Lupus cystitis: unusual cause of renal failure in systemic lupus erythematosus

Abstract

A 42-year-old woman presented with chronic fever, abdominal pain, intermittent loose stools and dysuria for 3 months. She had recently developed acute dyspnoea with acute kidney injury. She was found to have a contracted, thick-walled bladder with bilateral hydroureteronephrosis. She underwent bilateral percutaneous nephrostomies, following which her renal function recovered. She satisfied the clinical and immunological features of the Systemic Lupus International Collaborating Clinics criteria for systemic lupus erythematosus (SLE). She was initiated on immunosuppression. Lupus cystitis with a contracted bladder is an uncommon presentation of SLE.

Background

In low-income countries, the first and most valuable differential diagnosis for patients presenting with chronic fever and lower urinary tract symptoms is tuberculosis. Though uncommon, systemic lupus erythematosus (SLE) with cystitis is also a valid differential which might mimic tuberculosis. Lupus cystitis is an uncommon presenting manifestation of SLE and is often associated with lupus enteritis. Over time, lower urinary tract involvement can progress to a contracted bladder with obstructive uropathy. Since delaying potent immunosuppression in this scenario can be life-threatening, it is crucial to have a reasonable index of suspicion. We present a patient with SLE who developed lupus cystitis with a contracted bladder and obstructive uropathy.

Case presentation

A 42-year-old woman with no comorbid illness had recurrent fever for 3 months. She also had abdominal pain, dysuria, increased frequency of micturition and diarrhoea for 1 month. She had significant loss of weight and appetite. She gave a history of arthralgia, alopecia and Raynaud’s phenomenon. She was not a smoker and did not have any significant history of chemical exposure. Her history was significant for multiple first and second trimester abortions and chronic anaemia, which required multiple blood transfusions. She had been diagnosed with recurrent urinary tract infection by a general physician and had received multiple courses of antibiotics without symptomatic improvement.

On examination, she was febrile (100.2°F), with a pulse rate of 110 beats/min and a respiratory rate of 26 breaths/min. Blood pressure was 100/70 mm Hg without evidence of pulsus paradoxus. She had pallor, anasarca, non-scarring alopecia and an erythematous malar rash that spared the nasolabial folds. Lymphadenopathy was absent. Her jugular venous pressure was elevated. Heart sounds were muffled. There was dullness to percussion in both infrascapular regions with absent breath sounds. Abdominal examination revealed shifting dullness. There was no palpable organomegaly. She was persistently drowsy but arousable.

Differential diagnosis

The differential diagnosis considered were disseminated tuberculosis and autoimmune disorders, including systemic lupus erythematosus, mixed connective tissue disease, vasculitis, inflammatory bowel disease and rheumatoid arthritis. Other possibilities considered were human immunodeficiency disease, lymphoma and disseminated malignancy.

Investigations

Her blood investigations revealed pancytopenia and raised inflammatory markers. Urinalysis showed microscopic red blood cells with no pyuria (table 1). Blood and urine cultures were negative. Serum creatinine was elevated. Autoimmune workup showed positive antinuclear antibodies (ANA 2+), high positive titres of antidouble-stranded DNA antibodies, low complement and positive lupus anticoagulant. Rheumatoid factor assay was negative. Since she satisfied the Systemic Lupus International Collaborating Clinics classification criteria, a diagnosis of SLE was made.

Table 1.

Lab investigations

Investigations	Results	Normal values
Haemoglobin (g/L)	81	140–170
Total white cell count (×109/L)	8.1	4.5–11.0
Differential cell count (%)	N 71, L 14, M 13, E2, B 0
Platelet count (×109/L)	301	150–350
HIV, HBV, HCV serology	Negative
Thyroid-stimulating hormone (mIU/L)	1.8	0.4–4.2
Serum sodium (mmol/L)	135	135–145
Serum potassium (mmol/ L)	2.7	3.5–5.0
Serum creatinine (µmol/L)	272.98	38–106
Serum urea (mmol/L)	14.6	2.9–8.2
Total and direct bilirubin(µmol/L)	6.84/3.42	5–21/1.7–5.1
Serum total protein/albumin (g/L)	59/21	60–80/35–50
Serum aspartate aminotransferase (U/L)	12	10–35
Serum alanine aminotransferase (U/L)	5	10–40
Serum alkaline phosphatase (U/L)	52	30–120
Erythrocyte sedimentation rate (mm/hour)	10	0–20
C reactive protein (mg/L)	<3.16	<3.16
Prothrombin time/INR (s)	14.0/1.31	10.0–12.5/0.8–1.1
Activated partial thromboplastin time (s)	36.2	24.7–37.5
Antinuclear antibody	2+ homogenous	Negative
Double stranded DNA(IU/ml)	167	<100
Serum complements C3/C4 (mg/dL)	48.4/12.8	90–180/10–40
Anti-SSA ELISA (Ru/mL)	199	<20
Anti-SSB ELISA (Ru/mL)	12	<20
Anti-Smith ELISA(Ru/mL)	3	<20
Antiribonuclear protein	Negative
Antiproteinase-3 antineutrophil cytoplasmic antibodies (U/mL)	2.4	<15
Antimyeloperoxidase antineutrophil cytoplasmic antibodies (U/mL)	<2	<15
Pleural fluid total white cell count (/µL)	230 (N 55%, L 45%)	–
Pleural fluid protein (g/L)	42	0–30
Pleural fluid lactate dehydrogenase (U/L)	144	–
Pleural fluid glucose (mmol/L)	5.77	–
Ascitic fluid total white cell count (/µL)	350 (N 75%, L 25%)	<500
Ascitic fluid protein (g/L)	23	–
Ascitic fluid albumin (g/L)	9	–
Urinalysis	RBC:22, WBC:2–3/hpf, No casts No dysmorphic RBC on phase contrast microscopy. Glucose-Negative Bilirubin-Negative, Ketone-Negative Specific gravity-1.004
24 hours’ urine protein(mg/day)	430	<150
Stool cultures	Negative
Stool ova/parasites	Negative
Stool test for Clostridium difficile antigen	Negative
HIV test	Negative
HBV test	Negative
HCV test	Negative

Anti-SSA, Anti-Sjogren's-syndrome antigen A; Anti-SSB, Anti-Sjogren syndrome antigen B; E, Eosinophil; HBV, hepatitis B virus; HCV, hepatitis C virus; INR, International Normalized Ratio; L, Lymphocyte; M, Monocyte; N, Neutrophil.

Ultrasound scan on the kidneys showed severe bilateral hydroureteronephrosis (figure 1). Echocardiogram showed pericardial effusion with no evidence of tamponade (. Pericardiocentesis showed exudative pericardial effusion with lymphocytic predominance and no microbiological growth on culture. She had bilateral pleural effusion, which was exudative by Light’s criteria.

Figure 1.

(A) Ultrasound scan showing severe hydroureteronephrosis. (B) CT of the abdomen without contrast, showing severe hydroureteronephrosis. (C) PCN and nephrostogram showing a dilated pelvicalyceal system. (D) CT of the abdomen with contrast 1 month later showing bilateral PCN tubes in situ and reduction in hydroureteronephrosis. PCN, percutaneous nephrostomy.

Treatment

She had received multiple courses of antibiotics for presumed urinary tract infection at other hospitals. She presented with obstructive uropathy secondary to a small capacity bladder. She underwent bilateral percutaneous nephrostomy (PCN) placement after which serum creatinine fell to baseline (figure 1). Urine cultures did not grow any organism. Examination of urine did not reveal acid-fast bacilli. Cartridge-based nucleic acid amplification test and Mycobacteria Growth Indicator Tube cultures from urine were negative. She underwent cystoscopy, which showed a small bladder with a capacity of 80 mL. The ureteric orifices were not visualised, and the bladder showed multiple sacculations with small diverticulae (figure 2). Biopsy of the urinary bladder showed chronic cystitis with focal ulceration and dense chronic inflammation with infiltrates of many plasma cells, lymphocytes and occasional neutrophils without granulomas (figure 2). It was therefore concluded that the cause of chronic cystitis leading to obstructive uropathy and renal failure was lupus cystitis.

Figure 2.

(A) Cystoscopy showing a grossly trabeculated bladder with reduced capacity, (B) Left: photomicrograph of the bladder mucosa showing an inflammatory cell infiltrate in the subepithelial stroma and von Brunn’s nests (×20), Right: photomicrograph showing the bladder mucosa with a mixed inflammatory cell infiltrate composed predominantly of lymphocytes and plasma cells (×40).

She continued to have abdominal pain, diarrhoea and a high disease activity score. CT scan of the abdomen did not show any conclusive evidence of lupus enteritis. Colonoscopy showed normal mucosa and biopsy showed no specific lesion. The patient was not willing to undergo a renal biopsy. Since the disease activity was high, she was initiated on immunosuppression with intravenous pulse methylprednisolone, followed by intravenous cyclophosphamide and maintenance oral azathioprine, with which she had a significant resolution of symptoms. Her Systemic Lupus Erythematosus Disease Activity Index score, which was 23 at the time of presentation, improved to 8 at the time of discharge, indicating a significant reduction in disease activity.

Outcome and follow-up

She is on regular outpatient follow-up and is being administered maintenance doses of immunomodulation. She has not had any disease flare. She remains on bilateral PCNs and is being prepared for a urinary diversion with an ileal conduit. The chronology of events from admission to discharge and follow-up is given in table 2.

Table 2.

Chronology of events

Days from presentation	Event	dsDNA (IU/mL)	Serum complements C3/C4 (mg/dL)	Serum creatinine (µmol/L)	Disease activity (SLEDAI)
Day 0	Patient presents with fever for 3 months, and abdominal pain, dysuria, increased frequency of micturition and diarrhoea for 1 month	167	48.4/12.8	272.98	23
Day 4	Bilateral PCN placed
Day 13				203.32
Day 25	Normalisation of creatinine.			95.47
Day 37	Discharge from hospital			99.89	8
Day 74	Review while on maintainance immunosuppression; patient is on bilateral PCN and is being prepared for a urinary diversion with an ileal conduit	<100	52.2/9.66	81.33	0

dsDNA, double-stranded DNA; PCN, percutaneous nephrostomy; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

Discussion

SLE is an autoimmune disease that is characterised by tissue-binding autoantibodies and immune complexes that cause organ damage. SLE can affect any organ in the body; however, the involvement of some organs is more common than others.

Immune-mediated cystitis in patients with SLE was first described by Boye et al in 1979. However, the term ‘lupus cystitis’ was coined later by Orth et al.^{1 2} It remains a rare entity, and description of the disease is confined predominantly to case reports, small case series and a few retrospective studies.

Although benign at presentation, if left untreated, it can lead to irreversible obstructive uropathy and end-stage renal disease. Urinary symptoms include urinary frequency, urgency, suprapubic pain and discomfort, nocturia, dysuria and haematuria. The disease may remain indolent for prolonged periods and patients may not seek the medical care; diagnosing the disease in such patients remains a challenge. Patients with SLE who have been in clinical remission for many years may present later with obstructive uropathy. Alternatively, a progressive decline in bladder capacity may be observed.³ The pathogenesis of lupus cystitis is presumed to be immune complex-mediated and complement activation; however, vasculitis may also play a role.¹ Cystoscopy may reveal diffuse inflammation with erythema and haemorrhage at the trigone.⁴ Histopathology shows a chronic inflammatory infiltrate in the subepithelium, suggesting a low-level inflammatory process that later progresses to fibrosis and obstruction of the ureter.⁵

The common causes of renal failure in SLE are glomerulonephritis, thrombotic microangiopathy and antiphospholipid antibody syndrome. However, lupus cystitis can also present with renal failure once obstructive uropathy develops. This is important to recognise as it has a different approach to management. The diagnosis of lupus cystitis can be challenging, especially in low-income countries where chronic infections such as genitourinary tuberculosis are far more prevalent. All efforts to exclude this and other infectious causes must be undertaken before making the diagnosis of lupus cystitis and initiating immunosuppression. Despite challenges regarding diagnosis, early diagnosis and initiation of therapy are associated with a good prognosis.⁶ There is no consensus on the best treatment for lupus cystitis. Steroids such as methylprednisolone and prednisolone, along with other immunosuppressive drugs such as mycophenolate mofetil and cyclophosphamide, have been tried with excellent results.^{7 8}

It is interesting to note that lupus cystitis has been observed to coexist with lupus enteritis or lupus mesenteric vasculitis (LMV) in several cases. Therefore, bowel symptoms such as abdominal pain and watery diarrhoea may precede urinary symptoms in most patients.⁹ Often, the terms lupus enteritis and LMV are used interchangeably. This has created some confusion in the literature. The British Isles Lupus Assessment Group 2004 defines lupus enteritis as either vasculitis or inflammation of the small bowel, with supportive imaging or biopsy findings.¹⁰ Therefore, lupus enteritis should refer to the inflammation of the layers of the small or large intestine, while LMV should refer to the inflammation of the mesenteric vessel wall. In addition to focal or diffuse abdominal pain, which is seen in 97% of cases, patients with lupus enteritis may have ascites, nausea, vomiting, diarrhoea and fever.¹¹ CT scan findings include bowel-wall oedema, abnormal bowel-wall enhancement (double halo or target sign) or dilatation of bowel lumen.¹¹ Engorgement of mesenteric vessels, increased number of visible vessels (comb sign) and increased attenuation of mesenteric fat may also be seen.¹¹ The most common part of the gastrointestinal tract that is involved is the ileum, followed by the jejunum, colon, duodenum and rectum.¹¹ Histopathological findings in biopsied cases of lupus enteritis include macroscopic findings of oedema, hyperemia, ischaemia, ulceration, necrosis, wall thinning, perforation and microscopic findings of haemorrhage within the muscular and subserosal layers, vasculitis (necrotising vasculitis with fibrinoid necrosis and inflammatory cell infiltrate, which may be eosinophilic, neutrophilic or both), microvascular thrombus formation, and complement deposition on immunofluorescence in veins and the basement membrane.¹¹ A systematic review of 125 studies showed that more than 50% of patients with SLE with intestinal pseudo-obstruction had hydroureteronephrosis or cystitis.¹² A retrospective study from Korea, which included 62 patients with SLE with enteric symptoms over a 7-year period, concluded that involvement of colon and coexistent cystitis was associated with recurrence of lupus enteritis.¹³

We reviewed all case reports of lupus cystitis in the literature over the past 10 years (table 3). Lupus enteritis was present in about 40% of these cases. It is unclear why there is an association between lupus enteritis and cystitis. Koh et al identified 24 patients with lupus cystitis admitted to a hospital in Korea from 1998 to 2013 and found three-fourths had concurrent LMV.¹⁴ One possibility is the existence of a hitherto undiscovered autoantibody to the bladder and gastrointestinal tract. This antibody may then form immune complexes that activate complements, leading to local tissue damage and destruction. The rarity of both manifestations suggests that the antibody may not be seen in all patients with SLE. Thus, testing this hypothesis will require measurement of autoantibodies in individuals having concurrent lupus enteritis and cystitis. Treatment of lupus enteritis is by pulsed steroid or cyclophosphamide in case of severe disease or coexistent significant organ involvement.¹¹ Given the rarity of this manifestation, it is unsurprising that there are no well-designed trials comparing the efficacy of treatment options. Additional immunosuppressants such as azathioprine, mycophenolate mofetil and rituximab have also been used.¹⁵ In our case, we did not find any conclusive evidence of lupus enteritis on cross-sectional imaging and colonoscopy. However, the patient did have symptoms of gastrointestinal tract involvement (abdominal pain and diarrhoea), along with lupus cystitis. Given the propensity of lupus cystitis and enteritis to occur together, we made a diagnosis of probable lupus enteritis after excluding other causes. The patient did respond to therapy, and now that the disease is in remission, it is difficult to determine if she indeed had lupus enteritis.

Table 3.

Review of case reports of lupus cystitis reported in the literature from 2008 to date

Case number	Age of onset (years)/sex	Duration of urinary symptoms	Treatment	Lupus enteritis	Other systemic manifestations/comments	Reversal of hydronephrosis	Reference
1	40/F	–	Intravenous methylprednisolone and intravenous cyclophosphamide, oral MMF	No vasculitis	Intestinal pseudo-obstruction, glomerulonephritis. Hydronephrosis resolved	Yes	16
2	44/F	5 days	Intravenous methylprednisolone, intravenous cyclophosphamide, oral prednisolone taper, azathioprine	Yes	–	–	17
3	22/F	–	Intravenous methyl prednisolone, oral methylprednisolone	No	Lupus nephritis	–	18
4	41/F	–	Methylprednisolone	Yes	–	Yes	19
5	16/F	15 days	Intravenous methylprednisolone, oral prednisolone; prednisolone with azathioprine; prednisolone with MMF	Yes	–	Partially reversed	20
6	48/F	–	Intravenous methylprednisolone, intravenous cyclophosphamide, oral prednisolone	Yes	–		7
7	28/F		Prednisolone, MMF	No	–	Yes	4
8	27/F	<1 month	Intravenous methylprednisolone, MMF	Yes	Lupus nephritis, thrombotic microangiopathy	–	3
9	20/F	–	Intravenous methylprednisolone, intravenous cyclophosphamide, oral prednisolone, MMF	No	Lupus nephritis, subacute intestinal obstruction	Yes	21
10	23/F	3 months	Intravenous methylprednisolone, oral prednisolone	No	Presence of gastrointestinal symptoms	Partially reversed	22
11	14/F	–	Intravenous methylprednisolone, oral prednisolone, MMF	No	Lupus nephritis, presence of gastrointestinal symptoms	–	23
12	56/M	–	Oral prednisolone	Yes	Lupus nephritis	–	24
13	37/F	<1 month	Intravenous methylprednisolone, oral prednisolone		Lupus nephritis	Yes	9
14	38/F	–	Intravenous methylprednisolone, oral prednisolone	Yes	–	–	25
15	27/F	–	Intravenous methylprednisolone, oral prednisolone	No	Lupus nephritis	Partially reversed	26
16	33/F	–	Intravenous methylprednisolone, oral prednisolone	Yes	Lupus nephritis, presence of gastrointestinal symptoms	Yes	26
17	20/F	<1 month	Intravenous methylprednisolone, intravenous cyclophosphamide	No	Lupus nephritis with obstructive uropathy; patient required chronic hemodialysis and died later	No	27
18	48/F	–	Oral prednisolone, azathioprine	No	Antiphospholipid syndrome; renal function declined, requiring dialysis and diet of probable acute pulmonary embolism	No	5

‘–’ indicates lack of data.

F, female; M, male; MMF, mycophenolate mofetil.

This case highlighted several essential points. First, lupus cystitis can lead to renal failure and must be considered in the list of differentials in a patient with SLE presenting with renal failure. There can be a dramatic improvement with decompression of the obstructed system. Second, lupus cystitis may coexist with lupus enteritis, and therefore evidence for the latter must be actively sought in such patients. Lastly, these are relatively rare and poorly understood manifestations of SLE, which require more research in order to elucidate the mechanism of pathogenesis and define optimal treatment modalities.

Patient’s perspective.

This illness has been very difficult for me and my family. It is causing a heavy financial burden. My relatives have to accompany me to the hospital each time and that is inconvenient for them. I have been to the hospital countless times and I am still not cured. The doctors have told me that my disease cannot be cured, only controlled, and I will need to take medicines for a long time. I will also need surgery to remove these tubes from my back. I do not know why all this happened to me. I know the doctors are trying their best, but this is still very difficult.

Learning points.

• Lupus cystitis is an uncommon manifestation of systemic lupus erythematosus (SLE).

• Lupus cystitis can cause renal failure and must be considered in the list of differentials for a patient with SLE presenting with renal failure.

• Lupus cystitis can lead to hydroureteronephrosis and obstructive uropathy. Immediate treatment is by relief of the obstruction by percutaneous nephrostomy.

• Lupus enteritis, which is another uncommon manifestation of SLE, frequently occurs in association with lupus cystitis.