Clinical Considerations for Kidney Biopsy in Non-Specialists

Despite advances in biochemical investigations and non-invasive imaging, kidney biopsies play a fundamental role in the diagnosis of kidney diseases.

They provide information about prognosis, which can result in treatment modification in up to 74% of patients.

This review is limited to the use of percutaneous kidney biopsies, the diagnosis and management of native parenchymal kidney diseases in adults and not for the diagnosis of tumors or growths, children or kidney transplant recipients.

> Urinary sediment

Dipstick urinalysis is an essential initial investigation for acute and chronic presentations of kidney disease, as well as for the follow-up of patients with known kidney disease. The presence of blood and/or protein suggests inflammation in the kidney and damage to the filtration barrier, indicating that the origin of the inflammation may be the glomerulus.

The dipstick with minor abnormalities (low-grade proteinuria, without hematuria or minimal hematuria, with or without leukocytes) in the presence of impaired renal function may suggest tubulointerstitial nephritis. In addition to urinalysis, decreased kidney function should be immediately evaluated with the investigations listed in the table below.

Immunologic testing is particularly important in patients with acute kidney injury (AKI) and an active urinary sediment (i.e., blood and protein).

> Hematuria

Hematuria can be classified as "visible" or "not visible." Both may be due to nephrological (e.g., glomerulonephritis) or urological (e.g., malignancy, infection, or stones) pathologies whose clinical presentation will guide remission.

> Malignancy

Urological malignancies can cause both visible and non-visible hematuria. History is important to identify risk factors: smoking, drug history (e.g., cyclophosphamide), occupation, chemical exposure, and history of travel history (e.g., schistosomiasis).

Urgent referral for evaluation of urological malignancy depends on age. Once malignancy has been excluded, other causes of visible hematuria should be considered. A single episode of visible hematuria warrants investigation. Transient causes should be excluded by rechecking urine using a dipstick after resolution of the acute episode.

Anticoagulant and antiplatelet treatment will worsen any hematuria but will not be the precipitating factor. The appearance of visible hematuria is a useful indicator of the origin of the pathology. Pink-tinged urine or the frank presence of blood suggests fresh bleeding along the urinary tract, pointing toward urological causes. In contrast, dark visible hematuria (“cola drink color”) suggests a nephrologic cause because hemoglobin is converted to methemoglobin in the acidic environment.

Coexisting symptoms also provide information. In urologic pathology, flank pain suggests ureteral colic, while intercurrent illness (typically upper respiratory tract infection) followed by cola-colored urine suggests a nephrologic cause (e.g., postinfectious glomerulonephritis or immunoglobulin nephropathy ( Ig) A.

> Isolated non-visible hematuria with normal kidney function

Renal biopsy to investigate isolated non-visible hematuria, in the absence of proteinuria and renal failure with normotension, is unlikely to change the management of the disease.

Common causes are thin basement membrane nephropathy and IgA nephropathy. However, isolated persistent non-visible hematuria has been associated with a significant, although small, incidence of end-stage renal disease (ESRD).

An annual blood pressure evaluation in primary care is necessary along with urinalysis and determination of serum creatinine levels. Biopsy can help in the diagnosis of hereditary conditions and rapid screening of family members, genetic derivation and follow-up.

Thin basement membrane nephropathy usually has a good prognosis with only a minority of patients progressing to ESKD, while such a clear diagnosis may provide reassurance and avoid further investigation. Alport syndrome has a low prevalence but higher risk of progression to ESKD, especially in men, and has extrarenal manifestations, such as hearing impairment. It is essential to make a diagnosis and family evaluation to identify the affected family.

> Non-visible hematuria with markers of impaired renal function

Non-visible hematuria with abnormal markers of renal function (increased serum creatinine, oliguria, hypertension, or proteinuria) has a variety of possible urologic effects and nephrologic causes.

Regarding intrinsic kidney disease, non-visible hematuria with impaired kidney function usually reflects glomerular inflammation (glomerulonephritis). These patients may have systemic distress and, in the presence of an acute decline in their renal function, will require close monitoring and follow-up.

Renal biopsy is a key component for diagnosis, management, and prognosis, so the therapeutic goal is underlying glomerulonephritis, supportive care to manage complications (e.g., fluid overload), and preservation of renal function ( e.g., blood pressure control).

The biopsy may be postponed or not completed if management is unlikely to change, the patient is high risk, or to avoid delaying treatment if the diagnosis is clear. For example, in antiglomerular basement membrane disease, the presence of circulating antibiotics, rapidly progressive AKI, and hematuria (with or without pulmonary hemorrhage) confirms the diagnosis.

> Proteinuria

Proteinuria should be quantified using both the urine protein/creatinine ratio (CRP) and the albumin/creatinine ratio (ACR). For the detection and management of chronic kidney disease (CKD), it is preferable to base it on the presence of albuminuria, defined by an ACR ≥30 mg/g, due to its prognostic value, considering glomerular injury. Even with an estimated glomerular filtration rate (eGFR) within expected limits, the presence of albuminuria for >3 months reflects persistent glomerular dysfunction and CKD.

Albuminuria can be subdivided into microalbuminuria (moderate increase in ACR ≥30 to ≤300 mg/g) and macroalbuminuria (severe increase in ACR >300 mg/g) which influence decisions about monitoring and referral. The urinary ACR is a study that evaluates new kidney disease, known CKD, and the risk of kidney damage. This is because urinary ACR will early detect low-grade proteinuria that has a high risk of not being detected by the urine dipstick.

It is important to note that proteinuria can occur as a result of excess free light chains in serum or impaired absorption in the proximal tubule. This results in proteinuria with minimal albuminuria, highlighting the risk of false negative results if urine ACR is used in isolation. Unless there is a clear history of renal disease secondary to systemic disease (e.g., diabetes mellitus and hypertension) or the risks of biopsy outweigh the benefits, biopsy in patients with unexplained proteinuria provides valuable information.

The presence of proteinuria should be confirmed in the early morning urine sample. Benign phenomena, such as orthostatic (postural) proteinuria, usually occur in individuals <30 years of age and present as isolated proteinuria. The absence of proteinuria in an early morning urine sample confirms the diagnosis and no further investigation is indicated.

Nephrotic range proteinuria is defined as a urinary CRP >3,000 mg/g or an ACR >2.20 mg/g, and may or may not occur in nephrotic syndrome: intense proteinuria in combination with hypoalbuminemia (<25 g/l) and edema, with or without significant hypercholesterolemia. Nephrotic syndrome is a clinical presentation and the underlying diagnosis should be sought.

There are some situations associated with nephrotic syndrome (such as diabetic kidney disease or amyloidosis) in which clinical features and less invasive investigations may indicate the diagnosis and biopsy may be avoided. However, if common clinical diagnoses have been ruled out in adult patients, it would be important to consider biopsy.

Renal biopsy is a useful diagnostic tool in both the acute and chronic phases, especially in the presence of active urinary sediment. However, active urinary sediment does not confirm intrinsic renal disease and biopsy poses an unnecessary risk in cases of renal failure of prerenal and postrenal etiologies. Furthermore, an active urine sediment is not a prerequisite for further investigation.

Renal biopsy may also be appropriate in cases of unrepresentative urinary sediment, for example, AKI that does not recover and tubulointerstitial nephritis is suspected.

> Diabetic kidney disease

In the UK, 30-40% of people with type 1 and type 2 diabetes mellitus (DM) develop CKD and their risk of requiring renal replacement therapy is more than 3 times that of the general population. Diabetic kidney disease refers to the structural and functional changes caused by DM, while “diabetic nephropathy” refers to specific histological findings in the biopsy.

Alternative or added diagnoses may coexist (eg, hypertensive disease, unresolved AKI, or glomerulonephritis). The distinction is important for future treatment, prognosis, and therapeutic decisions.

The natural history of diabetic kidney disease in type 1 and type 2 DM is well defined and the occurrence of albuminuria is a consistent predictor for progression to ESKD.

In most patients, clinical history, disease progression, and non-invasive investigations can identify CKD as a consequence of DM. The National and Kidney Foundation guidelines warn that CKD can be attributed to DM in the presence of macroalbuminuria or microalbuminuria with retinopathy, or microalbuminuria in patients whose type 1 DM has lasted >10 years. In these cases, the risks of biopsy are thought to outweigh the benefit of confirming a diagnosis.

Features suggestive of non-diabetic causes of kidney damage that should prompt further study are:

• Refractory hypertension or great decrease in kidney function after starting inhibitors of the renin-angiotensin-aldosterone system (suggestive of renovascular disease).
   
•  The absence of diabetic retinopathy in the presence of proteinuria is predictive of nondiabetic kidney disease and reinforces the need for further investigation.
   
• Hematuria
   
• Evidence of other systemic disease.

On the other hand, the rapid decrease in renal function and the rapid increase in the proteinuria/proteinuria ratio in the nephrotic range may be caused by DM or could indicate another diagnosis; which requires further studies and referral to nephrology.

> Lupus nephritis

Lupus nephritis (LN) occurs in almost 50% of patients with systemic lupus erythematosus (SLE). Patients may lack clinical signs of kidney disease, so monitoring kidney function and urinary sediment are important. The gold standard for diagnosing LN is renal biopsy, which, if early, is associated with better results. The role of repeated biopsy during the course of the disease is also relatively clear.

> Initial presentation

Any patient with SLE and decreased renal function, proteinuria >0.5 g/24 hours, or active urinary sediment gives rise to suspicion of LN. Each histological class is associated with different therapeutic decisions and prognoses, so biopsy and its repetition are indicated, essential for diagnosis and guidance for management. Biopsy also serves to detect alternative causes of kidney damage in SLE (such as drug-induced nephrotoxicity, lupus podocytopathy, or thrombosis, microangiopathy).

> Repeat biopsy

Biopsy can be used to diagnose relapses or disease progression. Histological transformation can occur as a consequence of relapses, a potential change in required treatment and prognosis. On the other hand, relapses are an independent predictor of progression to ESRD. In patients with suspected relapse, there is a low threshold for repeat biopsy.

There are no precise clinical predictors of class transformation, reinforcing the value of histological restaging of the disease to guide immunosuppression and inform the risk of progression to ESKD.

The average age of a person hospitalized with acute kidney failure is 76 years. Almost 54% of people >75 years old live with CKD with clear comorbid consequences. The GFR index decreases physiologically with age. Identification of patients with pathological, non-senescent kidney disease remains difficult. An abnormal urinary sediment warrants investigation.

Histological findings may highlight a discrepancy in the clinical diagnosis in up to a third of older patients. A retrospective cohort study from the United Kingdom, of biopsies in patients >70 years, 38% showed scarring due to DM and hypertension while the remainder included pauciimmune glomerulonephritis (12%), tubulointerstitial nephritis (11%), membranous glomerulonephritis (7 %) and other diagnoses. In this group, appropriate treatment with immunosuppressants may still alter progression to ESKD and survival.

Biopsies also provide prognostic information. Patients diagnosed with vasculitis and paraprotein-related kidney disease were at higher risk of progression to ESRD compared with other diagnoses. Prognostic information facilitates the decision to use conservative management in primary care or start dialysis. Some studies have found that older patients have a higher risk of bleeding after biopsy, while others have found no increased risk compared to other age groups.

As with all data from registries, case series or retrospective cohort studies, there will be an element of selection bias related to the population investigated. However, the findings of these studies highlight that if these patients meet the requirement criteria for a kidney biopsy, it is generally safe to proceed and age alone should not be an exclusion criterion.

> Myeloma

Multiple myeloma is a malignant neoplasm of bone marrow plasma cells characterized by the clonal proliferation of these cells (derived from B cells) and the subsequent production of a monoclonal paraprotein.

The diagnosis implies the presence of target organ damage attributable to the proliferation of plasma cells: hypercalcemia, bone lesions, anemia or renal failure. Up to a third of people have kidney failure at the time of myeloma diagnosis.

Renal injury may occur directly (e.g., light chain cast nephropathy, Ig deposition, or amyloidosis) or indirectly, due to sepsis, dehydration, hypercalcemia, or drug toxicity.

There may be pre-existing CKD secondary to conditions such as hypertension or DM. Light chain cast nephropathy is considered a “myelomatous” event. Urinalysis will show proteinuria due to the presence of filtered light chains (Bence-Jones protein), with minimal albuminuria as the glomerular basement membrane is intact.

The histological diagnosis confirms the presence of light chain cast nephropathy; however, a presumptive diagnosis can be made, b based on high levels of free light chains in the serum (>1,500 mg/l) and AKI. In these cases, kidney biopsy should not delay treatment.

 Biopsy should be considered when the diagnosis is uncertain (e.g., when serum free light chain levels are <500 mg/L) to exclude other causes of AKI and CKD. Plasma cell dyscrasias in the absence of target organ damage are called monoclonal gammopathies of undetermined significance (MGUS) and are considered premalignant conditions. MGUS can lead to kidney injury through glomerular and tubular dysfunction.

The term “monoclonal gammopathy of renal significance” (MRGI) has been coined to discriminate non-myeloma plasma cell dyscrasias that result in kidney injury. The prognostic significance of findings of plasma cell dyscrasias on biopsy is unclear. Ultimately, management should focus on the underlying plasma cell dyscrasia. Hematologic response is associated with overall and kidney-specific survival in multiple myeloma and amyloidosis.

> Safety of the procedure

Kidney biopsy is an invasive procedure that is not without risk. The decision to proceed requires supervision (and usually execution) of the nephrology team and participation of the patient. Biopsies should only be performed if their results can guide treatment, help make a diagnosis that will modify treatment, or inform prognosis. Thorough patient preparation and consideration of contraindications are very important.

The essential study before biopsy is ultrasound , to ensure that the kidneys can be visualized, rule out anatomical abnormalities and provide more information to determine the risk-benefit balance of the procedure. For example, small kidneys and poor corticomedullary differentiation indicate chronicity (not quantifiable) of the kidney disease and limited potential for reversibility, which may make it difficult to differentiate the kidneys from the surrounding retroperitoneal structures.
 

Patients may be concerned about the effect of removing kidney tissue on kidney function. Reassuringly, one study estimated that, in transplant patients, the loss of GFR due to biopsy is 0.77 ml/min.

The main complications of kidney biopsy are related to bleeding: hematoma formation (11%); bleeding requiring transfusion (1.6%); pain (4.3%); macroscopic hematuria (3.5%); and, rarely, death (0.06%). Candidates with hypertension, elevated creatinine, thrombocytopenia, anemia, or a requirement for early resumption of anticoagulation are at increased risk of major bleeding.

If this cannot be corrected before biopsy and biopsy is essential, monitoring after closure is recommended, and additional risks should be discussed with the patient.

After the procedure, patients should be monitored for 6-8 hours while higher-risk candidates should be admitted overnight. Postbiopsy hematuria requires hospitalization to obtain intravenous access and evaluate the complete blood count.

Computed tomography angiography may be necessary to identify active bleeding sites amenable to endovascular intervention.

It is important to note that histological specimens do not always provide a definitive answer and findings must be interpreted in the context of history and other research.

Accurate diagnosis and prognosis can be affected by sampling error, especially in focal pathologies, or when too few glomeruli have been captured. Histological findings are not always specific; For example, institial fibrosis and tubular atrophy are more signs of chronic damage than diagnostic.

Renal biopsy is a key tool in the evaluation of both acute kidney injury, chronic kidney disease, and established intrinsic kidney disease, to guide management strategies and confirm the diagnosis.

It is a procedure that is not free of risks , so it is essential that preliminary studies be carried out before performing it to guide differential diagnoses and referral to secondary care, and allow pre-renal and post-renal causes to be excluded.

Although important, kidney biopsy should not delay treatment when the diagnosis is established from other investigations.