ANNALS OF GASTROENTEROLOGY 2002, 15(1):41-52 Review The kidneys in inflammatory bowel disease K.H. Katsanos1, E.V. Tsianos2 SUMMARY bowel surgery include ureteral injury, urinary vetention and sexual dysfunction. Extraintestinal manifestations and complications are com- mon in patients with inflammatory bowel disease (IBD) and Key words: renal, urinary, genital, drugs, therapy, inflam- may involve almost any organ or system. Renal or urinary matory bowel disease, Crohns, ulcerative colitis, glomeru- complications occur in 4-23% of patients often in those with lar, tubular, interstitial, kidneys. severe long-standing disease. The most common manifes- tations are kidney stones, enterovesical fistulas and ure- 1. EPIDEMIOLOGY teral obstruction. Genital involvement is uncommon in IBD. Patients with IBD have a risk of nephrolithiasis 10-100 Extraintestinal manifestations and complications are times greater than that for the general hospital population. common in patients with inflammatory bowel disease Glomerulonephritis (GN) in IBD has been reported in at (IBD) and can involve almost any organ or system. Re- least 27 patients; of these 7 had CD, 17 had UC and 3 were nal or urinary complications occur in 4-23% of patients, indeterminate.Histology changes range from minimal often in those with severe long-standing disease (Tables change nephropathy to rapidly progressive crescentic GN 1, 2). The most common manifestations are kidney stones, which may be accompanied by active tubulointerstitial ne- enterovesical fistulas and ureteral obstruction1. Fistulas phritis. Tubulointerstitial abnormalities are not uncom- between the gastrointestinal tract and the urinary sys- mon in autopsy studies of IBD patients. Granulomatous tem are uncommon, occuring in 1-8%, being more com- interstitial nephritis, interstitial nephritis with hyper- mon in patients with ileal or ileocecal disease than in oxalouria and renal tubular acidosis have also been report- those with colonic disease. Ureteral obstruction is not ed. Inflammatory bowel disease is an uncommon cause of caused by stones in 50-73% of cases of CD and in 50% of secondary amyloidosis. Complications from medical ther- cases of UC2. This non-calculus obstruction (NCO) is on apy are relatively rare in the majority of drugs used to treat the right in the great majority of patients. Genital in- IBD. There is little or no nephrotoxicity with many drugs used including corticosteroids, azathioprine or 6-mercap- topurine, metronidazole and low dose methotrexate. The Table 1. Renal complications in IBD drugs with significant potential renal toxicity are the ami- 1. Glomerulonephritis (from minimal change nephropathy to nosalicylates (sulfasalazine, mesalamine, 5-ASA, olsala- rapidly progressive crescentic GN) zine) and cyclosporine. Surgical complications following 2. Tubulointerstitial abnormalities (interstitial nephritis, gra- noulomatous interstitial nephritis, nephrocalcinosis, renal tubulor acidosis) 1House Officer in Gastroenterology, 2Professor of Medicine, Department of Internal Medicine, Hepato-Gastroenterology Unit, 3. Amyloidosis Medical School, University of Ioannina, Greece 4. Renal hypertension 5. Iatrogenic complications: medications, aminosalicylates, Author for correspondence: cyclosporine, xylitol at high dose, sodium phosphate (co- Dr Epameinondas V. Tsianos, Professor of Medicine, Department lon cleansing) of Internal Medicine, Medical School, University of Ioannina, 6. Miscellaneous complications Greece, PC 45 500 Ioannina, Fax/phone:++30-651-99736, e-mail: [email protected] 7. Pyonephrosis/Pyelonephritis 42 K.H. KATSANOS, et al Table 2. Urologic complications in IBD tory bowel disease is an uncommon cause of secondary 1. Fistulas amyloidosis. Only a few dozen with CD have been re- - enterovesical ported with amyloidosis, the association with UC being 2 - rectovesical even less common . The reported prevalence of second- ary amyloidosis in IBD patients varies from 0,5-29% in - rectourethral CD and from 0-0,4% in UC with a lower prevalence clin- - anourethral ically and a higher prevalence at autopsy5. Complications - urethrocutaneous from medical therapy are relatively rare in the majority - vesicocutaneous of drugs used to treat IBD. There is little or no nephro- - ileoureteral toxicity with many drugs used including corticosteroids, - enterourachovesical azathioprine or 6-mercaptopurine, metronidazole and - ileal pouch-vesical low dose methotrexate. The drugs with significant po- 2. Acute/chronic pyelonephritis tential renal toxicity are the aminosalicylates (sulfasala- 3. Nephrolithiasis (uric acid, calcium oxalate, calcium phos- zine, mesalamine, 5-ASA, olsalazine) and cyclosporine. phate) Surgical complications following bowel surgery include 6 4. Non calculous obstructive uropathy ureteral injury, urinary vetention and sexual dysfunction . 5. Genital involvement (penis, scrotum, vulva, prostate gland) These are uncommon according to some studies where- as higher rates are reported in others, particularly with 6. Iatrogenic complications (Surgical complications) proctocolectomy7. There are reports of various genitouri- 7. Miscellaneous complications nary malignancies in IBD patients, inclunding renal cell, bladder, prostate and vulvar carcinoma. However, two large studies found no increased risk of renal or urinary volvement is uncommon in IBD. Patients with IBD have malignancies in IBD patients8,9. a risk of nephrolithiasis 10-100 times greater than that for the general hospital population. The risk is higher in adults than children and in patients with CD compared 2. IMMUNOLOGY with UC Kidney stones in IBD are composed primarily A study of 13 patients diagnosed with ulcerative col- of calcium oxalate or uric acid (Table 3). Glomerulone- itis was conducted to determine whether the presence of phritis (GN) in IBD has been reported in at least 27 pa- ANCA in those patients is associated with renal pathol- tients; of these 7 had CD, 17 had UC and 3 were indeter- ogy10. Renal damage was not observed in ANCA-posi- minate. Histology changes range from minimal change tive patients with colitis even after 1 year of follow up, nephropathy to rapidly progressive crescentic GN and suggesting that the ANCA found in these patients did may be accompanied by active tubulointerstitial nephri- not share the antigenic targets with the ANCA commonly 3 tis . Tubulointerstitial abnormalities are not uncommon found in renal vasculitis11. Therefore the potential of in autopsy studies of IBD patients. Tubular degenera- ANCA of inducing renal lesions (if any) is dependent on tion was seen in 31% of CD and in 23% of UC patients their own antigenic specificity. As far as anti-brush bor- who were not on ASA. Granulomatous interstitial ne- der antibodies (ABBA) are concerned, seventy-four se- phritis, interstitial nephritis with hyperoxalouria and re- rum samples from patients with Crohns disease were an- 4 nal tubular acidosis have also been reported . Inflamma- alysed for the presence of antibodies against various tis- sue antigens12. With indirect immunofluorescence micro- scopy, 61% of the patient sera were shown to possess Table 3. Stone types and pathophysiology in IBD (Adopted from reference 2) antibodies (in a titre of 1:25 or more) reacting with rat brush border membrane antigens in the proximal tubules Stone type Risk factors of the kidneys, in the gastric parietal cells, and in the 1. Uric acid Diarrhea, ileostomy, hyperurichemia bile canaliculi of the liver. Serum samples submitted for 2. Calcium oxalate Ileal resection or disease,enteric routine immunofluorescence antibody screening served hyperoxaluria as controls; 10% of these sera contained anti-brush bor- 3. Calcium phosphate Bed rest, steroids,increased urine Ca der anti-bodies. There is also an antigenic relationship (mobilization from bone and de between human kidney, colon and the common antigen creased ubularresorption of Ca) of enterobacteriaceal13,14. IGF system and IBD 43 3.ANIMAL MODELS OF IBD infusion24. A renographic monitoring of the renal func- NEPHROTOXICITY tion with Hippuran in patients with Crohns disease treat- ed with low dose was cyclosporin was proposed in a con- In cats the diagnosis of cholangiohepatitis should be trolled study where a correlation has been found between further evaluated for IBD and pancreatitis but there is the residual activity 20 minutes after the injection and no indication to search for nephritis15. Rabbits which were the degree of intertitial fibrosis seen in renal biopsies25. immunized with intestinal antigens derived from rabbits, guinea pigs, and germ-free rats revealed interstitial ne- phritis16. These changes did not occur when non-intesti- 5. OTHER ASSOCIATIONS WITH IBD RENAL nal antigens were used for immunization. In rats the use INVOLVEMENT of hyperosmolar enemas can induce nephritis throughout Inflammatory bowel disease and IBD-related renal massive acidosis and electrolyte disturbances with hypoc- involvement can coexist with other organ or system de- alcemia and hypernatremia. Consequently, sodium phos- teriorations or disease. The rare triad sclerosing cholan- phate solutions should probably not be used in patients gitis, IBD and gromerulonephritis has twice been re- with inflammatory bowel disease with a high risk of lac- ported26. Also nonspecific ulcerative rectocolitis and eration of the mucosa or perforation of the bowel or di- lupus erythrematosus with renal involvement has been rect toxic effect on kidneys17,18. E 3040, a new class of anti-flammatory drug used