Retroperitoneal Fibrosis (RPF)

1. Clinical Overview

Summary

Retroperitoneal Fibrosis (RPF), also known as Ormond's Disease, is a rare fibro-inflammatory condition characterised by the development of dense fibrous tissue in the retroperitoneum, typically surrounding the infrarenal abdominal aorta and iliac vessels, and commonly encasing the ureters, leading to bilateral ureteric obstruction, hydronephrosis, and renal impairment. [1,2]

RPF is classified as:

• Idiopathic (Primary): ~60-70% of cases, increasingly recognised as part of the IgG4-Related Disease (IgG4-RD) spectrum
• Secondary: ~30-40%, caused by medications (ergot derivatives, methysergide, beta-blockers), malignancy (lymphoma, sarcoma, metastases), infection (tuberculosis), radiotherapy, inflammatory abdominal aortic aneurysm, or asbestos exposure [3,4]

The condition presents insidiously with dull lower back or flank pain, constitutional symptoms (weight loss, malaise, low-grade fever), and symptoms of renal impairment. The hallmark imaging finding is a peri-aortic soft tissue mass with medial deviation of the ureters on CT or MRI. [5,6]

Diagnosis requires exclusion of malignancy (often necessitating biopsy), assessment of inflammatory markers (ESR, CRP), and evaluation for IgG4-RD (serum IgG4 levels, tissue IgG4+ plasma cell infiltration). Treatment involves urgent relief of ureteric obstruction (stenting or nephrostomy), corticosteroid therapy (first-line for idiopathic/IgG4-RD), immunosuppressive agents (steroid-sparing or refractory cases), and surgical ureterolysis (for refractory obstruction). [7,8,9]

Prognosis is generally favourable with early treatment, with excellent response to corticosteroids (~85-90% in idiopathic cases), though relapse rates of 20-50% necessitate long-term monitoring. Untreated or delayed diagnosis can lead to irreversible renal failure. [10,11]

Clinical Pearls

"Peri-Aortic Mass with Medial Ureteric Deviation": Pathognomonic imaging appearance on CT. Normal ureters are laterally displaced; RPF causes medial deviation and encasement.

"Exclude Malignancy First": Lymphoma, retroperitoneal sarcoma, and metastatic disease can mimic idiopathic RPF. Biopsy is often mandatory.

"IgG4-RD Association": ~50-60% of idiopathic RPF cases show elevated serum IgG4 and tissue IgG4+ plasma cells. Consider screening for multi-organ IgG4-RD.

"Dramatic Steroid Response": Most idiopathic/IgG4-RD cases respond rapidly to corticosteroids within weeks. Lack of response should prompt reconsideration of diagnosis.

"Bilateral Obstruction = Urgent Decompression": AKI from bilateral ureteric obstruction requires immediate nephrostomy or retrograde stenting before initiating medical therapy.

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2. Epidemiology

Demographics

Risk Factors

Classification

Exam Detail: ### Molecular Pathophysiology of Idiopathic RPF

The pathogenesis of idiopathic RPF remains incompletely understood but involves:

1. Periaortic Inflammation (Periaortitis) Theory [11,12]:

   • Chronic inflammation in response to atherosclerotic plaque antigens (ceroid, oxidised LDL) leaking from aortic wall
   • Immune complex deposition and complement activation
   • T-cell mediated inflammation with CD4+ T-helper cells and macrophage infiltration
   • Progression to fibrous tissue deposition surrounding aorta

2. IgG4-Related Disease Mechanisms [7,8,13]:

   • Oligoclonal expansion of IgG4+ B-cells and plasma cells
   • Th2-skewed immune response with IL-4, IL-5, IL-13 production
   • Regulatory T-cell (Treg) dysfunction with increased TGF-β and IL-10
   • TGF-β-driven fibrosis: Transforming growth factor-beta stimulates fibroblast proliferation and collagen synthesis
   • Storiform fibrosis: Characteristic cartwheel/storiform pattern of collagen deposition
   • Obliterative phlebitis: Inflammatory destruction of venules within fibrotic tissue

3. Fibrotic Cascade:

   • PDGF, CTGF, TGF-β drive fibroblast activation
   • Myofibroblast transformation with α-SMA expression
   • Extracellular matrix deposition: Type I and III collagen, fibronectin
   • Tissue hypoxia and further inflammatory perpetuation

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3. Pathophysiology

Anatomical Distribution

RPF most commonly involves:

Consequences of Ureteric Obstruction

1. Hydronephrosis: Dilation of renal pelvis and calyces
2. Renal Parenchymal Damage:
   • Increased intrapelvic pressure → decreased GFR
   • Tubular atrophy and interstitial fibrosis
   • Progressive nephron loss
3. Acute Kidney Injury: Bilateral obstruction → anuria/severe oliguria
4. Chronic Kidney Disease: Prolonged obstruction → irreversible fibrosis
5. Post-Obstructive Diuresis: After relief of bilateral obstruction

Secondary RPF Mechanisms

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4. Clinical Presentation

Symptoms

RPF typically presents insidiously over weeks to months.

Examination Findings

Presentation Patterns

1. Insidious Renal Impairment (Most common):

   • Progressive rise in creatinine over weeks/months
   • Vague back/flank pain
   • Constitutional symptoms

2. Acute Presentation:

   • Acute bilateral ureteric obstruction
   • AKI with oliguria/anuria
   • Rapid deterioration

3. Incidental Finding:

   • Asymptomatic, discovered on imaging for other indications
   • Mildly elevated creatinine on routine bloods

4. Extra-urinary Manifestations:

   • Lower limb DVT/oedema (IVC involvement)
   • Hypertension (renal artery stenosis)
   • Multi-organ IgG4-RD features

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5. Differential Diagnosis

Key Differentials

Comparison: Idiopathic RPF vs. Malignant Retroperitoneal Disease

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6. Investigations

Laboratory Investigations

Imaging

CT Abdomen and Pelvis (Contrast-Enhanced)

First-line and gold standard imaging modality. [5,6,14]

CT Staging: Assess extent of fibrosis, degree of ureteric obstruction, and vascular involvement.

MRI Abdomen and Pelvis

Superior soft tissue characterisation. Useful for:

• Contraindication to CT contrast (severe CKD, contrast allergy)
• Monitoring treatment response (no radiation)
• Differentiating active inflammation from chronic fibrosis

Ultrasound Abdomen

Limited sensitivity for retroperitoneal mass. Useful for:

• Detecting hydronephrosis (bilateral/unilateral)
• Assessing renal parenchymal thickness
• Bedside evaluation in AKI
• Follow-up of hydronephrosis after stenting

PET-CT

Increasingly used for:

1. Differentiating Inflammation from Fibrosis: FDG-avid lesions indicate active inflammation (treatable with immunosuppression). Low uptake suggests chronic fibrosis. [19]
2. Excluding Malignancy: Patterns of uptake (diffuse peri-aortic vs. focal nodal) help distinguish RPF from lymphoma/sarcoma.
3. Assessing Multi-organ IgG4-RD: Detect pancreatic, salivary gland, lymph node involvement.
4. Monitoring Treatment Response: Reduction in FDG uptake indicates response to therapy.

Intravenous Pyelography (IVP)

Historically used, now largely replaced by CT/MRI. Shows:

• Delayed contrast excretion (obstruction)
• Medial ureteric deviation
• Hydronephrosis

Tissue Biopsy

Indications:

• Exclude malignancy (mandatory if imaging atypical or lymphadenopathy present)
• Confirm IgG4-RD (tissue IgG4+ plasma cells)
• Atypical presentation or poor response to treatment

Methods:

• CT-guided percutaneous biopsy: Most common, relatively safe
• Laparoscopic/open biopsy: If percutaneous non-diagnostic or high suspicion of malignancy

Histopathology [7,8,20]:

Renal Tract Imaging for Obstruction Relief

• Antegrade Pyelography: Via percutaneous nephrostomy; delineates anatomy for ureteric stenting
• Retrograde Pyelography: Via cystoscopy; confirms ureteric obstruction level and guides stent placement

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7. Management

Management Algorithm

SUSPECTED RETROPERITONEAL FIBROSIS
(Back/flank pain, ↑creatinine, constitutional symptoms)
                    ↓
┌──────────────────────────────────────────────────┐
│  CONFIRM DIAGNOSIS                               │
│  - CT abdomen/pelvis (contrast): Peri-aortic mass│
│  - MRI (if CT contraindicated)                   │
│  - Labs: U&Es, ESR, CRP, FBC, serum IgG4         │
│  - PET-CT (if available): Assess activity,       │
│    exclude malignancy                            │
└──────────────────────────────────────────────────┘
                    ↓
┌──────────────────────────────────────────────────┐
│  EXCLUDE MALIGNANCY                              │
│  - Atypical imaging: BIOPSY (CT-guided)          │
│  - Lymphadenopathy: BIOPSY                       │
│  - If typical imaging + IgG4 elevation: May      │
│    proceed without biopsy in select cases        │
└──────────────────────────────────────────────────┘
                    ↓
┌──────────────────────────────────────────────────┐
│  ASSESS OBSTRUCTION SEVERITY                     │
│  - Serum creatinine, eGFR                        │
│  - Degree of hydronephrosis (imaging)            │
└──────────────────────────────────────────────────┘
        ↓                               ↓
SIGNIFICANT OBSTRUCTION          NO/MILD OBSTRUCTION
(Cr > 200 μmol/L, bilateral       (Cr less than 200 μmol/L, stable)
hydronephrosis, AKI)
        ↓                               ↓
**URGENT DRAINAGE**              PROCEED TO MEDICAL THERAPY
 - Retrograde ureteric stent
   (via cystoscopy) [First choice]
   OR
 - Percutaneous nephrostomy
   (if retrograde fails)
        ↓
   Reassess renal function 24-72 hrs
   Expect improvement if obstruction relieved
        ↓
┌──────────────────────────────────────────────────────────┐
│  MEDICAL THERAPY (IDIOPATHIC / IgG4-RD)                  │
│                                                          │
│  **FIRST-LINE: CORTICOSTEROIDS**                         │
│  - Prednisolone 0.5-1 mg/kg/day (30-60 mg/day)          │
│  - Continue 4-6 weeks, then gradual taper over 6-12 mths│
│  - Monitor ESR/CRP (monthly), renal function (weekly     │
│    initially, then monthly), imaging at 3-6 months       │
│  - Response expected: ESR/CRP ↓ within 2-4 weeks,       │
│    renal function improvement, reduction in mass size    │
│                                                          │
│  **If no response after 4-6 weeks**: Reconsider diagnosis│
│  (malignancy?), increase dose, or add steroid-sparing    │
│  agent                                                   │
│                                                          │
│  **STEROID-SPARING / REFRACTORY (Second-Line)**          │
│  - Tamoxifen 20 mg BD (anti-fibrotic)                   │
│  - Mycophenolate Mofetil 1-2 g/day                      │
│  - Azathioprine 1-2 mg/kg/day                           │
│  - Methotrexate 10-25 mg/week                           │
│  - Rituximab (For IgG4-RD, refractory cases)            │
│                                                          │
│  **Indications for steroid-sparing agents**:             │
│  - Steroid intolerance/contraindication                  │
│  - Relapse on steroid tapering                          │
│  - Steroid-dependent disease                            │
└──────────────────────────────────────────────────────────┘
        ↓
┌──────────────────────────────────────────────────────────┐
│  SURGICAL THERAPY (URETEROLYSIS)                         │
│                                                          │
│  **Indications**:                                        │
│  - Failed/inadequate response to medical therapy         │
│  - Recurrent ureteric obstruction despite stenting       │
│  - Steroid contraindication + severe obstruction         │
│  - Patient preference (avoid long-term immunosuppression)│
│                                                          │
│  **Procedure**:                                          │
│  - Surgical freeing of ureters from fibrotic tissue      │
│  - Intraperitonealisation: Ureters wrapped in omentum    │
│    or moved intraperitoneally (prevents re-encasement)   │
│  - Approach: Open (midline laparotomy) or Laparoscopic   │
│                                                          │
│  **Outcomes**:                                           │
│  - Success rate 80-90% (freedom from obstruction)        │
│  - Lower relapse rate than medical therapy alone         │
│  - May still require adjunct medical therapy             │
└──────────────────────────────────────────────────────────┘
        ↓
┌──────────────────────────────────────────────────────────┐
│  SECONDARY RPF                                           │
│  - Identify and treat underlying cause:                  │
│    • Malignancy: Chemotherapy/radiotherapy               │
│    • Medications: STOP causative drug                    │
│    • Infection (TB): Anti-tuberculous therapy            │
│    • Inflammatory AAA: May still benefit from steroids   │
│  - Ureteric drainage as above                            │
│  - May require surgical debulking if mass effect         │
└──────────────────────────────────────────────────────────┘
        ↓
┌──────────────────────────────────────────────────────────┐
│  LONG-TERM MONITORING                                    │
│  - Renal function (U&Es, eGFR): 3-monthly initially,     │
│    then 6-monthly                                        │
│  - Inflammatory markers (ESR, CRP): 3-monthly            │
│  - Imaging (CT/MRI): 6-monthly for first 2 years, then   │
│    annually                                              │
│  - Monitor for relapse (20-50% on steroid taper)         │
│  - Stent changes: Every 3-6 months if long-term stenting │
│  - Screen for multi-organ IgG4-RD (if applicable)        │
└──────────────────────────────────────────────────────────┘

Medical Therapy Details

Corticosteroids (First-Line) [9,10,21]

Tamoxifen (Steroid-Sparing) [22]

Other Immunosuppressive Agents

Rituximab: Particularly effective in IgG4-related RPF. Depletes B-cells, reduces IgG4+ plasma cells. Reserved for refractory or relapsing disease.

Surgical Management

Ureteric Drainage Procedures

Complications of Long-term Stenting: UTI, encrustation, stent migration, patient discomfort, need for regular changes (every 3-6 months).

Ureterolysis [25,26]

Definitive surgical treatment for refractory ureteric obstruction.

Aortic Surgery

If inflammatory AAA coexists:

• May require aortic aneurysm repair (open or endovascular)
• Ureterolysis may be combined with aortic surgery
• Increased operative risk due to inflammation

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8. Complications

Renal Complications

Vascular Complications

Disease-Related Complications

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9. Prognosis and Outcomes

Overall Prognosis

Prognostic Factors

Long-Term Outcomes

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10. Evidence and Guidelines

Key Guidelines

Landmark Studies

Evidence Levels

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11. Examination Focus

High-Yield Exam Topics

Classic Viva Questions

Q1: A 58-year-old man presents with lower back pain, weight loss, and creatinine of 320 μmol/L (eGFR 18 mL/min/1.73m²). CT shows a peri-aortic soft tissue mass encasing the ureters with medial deviation and bilateral hydronephrosis. What is the most likely diagnosis?

Model Answer: The most likely diagnosis is Retroperitoneal Fibrosis (RPF), also known as Ormond's Disease. The key features are:

1. Peri-aortic soft tissue mass surrounding the infrarenal aorta
2. Medial ureteric deviation with encasement (pathognomonic for RPF; normal ureters are lateral)
3. Bilateral hydronephrosis causing obstructive renal impairment
4. Constitutional symptoms (weight loss) and back pain

The differential diagnosis includes malignancy (retroperitoneal lymphoma, sarcoma, metastatic disease), which must be excluded with biopsy if imaging is atypical or lymphadenopathy is present.

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Q2: What is the first-line management for idiopathic retroperitoneal fibrosis with bilateral ureteric obstruction and AKI?

Model Answer: Management is two-pronged:

1. Immediate ureteric drainage to relieve obstruction:

   • Retrograde ureteric stenting (via cystoscopy, first choice)
   • Percutaneous nephrostomy if retrograde stenting fails
   • Expect improvement in renal function within 24-72 hours

2. Medical therapy with corticosteroids (once obstruction relieved):

   • Prednisolone 0.5-1 mg/kg/day (40-60 mg/day)
   • Continue 4-6 weeks, then taper over 6-12 months
   • Monitor ESR/CRP (monthly), renal function, and imaging (3-6 months)
   • 85-90% response rate in idiopathic/IgG4-related cases

Important: Exclude malignancy first (biopsy if atypical features). Check serum IgG4 (elevated in 50-60% of idiopathic cases).

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Q3: What is the association between retroperitoneal fibrosis and IgG4-related disease?

Model Answer: 50-60% of idiopathic RPF cases are now recognised as part of the IgG4-Related Disease (IgG4-RD) spectrum. [7,8]

Diagnostic features of IgG4-related RPF:

1. Serum IgG4 elevation (> 135 mg/dL, often > 280 mg/dL)
2. Tissue histology:
   • Dense lymphoplasmacytic infiltrate with > 10 IgG4+ plasma cells per HPF
   • IgG4/IgG ratio > 40%
   • Storiform fibrosis (cartwheel pattern of collagen)
   • Obliterative phlebitis (inflammatory vein destruction)
3. Multi-organ involvement (may coexist):
   • Autoimmune pancreatitis (type 1)
   • Sclerosing cholangitis
   • Sialadenitis (salivary glands)
   • Orbital pseudotumour
   • Tubulointerstitial nephritis

Treatment implications:

• Excellent response to corticosteroids
• Rituximab (anti-CD20) highly effective in refractory IgG4-RD cases
• Screen for multi-organ involvement

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Q4: What are the causes of secondary retroperitoneal fibrosis?

Model Answer: Secondary RPF accounts for 30-40% of cases. Key causes:

Key point: Always exclude malignancy (particularly lymphoma) with biopsy if imaging atypical.

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Q5: Describe the surgical procedure of ureterolysis. What are the indications?

Model Answer:

Ureterolysis is the surgical freeing of the ureters from surrounding fibrotic tissue.

Indications:

• Failed or inadequate response to medical therapy (steroids/immunosuppression)
• Recurrent ureteric obstruction despite stenting
• Steroid intolerance or contraindication with severe obstruction
• Patient preference to avoid long-term immunosuppression

Technique:

1. Approach: Open (midline laparotomy) or Laparoscopic/Robotic
2. Dissection: Careful dissection and freeing of ureters from dense fibrotic plaque
3. Intraperitonealisation (critical to prevent recurrence):
   • Omental wrap: Ureters wrapped in omentum (provides vascular supply and barrier)
   • Lateralisation: Ureters moved laterally and fixed to psoas muscle
4. Biopsy: Often performed to confirm diagnosis and exclude malignancy

Outcomes:

• Success rate: 80-95% long-term freedom from obstruction [25,26]
• Recurrence: 10-20% (usually years later)
• Complications: Ureteric injury, bleeding, infection, ileus

Adjunct: Often combined with postoperative steroids to prevent fibrosis recurrence.

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Examination Pearls

"Medial Ureteric Deviation = RPF Until Proven Otherwise": Normal ureters lie lateral to transverse processes. RPF causes characteristic medial displacement and encasement.

"Exclude Malignancy Before Starting Steroids": Lymphoma can mimic RPF. Biopsy if any atypical features or lymphadenopathy.

"Tamoxifen is Anti-Fibrotic": Used as steroid-sparing agent. Inhibits TGF-β. Dose 20 mg BD. Monitor for VTE.

"PET-CT Differentiates Inflammation from Fibrosis": FDG-avid = active inflammation (treat with immunosuppression). Low uptake = chronic fibrosis (less likely to respond).

"Intraperitonealisation Prevents Recurrence": Key step in ureterolysis. Omental wrap or lateral fixation stops ureters being re-encased.

"ESR/CRP Track Disease Activity": Normalisation indicates response to treatment. Rising markers suggest relapse.

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Common Exam Pitfalls

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12. Patient and Layperson Explanation

What is Retroperitoneal Fibrosis?

Retroperitoneal Fibrosis (RPF), also called Ormond's Disease, is a rare condition where scar-like fibrous tissue develops in the space behind the abdomen (called the retroperitoneum). This tissue usually forms around the main blood vessel (aorta) that runs down the back of your tummy.

The problem is that this fibrous tissue can wrap around and squeeze the tubes (ureters) that carry urine from your kidneys to your bladder. When these tubes get blocked, urine backs up into the kidneys, causing them to swell (hydronephrosis) and potentially leading to kidney damage or failure.

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What Causes It?

In about 2 out of 3 cases, we don't know the exact cause (idiopathic). It may be related to:

• Your immune system overreacting and causing inflammation
• A condition called IgG4-Related Disease, where the immune system attacks your own tissues
• Cholesterol buildup in the blood vessel wall triggering inflammation

In the other 1 out of 3 cases (secondary), RPF is caused by:

• Certain medications (some migraine drugs, blood pressure tablets)
• Cancer (lymphoma, tumours in the abdomen)
• Infections like tuberculosis
• Radiation therapy to the abdomen
• Swelling of the aorta (inflammatory aneurysm)

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What Are the Symptoms?

RPF usually develops slowly over weeks to months. Common symptoms include:

• Lower back pain or flank pain: Dull, constant ache (not sharp like kidney stones)
• Feeling unwell: Tiredness, weight loss, low-grade fever
• Reduced urine output: If both ureters are blocked
• Leg swelling: If the large vein (IVC) is compressed
• High blood pressure: From kidney problems

Many people don't have obvious symptoms early on and are diagnosed when routine blood tests show kidney function problems.

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How is it Diagnosed?

1. Blood Tests:

   • Kidney function (creatinine, eGFR): Usually abnormal
   • Inflammation markers (ESR, CRP): Often elevated
   • IgG4 level: May be high if related to IgG4 disease

2. CT or MRI Scan:

   • Shows the fibrous tissue around the aorta
   • Shows the ureters being squeezed and pulled inward (medial deviation)
   • Shows swollen kidneys (hydronephrosis)

3. Biopsy (sometimes needed):

   • A small sample of the fibrous tissue is taken (using a needle or keyhole surgery)
   • This is checked under a microscope to rule out cancer and confirm the diagnosis

4. PET Scan (in some cases):

   • Shows if the tissue is actively inflamed (can be treated) or just scar tissue

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How is it Treated?

Treatment has two main goals: (1) relieve the blockage in the ureters to protect your kidneys, and (2) reduce the inflammation and stop the fibrosis from getting worse.

1. Relieve the Blockage (Urgent if Kidneys Failing)

• Ureteric stent: A thin plastic tube is placed inside the ureter (through a camera in your bladder) to keep it open and allow urine to drain.
• Nephrostomy: If a stent can't be placed, a tube is inserted directly into your kidney through your back to drain urine.

These procedures usually improve kidney function within days.

2. Steroid Medication (First-Line Treatment)

• Prednisolone tablets (40-60 mg per day) for 4-6 weeks, then slowly reduced over 6-12 months
• How it works: Reduces inflammation and stops the fibrosis from spreading
• Success rate: About 85-90% of people improve with steroids
• Side effects: Weight gain, high blood sugar, high blood pressure, weak bones, increased infection risk (your doctor will give you bone protection tablets and monitor you closely)

3. Other Medications (If Steroids Don't Work or Cause Side Effects)

• Tamoxifen: An anti-fibrosis drug (20 mg twice daily). Often used alongside steroids or if you can't tolerate steroids.
• Other immune-suppressing drugs: Mycophenolate, azathioprine, methotrexate
• Rituximab: A strong immune drug given by drip, used for IgG4-related disease that doesn't respond to other treatments

4. Surgery (Ureterolysis)

If medication doesn't work or the blockage keeps coming back, you may need an operation to free the ureters from the scar tissue.

• Procedure: The surgeon cuts away the fibrous tissue around the ureters and wraps them in a protective layer (omentum, a fatty tissue from your abdomen) to stop them getting stuck again.
• Success rate: About 80-90% of people have long-term improvement.
• Approach: Can be done as open surgery or keyhole (laparoscopic) surgery.

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What is the Outlook?

• With early treatment, most people do very well. Kidney function stabilises or improves, and the fibrosis stops progressing.
• Response to steroids is usually seen within a few weeks (blood tests improve, pain reduces).
• Long-term monitoring is essential because the condition can come back in 20-50% of people when steroids are reduced. You'll need regular blood tests and scans for several years.
• Kidney function: If the ureters are unblocked early, kidney function usually recovers. If the blockage has been there for months, some kidney damage may be permanent.
• Life expectancy: With treatment, life expectancy is normal. The main risk is untreated kidney failure.

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Important Points to Remember

✅ RPF is treatable. Most people respond well to steroids.

✅ Early diagnosis matters. The sooner the ureters are unblocked, the better the kidney function recovery.

✅ You'll need long-term follow-up. Blood tests, scans, and monitoring for relapse are crucial.

✅ If you're on steroids long-term, you'll need bone protection (calcium, vitamin D, bisphosphonates) and stomach protection (PPI).

✅ If you have a ureteric stent, it needs changing every 3-6 months to prevent blockage and infection.

✅ It's not cancer. RPF is a benign (non-cancerous) condition, though we always check to make sure it's not caused by cancer.

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Primary Sources

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