), skin (erythema nodosum, pyoderma gangrenosum), eyes (sicca syndrome, episcleritis, uveitis) and the liver/biliary tract (primary sclerosing cholangitis and gallstones).  Renal disease, including acute kidney injury (AKI) and chronic kidney disease (CKD) are also not infrequently encountered in association with IBD. In a recent 2022 study that included data from the United Kingdom Biobank, the hazard ratios for CKD and AKI related to IBD were 1.57 and 1.96 respectively, after adjustments for age, sex, and race. In fact, a diagnosis of IBD was associated with a higher risk for CKD and AKI, independent of other known risk factors for progressive kidney disease.

Renal Involvement in IBD

Inflammatory bowel disease has been found to be associated with kidney disease in 4 to 23% of patients.  The most frequently encountered renal manifestations in patients with IBD include glomerulonephritis, acute and chronic tubulointerstitial nephritis, and amyloidosis. A recent review by Federico Yandian et al specifically looked at the impact of histology, treatments and outcomes of patients with IBD and biopsy proven kidney disease. This study looked at the incidence of various kidney diseases as well as the predictors of worsening kidney function. The pathogenesis behind renal manifestations is believed to be similar to that triggering intestinal inflammation, mainly immune system dysregulation. The current literature suggests that kidney outcomes are directly related to the course of the intestinal disease in IBD-associated renal disorders.

From Yandian F et al. Kidney disease associated with Inflammatory bowel disease: impact of chronic histologic damage, treatments, and outcomes. Kidney Int Rep, 2024. Visual abstract by Denisse Arellano

Hematuria is a very frequent finding. The various etiologies of glomerular pathology seen on biopsy, are summarized in the figure below. Similarly, in a previous study of 83 patients with IBD with kidney biopsies, the most common diagnoses included IgA nephropathy (IgAN), acute and chronic tubulointerstitial nephritis, arterionephrosclerosis, acute tubular injury, and focal segmental glomerulosclerosis.

From Figure 1, Yandian F et al. Kidney disease associated with Inflammatory bowel disease: impact of chronic histologic damage, treatments, and outcomes. Kidney Int Rep, 2024.

Patients are often treated with steroids, and 5-aminosalicylic acid (5-ASA) for IBD. As a reminder, it is prudent to monitor eGFR both before and after initiating treatment with 5-ASA, calcineurin inhibitors and/or tumor necrosis factor-alpha inhibitors. Immunosuppression for glomerular disease may also include additional immunosuppressive agents such as mycophenolate mofetil, rituxan and azathioprine. Changes in immunosuppression is often warranted in patients with IBD and kidney disease, based upon kidney biopsy findings .

Unfortunately, progressive kidney failure and end stage kidney disease (ESKD) are not uncommon in patients with IBD. Risks for progressive kidney disease included older age, lower baseline eGFR, nephrotic range proteinuria, and more severe anemia. The etiology of glomerular pathology is less significant in determining prognosis. Histologically, patients with more glomerulosclerosis, interstitial fibrosis, tubular atrophy (IFTA) and arteriosclerosis have a greater risk of kidney failure. Patients with complete or partial remission of proteinuria or stable/improving kidney function have significantly better survival. In at least one study, one-quarter of patients with IBD and kidney disease progressed to ESKD.

Let’s look a little closer at some of the more common kidney pathologies associated with IBD (Figure 2).

IgAN

A study by Ambruzs et al, consisting of 83 patients with IBD, showed that IgAN was the most common classification of glomerulonephritis on biopsy (24% of study patients), similar to the current study with 19-22% of patients. The pathophysiology of IgA nephropathy and IBD share a common pathway, and are likely related to a complex of interaction of mucosal inflammation (Peyer’s patches and mucous membranes), loss of antigenic exclusion and tolerance, chronic immune stimulation, and dysregulated IgA production. Underlying pathogenic mechanisms suggest either the initiation of antigen-specific immune responses in the inflamed gut that cross react with non-intestinal sites, such as the glomerulus, or that extraintestinal manifestations are gut-independent events that occur due to an interaction between common genetic and environmental risk factors. Studies have shown a dramatic linkage between IgA nephropathy and IBD related to the presence of HLA-DR1 in IgA nephropathy and HLA-DR1/DQw5 in Crohn’s disease. Finally, treatment of IBD with budesonide has been long established, and there is a growing body of evidence for budesonide use in IgAN as well.

Tubulointerstitial Nephritis

Data has also shown acute and chronic tubulointerstitial nephritis to be the second and third most commonly diagnosed kidney biopsy findings after IgAN in association with IBD. In the above study 71% of patients with chronic interstitial nephritis (CIN) and 51% of the patients with acute interstitial nephritis (AIN) were treated with 5-ASA. Tubulointerstitial nephritis has specifically been associated with 5-ASA treatment in patients with IBD. After a proven diagnosis of tubulointerstitial nephritis on kidney biopsy, trials of discontinuing 5-ASA, with the addition of prednisolone, showed partial improvement in acute kidney injury in at least one series of patients. Because interstitial nephritis is often associated with a slow, subacute rise in serum creatinine, a high level of vigilance is needed to recognize this disease early in its course. 

Renal AA amyloidosis

Secondary amyloidosis is a rare but fatal complication of IBD, which can influence the prognosis even more than the underlying disease. Published data reported the incidence of AA amyloidosis ranges from 1.3% to 10.9% in patients with Crohn's, and from 0 to 0.7% in patients with ulcerative colitis. Renal amyloidosis usually presents as nephrotic range proteinuria, and can progress rapidly to renal failure. Renal biopsies have the pathognomonic congo red (bright apple green) positive fibril deposition within the glomerulus.  Early diagnosis of renal amyloidosis associated with IBD improved patients’ prognosis.

Nephrolithiasis

Urologic complications like urolithiasis, intestine-ureteral fistulas, and ureteral obstruction are even more common than renal parenchymal disease. The prevalence of nephrolithiasis among patients with IBD ranges from 12% to 28%. Calcium oxalate and uric acid stones are the predominant stone types seen in patients with IBD. The pathophysiology of enhanced nephrolithiasis risk in IBD patients can be related to hypovolemia (diarrhea), urine supersaturation related to low urine volume and altered urine pH (uric acid stones), and increased intestinal oxalate absorption causing hyperoxaluria (calcium oxalate stones). Furthermore, patients with IBD-related surgeries (i.e. total colectomy, intestinal bypass, small bowel resection), and extensive ileocolonic involvement are among the highest risks for kidney stone formation.

From Corica D et al. Renal involvement in inflammatory bowel disease. Journal of Crohn's and Colitis, 2016.

Conclusion

Extraintestinal symptoms associated with inflammatory bowel disease primarily affect the skin, joints and eyes. Although renal complications related to IBD are less frequent, they can be devastating to the patients health and prognosis. Kidney pathology encompasses such diverse conditions as nephrolithiasis, tubulointerstitial nephritis, glomerulonephritis and renal amyloidosis. Renal complications may be related to common immunologic dysregulation pathways, or even from exposure to medications intended to treat IBD. Individuals with IBD should undergo routine surveillance of renal function and serum electrolytes. Consistent evaluation and interventions aimed at mitigating disease progression, coupled with a comprehensive multidisciplinary team approach, are recommended in the management of renal complications associated with IBD. Given that progressive kidney failure can significantly impact the quality and quantity of a patient’s life, active monitoring of kidney disease is recommended in all patients with IBD.

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.