Post-renal acute renal failure

A 54-year-old Hispanic man with type 2 diabetes mellitus and hypertension was initially evaluated at another institution for difficulty voiding urine. He was found to have a serum creatinine of 7.1 mg/dl that had increased from his baseline of 1.0 mg/dl 2 years earlier. Renal ultrasound revealed bilateral hydronephrosis with hydroureter. In addition, he had significant enlargement of his prostate. Over the ensuing 4 months, he underwent three transurethral resections of his prostate for persistent symptoms. His serum creatinine plateaued at 3.8 mg/dl. He was referred to our institution for further evaluation and management of his persistent symptom of voiding difficulty and elevated creatinine. At our institution, a detailed history and physical examination was performed. His International Prostate Symptom Score (IPSS) was 35, suggesting severe lower urinary tract symptoms.1 He denied poly- or oliguria, dysuria, fever, chills, and change in weight or appetite. His medications included NPH insulin and amlodipine. He denied tobacco, alcohol, and occupational chemical exposure, exposure to asbestos, tuberculosis, or use of over-the-counter medications. His family history was not significant. Physical examination revealed a well-appearing man with blood pressure of 126/80 mm Hg, body mass weight 34 kg/m2. Jugular venous pressure was 9 cm H2O, lungs were clear to auscultation, cardiovascular exam revealed a displaced left ventricle apical impulse, the abdomen was obese, non-tender with no palpable kidneys, and prostate enlargement on digital rectal exam. Examination of the testicles was unremarkable. Extremities did not reveal edema or changes of chronic venous stasis. Normal dorsalis pedis pulses were present on palpation. Renal ultrasound revealed mild bilateral hydronephrosis and hydroureter. Urodynamic measurements showed no evidence of outlet obstruction. A trial of indwelling urinary catheter was without benefit. Magnetic resonance imaging of the abdomen showed fibrosed soft tissue in the retroperitoneum, narrowing of the inferior vena cava and hydronephrosis consistent with retroperitoneal fibrosis (Figure 1a). Serology revealed an elevated acute-phase reactants 126 mm/h, auto-antibodies 1:160 (speckled), and a positive anti-ribonucleo protein (anti-RNP) assay. Investigation for secondary causes was undertaken. Extensive drug history did not reveal any medications that could cause retroperitoneal fibrosis (e.g., methysergide, ergot derivatives, hydralazine, or -blocker). There was no history of trauma, radiation, or malignancy. Purified protein derivative test was negative. Prostate-specific antigen was 1.1 mg/dl (within normal limits). Therefore, the diagnosis of idiopathic retroperitoneal fibrosis (IRF) was presumptively made. Idiopathic retroperitoneal fibrosis. After counseling the patient, steroids were administered (prednisone 60 mg/day) and bilateral ureteral stents (7 French 24 cm double J-stents) were placed (Figure 1b). However, there was no improvement in the patient's symptoms or serum creatinine (3.4 mg/dl) after 3 months of intervention. The patient had worsening hyperglycemia, hypertension, and obesity, possibly due to high-dose steroid therapy. Over this period, he also developed lower extremity edema possibly due to progressive venous and lymphatic compression. Given the poor response to conservative medical therapy over the 7 months since presentation to our institution, steroid therapy was stopped and the patient underwent laparotomy with ureterolysis, lateralization, and omental wrapping of the ureters. The intraoperative images are shown in Figure 2. Postoperatively, serum creatinine improved to 1.7 mg/dl at 3 months after surgery. Six years after surgery, the patient remains symptom-free without immunosuppressive medications. The IPSS has improved to 10, suggesting mild lower urinary tract symptoms. His serum creatinine is 2.0 mg/dl and elevated acute-phase reactants (ESR) 31 mm/h. Magnetic resonance imaging (MRI) of the abdomen and pelvis with gadolinium showed stable retroperitoneal fibrosis without hydronephrosis or hydroureter after 6 years of follow-up care. Examination of the surgical biopsy specimen revealed dense fibrous tissue with foci of chronic inflammation, consistent with retroperitoneal fibrosis. No granulomatous disease or neoplastic cells were identified (Figure 3). The most common cause of post-renal acute renal failure (ARF) in men is benign prostatic hyperplasia. When treating patients with post-renal ARF, failure of therapy for the usual causes should prompt an investigation for less common etiologies. This case exemplifies the need for aggressively pursuing other diagnoses, such as retroperitoneal fibrosis, when there is suboptimal response to the initial management strategy. The first description of IRF dates back to 1905 when Albarran described a case in the French literature. However, in 1948, the disease became known as Ormond's disease because Ormond2 was the first to publish two cases of IRF in the English literature. IRF is a rare clinical entity characterized by the presence of chronic inflammation and marked fibrosis of the retroperitoneal tissue. The idiopathic form of the disease accounts for the more than two-thirds of cases.3 A case–control study from Finland reported an incidence of 0.1 per 100 000 person-years and a prevalence of 1.38 per 100 000 people in 2004. Men are affected twice as often as women; the mean age of presentation is 50 years, and there is no evidence of familial, ethnic, or geographic predisposition.4 The pathogenesis of IRF is multifactorial. Genetic studies have revealed linkage with HLA-DRB1*03, an allele linked to various autoimmune diseases, including type 1 diabetes mellitus, myasthenia gravis, and systemic lupus erythematosus.5 Environmental factors may also play a role. For instance, occupational exposure to asbestos increases the risk of developing IRF.4 IRF has been classified as a form of chronic periaortitis, a systemic inflammatory condition. Inflammatory abdominal aneurysm and perianeurysmal retroperitoneal fibrosis are the two other forms of periarotitis. Inflammatory abdominal aneurysm is characterized by deposition of inflammatory tissue around the abdominal aneurysm without causing obstruction, whereas perianeurysmal retroperitoneal fibrosis is marked by tissue around the aortic aneurysm causing obstruction of surrounding structures. The hallmark feature of chronic periaortitis is adventitial and periadventitial inflammation.6 The local inflammatory reaction is believed to result from oxidized low-density lipoprotein (LDL) and ceroid (a lipoproteic polymer resulting from LDL oxidation within macrophages). Recently, this theory has been validated by detecting increased immunoglobulin G (IgG)7 in the proximate extracellular ceroid, T and B lymphocytes in the media and markers of activation and proliferation in the adventitia.8 Plasma cells bearing IgG4 have been implicated in the pathogenesis, raising the possibility of a clonal B-cell disorder.9 Moreover, patients with IRF often have ESR and C-reactive protein (CRP) and positive auto-antibodies (ANA). This evidence makes a compelling argument that IRF is a manifestation of a systemic autoimmune disease. Secondary causes of IRF,3 account for the remaining one-third of the cases of retroperitoneal fibrosis, and have been most commonly associated with ergot derivatives (methysergide), dopamine agonists (methyldopa and peroglide), antihypertensive medications (-blockers and hydralazine), and analgesics (acetylsalicyclic acid and phenacetin). Causality has not been firmly established with most of these drugs. Certain infections, for example, tuberculosis, radiotherapy, trauma, and major abdominal surgery have also been implicated in development of retroperitoneal fibrosis. A number of malignancies are known to cause an intense desmoplastic response to retroperitoneal metastasis, particularly carcinomas of the prostate and colon. Carcinoids, Hodgkin's and non-Hodgkin's lymphoma, and sarcomas have also been associated with retroperitoneal fibrosis. IRF is a diagnosis of exclusion. There are no standardized diagnostic criteria. Imaging modalities are the non-invasive investigations of choice when IRF is suspected. They are also useful for following the disease. The presence of a soft tissue mass encasing the abdominal aorta with possible involvement of neighboring structures such as ureters and IVC, usually suggests retroperitoneal fibrosis. ESR support the diagnosis. Gross pathology of the idiopathic form shows thick, white, hard retroperitoneal plaque, which surrounds the abdominal aorta, IVC, and the ureters, usually between the origin of the renal vessels and the bifurcation of the common iliac vessels. The microscopic appearance of IRF is described as sclerotic tissue infiltrated by mononuclear cells. Malignancy-induced retroperitoneal fibrosis has irregular shape and may have atypical localization, in contrast to the idiopathic disease.10 Local invasion of neoplastic cells may be seen within the fibrous tissue. Presence of granulomas should suggest underlying chronic infection (e.g., tuberculosis). Clinical features of IRF include abdominal pain, backache, and renal colic and non-specific constitutional symptoms of low-grade fever, nausea, vomiting, and fatigue. Compression of surrounding structures, lymphatics, and visceral blood vessels may produce lower extremity edema, deep vein thrombosis, varicocele, hydrocele, constipation, and small bowel obstruction. Involvement of ureters is reported in more than 80% of cases.10 At presentation, such involvement is often bilateral, but in patients with an apparently unilateral obstruction, contralateral disease can develop within a short period. Hydronephrosis with ARF is rare as IRF is a gradual process.11 Some patients present with varying degrees of renal insufficiency, probably caused by long-standing hydronephrosis.12 As the clinical features are non-specific, there is often a significant delay between onset of symptoms and diagnosis. This frequently leads to the late complications of chronic renal failure from post-renal ureteral obstruction. In 80–100% of cases of IRF, acute-phase reactants are elevated. Measurements of ESR and CRP may also be used to monitor the disease. Normocytic, normochromic anemia due to chronic inflammation and renal insufficiency may be present. Azotemia may be present. Antinuclear antibodies in low titers are present in 60% of patients, as was the case in the patient described herein. Rheumatoid factor and ANA against smooth muscle, double-stranded DNA may also be positive. Their utility lies in detecting associated autoimmune disorders. The presence of antibodies against thyroid microsome and thyroglobulin usually indicates autoimmune thyroiditis, which is the most frequent autoimmune disease associated with retroperitoneal fibrosis.13 The frequency of the association between IRF and other autoimmune diseases is not known, mainly because the published reports are limited to case series or case reports. Imaging studies are essential for the diagnosis and management of retroperitoneal fibrosis, and can sometimes help to differentiate between the idiopathic and secondary forms of the disease. Ultrasound is usually performed for investigation for azotemia. Hypoechoic or isoechoic mass may be visible suggestive of retroperitoneal fibrosis. Intravenous urography may reveal a non-diagnostic triad of medial deviation, extrinsic compression of the ureters, and hydronephrosis.14 Computed tomography (CT) and MRI are the most reliable imaging modalities for the diagnosis of IRF. On non-enhanced CT, IRF appears as a homogeneous plaque, isodense with muscle, surrounding the lower abdominal aorta and the iliac arteries, and encasing the ureters and the inferior vena cava (IVC). Secondary IRF owing to malignancy usually displaces the aorta anteriorly and the ureters laterally. On MRI, IRF is hypointense in T1-weighted images. In T2-weighted images, IRF intensity is high in the early or active stages of the disease and low in the late stages. Intensity is high owing to edema and hypercellularity. The presence of an heterogeneous signal on T2-weighted images suggests malignant retroperitoneal fibrosis.13 Fluorodeoxyglucose-positron emission tomography (FDG-PET) is not considered useful for the diagnosis of the retroperitoneal fibrosis due to its low specificity. However, it can be considered a reliable means of assessing the metabolic activity of the retroperitoneal mass. FDG-PET may be helpful in detecting occult malignancy or infection.15 The aims of the treatment for IRF are three-fold: to arrest the progression of the disease, prevent recurrence, and to relieve the obstruction of the ureters or other retroperitoneal structures. Corticosteroids are the most commonly used drugs and have greatly improved outcome. Steroids suppress the synthesis of cytokines involved in the acute phase reaction, reduce the inflammatory component and inhibit collagen synthesis.15 They improve symptoms, reduce the size of the retroperitoneal mass and help in resolution of obstructive complications. However, the dose, duration, and efficacy of the steroids have not been well established. An initial daily dose of prednisone 40–60 mg is administered. To prevent relapse, treatment courses of up to 2 years are sometimes recommended. Treatment with Cyclophosphamide, Azathioprine, Methotrexate, Cyclosporine, and Mycophenolate mofetil has been reported. No randomized studies have compared the effectiveness of immunosuppressive drugs with steroids. In a recent case series, tamoxifen showed improvement in inflammatory markers and CT scan findings after 2.5 weeks. However, the major limitation of the study was that there was no placebo arm.16 A conservative approach with temporary placement of ureteral stents or nephrostomy tubes followed by medical therapy is recommended, although in refractory cases surgery is recommended.13 Open surgery usually involves ureterolysis and intraperitoneal transposition with omental wrapping of the entire length of the ureters to relieve ureteral obstruction, to help prevent invasion by the fibrotic tissue and to provide vascularity to the ureters. Surgery does not prevent disease progression or recurrence, and has no effect on systemic manifestations.11 Recently, laproscopic ureterolysis has been reported.17 The prognosis for IRF is generally good, provided that a timely diagnosis is made before the onset of complications. Monitoring symptoms, ESR, CRP, and imaging is generally recommended. Relapse rates are not known. Ureteral obstruction is estimated to recur in up to half of the patients who undergo surgery alone and in about 10% of those who are treated with steroids and surgery.18 In the patient we presented here, IRF was managed without long-term steroids and thus, avoided the significant risks associated with long-term corticosteroid therapy. This was particularly important given the fact that our patient has a history of diabetes and hypertension. In some instances, however, despite effective medical treatment, residual retroperitoneal fibrotic tissue is identified. Recently, a study using FDG-PET has shown that in most patients with a stable clinical condition and significantly decreased concentrations of acute-phase reactants, the residual masses have very little or absent FDG accumulation.19 This has suggested the presence of an inactive, sclerotic disease that would be probably unresponsive to further treatment. This case illustrates the importance of persistent investigation of post-renal ARF when the response to initial treatment for more common causes is suboptimal. A multidisciplinary approach and close collaboration between nephrologists, urologists, and rheumatologists is essential for the management of IRF. Follow-up of these patients is critical to prevent recurrence and to retard the progression of the disease.