Lisa Crowley, Kieron Donovan, Peter Topham
Since its introduction to clinical medicine in the 1950s, percutaneous renal biopsy has become a routine investigation in the evaluation of patients with kidney dysfunction. It provides a tissue diagnosis in more than 95% of cases, and is a relatively safe procedure with a life-threatening complication rate of less than 0.1%. However, the decision to proceed to biopsy should not be taken lightly and must be made by a consultant. It is important that trainees discuss the need for a biopsy with a consultant before booking it.
Aim of Renal Biopsy
Patients with renal disease often present with a ‘syndrome’ – such as nephrotic syndrome, AKI, or CKD. In themselves, these are not ‘diagnoses’. They are merely patterns of kidney disease that can have many causes.To aid the management of such patients, the histological analysis of a renal biopsy sample should therefore aim to:
- identify a specific diagnosis
- reflect the level of disease activity
- provide information to allow informed decisions about treatment.
Is the Biopsy Necessary?
This is a vital question to ask oneself at all stages of the process; as it is always a judgement of the balance of risk vs useful information. A renal biopsy is not without risk therefore before undertaking a biopsy, think carefully about whether the biopsy result is likely to alter management. Given the complexity of renal pathology, a discussion between the pathologist and the nephrologist is required, in order for the result to interpreted correctly within the clinical context.
The information gained subsequently affects management in approximately 30-40% of cases, and 85% of patients with nephrotic syndrome and unexplained AKI (Richards 1994, Stratta 2007). Nonetheless, at times, the role of renal biopsy has been debated (Madaio 1990, Adu 1996).
Most nephrologists would agree that renal biopsy is more likely to change management in symptomatic kidney disease (proteinuria, nephrotic syndrome), unexplained AKI or sudden changes in eGFR in CKD. It can also be useful for prognostic purposes, as well as helping to direct or change treatment.
In nephrotic syndrome and AKI, the biopsy may make the difference between giving immunosuppression or not, withdrawal of drugs or not etc. The role of renal biopsy in determining the quantity and intensity of treatment is widely but not universally accepted, particularly in lupus nephritis.
There are four common indications for renal biopsy:
- Significant proteinuria/nephrotic syndrome (>1g/L, or PCR > 100mg/mmol) with two normal sized, non-obstructed, kidneys and no obvious cause (usually considering the diagnosis of a glomerulo- or interstitial nephritis)
- Acute Kidney Injury (AKI) with two normal sized, non-obstructed, kidneys and no obvious cause
- Chronic Kidney Disease (CKD) with two normal sized, non-obstructed, kidneys and no obvious cause
- Renal transplant dysfunction
Other, less common (and more controversial) indications. Many of these patients may have normal renal function:
- Non-visible haematuria
- Renal dysfunction in systemic disease (eg diabetes, myeloma, amyloidosis, SLE)
- Familial renal disease (where diagnosis in this patient, benefits them and their family)
Biopsies are absolutely contraindicated in the following situation:
- Uncontrolled bleeding diathesis
Biopsies are relatively contraindicated when:
- Uncontrolled hypertension (>160/95)
- Uncooperative patient
- Patient unable to consent
- Solitary kidney. This is a 'big decision' and should be carefully made by a consultant and the patient
- Obstructed kidneys
- Small kidneys (less than 10 cm; less than 9 cm in a small patient)
- Anatomical abnormalities (eg vascular lesion)
- Renal neoplasm, multiple cysts, abscess or pyelonephritis
Note: when considering a diagnosis of amyloid, it may be advisable to biopsy other less vascular tissues (fat, rectum) first, since this may establish the diagnosis and avoid the inherent risk of the renal biopsy. Patients with amyloid (particularly those with blood vessel deposition) may be more likely to bleed. This view has been challenged by Fish in 2010.
Diabetes and Renal Biopsy
If the clinical presentation is consistent with diabetic nephropathy (ie signficant proteinuria [often nephrotic range], CKD3b-4, diabetes of over 10 years duration, normal soluble immunology, presence of other microvascular complications [eg retinopathy and neuropathy]), renal biopsy is not necessary and it can be assumed that the patient has diabetic nephropathy.
If however the presentation is atypical (haematuria, haematoproteinuria, diabetes of less than 5 years duration, abnormal soluble immunology, no microvascular complications, rapid fall in GFR), renal biopsy should then be considered. Patients with diabetes may develop a glomerulonephritis or another form of intrinsic renal disease. A higher than average risk of glomerulonephritis has been described in patients with diabetes (Soni, 2006) although this has not been universally seen (Waldherr, 1992).
Age, Race and Renal Biopsy
Moutzouris (2009) has published a series of biopsies in the elderly (> 80 years) suggesting this is still a useful technique with results that affect management in a significant number of patients.
There are racial differences between biopsy appearances. For example, Hoy (2012) has described a wide range of atypical findings in Australian aborginal people.
This talk by Vishal Golay (on 28.10.10) is a very good, especially regarding the practicalities of renal biopsy.
The organisation of a renal biopsy needs careful thought. It is always sensible to do a biopsy in the morning if possible, so that relevant services are available if a significant complication develops. Do not be afraid to ask ‘why it is necessary’ if you are asked to arrange an emergency biopsy in the late afternoon or out-of-hours. There are few situations where a renal biopsy cannot wait until the following morning.
Traditionally, patients who had a renal biopsy stayed in hospital one night and then went home the following day if there had been no significant complication. Because of the financial and resource implications of overnight hospital admission, most renal units now do renal biopsies as a day case with 6 to 8 hours of post-biopsy bed-rest and same-day discharge to home. This approach was justified by the perception that biopsy complications usually become apparent within 8 hours after the biopsy.
However, one recent study of 750 renal biopsies (Whitier, 2004) suggested that:
Key point: 33% of major complications occur more than 8 hours after the renal biopsy
This was a mixed population of patients however; and most centres now risk-stratify patients. Evidence indicates that those at lowest risk (preserved renal function [creatinine <250mcmol/L], normal sized kidneys, well controlled blood pressure) can safely undergo day-case renal biopsy. The small percentage (approximately 5%) that have a complicated post-biopsy course (visible haematuria, severe loin pain, fall in blood pressure) are admitted for extended bed-rest and observation. Complications that arise after day-case discharge are rare in this low-risk population. Day case biopsy is therefore regarded by most nephrologists as safe for selected low-risk patients (Carrington, 2011). High-risk patients should be admitted to hospital for planned overnight observation.
If an urgent biopsy result is required, ring the pathologist and explain why same day service is required and ensure that the samples are delivered to the laboratory promptly.
Before a biopsy is undertaken it is important to identify any issues that may compromise the safety of the procedure.
The evaluation should determine whether the patient has two normal sized, unobstructed kidneys, sterile urine, controlled blood pressure, and no abnormality of blood coagulation.
The evaluation should therefore include the following:
|Renal Imaging||2 normal-sized, unscarred, unobstructed kidneys (see comment below)|
|Blood pressure||Systolic BP < 160mmHg; diastolic BP < 95mmHg|
Key point: ensure renal ultrasound has been done, and that the patient has 2 normal sized non-obstructed, kidneys. This sounds obvious, but crucially important, as biopsy risks damage to the kidney. There are important medico-legal implications if this is not done, and the patient loses a kidney.
The need to stop aspirin and NSAIDs before a renal biopsy has been challenged (Mackinnon (2008) and Atwell (2010)). In Atwell's study of 15,181 biopsies (not just renal), the incidence of bleeding in patients taking aspirin within 10 days before biopsy was 0.6%, which was not statistically different compared with the incidence of bleeding in those not taking aspirin (0.4%). However:
Key Point: Most nephrologists would not undertake a renal biopsy if the patient was still taking anti-platelet therapy
Finally ensure that a sample has been sent for Group and Save and then obtain informed consent.
Consent, and Risks
This should be done by the person undertaking the biopsy. It is absolutely not the role of a junior doctor to obtain informed consent for a renal biopsy. They do not have the experience to be able to judge the pros and cons of a biopsy. It should be done by an experienced renal registrar or consultant.
The risks of renal biopsy that need to be explained, and accepted are:
- 60-85% peri-renal haematoma (on ultrasound) - this is usually asymptomatic
- 35% microscopic haematuria
- 3% macroscopic haematuria
- 2% symptomatic peri-renal haematoma
- <0.1% major bleed (possibly requiring transfusion), or kidney loss (or death, although this has only been reported once)
- 5% chance that biopsy will be insufficient for diagnosis and may need to be repeated (Preda, 2003)
It is advisable to warn the patient of these complications
Other rare complications include:
- biopsy of other organs (liver, spleen, pancreas, bowel and gallbladder)
- calyceal-peritoneal fistula
- dispersion of carcinoma
- Page kidney (compression of kidney by peri-renal haematoma leading to renin-mediated hypertension)
Bleeding Time, and Bleeding Prevention
Retrospective studies have shown that the risk of post-biopsy bleeding is increased by 3- to 5-fold if the bleeding time is prolonged. There is however a consensus view that the bleeding time is a poor predictor of post-renal biopsy bleeding. In addition, measurement of the bleeding time is difficult to standardise and therefore can be unreliable.
Some centres routinely measure bleeding time and if prolonged >10 mins, will prescribe Desmopressin (DDAVP, 1-desamino-8-D-arginine vasopressin) (0.4mcg/kg 3 to 4 hours pre-biopsy), which is a modified form of the normal human hormone arginine vasopressin. Others will give DDAVP routinely if the urea is > 20 mmol/L or creatinine > 250 mcmol/L, and not measure the bleeding time.
Percutaneous renal biopsy involves inserting a biopsy needle into the kidney under ultrasound guidance using local anaesthesia. Sedation is rarely required. Young children usually require general anaesthesia.
In the UK, renal biopsies have historically been performed by nephrologists although there is an increasing trend towards a radiologist-lead service in many centres. As a reflection of this trend, competence in percutaneous renal biopsy is no longer a mandatory part of specialty training in nephrology in the UK. Surgeons will occasionally do 'open' or laparoscopic renal biopsies in the operating theatre (eg as a baseline biopsy during a transplant, or during another operative procedure) although renal biopsy in this setting is not without risk (Stec, 2010).
The biopsy needle is usually part of a ‘biopsy gun’ (usually single-use, disposable device). 16G needles are commonly used as a compromise between the greater tissue yield of larger needles and the trend towards fewer bleeding complications with smaller needles.
'Native' renal biopsy
- Pre-medication or sedation is usually not required
- The patient lies prone with a pillow under the abdo-men to straighten the spine and splint the kidneys
- Ultrasonography is used to localise the lower pole of the kidney to be biopsied
- The skin is marked with an indelible pen at the point of entry of the biopsy needle and then cleaned with either an iodine-based or chlorhexidine solution
- A sterile fenestrated sheet is placed over the patient's back
- Local anaesthetic (2% lidocaine) is infiltrated into the skin
- The ultrasound probe is covered in a sterile sheath
- Sterile ultrasound jelly is applied to the skin
- Under ultrasound guidance a 10 cm, 21 gauge needle is advanced to the renal capsule and further local anaesthetic is infiltrated into the perirenal tissues and then along the track of the needle on withdrawal
- A stab incision is made through the dermis to ease passage of the biopsy needle
- The biopsy needle is directed under ultrasound guidance towards the kidney capsule
- As the needle approaches the capsule the patient is instructed to take a breath until the kidney is moved to a position where the lower pole rests just under the biopsy needle and then to hold their breath
- The biopsy needle is then advanced to the renal capsule, and the trigger mechanism is released. It is essential that the needle and its tip is visible (on ultrasound) at all times during the procedure
- The biopsy needle is withdrawn immediately and the patient is asked to resume breathing. The contents of the needle are examined (ideally with use of a dissecting microscope) to ensure that sufficient renal cortex (ie enough glomeruli) has been obtained
- Usually a second core of tissue is required for immunofluorescence and electron microscopy
- If insufficient material is obtained then further passes of the needle are made. Our experience indicates that a modest increase in the post-biopsy complication rate is observed if the needle is passed more than four times.
- Once sufficient renal tissue has been obtained the skin incision is dressed and the patient is rolled directly into bed for observation.
This is a native biopsy of the lower pole of the left kidney (the most common place to attempt a native biopsy).
No single fixative has been developed that allows good quality light, immunofluorescence, and electron microscopy to be performed on the same sample. The renal tissue is therefore divided into three samples and placed into:
- Formalin for conventional light microscopy
- Normal saline for subsequent snap freezing in liquid nitrogen for immunofluorescence.
- Glutaraldehyde for electron microscopy
There are a number of variations of the percutaneous renal biopsy technique. For examples some operators use ultrasound to localise the kidney and to determine its depth and the angle of approach of the needle. The biopsy is then performed without further ultrasound guidance. The success and complication rates of this technique appear to be no different from that seen with continuous ultrasound guidance.
Computed tomography guidance has been advocated for patients who present significant technical challenge to ultrasound-guided biopsy.
Renal transplant biopsy
The general technique for renal transplant biopsy is similar to that of the native kidney. The proximity of the allograft to the anterior abdominal wall and the lack of movement on respiration makes transplant biopsy technically less challenging than biopsy of native kidneys. The biopsy of the allograft is performed under real-time ultrasound guidance using an automated biopsy needle.
If the biopsy is being performed to identify the cause of acute allograft dysfunction a formalin-fixed sample for conventional light microscopy is usually sufficient. A snap frozen sample for C4d immunostaining should be obtained if antibody-mediated rejection is suspected. If recurrent or de-novo glomerulonephritis is suspected in patients with chronic allograft dysfunction, additional samples for electron microscopy and immunofluorescence microscopy should be collected.
Walker (2009) published an overview of the renal biopsy, including the techniques, its complications, and laboratory methods for processing renal biopsy tissue.
The High Risk Patient
Occasionally the need for kidney biopsy outweighs the contraindications for percutaneous biopsy alternative approaches to renal biopsy can be considered. The choice of technique in any situation depends on the safety, morbidity, recovery period, and adequacy of the technique, but above all on the local expertise that is available. Options available include transvenous, 'open', and laparascopic renal biopsy.
Transvenous (transjugular or transfemoral) renal biopsy
Transvenous sampling of the kidney is theoretically safer than the percutaneous approach because:
- The needle passes from the venous system into the renal parenchyma and is directed away from large blood vessels
- It is suggested that any bleeding that occurs should be directed back into the venous system
- If capsular perforation occurs, significant bleeding points can be immediately identified and controlled by coil embolisation.
This latter point is controversial because it is argued that if significant bleeding occurs it indicates an arterial breach that requires selective arteriography and arterial embolisation. ie in a separate procedure. The transjugular renal biopsy cannot be regarded as routine because it requires specialist skill, and involves additional time, and expense.
Indications for this approach are:
- An uncontrollable bleeding diathesis.
- Patients receiving artificial ventilation in the intensive care unit
- The need to obtain tissue from more than one organ including the kidney, liver, or heart; large volume ascites that precludes the prone position.
- Uncontrolled hypertension.
- Morbid obesity.
- Severe respiratory insufficiency.
- Solitary right kidney.
- Failed percutaneous approach.
Studies report diagnostic yields for transjugular biopsy of between 73 and 98%. The complication rate appears to be comparable to that seen in percutaneous renal biopsy, but these must be regarded as high risk patients.
'Open' renal biopsy
This as a safe alternative to percutaneous biopsy when uncorrectable contraindications exist. The largest study reported a series of 934 patients in which tissue adequacy was 100% with no major complications. However the risk of general anaesthesia and the delayed recovery time have prevented its widespread adoption. It is a useful approach however when a renal biopsy is required in patients who are undergoing an abdominal procedure.
Laparoscopic renal biopsy
This procedure requires general anaesthesia and two laparoscopic ports in the posterior and anterior axillary lines to gain access to the retroperitoneal space. Laparoscopic biopsy forceps are used to obtain cortical biopsy samples, and the biopsy sites are coagulated with laser and then packed to prevent haemorrhage.
The largest published study reported on 74 patients. Adequate tissue was obtained in 96%. Significant bleeding occurred in three patients, the colon was injured in one, and a biopsy was performed inadvertently on the spleen and liver in two others. This latter complication can be prevented by the use of intra-operative ultrasound.
Patients will be sore when the local anaesthetic 'wears off' (most describe the pain as like being kicked in the back), and need close monitoring. They will need to rest in bed for at least 6 to 8 hours (up to 12 hours if the biopsy is 'high-risk') afterwards. Monitoring the patient after biopsy will ensure any complications are dealt with swiftly. Each unit will have its own post-procedure protocol, but a typical protocol would include:
- The patient is placed supine and subjected to strict bed-rest for at least 6 to 8 hours.
- The puncture site is checked 2-3 hours after the biopsy and before discharge.
- Vital signs (BP, pulse, respiratory rate) are monitored every 15 minutes for 1 hour, every 30 minutes for 2 hours, hourly for 4 hours and 2 hourly for a further 12 hours.
- The patient is allowed to eat and is encouraged to drink plenty of fluid.
- The urine is examined for visible haematuria.
- If after the prescribed period of bed-rest there are no apparent complications, the patient can be sat up, then mobilsed, and then discharged.
- The patient should have someone with them for 24 hours after biopsy.
- Patients should be given clear (written) instructions regarding pain and haematuria. These should include 24 hour contact numbers in case of complications that arise after discharge. They should be advised not to carry out any heavy lifting, strenuous activity or contact sports for a week after the biopsy.
Interpretation of the Biopsy
The histological classification of glomerulonephritis was established within ten years of the introduction of the renal biopsy. Initially it was based on light microscopy alone. This has stood the test of time.
The subsequent addition of immunoflourescence (IF) improved the diagnosis of IgA nephropathy and crescentic GN. Membranous nephropathy is easier to diagnose by electron microscopy (EM) and immunoflourescence, than light microscopy. EM also led to the discovery of 'new' renal diseases such as fibrillary glomerulonephritis. IF and EM are more useful in determining the type of a GN; and light microscopy better at determining prognosis. Tubulointerstitial changes are better at predicting prognosis than those of the glomerulae.
The major complication of renal biopsy is bleeding. A degree of peri-renal bleeding post-biopsy is inevitable and the mean fall in haemoglobin after a renal biopsy is 1g/dL. Bleeds are usually small and self-limiting and manifest as:
- Peri-renal haematoma (Manno, 2004). Peri-renal haematomas are common, and usually self-limiting. If CT is carried out one day after the biopsy, haematomas are detected in 60-85% of patients. They are painful in 2%, ie most are clinically silent. Approximately 1% to 2% of patients bleed sufficiently to develop hypotension and a flank mass. Rarely, the onset of haemorrhage is delayed for as long as 2 months. Haematomas usually resolve within 3 months. They rarely become secondarily infected and require treatment with IV antibiotics and surgical drainage.
- Non-visible haematuria (35%).
- Visible haematuria (3%). This usually resolves spontaneously within 2 days, but in approximately 0.5% of patients, it continues for 2 to 3 weeks. Occasionally, gross hematuria first occurs several days after the biopsy, but it too usually resolves within a few days with rest.
A high index of suspicion is needed, with early discussion with a consultant. There should also be dialogue between a senior nephrologist, senior surgeon and interventional radiologist. This will help plan any diagnostics or intervention required.
Key point: if you suspect major bleeding post renal-biopsy involve the consultant at an early stage
Bleeding can rarely be more significant and potentially life-threatening. Transfusion may be necessary, and embolisation or surgery for persistent or massive bleeding is required in <0.2% of patients. In extreme cases bleeding can lead to kidney loss or death (both probably <0.1%).
In one large series, 345 biopsies were performed on renal allografts and 170 on native kidneys (Preda, 2003). The tissue specimen was adequate for histological evaluation in 95.3% of the cases (94.8% in the transplanted kidney group, 96.5% in the native kidney group). The overall complication rate was 12.2% and was significantly higher in the native kidney group (19.4%) than in the renal allograft group (8.7%). Major complications occurred in 2.7% of the cases (2.9% of the renal allografts and 2.4% of the native kidney biopsies), including one procedure-related death and the loss of the renal allograft in two other patients.
In a very large (1387) series (Stratta, 2007), there were no deaths and five major complications (0·36%). One nephrectomy (0·07%), two surgical revisions (0·1%) and two arterial-venous fistulae (0·1%) occurred. There were also 337 minor bleeding complications (24·2%; 16·4% gross haematuria and 7·8% clinically relevant haematomas needing at least prolonged bed rest). The risk of complications was significantly increased by systemic autoimmune diseases, end-stage kidney/acute-tubular necrosis, and a prolonged bleeding time test. Among the 1288 cases in which a clinical hypothesis before renal biopsy was recorded, renal pathology changed previous diagnoses in 423/1,288 (32·8%) of cases.
Conversely, in another very large series (1090 biopsies), virtually no serious consequences occurred (Hergesell, 1998). Nonetheless, signs and management of a major bleed are as follows:
- Tachycardia may be the first sign of bleeding – take it seriously
- Classic signs of shock and back pain may happen much later
- If shock develops call your blood bank and X-match 2 (or more) units of blood from the Group and Save sample done before the procedure
- Ensure the patient has good (wide bore) IV access, replace volume loss with IV saline/colloid in the first instance
- Arrange an urgent ultrasound to see if there is any bleed around the kidney (peri-renal haematoma). A CT angiogram can be useful to identify both a peri-renal haematoma and also the presence and site of active bleeding
- Occassionally heavy haematuria may cause clot colic or acute urinary retention
- Prolonged or severe bleeding may require angiography and coil embolisation. It is sensible to inform the urologists at this stage - if angiography and embolisation fail to stop the bleeding a nephrectomy will be required
- AV fistula - these are common and can be demonstrated by angiography in 10-20% of patients. Such lesions are usually clinically silent, and more than 95% resolve spontaneously within 2 years. In rare instances, embolisation or surgical correction of the fistula is required because of severe hypertension, persistent hematuria, congestive heart failure, or hydronephrosis
- Aneurysm - these occur in less than 1% of patients and the majority resolve spontaneously Rarely they can lead to significant steal/ischaemic problems and may require embolisation
- Biopsy of other organs (spleen, liver, pancreas, bowel, gall bladder)
- Pneumothorax, haemothorax
- Calyceal-peritoneal fistula
- Dispersion of carcinoma
- Small risk of damaging the kidney to the point where function is loss
- 'Page kidney' - compression of the kidney by peri-renal haematoma leading to renin-mediated hypertension
Key point: there is also an approximately 5% chance of obtaining an inadequate tissue sample. In other words, from the patients' perspective, the most important common 'complication' of biopsy is having to do it again
Risk Factors for Bleeding
Manno (2004) has shown an increased bleeding tendencies in women, younger patients, patients with abnormal clotting, and in patients with AKI. There is a common view that there is an increased risk of bleeding in patients with monoclonal gammopathies, especially amyloidosis. This view has been challenged by Fish in 2010.
Patients who have a native biopsy are probably more likely to bleed than those who have a transplant biopsy (Preda, 2003).
In 2010, Atwell described 15,181 percutaneous core biopsies (not just renal) performed during the study period. There were 70 serious haemorrhages (0.5%) within 3 months of biopsy. The incidence of bleeding after liver biopsy was 0.5%; 0.7% after kidney biopsy; 0.2% after lung biopsy; 1% after pancreas biopsy; and 0.2% after other biopsy. There were significant associations between major bleeding and serum platelet count and international normalised ratio, although the association between major bleeding and the size of the biopsy needle was not significant.
Warn the patient they will feel sore around the biopsy site for 3-4 days. Patients should be given clear (written) instructions regarding pain and haematuria before they go home. These should include 24 hour contact numbers in case of complications that arise after discharge.
Key point: all patients who have had a renal biopsy should be seen in clinic soon after discharge: transplant biopsy: 1-2 days; native biopsy: 2 weeks
Top Tip: Consider renal biopsy in any patient with AKI or CKD with non-obstructed normal sized kidneys and no obvious cause
- Four common indications for renal biopsy: significant proteinuria (>1g/L, or PCR >100mg/mmol), unexplained AKI and CKD (all with two normal sized, non-obstructed kidneys); and transplant graft dysfunction
- 95% will lead to a diagnosis, even if non-specific. 5% may need to be repeated (not enough tissue)
- 30-40% will affect management
- Biopsy sample is divided and may be sent off for light microscopy, immunoflourescence and electron microscopy
- Risks include: self-resolving peri-renal haematoma (60-85%; 2% symptomatic), non-visible haematuria (35%), visible haematuria (3%), major bleeding leading to kidney loss (<0.1%) or death (<0.1%)
- 33% of major complications occur >8 hours after a renal biopsy
- Involve consultants early if you suspect major bleeding
- All patients should be seen in clinic soon after discharge: transplant biopsy: 1-2 days; native biopsy: 2 weeks
- It is important that trainees discuss the need for a biopsy with a consultant before booking it
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