Inflammatory Bowel Diseases and Kidney Transplantation: A Narrative Review of Clinical Management Approaches
Inflammatory bowel disease is not uncommon among kidney transplant recipients. In transplant patients with chronic diarrhea and abdominal pain, de novo inflammatory bowel disease can be considered among differential diagnoses, after exclusion of infectious causes and drug-induced diarrhea. Inflammatory bowel disease, in the cnnnontext of organ transplant, is associated with a higher risk of morbidity, increased rate of hospitalization, and higher mortality. Therefore, a multidisciplinary approach, before and after transplant, among a gastroenterologist specialized in inflammatory bowel disease, a gastrointestinal surgeon, and a transplant clinician is essential, given the higher clinical complexity for this subgroup of patients. Limited data are available on management of inflammatory bowel disease in kidney transplant recipients, although the concurrent use of immuno-suppressive therapy can mitigate flare-ups but with increased infection risks. Colorectal cancer can be a serious complication of inflammatory bowel disease; hence, patient compliance with regular colonoscopy surveillance programs is crucial. Patients with inflammatory bowel disease who are undergoing kidney transplant have a shorter overall survival rate compared with matched control groups. However, inferences based on studies involving inflammatory bowel disease in kidney transplant recipients are blighted by small sample sizes, thus making it difficult to draw accurate conclusions. Our review was undertaken to comprehensively report the clinical approaches to kidney transplant recipients with inflammatory bowel disease, describing their clinical course, outcomes, and management plan.
Key words : Crohn disease, End-stage renal disease, Liver transplant, Renal transplant, Ulcerative colitis
Inflammatory bowel disease (IBD) is an autoimmune disorder caused by a dysregulated immune response to host intestinal microflora. Inflammatory bowel disease consists of Crohn disease (CD), a transmural illness affecting any segment of the gastrointestinal tract from the mouth to the anus involving “skip lesions,” and ulcerative colitis (UC), a disease of the colonic mucosa.1 Patient with IBD may develop extraintestinal manifestations. These include oral aphthous ulcers, episcleritis, uveitis, erythema nodosum, pyoderma gangrenosum, primary sclerosing cholangitis, and peripheral arthritis.2 Furthermore, patients can develop renal manifestations, such as glomerulonephritis, tubuloin-terstitial nephritis, nephrolithiasis (particularly calcium oxalate urolithiasis), and secondary amyloidosis.3 Renal dysfunction (acute and chronic) can be the result of dehydration, long-term malnutrition, and side effects of IBD medication.4 All of these factors can contribute to chronic kidney disease and eventually end with patients requiring dialysis or kidney transplant.
Inflammatory bowel disease is a chronic relapsing disease with an estimated global prevalence of 6.8 million, as reported in 2017.5 Some immune-mediated conditions, such as primary sclerosing cholangitis and autoimmune hepatitis, are strongly associated with IBD requiring liver transplant.6 Similarly, the incidence of end-stage renal disease is 5 times higher than in age-matched controls.3 Inflammatory bowel disease can recur posttransplant. Moreover, de novo IBD occurring posttransplant has an incidence of 5% to 18.8%.7 Several hypotheses have been proposed to explain the development of de novo IBD in kidney transplant recipients, including dysregulation of the intestinal immune environment induced by immunosuppressive therapy, which renders the intestinal mucosa more susceptible to various insults resulting in chronic immune stimulation by luminal antigens.8 The prevalence, risk factors, prognosis, and management of IBD in liver transplant patients have been extensively studied.7 However, data on outcomes and clinical management of IBD in kidney transplant recipients and the effects of IBD on the kidney allograft are limited.
Our study was undertaken to comprehensively review clinical approaches to kidney transplant recipients with IBD, describing the clinical course, optimal timing for transplant, risk factors for disease recurrence and flare-ups posttransplant, prognosis, and management plan, including optimum immuno-suppression therapy.
Inflammatory bowel disease, in the context of organ transplant, presents a challenging medical thera-peutic situation, which is associated with a higher risk of morbidity and mortality. Therefore, a close multidisciplinary approach among a gastroenterol-ogist specialized in IBD, a gastrointestinal surgeon, and a transplant clinician is recommended before and after transplant, given the higher clinical complexity of this subgroup of patients.9
Achieving remission of inflammatory bowel disease before transplant
Defining remission in IBD is not straightforward, as it is a broad concept that includes several aspects: (1) clinical remission (absence of symptoms); (2) endoscopic remission (mucosal healing); and (3) deep remission (no symptoms and mucosal healing). Clinically, remission is often defined as the absence or significant reduction of symptoms, such as abdominal pain, diarrhea, and rectal bleeding.10 Several indices are available to monitor IBD inflammatory activity, such as the Crohn Disease Activity Index, the Harvey-Bradshaw Index for Crohn Disease, and the Mayo score for UC. These indices are a composite of objective items (such as analytical determinations), subjective items (such as pain intensity or level of well-being), and self-reported items (such as the number of stools the patient passes each day). These indices are useful in monitoring disease progression and activity and therefore widely used in clinical trials, but they do not correlate perfectly with endoscopic/histological activity or analytical parameters, probably because of their subjective components.11,12 Moreover, patients may have varying thresholds for what they consider to be significant symptom relief.
Because clinical indices cannot predict remission solely based on their subjective components,12,13 these clinical indexes should be combined with additional tools to establish a reliable diagnosis of remission in IBD, particularly if transplant surgery is planned (such as endoscopic examination of the intestinal mucosa). Despite no clear or widely accepted criteria for endoscopic remission in IBD, endoscopy remains the gold standard to determine inflammatory activity and provide a more objective measure of remission.14 Endoscopic examination is also the gold standard in evaluating remission in patients with UC.15 However, in CD, endoscopic remission through ileocolonoscopy is an extreme of the severity spectrum, whereas the current scoring systems only rely on ulcerations (ie, depth and extension), stenosis, and surface affected by any lesions. Nevertheless, endoscopic examination in CD can only examine the mucosa, and not the deeper layers of the intestinal wall, and is subject to interobserver variability.14
The use of magnetic resonance imaging (MRI) is essential to evaluation of mural thickness when defining deep remission, a test gaining popularity in the management of CD patients due to its diagnostic accuracy16 and because endoscopy is invasive and not without risks. Evaluation of the proximal small bowel inflammation is difficult despite the advent of endoscopic capsules,10,14 but radiological imaging in IBD has recently experienced great advances. Ultrasonography scans, computed tomography (CT), and MRI are increasingly used to assess disease extent, presence of active inflammation, transmural involvement, and response to treatment. The use of radiological imaging can also help in unclear cases.10,17
Laboratory testing, such as testing C-reactive protein (CRP) and fecal calprotectin (FC) levels, can be used to assess the level of IBD, whereas a reduction in these biomarkers can indicate remission and reliably predict treatment response.18 Fecal calprotectin is a widely used stool marker to monitor intestinal activity in patients with IBD and yields a better diagnostic value compared with C-reactive protein alone in determining endoscopic disease activity; a decreasing calprotectin level has been shown to correlate well with clinical response and endoscopic activity and may predict treatment response.18-23 However, the FC sensitivity and specificity in assessing endoscopic disease activity differ between UC and CD, where FC appears as a better endoscopic disease activity marker in UC compared with CD.23-25 Nevertheless, FC also appears to be highly diagnostic in detecting endoscopic ulcerations in CD regardless of the disease location but requires a lower cut-off value in patients with pure ileal involvement.25 Unfortunately, FC lacks cut-off points that define endoscopic remission reliably.21
When is the optimal window to transplant?
The KDIGO guidelines do not exclude candidates with a history of IBD from receiving kidney transplants; however, the guidelines recommend delaying kidney transplant until active symptomatic inflammatory bowel disease has resolved.26 Similarly, guidelines from the National Health Service in the United Kingdom for IBD recommend proceeding with a transplant if the disease is in remission and nutritional status is good.27 The timing of transplant in such cases should be determined in consultation with a gastroenterologist with a special interest in IBD. Furthermore, screening for bowel cancer is recommended in patients with IBD in accordance with local recommendations.26 Other guidelines, such as the European Renal Best Practice Group, the British Transplantation Society guidelines, and the Caring for Australian and New Zealanders with Renal Impairment guidelines, do not include recommendations concerning recipients with IBD.
Inflammatory Bowel Disease in Patients With Renal Disease After Kidney Transplant
Incidence, clinical course, and prognosis
Inflammatory bowel disease is common among kidney transplant recipients, with an estimated incidence of 27.6% for recurrent disease and 5% to 18.8% for de novo IBD.7,28 However, compared with liver transplant recipients, recurrence of IBD in renal transplant recipients is lower (65% vs 27.6%).7,29 To date, only 53 kidney transplants recipients were reported to have de novo IBD.28 Most studies have focused on a small percentage of patients who underwent diagnostic colonoscopies for symptomatic diarrhea. The most common final diagnosis in such cases was nonspecific colitis, which is likely to underestimate the true prevalence of IBD in renal transplant recipients.28
The onset of IBD among organ transplant recipients is associated with higher morbidity and requires more complex medical management. In most cases, IBD occurs within 5 years of transplant.29,30 Posttransplant de novo disease may exhibit a more aggressive clinical course than a relapsing disease.31,32 The clinical manifestations are varied. Patients usually present with bloody diarrhea, abdominal cramps, and bright red hematochezia.28 Clinical, endoscopic, and histological features are useful to distinguish between different causes of gastrointestinal symptoms affecting renal transplant recipients.
The course of IBD after liver transplant is variable. One-third of patients may deteriorate, requiring an escalation of medical therapy or a colectomy in 9% (range, 0%-21%) of cases.9 Similarly, 19% to 30% of IBD patients who undergo renal transplant develop multiple IBD recurrences in the posttransplant period, and 20% of them may require a colectomy.9
Risk Factors for Disease Recurrence and Flare-Ups After Transplant
All risk factors described in the literature have been based, to our knowledge, on data in nontransplant patients or liver transplant recipients with IBD. Further research is required to determine whether the same applies to kidney recipients. Risk factors for disease recurrence and flare-ups posttransplant include several factors, as described below.
Active disease at the time of transplant
There is a 3-fold increased risk of IBD flare-ups and worsening intestinal disease after liver transplant in patients who had active disease at the time of liver transplant.29
The use of mycophenolate mofetil (MMF) has been shown to induce and maintain remission in severe refractory IBD in the general population.33,34 Nevertheless, MMF may promote posttransplant erosive enterocolitis and a CD-like pattern of colitis after transplant.9,35 Tacrolimus use after liver transplant has been reported as an independent risk factor for IBD recurrence.29,36,37
The presence of cytomegalovirus (CMV) infection in the donor organ has been linked to the development of de novo posttransplant IBD.38,39 A CMV infection could affect the epithelial barrier function and the mucosal immune system, both of which may contribute to the development of IBD.39
Smoking is a risk factor for CD but not for UC in nontransplant patients.40,41 Similarly, smoking at the time of liver transplant was predictive of a flare of IBD and active IBD at the time of transplant.42 Smoking can directly affect mucosal immune responses, gut permeability, smooth muscle tone, and microvasculatures.43
Age at transplant
Younger age at diagnosis, female sex, and long duration of the disease were not associated with posttransplant IBD in a study from Hansrivijit and colleagues7, although they are clinical predictors of relapse in nontransplant IBD patients.44 However, the small sample size in the analysis can be a confounding factor.
Risk Factors for Predicting Disease Recurrence in Nontransplant Patients
The following are other risk factors for predicting disease recurrence in nontransplant patients. Further research is required to determine whether the same can be applied to transplant patients.
Features that predict the recurrence of IBD include penetrating disease, intra-abdominal abscess, and concomitant abscesses and fistulas.44,45
Factors associated with increased risk of IBD recurrence include increased dietary intake of fat, especially polyunsaturated fatty acids,46,47 vitamin D deficiency,48 sleep deprivation,49,50 and stress.51
Gastroenteritis, particularly salmonella and campy-lobacter gastroenteritis, might play a role in the initiation and/or exacerbation of IBD.52,53 However, so far to our knowledge, no specific pathogen has been identified as a causal factor.54,55
Drugs such as nonsteroidal anti-inflammatory drugs,44,56,57 oral contraceptives, and hormone repla-cement therapy44,58 might increase the risk of IBD, although the magnitude of the risk appears small.
Clinical Management of Inflammatory Bowel Disease After Renal Transplant
The concomitant use of immunosuppressive therapy can increase the risk of infection in transplant recipients. Thus, it is extremely important to exclude intestinal infections (such as CMV and Clostridium difficile infection) in patients who develop diarrhea. Also of importance is exclusion of medications as potential causes of diarrhea before diagnosis of a patient as having IBD. Once a diagnosis is confirmed, the management approach requires close coordination among a gastroenterologist with experience in IBD, a transplant clinician, and a gastrointestinal surgeon.
Management of IBD
After confirmation of active IBD symptoms by colonoscopy and histological examination, the patient can begin treatment for the disease. The treatment of IBD in transplant recipients is similar to that in nontransplant patients.
5-Aminosalicylate at a dose of 2.4 g/day to 4.8 g/day is indicated as induction therapy and as a maintenance regimen in patients with mild to moderate UC,58,59 whereas, for patients with ulcerative proctitis, topical is more effective than oral 5-aminosalicylate.9,60 In contrast, the therapeutic efficacy of aminosalicylic acid preparations in maintaining remission in patients with CD remains controversial.61,62 A meta-analysis of 3 large clinical trials found no significant clinical efficacy with mesalazine in patients with an ileocecal CD of mild-to-moderate activity.63 However, patients with colonic CD and mild active disease may benefit from sulfasalazine.64
Despite these analyses, 5-aminosalicylates have been still used extensively and efficiently worldwide as a long-term treatment for CD and for prolonged periods, which may extend in some centers up to 10 years.9,65 Combining aminosalicylates with azathioprine results in increased therapeutic efficacy, unrelated to the inhibition of thiopurine methyltrans-ferase activity. This combination therapy increases the risk of leukopenia by 47%, necessitating careful blood monitoring and a reduction in azathioprine dosage.66,67
The use of oral or intravenous corticosteroids is necessary for patients with moderate to severe IBD. Prednisolone at a dose of 40 to 60 mg per day may be prescribed based on the patient’s body weight (60-80 kg), to be tapered gradually.68
Maintenance immunosuppression therapy
Maintenance immunosuppression includes azathio-prine at a dose of 2.0 to 2.5 mg/kg body weight/day is effective in reducing the risk of active disease after transplant.36
Biologics used in IBD include proinflammatory cytokine inhibitors (anti-tumor necrosis factor [TNF]-α and anti-interleukin [IL]-12/23, since proinflammatory cytokines play an important role in the pathogenesis of IBD) and integrin antagonists.
Anti-TNF-α medications were the most frequently prescribed biologics in 77.5% of the patients and are considered a safe and effective therapeutic option in organ transplant recipients with refractory IBD.61,69-71 Treatment with infliximab or adalimumab can induce remission or result in stabilization of the disease course in kidney transplant recipients with mild to moderate IBD.61,72 Golimumab is another immunoglobulin G1 (IgG1) monoclonal antibody against TNF-α with good efficacy and safety in patients with moderate to severe UC73 and CD74 who fail to respond to conventional therapy. However, to date, there are no reported cases of golimumab use in transplant recipients.
Anti-IL-12 and IL-23 therapy include ustekinumab, a humanized IgG1 monoclonal antibody that has been approved to treat moderate to severe CD and UC.75 Ustekinumab has been shown to be safe and effective in organ transplant recipients.76-78 Mirikizumab and risankizumab have been shown to be effective in patients with moderate to severe UC and moderate to severe CD, respectively, in clinical trials.75 However, both were not used in organ transplant recipients. Currently, IL-12 and IL-23 antagonists are recommended as first-line or second-line therapy in managing IBD.61
Anti-integrin therapy blocks the effect of integrin on the leukocyte surface and endothelial cell adhesion molecules, thereby inhibiting leukocytes from interacting with the intestinal mucosa. Vedolizumab, a recombinant human IgG1 monoclonal antibody, has been approved for treatment of moderate to severe UC and CD, in severe refractory cases, or in patients with intolerance to conventional therapy or anti-TNF-α antibodies. Vedolizumab therapy has shown excellent tolerability and high efficacy among organ transplant recipients, possibly due to its intestinal selectivity, which reduces the adverse effects of systemic immunosuppression.61,76,79
No dose adjustment of biologics is required among organ transplant recipients. However, the use of biologics in transplanted patients, in conjunction with concurrent immunosuppression, has been associated with an increased risk of mortality and rate of hospitalization secondary to an increased infection rate,61,76 suggesting a need for careful surveillance for active infections and neoplasms before therapy.79 Among the reported infectious complications, Clostridium difficile colitis, urinary tract infections, and CMV infections or reactivations were the most commonly encountered.76 Furthermore, biologic agents are expensive despite their high selectivity, high efficiency, and low toxicity.61
Continuous immunosuppression has been suggested to play a substantial role in preventing relapse of IBD following kidney transplant. Tacrolimus, a well-known potent immune suppressant, has shown a remarkable therapeutic efficacy in treating refractory UC patients, as shown in more than 23 observational studies and randomized controlled trials with remarkable reduction in colectomy rates,80,81 as well as in some cases of luminal CD.82 This effect was attributed to their inhibitory effects on the production of proinflammatory cytokines (IL-12/IL-23 and TNF-α).61 Use of tacrolimus in organ transplant recipients with IBD was associated with unfavorable outcomes.
As suggested in a large Scandinavian meta-analysis, switching from tacrolimus-based to cyclosporine-based antirejection regimens after liver transplant was associated with a better outcome in reducing IBD activity, whereas continuing treatment with tacrolimus and mycophenolate mofetil was associated with increased IBD activity after liver transplant.37 Dvorchik and colleagues also found that the risk of relapsing IBD at 1 year and 5 years was 13% and 64%, respectively, compared with 4% and 10% in patients with tacrolimus-free regimens.83 Although tacrolimus is superior to cyclosporine in terms of improving graft survival and preventing graft rejection posttransplant, several other retrospective studies also suggest that it was associated with a 4-fold increase in relapse after liver transplant.29,36
Cyclosporine does not appear to worsen the course of IBD in the posttransplant period.9,29 Indeed, cyclosporine, like anti-TNF-α, is used to treat severe steroid-refractory UC in nontransplant patients.84,85 Compared with tacrolimus, cyclosporine significantly increases the frequency of regulatory T cells expressing IL-2 in renal transplant recipients,86 whereas tacrolimus is a strong inhibitor of IL-2 production and was shown to increase intestinal permeability, which enhances the intestinal immune response to luminal antigens in liver transplant recipients, leading to chronic intestinal inflammation status.9,36 In contrast, Schnitzler and colleagues87 could not confirm this unfavorable outcome in their analysis of transplant recipients with IBD taking tacrolimus-based regimens.
The efficacy of MMF has been demonstrated in organ transplants, but its role in IBD is unclear.88 In addition, MMF is associated with enterocolitis, which can mimic the symptoms of IBD flare-ups. On the other hand, azathioprine has proven its efficacy in reducing the risk of active flare-ups following a transplant.36
The role of corticosteroids in preventing acute and chronic rejection in organ transplant recipients is well established. In addition, corticosteroids facilitate clinical remission in patients who have active IBD and play a possible protective role against further episodes during posttransplant follow-up.28
On the basis of the above-mentioned discussion, it is worth recommending a switch from tacrolimus to a cyclosporine-based regimen as well as from MMF to azathioprine in transplant patients with IBD to prevent flare-ups of IBD while allowing continuation of steroids. There is, however, a lack of substantial evidence supporting such recommendations, and further research is necessary. Moreover, the risk of possible graft rejections with this standard regimen must be weighed against the benefits.
Because the risk of colorectal cancer is higher in complex cases of IBD that are refractory to intensive medical treatment, surgery remains an essential treatment option.89
Complications in Kidney Transplant Recipients With Inflammatory Bowel Disease
Allograft acute rejection
In a meta-analysis of 7 studies by Hansrivijit and colleagues, the pooled acute rejection rate and retransplant rate were reported as 31.4% and 30.4%, in IBD patients.7 Infections or undersuppression of the immune system may contribute to such rejection episodes.
Patients with IBD are at increased risk of developing colorectal cancer (CRC).90 Moreover, several analyses established an association between increased risk of CRC in solid-organ transplant recipients.91 This suggests that IBD is associated with an additional increase in the risk of development of CRC in organ transplant recipients. Despite being in clinical remission, patients with IBD who receive a liver transplant may develop high-grade dysplasia or colonic adenocarcinoma.23 The incidence of CRC in such patients varies from 0 to 43.5 per 1000 people per year, and the lesion is typically localized to the cecum and ascending colon.29,92 Posttransplant immunosuppressive therapy,93 the duration of IBD,83 and CMV infection94 are associated with an increased risk of CRC in liver transplant recipients.
Colonoscopy surveillance for follow-up of patients with IBD is recommended based on the following patient high-risk factors: primary sclerosing cholangitis, prior colorectal dysplasia, chronic active inflammation, evidence of intestinal damage with colonic stricture, pseudopolyps, foreshortened tubular colon, or family history of CRC at age ≦50 years; annual colonoscopy is recommended.90,95 On the other hand, colonoscopy is recommended every 3 years for patients with intermediate-risk factors and every 5 years for patients with low-risk or no risk factors.90,95 Transplant recipients are at greater risk of CRC versus the general population96 and may qualify as high-risk patients if they have concurrent IBD, which may necessities annual surveillance, although there are no definite guidelines to support this recommendation.
Thrombotic events are frequent in patients with active IBD and are probably related to a hyper-coagulable status caused by chronic inflammation of the bowel.97 Severe disease activity, parenteral nutrition, and oral contraceptives can all increase the risk of venous thromboembolism.97 Venous throm-boembolism occasionally occurs as pulmonary embolism and cerebrovascular events; however, it may occur in the cerebral sinuses, lower extremities, and portal vein. The risk is generally higher for patients with IBD and primary sclerosing cholangitis who receive a liver transplant.30
Infections and septic complications
Increases in rehospitalization rates and deaths occur with increases in infection rates.88 Patients with IBD are more likely to develop opportunistic infections, which may be attributed to a poor nutritional status, evident in lower body mass index and hemoglobin levels, or as a consequence of the immunosup-pressive and biologic drug therapy.28,98
Patient Survival in Renal Transplant Patients With Inflammatory Bowel Disease
In a recent analysis by Grupper and colleagues, in which 12 IBD patients underwent a kidney transplant (secondary to IgA nephropathy and polycystic kidney disease), 5-year survival rates among patients with IBD compared with those without IBD were 80.8% versus 96.8% (P = .001).88 Nevertheless, the death-censored graft survival of the IBD group was comparable with that of the non-IBD group.88 In a prospective analysis of 15 patients with severe IBD who developed end-stage renal disease due to systemic amyloidosis between 1989 and 2010, 6 patients required kidney transplantation, with 5 grafts remaining functional at 0.8, 3.2, 4.2, 20.1, and 24.6 years after transplant. There was 1 graft failure secondary to amyloid recurrence 14.5 years after transplant, which occurred in a patient with sustained chronic inflammation.99 Similarly, Schnitzler and colleagues reported favorable outcomes in 31 transplant recipients, with a survival rate of 84% during a follow-up period of 103.0 months.87 Despite the favorable prognosis, these studies have small sample sizes, making it difficult to draw accurate conclusions.
Inflammatory bowel disease is not uncommon among kidney transplant recipients. Moreover, de novo IBD after kidney transplant should be considered in the differential diagnosis for patients with chronic diarrhea and abdominal pain, after excluding infectious causes and drug-related side effects. Management of posttransplant IBD can be challenging with the concurrent use of immuno-suppressive therapy. Switching from a tacrolimus-based to a cyclosporine-based regimen and MMF to azathioprine in patients with IBD might be beneficial in reducing or preventing flare-ups of IBD. However, there is a lack of substantial evidence supporting such recommendations, and physicians should weigh the risk of developing acute rejection versus the risk of relapse when considering the above-mentioned changes in immunosuppressive medications. Biologic therapy is safe and highly efficient in organ transplant recipients; however, biologics have been associated with increased mortality and high infection rates, suggesting careful patient selection and pretherapy surveillance for active infections and neoplasms.
Volume : 21
Issue : 10
Pages : 791 - 800
DOI : 10.6002/ect.2023.0196
From the 1Department of Nephrology, Dubai Academic Health Corporation (DAHC), Dubai, United Arab Emirates; the 2Royal Liverpool University Hospitals, Liverpool, UK; and the 3Sheffield Teaching Hospitals, Sheffield, UK
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Fakhriya Alalawi, Department of Medicine at DMC, Department of Nephrology, Dubai Hospital, Dubai Academic Health Corporation (DAHC), Dubai, United Arab Emirates