Inferior vena cava and renal vein thrombosis: a rare cause of acute kidney injury in tuberculosis

Abstract

Recent studies show active tuberculosis induces a prothrombotic state and increases the risk of venous thromboembolism. We report a recently diagnosed case of tuberculosis who presented to our hospital with painful bilateral lower limb swelling and several episodes of vomiting with abdominal pain for 2 weeks. Investigations by a hospital elsewhere 2 weeks ago showed abnormal renal function, misdiagnosed as antitubercular therapy-induced acute kidney injury. D-dimer levels were increased on admission with us, with still deranged renal function. Imaging revealed thrombus at the origin of left renal vein, inferior vena cava and bilateral lower limbs. We started treatment with anticoagulants, which gradually improved kidney function. This case highlights that early diagnosis of renal vein thrombosis and prompt treatment are associated with good clinical outcomes. It also highlights the importance of further studies for risk assessment, prevention strategies and reduction of the burden of venous thromboembolism in patients with tuberculosis.

Background

Mycobacterium tuberculosis is a bacterium that causes the infectious disease, tuberculosis (TB). TB is a significant health epidemic with massive incidence, mortality and morbidity due to acute and chronic complications worldwide. It can affect a myriad of systems.¹ Apart from anatomical damage, complications can occur due to the toxic effects of systemic inflammation due to the infection, as well as drugs used for its treatment.^1–3

Acute kidney injury (AKI) is the sudden reduction in glomerular filtration rate, which increases serum creatinine concentration (a marker of kidney excretory function) or oliguria (decreased urine volume), or both. The common aetiology includes dehydration, blood loss, heart failure, sepsis, major surgeries and nephrotoxic drugs. Acute vascular events such as renal vein thrombosis (RVT) are relatively uncommon causes.⁴ According to the literature, this holds in the case of TB as well. Almost all reported cases have been due to the toxic effects of standard anti-TB drugs, with rifampicin being the most common culprit.³

RVT is a rare phenomenon in which a clot is present in significant renal veins and branches. It is usually seen in the left renal vein but can also affect bilateral veins. It has a variable clinical presentation: it can go unnoticed or present acutely with nausea, vomiting, flank pain, haematuria and AKI. Malignancy and nephrotic syndromes were found to be the most common aetiologies, according to an extensive cohort study of 218 people newly diagnosed with RVT.⁵ Other diseases that induce a hypercoagulable state, such as hereditary thrombophilia, antiphospholipid syndrome and postrenal transplant graft rejection, are also known causes.⁶ An emerging risk factor for systemic hypercoagulability is TB.²

The thrombus in the renal vein can either extend from the renal vein into the inferior vena cava (IVC) or vice-versa. When the latter happens, it can be the cause of AKI.⁷ While there have been a few case reports of TB presenting with IVC thrombus, none have described a subsequent RVT and AKI.^8–12 We report a case of TB that developed RVT as a complication resulting in AKI. To our knowledge, this is the first time such a case has been reported.

Case presentation

A woman in her late 40s presented to a tertiary hospital in South India with an intermittent fever of 4 months which was associated with anorexia, fatigue and weight loss of 10 kg. She reported a productive cough for 3 months. She also noticed bilateral lower limb swelling for the past 2 weeks, which was initially non-tender but progressively became painful. There is no history of haemoptysis, breathlessness or decreased urine output. There was a history of missed abortion at 13 weeks of pregnancy 17 years ago. She does not smoke or drink alcohol and denies using contraceptive pills. There is no history of COVID-19.

Three weeks ago, she was diagnosed in a hospital elsewhere to have pulmonary TB based on sputum-positive staining for acid-fast bacilli, chest X-ray findings of consolidation and CT of the chest showing bilateral cavitary lesions. Ultrasound scan of the abdomen and pelvis was unremarkable. Anti-TB therapy (ATT) (rifampicin, isoniazid, ethambutol and pyrazinamide) was immediately started. Her fever subsided. But 6 days later, she had episodes of vomiting and abdominal pain. On further evaluation, renal function test showed elevated blood urea of 88 mg/dL (10–50 mg/dL), creatinine of 2.1 mg/dL (0.5–1.5 mg/dL), potassium of 5.8 mmol/L (3.5–5.1 mmol/L) and decreased sodium of 122 mmol/L (136–145 mmol/L). She was advised to stop ATT because of probable drug-induced AKI. However, she continued taking the drugs and only stopped taking them 3 days before presenting to our hospital. There was no improvement in symptoms during this time.

On examination, vital signs were unremarkable. Pallor and bilateral, tender pitting oedema was present. Chest auscultation revealed bilateral upper lobe crepitations with bilateral infraclavicular cavernous breath sounds. Other system examinations were clinically normal.

Investigations

Laboratory findings on admission are given in table 1. Urine culture was sterile. The 24-hour urine protein and liver function tests were within normal limits. Viral markers (HIV, hepatitis C, hepatitis B) were non-reactive.

Table 1.

Laboratory findings

Parameter	Finding	Reference range
Urea	73	10–40 mg/dL
Creatinine	2.17	0.5–0.9 mg/dL
Sodium	122	136–145 mmol/L
Potassium	4.9	3.5–5.1 mmol/L
Uric acid	6.2	2.4–6 mg/dL
Albumin	2.4	3.4–5.4 mg/dL
Haemoglobin	82	120-150 g/L
White cell count	10	4–12 109/L
Platelet	341	150 –400 /109/L
Erythrocyte sedimentation rate	86	0–20 mm/hour
C reactive protein	76.02	0–5 mg/L
Procalcitonin	1.34	<0.5 µg/L
D-dimer	4.6	0–0.5 µg/mL FEU
PT	11	10.4–12.20 s
APTT	28.5	26.30–31.3 s
ANCA	Negative
ANA	Negative
Hep20-10	Negative
Anticardiolipin antibody (IgM and IgG)	Negative
Anti- ß2-glycoprotein antibody	Negative
Lupus anticoagulant	Negative
Urine blood	13.70	0–3/hpf
Urine WBC	66	0–5/hpf

ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; APTT, activated partial thromboplastin time; FEU, fibrinogen equivalent units; hpf, high power field; PT, prothrombin time; WBC, white blood cell.

The patient’s bilateral, tender lower limb oedema and increased D-dimer warranted venous Doppler, which showed acute thrombosis of the right femoral vein and one of the left calf veins. AKI, along with thrombosis in lower limbs, prompted us to do an ultrasound of the abdomen and pelvis. It revealed focal intraluminal hyperechogenicity measuring 2.6×0.9 cm in the region of origin of the left renal vein. Due to financial constraints, contrast-enhanced CT of the abdomen and pelvis could not be performed initially. However, on her eighth day of admission, we were able to get contrast-enhanced CT of the abdomen and pelvis done to check the extent and any resolution or progression of the thrombus. It showed a partial IVC thrombus at the infrahepatic suprarenal segment (figures 1 and 2).

Figure 1.

CT of the abdomen and pelvis showing thrombus in the inferior vena cava at infrahepatic suprarenal segment: coronal section.

Figure 2.

CT of the abdomen and pelvis showing thrombus in the inferior vena cava at infrahepatic suprarenal segment: sagittal section.

Differential diagnosis

Considering that the most common cause of AKI in patients with TB is drug toxicity, we did not restart the anti-TB drugs until imaging confirmed another diagnosis. Two different retrospective studies in Japan and Taiwan showed that rifampicin is the leading causative drug in AKI during anti-TB treatment.^{3 13} Acute interstitial nephritis (AIN) is thought to be the most common pathogenesis. A rash and fever usually accompany it. Restarting rifampicin after diagnosing AKI may be lethal and should be avoided.³ AKI due to ATT was also unlikely as she had continued taking the medications after the initial diagnosis with no rapidly progressive renal failure. Also, the presence of bilateral lower limb deep vein thrombosis prompted us to look for thrombotic causes of AKI. Identifying the exact cause of AKI is crucial to prevent treatment delays and drug resistance due to treatment interruption. We did not consider taking a renal biopsy to look for ATT-associated AIN because it is an invasive procedure that had no diagnostic value in our case since the renal function improved upon starting unfractionated heparin. Our treatment would have remained the same.

The diagnosis of COVID-19 vaccine-induced thrombotic thrombocytopenia was entertained initially, but we quickly ruled it out as the cause of thrombosis since her last COVID-19 vaccine was more than 2 months ago; there was no thrombocytopenia, and D-dimer levels were <2000 µg/mL fibrinogen equivalent units.¹⁴ Also, given her history of abortion, we did a full work-up for antiphospholipid syndrome, which was negative, to look for other causes of hypercoagulability.⁶ Antineutrophil cytoplasmic antibody and antinuclear antibody work-ups were also negative. However, we could not test for hereditary thrombophilia due to unavailability.

Treatment

We started weight-adjusted subcutaneous unfractionated heparin of 333 units/kg loading dose followed by 250 units/kg every 12 hours for 13 days.¹⁵ Subcutaneous unfractionated heparin was preferred over low-molecular weight heparin due to the patient’s severe renal insufficiency.¹⁵ She was transitioned to tablet dabigatran 150 mg after that.

Weight-based ATT, rather than her initial fixed-dose regimen, was also steadily reintroduced (figure 3). This was done to avoid adverse side effects of high doses, as the patient had significant weight loss and hypoalbuminaemia. Levofloxacin was used instead of pyrazinamide since the patient had slight hyperuricaemia. Each ATT drug was started at a low dose, and new drugs were added after a few days with careful monitoring of any side effects.

Figure 3.

Urea and creatinine levels with treatment.

Outcome and follow-up

Upon starting unfractionated heparin, there was a gradual improvement in renal function (figure 3). She tolerated the ATT well without significant biochemical side effects. The swelling and pain in her lower limb resolved, along with an improved appetite. She had no new episodes of vomiting, fever or cough, and her renal functions tests were normal on her 2-week, 1.5-month and 3-month follow-up visits. Her chest X-ray also had cleared up. She continues to take dabigatran and ATT.

Discussion

According to multiple retrospective studies, there is a higher risk of venous thromboembolism in patients with active TB than in the general population.^{2 16} A recent meta-analysis estimated that 35 out of 1000 people with active TB might experience venous thromboembolism. Furthermore, they found a prevalence of pulmonary thromboembolism (PTE) at 5.8% and deep vein thrombosis at 1.3%.²

This increased risk may be because TB acts on all three elements of Virchow’s triad stasis of blood flow, hypercoagulability and endothelial injury. Active TB can induce the enlargement of lymph nodes which can compress the venous system. It can also cause the patient to be on bed rest, which limits peripheral muscle contraction for blood circulation. These two factors contribute to stasis. Our patient had a long history of bed rest due to anorexia and fatigue. The chronic inflammation induced by TB disturbs the clotting mechanism by increasing the plasma levels of factor VIII, plasminogen activator inhibitor 1 and fibrinogen while reducing the plasma levels of antithrombin III and protein C.² There is also impaired fibrinolysis that causes elevated fibrinogen and fibrin degradation product levels.¹⁶ This chronic inflammation due to M. tuberculosis and the use of rifampicin for its treatment may also cause endothelial injury.²

Interestingly, White, in a retrospective study, showed a relative risk of 4.74 of deep vein thrombosis in patients treated with rifampicin regimens compared with others. It is thought that the induction of cytochrome P450 caused by rifampicin alters the balance of anticoagulant and coagulant factors produced by the liver. The risk is highest within 2 weeks of starting treatment.¹⁷ Our patient reported painful bilateral lower limb swelling within 1 week of starting ATT. The disturbance of Virchow’s triad and, with it, the risk of venous thromboembolism is the highest during the first month of treatment.¹ The haemostatic changes improve with continuous use of anti-TB medication within 1 month.²

The risk of thrombosis is directly proportional to the severity of TB. Studies show that the clinical findings of pulmonary TB directly correlate with haematological abnormalities. The COVID-19 pandemic saw extensive TB disease increase due to delayed presentation to physicians and diagnosis. A recent retrospective study in an Italian referral hospital evaluated PTE prevalence in patients with TB in the last 6 years. They found an increase in the prevalence of PTE from 0.6% in the pre-COVID-19 pandemic period to 4.6% in the pandemic period. The authors speculate this increase is due to the increased severity of TB in patients. The study excluded a correlation between PTE and COVID-19 pneumonia.¹⁸

Our case highlights how the prothrombotic state induced by TB can cause thrombosis in rare locations such as the renal veins. RVT can progress into the IVC or vice-versa. It was hard to determine the origin of the thrombus in our patient. Regardless of the source, bilateral deep vein thrombosis, unexplained AKI and back pain should raise a strong suspicion of thrombus involving both the renal vein and IVC.⁷

Contrast-enhanced CT is the imaging of choice for diagnosis, which can show a thrombus in the renal vein and the IVC if present.⁶ Ultrasonography is a less sensitive but quick, safe and non-invasive test. It is usually the first-line imaging for patients with lower extremity symptoms.⁷ A renovascular duplex ultrasound is superior and can be used in patients with renal insufficiency. Magnetic resonance angiography can also be used in such cases.⁶

Prompt diagnosis and treatment of RVT prevent complications such as loss of renal function, extension into the IVC and pulmonary embolism. Preventing progression into pulmonary embolism is especially important in TB, where the lungs are already damaged. Treating RVT includes using low-molecular weight heparin with warfarin bridge. Those with a solitary kidney or renal transplant require more aggressive therapy, such as catheter-directed thrombolysis with or without pharmacological or mechanical thrombolysis.^{7 19} Using novel oral anticoagulants is preferred over warfarin in those taking ATT as they do not interact with rifampicin while being equally effective.¹⁶

Presently, there are no standard guidelines for additional thromboprophylaxis in patients with TB as part of their treatment. We believe this case highlights the importance of further studies for risk assessment, prevention strategies and reduction of the burden of venous thromboembolism in patients with TB.

Patient’s perspective.

For the many months, I had been feeling exhausted and had lost my appetite and weight. Even after being diagnosed with Tuberculosis and starting therapy, I felt my condition didn’t improve much. After further testing and treatment at this hospital, my appetite is normal, and I don’t feel weak anymore. I am delighted I can go back to living my life as usual and be more involved in my daughters’ lives again.

Learning points.

• Active tuberculosis induces a prothrombotic state and is an emerging risk factor for venous thromboembolism. It can cause thrombosis in unusual locations, such as the renal veins and inferior vena cava.

• In patients with tuberculosis, acute kidney injury (AKI) with tender bilateral lower limb oedema and pelvic/back pain should raise a strong suspicion of thrombus involving both renal vein and inferior vena cava as the cause of AKI rather than antitubercular drug-induced AKI. Identifying the exact cause of AKI is crucial to prevent treatment delays and drug resistance.

• Early diagnosis of renal vein thrombosis and prompt initiation of treatment with anticoagulants and antitubercular therapy are associated with good clinical outcomes and improvement of renal function.

Ethics statements

Patient consent for publication

Obtained.