Retroperitoneal fibrosis is a variant of mesynchymopathy, a nonspecific fibrosclerotic process that develops in the connective tissue of the retroperitoneal space. Manifestations are caused by compression of the ureters, blood vessels and kidneys. The main symptoms are lumbar and abdominal pain, discomfort in the groin area. In advanced cases, CRF is joined, edema, nausea, and decreased diuresis are observed. The diagnosis is confirmed by CT, MRI, PET and morphological examination, determination of the level of IgG4. Treatment is conservative (hormone therapy), in case of urodynamic disorders – operative.
ICD 10
K66.2
Meaning
Retroperitoneal fibrosis (Ormond’s disease) was first described by the French researcher I. Albarran at the beginning of the XX century, more extensive work on the study of pathology was carried out by the American urologist D.K. Ormond in 1948. Specialists in the field of modern urology consider most cases of the disease as an immune-dependent systemic pathology associated with IgG4-CZ immune complexes, characterized by total or partial inflammatory infiltration of organs and tissues by plasma cells. They produce IgG4, which initiates obliterating phlebitis and fibrosclerosis. Ormond’s disease is a special case of mesynchymopathy, similar changes are registered in other organs and systems. Pathology is more often diagnosed in men over 50 years of age.
Causes
The causes of retroperitoneal fibrosis remain debatable to date. It is believed that etiological factors provoke an immune response, which contributes to an inflammatory lesion of the peritoneum, the outcome of which is fibrosis. The aggressiveness of the pathology varies, the causes of variability are unknown. The main pathogenetic trigger is the increased expression of the IgG4 complex by plasma cells. Ormond’s disease may be secondary, experts identify a number of conditions that potentially lead to retroperitoneal fibrosis:
- Some diseases. Inflammation of the kidneys, ureters and other organs adjacent to the retroperitoneal tissue can initiate fibrotic-sclerotic processes. Malignant neoplasms (cancer of the rectum, prostate, bladder), infections (tuberculosis, toxoplasmosis, brucellosis) also provoke retroperitoneal fibrosclerosis. Pyelorenal reflux, extravasation of urine with dissolved antibiotics play a special role in infiltration of the ureter and often lead to hydronephrosis.
- Tissue damage. Abdominal trauma, especially with the formation of retroperitoneal hematoma, can be complicated by lymphoproliferative disorders of plasma cells. Similar changes are sometimes potentiated by surgical interventions: lymphadenectomy, colectomy, operations for aortic aneurysm. Fibrosis of one degree or another is registered after undergoing radiation therapy on the pelvic organs.
- Taking a number of medications. Bromocriptine, hydralazine, methyldopa, ergot derivatives cause sclerosing retroperitoneal granulomatosis with prolonged use. Some experts mention treatment with high doses of antibiotics and beta-blockers as the cause of pathology. Ormond was convinced that fibrosclerotic growths were the result of hypersensitivity reactions to drugs or chemicals.
Predisposing factors include smoking, exposure to asbestos. The presence of several patients within the same family indicates a possible role of genetic factors. In some patients suffering from Ormond’s fibrosclerosis, the human leukocyte antigen HLA–B27 (an immunogenetic marker) is detected, the carrier of which indicates a predisposition to autoimmune diseases, including retroperitoneal fibrosis. There are other genetic associations that increase the likelihood of pathology.
Pathogenesis
According to recent data, 50-75% of Ormond’s disease is associated with the presence of plasma cells producing IgG4. Pathology is more often manifested systemically, similar tissue changes are almost always detected in the pancreas, lymph nodes, pituitary gland. There is tumor-like edema of the involved organs, lymphoplasmic infiltration and fibrotic-sclerotic process of varying severity. The altered fiber compresses the ureter, large main vessels, lymphatic pathways, and, less often, the kidneys.
Retroperitoneal fibrosis as a consequence of malignant neoplasms accounts for 8-10% of the total number of cases of the disease. Active collagen synthesis is promoted by desmoplasia (the formation of fibrous connective tissue as a response to the presence of cancer cells in the retroperitoneal space) or a primary tumor, for example, lymphoma, sarcoma or metastatic lesions from other organs: stomach, prostate, kidneys.
The infiltrate consists of numerous lymphocytes, plasma cells, macrophages, and sometimes neutrophils. Inflammatory cells are embedded in collagen bundles, organized by nodular clusters around small vessels. Pathology is classified as associated with IgG4 in the presence of storiform fibrosis, infiltration of eosinophils, obliterating phlebitis. Mast cells are in a degranulated state, which is consistent with their active participation in the fibroinflammatory reaction.
Classification
Retroperitoneal fibrosis may be isolated, associated with autoimmune diseases, or it may occur against the background of a multi-focal fibroinflammatory disease associated with IgG4. The lesion more often affects both ureters. There are no standardized criteria for the classification of retroperitoneal fibrosis, the pathology is considered on a par with chronic periaortitis, perianeurysmic fibrosis and inflammatory aneurysms of the abdominal aorta, which have common histological and clinical signs. Forms of retroperitoneal fibrosis:
- Primary (idiopathic). The cause of the disease cannot be detected. Systemic autoimmune pathologies, the fact of traumatization, oncological processes are absent.
- Secondary. There is a connection with medications, trauma, radiation exposure. In 10% of patients, retroperitoneal fibrosclerosis is caused by the progression of malignant neoplasm.
- IgG4- associated. Approximately half of the cases are a symptom of a relatively clinically heterogeneous disease associated with IgG4.
Symptoms
Initially, in 60-90% of cases, systemic symptoms are observed: weakness, anorexia, weight loss. Clinical manifestations of the expanded form are diverse, including discomfort in the lumbar region, abdomen and above the womb (70-90%). The pain is usually dull, does not change depending on the position of the body, temporarily reacts to nonsteroidal anti-inflammatory drugs. When the ureter is affected, it imitates renal-ureteral colic, for which sharp soreness, a positive symptom of beating, vomiting are typical.
In 20% of cases, compression disrupts normal intestinal motility, provoking constipation. 35% of men with Ormond’s disease have testicular pain, retrograde ejaculation and erectile dysfunction. Less common urological symptoms include frequent urination, cramps and an admixture of blood in the urine. An increase in temperature to febrile figures, stunning chills and pronounced lumbar pain indicate the addition of acute pyelonephritis.
Vascular compression is manifested by hydrocele and varicocele (30%). Complaints of discomfort in the perineum, a feeling of distension of the scrotum are characteristic. Compression of the inferior vena cava and lymphatic pathways causes swelling of the lower extremities and lameness in every tenth patient. When the renal arteries are involved, reno-vascular hypertension occurs. The increase in pressure is steady. With pre-existing hypertension, its course worsens. High blood pressure at diagnosis is detected in a third of patients.
Complications
Complications of the disease are very serious, associated with high mortality (10-20%). Narrowing of the ureteral lumen and their hypotension lead to recurrent pyelonephritis, hydronephrotic transformation of the kidneys (55-100%), chronic renal failure (40-90%). In 32% of patients, kidney atrophy is diagnosed, whether it is due to ureteral obstruction, renal artery stenosis or other causes remains unclear. Often, after the defeat of one ureter, the other is involved in the process for a period of several weeks to several years.
Deep vein thrombosis and pulmonary embolism – formidable complications of venous compression in Ormond syndrome – are rare, due to the compensatory capabilities of the body (the formation of collateral pathways for blood outflow). In retroperitoneal fibrosclerosis, mesenteric and abdominal arteries may be affected with the development of stenosis and ischemic complications resembling mesenteric vasculitis. In 30% of patients with retroperitoneal fibrosis, the thoracic aorta is altered, which can lead to its aneurysm.
Diagnostics
Autoimmune sclerosing disease is difficult to suspect due to the variety of complaints. Changes in the analyses are nonspecific, occur in other pathologies. Often, under-examined patients receive inadequate treatment from a urologist or gastroenterologist, which worsens the prognosis. It is proved that at the initial stage it is possible to achieve remission of the disease with the help of exclusively conservative therapy, therefore, experts consider early detection of the pathological process a priority. The examination algorithm for retroperitoneal fibrosis of Ormond includes:
- Laboratory tests. Inflammatory markers (ESR, C-reactive protein) are higher than normal in more than half of patients, but this indicator does not allow differentiating idiopathic and secondary retroperitoneal fibrosclerosis. An increase in serum IgG4 levels >135 mg/dl in combination with histological signs is the main criterion for confirming IgG4-SZ. In all forms of pathology, the level of urea, creatinine and GFR is evaluated to determine the functional ability of the kidneys. Urine analysis shows low specific gravity, proteinuria, hematuria.
- Visualization techniques. MRI and CT are the main studies in Ormond’s disease. Layer-by-layer scanning helps to distinguish between idiopathic and secondary forms of fibrosclerosis. Ultrasound is performed to confirm the disease in the initial stages, assess the degree of hydronephrosis, detect aneurysms and dilatation of the aorta. A contrast agent is used to improve visualization. In recent years, PET has been performed, which reveals hidden tumor and infectious processes.
- Biopsy. With ambiguous results of instrumental studies and no response to steroid therapy, a biopsy is justified. As a limitation to the study, the suspicion of a tumor process with the risk of spreading cancer cells is considered. In the early stages of fibrosis, hypervascular tissue with perivascular lymphocytic infiltrate, macrophages with fatty inclusions are determined. For the late stage, a vascular-free mass, devoid of cellular structures, is typical.
Differential diagnosis is carried out with tumors of the retroperitoneal space, obstructive uropathy of a different genesis (with nephrolithiasis, radiation damage, nonspecific urethritis). A similar pattern is observed in inflammatory processes of fiber, post-traumatic conditions and neoplasms of the ureter. The differential diagnosis between idiopathic IgG4-related and secondary fibrosclerosis is crucial because management tactics can vary dramatically.
Treatment
Therapeutic measures are aimed at preserving the functional ability of the urinary organs, preventing the spread of the pathological process to neighboring structures, relieving or relieving adverse symptoms. Treatment tactics (conservative or surgical with medication) depends on the stage of retroperitoneal fibrosis. In the absence of uropathy and pronounced vascular compression, drug therapy with mandatory supervision is possible (CT, MRI and ultrasound of the abdominal cavity and kidneys, assessment of ESR, C-reactive protein levels).
Conservative therapy
Conservative treatment makes it possible to achieve positive dynamics in 80-83% of patients. The effect of corticosteroids is due to their anti-inflammatory effect, the ability to slow down the maturation of connective tissue. Tamoxifen is prescribed in the presence of contraindications to corticosteroids or simultaneously with hormonal agents. The combination of glucocorticoids with azathioprine is most useful in inflammation. Azathioprine is also used as an immunosuppressive drug when glucocorticoid therapy is ineffective. The immunosuppressant mycophenolate inhibits purine synthesis and lymphocyte proliferation.
Surgical interventions
Obstructive uropathy with urodynamic disorders and a tendency to kidney hydronephrosis implies a solution to the issue of urine excretion. Primary treatment of retroperitoneal fibrosis includes ureterolysis, lateral or intraperitoneal transposition of the ureters, their isolation. Next, a course of anti-relapse therapy is necessarily carried out, which reduces the likelihood of relapse from 50 to 10%.
- Ureterolysis. The operation consists in removing the fibrous tissue compressing the ureter. It does not always provide a satisfactory result, since uropathy is caused not only by compression, but also by hypotension of the muscle layer. The intervention is performed in an open and laparoscopic manner. The latter is less traumatic, its effectiveness reaches 93.8%. Ureterolysis with enveloping the ureter with a large omentum is performed more often and is considered an operation of choice, which is associated with fewer relapses (10%).
- Manipulations to restore the outflow of urine. Ureteral stenting is used as a primary aid to restore urodynamics. After the inflammation is relieved, surgical intervention is possible. In elderly patients, with the identification of contraindications and a serious condition that does not allow surgery, a stent-type catheter can function for a long time with replacement as needed. Sometimes percutaneous puncture nephrostomy is performed – drainage is installed in the pelvis under the control of ultrasound equipment.
- Innovative methods. New surgical techniques are described: ureterolysis and wrapping with membrane-breathing tissues, ureteral excision and reanastomosis, renal autotransplantation. Uropathy is resolved by balloon dilation – a balloon is inserted endourologically, and then, under visual control, it is expanded in the desired area of the ureter. The effectiveness of these interventions is variable.
Experimental methods
Recently, effective extracorporeal therapies based on the removal of pathogenic and toxic substances from the blood have begun to be used. There are several options: plasmapheresis, lymphocytapheresis (separate extraction of lymphocytic cells), cascade filtration of plasma. Good results are obtained by perfusion of the liquid part of the blood through a carrier that cuts off the corresponding antibodies.
Rituximab (monoclonal antibodies obtained by genetic engineering) is isolated from new drugs that provide improvement in idiopathic and IgG4-related pathologies. It is prescribed as monotherapy or in combination with corticosteroids. Rituximab is used for prophylactic purposes after achieving remission. Large randomized trials have not been conducted, approaches to therapy are largely under development.
Prognosis and prevention
If the disease is diagnosed at an early stage with the condition of adequate therapy, the prognosis is favorable. Hydronephrosis and chronic kidney disease worsen the outcome. Improvement of kidney function occurs in 14-18 days, then patients are subject to careful monitoring: at first every three months, if there is no negative dynamics – once every six months. Retroperitoneal fibrosis initiated by tumor diseases has an unfavorable prognosis with mortality within six months.
Preventive measures to prevent idiopathic forms of the disease have not been developed. To prevent secondary retroperitoneal fibrosis, you should give up smoking and adhere to a healthy lifestyle. It is unacceptable to take medications exceeding the recommended dosages and duration of therapy, self-medication. Previously, contacting a specialist when unpleasant symptoms appear, passing a full diagnosis significantly increases the chances of a favorable outcome – acute forms of fibrosis or existing for no more than 6 months are better treated.