Wunderlich syndrome in a patient with pyelonephritis

Abstract

An elderly female patient with left pyelonephritis developed worsening left flank pain, hypotension and a drop in haemoglobin (Hb) from 97 g/L to 67g/L on the third day of her admission. There was no recent trauma, history of coagulopathy or risk factors for renal malignancy or vascular disease.

A contrasted CT scan of the kidneys revealed a 3.8 cm left renal subcapsular haematoma with no active contrast extravasation. Her atraumatic subcapsular haematoma fulfils two out of three clinical features of Lenk’s triad (acute flank pain, hypovolaemic shock), suggestive of Wunderlich syndrome. Urine and blood cultures grew Klebsiella pneumoniae and she was managed conservatively with culture-directed antibiotics, fluids and blood products.

Wunderlich syndrome is a rare complication of pyelonephritis and should be considered in patients with pyelonephritis who develop acute severe flank pain, Hb drop and haemodynamic instability. Appropriate medical and surgical therapies need to be instituted early to ensure good outcomes.

Background

Wunderlich syndrome is characterised by atraumatic spontaneous haemorrhage in the subcapsular or perinephric space.^1–5 The classical presentation described in literature is that of Lenk’s triad—acute flank pain, flank mass and hypovolaemic shock.^{3 5–9} It is a rare condition with an incidence between 0.07% and 0.3% in the general population.¹⁰ A meta-analysis of Wunderlich syndrome by Qing Zhang et al found that most cases occurred in patients aged 20–70 years (85%), with slightly more cases reported in males (55%) compared with females (45%).⁴

The most common aetiology of Wunderlich syndrome is an underlying renal neoplasm.2–6 11 12 Other aetiologies include renal vasculature disorders such as a ruptured renal artery, arterio-venous malformation, cyst rupture and vasculitis.^{2–6 12} Wunderlich syndrome can also occur as a complication of renal infections,^{4–6 12} haematological causes such as a primary coagulation disorder, blood dyscrasias, anticoagulation or antiplatelet use.^{11 12}

Pyelonephritis is an extremely common infection that can be treated on an inpatient or outpatient basis. Complications of pyelonephritis include bacteraemia, renal abscess formation, emphysematous pyelonephritis and renal impairment, among many others. Atraumatic spontaneous haemorrhage is a rare complication of pyelonephritis which can result in hypovolaemic shock if diagnosis and treatment are delayed. We present a case of a patient with pyelonephritis who subsequently developed flank pain and hypovolaemic shock as a result of atraumatic spontaneous haemorrhage (Wunderlich syndrome). Early recognition and timely intervention of this rare but potentially serious complication of pyelonephritis is crucial to avoid the mortality rate of up to 14% in Wunderlich syndrome.⁵

Case presentation

A female patient in her 70s with a history of stage four chronic kidney disease, hypertension, diabetes mellitus, ischaemic heart disease, Child’s A liver cirrhosis secondary to nonalcoholic steatohepatitis and lumbar spondylosis presented to the emergency department with severe left flank pain. Her pain radiated from loin to groin and pain score was 10/10 on the Visual Analogue Scale. This was associated with dysuria, fever and vomiting for 5 days.

Two and a half months prior, she was treated for Klebsiella pneumoniae urinary tract infection and bacteraemia with culture-directed antibiotics. Ultrasound (US) kidneys performed then showed a 0.6 cm by 0.4 cm by 0.4 cm left lower renal cyst with no hydronephrosis or suspicious solid lesions. She was afebrile with complete resolution of symptoms prior to discharge. A routine US abdomen for surveillance of liver cirrhosis 1 month prior to her current presentation also showed increased echogenicity of bilateral kidneys suggestive of parenchymal disease but with no evidence of hydronephrosis or cyst complications.

Systemic review on admission did not reveal any recent trauma, loss of weight or loss of appetite. She did not have a personal or family history of coagulopathy or malignancy. Significant medication history includes aspirin for ischaemic heart disease and no other antiplatelet medication or anticoagulants.

On examination, she had a low-grade fever of 37.9°C, blood pressure (BP) was 113/89 mm Hg, heart rate was 91 beats per minute and oxygen saturation was 95% on room air. There was tenderness over her left flank and left iliac fossa, with a positive left renal punch but no flank bruising or palpable left flank mass. In-dwelling catheter (IDC) drained clear yellow urine. The rest of the systemic examination was unremarkable.

Investigations done on admission revealed raised inflammatory markers with C reactive protein (CRP) of 258 mg/L, procalcitonin of 100 µg/L, white cell count (WCC) of 10.58×10⁹/L and raised absolute neutrophils count of 9.02×10⁹/L. There was a slight decrease in haemoglobin levels from a baseline of 111 g/L to 97 g/L. She also had acute kidney injury with an increase in creatinine from 150 µmol/L to 222 µmol/L.

There was pyuria on urinalysis with urine WCC of >2000 cells/uL, no red cell count, epithelial cells or casts. Blood cultures and urine cultures were also obtained on admission. An X-ray of the kidneys, ureter and bladder did not reveal any radiopaque renal calculi over the course of both ureters.

Our provisional diagnosis was left pyelonephritis and she was empirically treated with intravenous ceftriaxone based on blood culture sensitivities from her previous admission. Although her fever lysed the next day, she continued to have severe left flank pain that did not improve with paracetamol.

On the third day of admission, our patient developed relative hypotension with a drop in systolic BP from a baseline of 130–140 mm Hg to 95 mm Hg, tachycardia of 113 beats per minute and a new fever spike of 38.2°C. Her left flank pain remained severe. On physical examination, she had persistent tenderness over her left flank and left iliac fossa with no palpable mass or bruising. Other physical examination findings were similar to that on initial presentation. Her IDC continued to drain clear urine. Per rectal and per vaginal examination were normal.

Investigations

Investigations were performed to evaluate the patient’s deterioration. Significant findings included an acute drop in haemoglobin from 97 gL to 67 g/L. Creatinine increased from 222 µmol/L to 248 µmol/L with no decrease in urine output. CRP rose from 258 mg/L to 384 mg/L while WCC was 9.67×10⁹/L. Platelet count was normal. PT remained normal but aPTT was prolonged at 39.4 s.

In view of her prolonged aPTT, mixing study was performed and showed that the prolonged aPTT was fully correctable. Factor XIII assay was within normal range at 62%. Screening for von Willebrand disease was negative: von Willebrand factor antigen was raised at 405%, von Willebrand factor activity was raised with glycoprotein Ib-binding at 318%, likely due to ongoing infection and inflammation.

Blood and urine cultures both returned positive for the same species of K. pneumoniae as her previous admission. The strain of K. pneumoniae isolated was sensitive to ceftriaxone, co-amoxiclav and ciprofloxacin.

A non-contrasted CT imaging of the kidneys, ureters, bladder was performed in view of her raised creatinine (figures 1 and 2). This revealed left renal subcapsular hyperdense material measuring up to 3.9 cm suggestive of subcapsular haematoma. There was also thickening of the pararenal fascia with perinephric and pararenal fat stranding. The right kidney was unremarkable and there was no urinary calculus.

Figure 1.

Axial non-contrast CT scan of the abdomen shows a high density collection in the subcapsular region of the left kidney (star), consistent with acute haemorrhage. Fat stranding is also seen in the perinephric space. Note haemorrhage also tracking along the anterior pararenal space (arrow).

Figure 2.

Coronal non-contrast CT of the abdomen shows the subcapsular haematoma (star) and pararenal haemorrhage (arrow).

In view of these findings, an urgent CT mesenteric angiogram (CTMA) was arranged to look for active bleeding. The CTMA done about 13 hours later revealed no contrast extravasation to suggest active haemorrhage and the subcapsular haematoma remained grossly stable at a size of 3.8 cm (figure 3). Venous phase CT images also showed hypoenhancement of the left kidney compared with the right with patchy hypodense areas, which in the clinical context of infection is suspicious for severe pyelonephritis (figures 4 and 5).

Figure 3.

After intravenous contrast administration, arterial phase axial CT images showed no contrast extravasation to suggest active arterial haemorrhage or pseudoaneurysm.

Figure 4.

Venous phase axial CT image.

Figure 5.

Venous phase coronal CT image. Patchy hypoenhancement of the left kidney compared with the normal right kidney. In the setting of infection, this is compatible with acute pyelonephritis.

Differential diagnosis

Our patient initially presented with fever, vomiting, dysuria, left flank tenderness and loin pain. These symptoms were suggestive of left pyelonephritis and the diagnosis was supported by the presence of K. pneumoniae isolated from urine and blood cultures.

Despite broad-spectrum antibiotics, our patient’s fever and flank pain failed to improve. This was accompanied by new-onset hypotension and tachycardia 3 days into treatment, as well as rising CRP levels and a drop in haemoglobin by 30g/L. At this juncture, differential diagnoses for her deterioration include worsening sepsis with impending septic shock due to local complications of pyelonephritis such as abscess formation, pyonephrosis from an obstructed urinary tract or emphysematous pyelonephritis. She was at risk for complicated renal infections given that this was her second episode of pyelonephritis and history of poorly controlled diabetes mellitus (with a recent haemoglobin A1C of 8.2% 1 month prior). However, recent US of the genitourinary tract performed outpatient did not show any renal calculi or hydronephrosis which would have increased her risk of urinary obstruction.

The acute drop in haemoglobin level raised concerns of occult haemorrhage given that the patient did not have any overt bleeding manifestations. Renal causes of bleeding include cyst haemorrhage and/or rupture, tumour-related bleeding or in this case, pyelonephritis-related bleeding. She was unlikely to have developed cyst haemorrhage or rupture given that the size of her renal cyst was sub-centimetre on recent imaging. There was also no renal tumour visualised previously. Hence, Wunderlich syndrome as a complication of pyelonephritis remained a possible differential despite its rarity. The patient also had other features of Lenk’s triad (acute flank pain and hypovolaemic shock) to support the differential diagnosis of Wunderlich syndrome.

Other differentials of her hypotension, haemoglobin drop and prolonged aPTT include disseminated intravascular coagulation (DIC) secondary to sepsis, and retroperitoneal haematoma given the location of her pain.

Treatment

Our patient was transferred to the urology high-dependency unit for closer monitoring. She was resuscitated with a total of 2.5 L of intravenous fluids to restore normal mean arterial pressure and achieve a urine output of 0.5 mL/kg/hour. She was also transfused with two units of packed red cells. Aspirin, which was one of her chronic medications for ischaemic heart disease, was held off. Her haemoglobin levels improved to 96 g/L after blood transfusion and remained stable thereafter.

Pain control was an important aspect of our patient’s management. She had severe persistent left flank pain at the start of the admission despite her usual medications of paracetamol, amitriptyline and pregabalin (for lumbar spondylosis associated with radiculopathy). Pain control remained suboptimal even with addition of oral codeine phosphate and tramadol, and she eventually required 5 µg of intravenous fentanyl every four hours to achieve pain control. Her pain improved with treatment of the underlying infection and fentanyl was subsequently converted to oral tramadol after 6 days.

The patient was continued on intravenous ceftriaxone for treatment of pyelonephritis complicated by Klebsiella bacteraemia. Ceftriaxone was empirically chosen as the Klebsiella isolated during her recent episode of urinary tract infection had been sensitive to ceftriaxone. It was then continued based on current blood and urine culture sensitivity results. Subcapsular renal haematoma was managed conservatively and surgical intervention was held off as she improved clinically with the above measures. She was reviewed by ophthalmology and found to have no evidence of Klebsiella endophthalmitis. However, her persistent fever trend necessitated a 6-week course of antibiotics for empirical treatment of an infected haematoma.

Our patient’s stay was also complicated by type 2 myocardial infarct on the second day of admission, likely precipitated by her ongoing infection. However, her left renal subcapsular haematoma precluded her from receiving any antithrombotic therapy. Aspirin, which was her chronic medication, continued to be held off and was only resumed after 2 weeks when her clinical condition and haemoglobin remained stable. She was, however, continued on other guideline-directed therapy such as bisoprolol and atorvastatin. Her cardiovascular risk factors were also optimised by ensuring good cholesterol, BP and glycaemic control. Transthoracic echocardiogram was performed on the eighth day of admission and showed an ejection fraction of 60% with no regional wall abnormality.

During her stay, she developed hypoactive delirium which resolved after a few days with treatment of her infection and the use of non-pharmacological measures such as frequent reorientation and ensuring regular bowel movements. No psychotropics were required. In the later half of her admission, she also participated in regular physiotherapy sessions in the ward to regain her strength and mobility prior to discharge.

Outcome and follow-up

Our patient received a total of 14 days of intravenous ceftriaxone while inpatient with improvement of clinical symptoms and haemodynamic status. Her fever finally lysed after 9 days with a downtrend of her inflammatory markers: CRP improved from a peak of 415 mg/L to 69.9 mg/L on discharge, while procalcitonin improved from a peak of 100 µg/L to 3.3 µg/L. Antibiotics were converted to oral ciprofloxacin based on blood and urine culture sensitivities for K. pneumoniae and she completed another 4 weeks of oral ciprofloxacin outpatient. She received a total of 6 weeks of antibiotics as her prolonged fever inpatient raised the suspicion of an infected renal haematoma. Haemoglobin level remained stable inpatient between 8.3 and 10.2 g/dL and aspirin was restarted after 2 weeks. Her creatinine level had also returned to baseline.

The cause of the mildly raised aPTT was attributed to early DIC, and the aPTT subsequently improved with one dose of intravenous vitamin K 10 mg and treatment of the underlying infection.

Analgesia was adjusted and our patient was able to tolerate rehabilitation in the ward during the later half of her admission. She was able to ambulate 50 m with supervision and was assessed to be safe for homebound ambulation with a caregiver by the time she was discharged on day 16 of admission. This was similar to her baseline functional status prior to admission.

Our patient was reviewed outpatient by the infectious diseases and urology specialists 1 month after discharge. She reported that her left flank pain had completely resolved, and she had remained afebrile. CRP had further improved to 10.9 mg/L and her haemoglobin also returned to her baseline level of 113 g/L. Creatinine remained stable.

A repeat CT Kidney, Ureter and Bladder (KUB) (figure 6) done approximately 6 weeks after discharge showed that the haematoma now appeared hypodense with interval improvement in size. There was also interval improvement of thickening of the left anterior pararenal and lateroconal fascia. She was followed up with her urologist and remained well with no urinary tract symptoms during her last review, 8 months after discharge.

Figure 6.

Follow-up axial non-contrast CT scan 2 months later demonstrates interval decreased density and size of the subcapsular renal haematoma (star). The pararenal haemorrhage has also significantly decreased.

A summary of our patient’s progress is summarised in figure 7.

Figure 7.

Summary of patient’s clinical course. UTI, Urinary Tract Infection, CTMA, CT mesenteric angiogram; Hb, haemoglobin; US, ultrasound; KUB, Kidney, Ureter, Bladder.

Discussion

Wunderlich syndrome was first described by the German physician Carl Wunderlich in 1856.2–5 7 8 10 12 The classic presentation of Lenk’s triad consisting of flank pain, flank mass and hypovolaemic shock described in literature is only present in 20%–30% of patients.¹¹ Other symptoms reported include gross and microscopic haematuria, fever, nausea and vomiting.⁵ Common aetiologies of Wunderlich syndrome include tumour and vascular causes. Although infective aetiologies of Wunderlich syndrome such as pyelonephritis are rare, there is a need to increase awareness of this condition so that physicians managing patients with renal infections can recognise this potentially life-threatening complication and institute timely treatment.

There has been a change in the prevalence of underlying aetiology of Wunderlich syndrome in recent years. Prior to 2002, renal tumours were the leading cause of Wunderlich syndrome, accounting for 61.5% of cases.⁴ Among these tumours, 51.4% were benign tumours such as angiomyolipoma, while 48.6% were malignant tumours, most commonly renal cell carcinoma.⁴ Vascular causes accounted for 17% of cases.⁴ However, in a subsequent systematic review by Ahn et al, there was an increase in vascular causes to 27% of cases.⁵ The main vascular cause reported was vasculitis (15.7%), of which polyarteritis nodosa accounted for up to 75% of cases.⁵ Renal tumours remained as the leading cause of Wunderlich syndrome with 56.9% of cases, however, a larger majority were due to benign lesions with angiomyolipoma accounting for 74.1% of neoplastic cases.⁵ It is postulated that the decreasing prevalence of Wunderlich syndrome due to malignancies could be attributed to earlier detection and management of renal malignancies before they become at risk of progression to Wunderlich syndrome.⁵ Other less common aetiologies include renal infections (2.4%–2.9%), cyst rupture, pre-eclampsia, coagulopathy and anticoagulant use.4 5 8 9 12

Despite its rarity, Wunderlich syndrome should be considered in patients with renal infections with persistent or worsening flank pain despite treatment with appropriate antibiotics,^{13 14} or worsening anaemia concerning for occult bleeding.¹⁴ A literature search of cases of renal infections causing Wunderlich syndrome revealed eight cases of pyelonephritis and two cases of renal abscess. The pathophysiology of Wunderlich syndrome in the setting of infection has been postulated to be a result of endothelial damage due to cytokine activity.⁶ Relevant details of these case reports are summarised in table 1.

Table 1.

Summary of cases of Wunderlich syndrome secondary to renal infections

No	Case	Age (years)/gender	Comorbidities	Type of infection	Significant investigations (if available)	Size of haematoma	Management	Outcome
1	Kim et al14	60/female	Diabetes mellitus	Pyelonephritis	Hb drop from 111 g/L to 79 gL WCC 12.5×109/L Urine and blood culture- Escherichia coli	NA	Percutaneous drainage	Discharged
2	Lin et al18	45/female	Impaired glucose tolerance	Pyelonephritis	Leucocytosis with left shift Urine and blood culture-Klebsiella pneumoniae	NA	Percutaneous drainage followed by incision and drainage	Complicated by disseminated necrotising fasciitis requiring left above knee amputation, subsequently discharged
3	Canale et al19	36/female	NA	Pyelonephritis	Hb 82 g/L WCC 12.0×109/L CRP 20.6 mg/dL Urine culture- negative Tissue culture- Streptococcus anginosus	NA	Medical management followed by right nephrectomy	Discharged
4	You et al13	67/female	Diabetes mellitus	Pyelonephritis	Hb 135 g/dL WCC 8.8×109/L CRP 23.0 mg/dL Urine culture-E. coli	NA	Medical management	Discharged
5	Sureka et al20	41/male	Pulmonary tuberculosis	Renal abscess	Hb 70 g/L WCC 14.2×109/L	37×30 mm on admission, 20×22 mm after 2 weeks	Medical management	Discharged
6	Ballentine et al21	58/female	Bipolar disorder, chronic right foot wounds with chronic osteomyelitis	Pyelonephritis	Urine culture- negative	83×65×49 mm	Partial nephrectomy	Discharged
7	Kaleta et al6,6	77/male	Prostate cancer in remission, atrial fibrillation on aspirin	Pyelonephritis	Hb 40 g/L Urine culture-E. coli	NA	Angioembolisation	Discharged
8	Bajaj et al22	52/female	Diabetes mellitus, hypertension, chronic kidney disease, traumatic brain injury, previous renal laceration	Pyelonephritis	Hb 55 g/L Blood culture-E. coli Intraoperative culture-Candida albicans	Increase from 8.4×7.8×15 cm to 10.7×10.7 ×16.8 cm, in 1 hour	Medical management, angioembolisation followed by percutaneous drainage and subsequently nephrectomy and partial uretectomy	Discharged
9	Nayyar et al23	42/male	Diabetes mellitus	Pyelonephritis	Hb 109 g/L WCC 14.3×109/L Urine culture-E. coli	NA	Percutaneous drainage	Discharged
10	García-Chairez et al24	38/female	Diabetes mellitus, hypertension	Renal abscess	Hb 126 g/L WCC 38.8×109/L Tissue culture-E. coli	10×7.3×5.4 cm	Nephrectomy	Discharged

CRP, C reactive protein; Hb, haemoglobin; NA, not available; WCC, white cell count.

CT is the preferred imaging modality in the evaluation of patients with suspected Wunderlich syndrome6 8 10 15 and has a sensitivity of 100% in identifying perinephric haemorrhage.1 4 10 16 It also identifies underlying aetiologies such as the presence of a renal mass with a sensitivity and specificity of 0.57 and 0.82, respectively.⁴ CT angiography can be used to determine the site of active bleeding which may guide further intervention.⁵

Wunderlich syndrome may be managed conservatively in stable patients with no evidence of active haemorrhage and no underlying malignancy.^{2 3 9} A single-centre retrospective study reported that independent factors that predicted successful conservative management included low serum creatinine levels, high prothrombin concentration, smaller-sized haematoma and cases that were not due to angiomyolipomas.⁹ Nonetheless, patients managed conservatively should continue to be monitored carefully as 43% of patients subsequently required definitive surgery or angioembolisation in a meta-analysis by Ahn et al.⁵

With advancement in angioembolisation techniques and increased availability of interventional radiologists, transarterial embolisation (TAE) has become widely adopted given its effectiveness and renal-preserving benefit.^{5 10} However, surgical interventions such as partial or total nephrectomy as first-line management may be indicated in patients with an underlying malignancy requiring resection.^{5 6} Another indication for surgery is the presence of an angiomyolipoma in the setting of tuberous sclerosis as these patients have a higher rate of recurrence after a trial of TAE.⁵

As our patient was managed conservatively, a limitation of our case was the inability to definitively prove our clinical suspicion of an infected haematoma which necessitated a longer course of antibiotics beyond the usual duration for pyelonephritis with bacteraemia.¹⁷ Nonetheless, the clinical picture of prolonged fever lasting 9 days and persistently raised inflammatory markers initially which only improved after an extended course of antibiotics, supported our clinical suspicion of an infected renal haematoma.

In conclusion, Wunderlich syndrome is a rare complication of renal infections and needs to be considered in patients with non-resolving or acute severe flank pain, haemodynamic instability or signs of haemorrhage. Prompt diagnosis is critical. Conservative management can be considered in patients who are stable, have no active haemorrhage and no underlying malignancies.

Learning points.

• Wunderlich syndrome is a rare complication of renal infections and the diagnosis should be considered in a patient who develops severe or worsening flank pain, haemodynamic instability or evidence of ongoing haemorrhage.

• CT scan is the preferred radiological modality to diagnose Wunderlich syndrome and evaluate for underlying aetiologies such as neoplasms or vascular pathologies concurrently.

• Patients who remain clinically stable with no active haemorrhage or underlying malignancy can be managed conservatively. Emergent radioembolisation and/or nephrectomy may be indicated in severe cases.

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