Renal Biopsy: Indications and Evaluation
David I. Weiner
Craig C. Tisher
Byron P. Croker
This chapter discusses the indications for performing a renal biopsy, describes the procedure and methods of tissue preparation, and demonstrates the manner in which biopsy specimens are interpreted using a combination of light microscopy, electron microscopy, and immunohistologic microscopy. The technique of percutaneous renal biopsy was introduced clinically in the early 1950s. Iversen and Brun1 are generally credited with describing its initial use. They believed the technique would be quite useful in obtaining more information about diseases that caused acute kidney injury. At that time, the diseases were referred to as lower nephron nephrosis. The renal biopsy technique was used with increasing frequency during the 1950s, and it has enjoyed wide usage throughout the world since the early 1960s. The technique has provided a wealth of information about the histopathology, pathogenesis, and classification of renal disease that could not have been obtained by any other means.
Proponents of the biopsy procedure employ this technique to diagnose kidney disease, to assess prognosis, to monitor disease progress, and to aid in the selection of a rational approach to therapy. It is used extensively both in younger2,3,4,5,6,7 and older patients.8,9,10,11,12,13,14 However, the procedure is not without morbidity and, occasionally, mortality. Therefore, the risk/benefit ratio must be considered carefully in each patient who is being evaluated for a biopsy.
As originally described, the biopsy was performed with the patient in the sitting position, and the procedure involved aspiration of the tissue sample. Brun and Raaschou15 used the Iversen-Rohlm cannula and syringe, which yielded a cylinder of tissue approximately 1.5 mm in diameter and of variable length. Kark and Muehrcke16 chose to place the patient in the prone position and initiated the use of the Franklin modification of the Vim-Silverman cutting needle (Popper & Sons, Inc., New Hyde Park, NY) in place of the aspiration technique. Today, most nephrologists position the patient in the prone position and use a spring-loaded, semiautomatic biopsy device. The use of either ultrasonography (US) or computed tomography (CT) to locate the kidneys and to aid in positioning the biopsy needle has greatly simplified the technique and improved its safety.
Adequate tissue samples are obtained in greater than 95% of procedures. In a retrospective study, Bolton and Vaughn17 reported that renal tissue was obtained in 97% of their patients with the use of image-amplification fluoroscopy, compared with 81% without the use of fluoroscopy. Percutaneous renal biopsies performed with renal imaging using either US or CT were successful in ˜98% of patients in several series.18,19,20,21
The percutaneous renal biopsy is a safe and reliable technique in the hands of the experienced operator. The most common complication is bleeding, which occurs in the majority of patients if they are studied carefully after biopsy using ultrasonography22 or CT.23,24 However, the bleeding is self-limited and rarely requires an operative intervention or a blood transfusion. In a survey25 of the results of over 5,500 percutaneous renal biopsies, the rate of complications, including the need for a blood transfusion or a nephrectomy, the puncture of other organs, or the presence of a clinically evident perinephric hematoma, was 2.1%. The overall mortality is approximately 0.1% to 0.2%,25,26,27 which is comparable to that reported for percutaneous liver biopsy or coronary angiography.25 In a study from a single institution28 in which 1,000 consecutive percutaneous renal biopsies were analyzed, a total of 94 complications were observed in 81 patients. Gross hematuria, including the passage of blood clots, represented 73% of the complications. Two patients underwent exploration for the evacuation of perirenal hematomas, but no kidneys were lost. One patient died of multiple complications after biopsy.
Multiple factors are associated with an increased risk of complications from the renal biopsy procedure. In one study, the presence of a serum creatinine of at least 5.0 mg per deciliter was associated with a 2.3-fold increase in the risk of a complication.29 Other studies have identified uncontrolled hypertension, thrombocytopenia, and anemia as predictors of increased risk for complications.30,31,32 The simultaneous presence of both hepatitis C and HIV infection is associated with as much as a 5.7-fold increase in complications,31 but the presence of amyloidosis or monoclonal gammopathy is not.33,34
The timing of postprocedure complications has important implications regarding how long patients should be observed prior to discharge. Most studies have shown that the great majority of complications can be identified in the initial 6 to 8 hours after the procedure,32,35 suggesting that a renal biopsy can be performed safely as an outpatient procedure. However, some studies report that as many as 33% of complications are not identified after 8 hours of observation.29 Screening tests such as the presence or absence of a postprocedure perirenal hematoma may be helpful in assessing the risk of a clinically significant complication.36,37
TECHNIQUES
Prior to an elective renal biopsy, it is important to screen the patient for the presence of bleeding disorders. A careful history should be obtained to determine whether abnormal bleeding occurred during previous surgical procedures. A history of severe menorrhagia, if female, and other evidence of abnormal bleeding, as well as a family history of bleeding disorders should be sought. Screening laboratory studies may include an assessment of the platelet count and bleeding time. In addition, it is advisable to obtain the hematocrit and hemoglobin levels within 24 hours prior to the procedure. Renal imaging, typically by ultrasonography, should be performed prior to a biopsy to assess for the presence of anatomic abnormalities, including solitary kidney, horseshoe kidney, hydronephrosis, small kidneys, or other anatomically abnormal kidneys, which may adversely affect the risk of a renal biopsy. Currently, most percutaneous biopsies are performed with the guidance of US or CT to permit an accurate localization of the kidney. The use of a premedication, such as midazolam (Versed), to help alleviate patient anxiety may make the procedure less unpleasant for the patient. We routinely place an intravenous access in the patient.
Most operators prefer to biopsy the lower pole of the left kidney to reduce the risk of inadvertently passing the biopsy needle through a major renal artery or vein. After the completion of the biopsy, patients are instructed to remain at bed rest for 6 to 8 hours. In our institution, we screen with US or CT in the immediate postprocedure period for the presence or absence of a perirenal hematoma and its size, if present. We assess the blood pressure and pulse every 15 minutes for 1 hour, every 30 minutes for 1 hour, then hourly for the next 4 to 6 hours. The patient is asked to save an aliquot of each voided urine in a separate clear plastic specimen jar labeled with the date and time, which is kept at the patient’s bedside for inspection. This provides a visual check for evidence of bleeding into the intrarenal collecting system. The hemoglobin and hematocrit are determined 6 to 8 hours after the biopsy, or earlier if hemodynamic instability or gross hematuria is observed. If the hemoglobin and hematocrit are stable, the patient is relatively pain free and there is no hemodynamic instability or gross hematuria, we discharge the patient home with instructions to call immediately should there be a change in his or her clinical condition. If the patient does not meet these criteria, we admit the patient overnight for further observation.
An outpatient renal biopsy, as described in the previous paragraph, is a component of an ongoing trend to identify approaches to optimize the use of health care resources. An ample amount of literature demonstrates the safety of this approach in both native and transplanted kidney biopsies in both children and adults.38,39,40 Ultrasonographic evidence suggests that most episodes of major bleeding occur within the initial 6 hours after a renal biopsy and that the size of perirenal hematomas actually decreases thereafter.39 These data confirm an earlier report by Carvajal et al.2 who found only three significant bleeding episodes in 890 consecutive percutaneous biopsies performed in pediatric patients. These data, when linked with the experience in the outpatient setting thus far, suggest that in carefully selected patients in whom the procedure is performed without difficulty, the use of ambulatory percutaneous renal biopsy can be justified. If patients are free of pain at the site of biopsy, have clear urine, and have stable cardiovascular signs for a minimum of 4 to 6 hours after the procedure, they can be safely discharged.40 Activity should be restricted for at least 24 hours, and patients should be cautioned to seek medical attention immediately if there is macroscopic hematuria or pain over the biopsy site.
Several types of spring-loaded automatic or semiautomatic biopsy guns are employed to perform percutaneous biopsies of both transplanted21,39,40,41,42,43,44,45,46,47,48,49,50 and native kidneys.21,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63 Based on a sample of almost 2,000 percutaneous biopsy procedures, the rate of complications, including a clinically evident hematoma, nephrectomy, blood transfusion, acute urinary tract obstruction, or biopsy of another organ, was 1%. Adequate samples of tissue were obtained 94% of the time on the initial attempt at biopsy. These data compare very favorably with the published experience with either the Franklin modification of the Vim-Silverman needle or the Travenol Tru-Cut disposable needle (Travenol Laboratories, Deerfield, IL).17,25 Furthermore, when direct comparisons have been made, the results obtained with the biopsy gun were easily comparable to those achieved with the Travenol disposable needle.44,48,54,55,60,61 In another study,21 1,090 percutaneous kidney biopsies were performed using US guidance and an automated spring-loaded biopsy device. A total of 114 (10.4%) were performed on renal allografts and 976 (89.6%) were performed on orthotopic kidneys. No serious complications, including the loss of kidney, lifethreatening hemorrhage, or a persisting hemodynamically relevant arteriovenous (AV) fistula, were encountered. In 98.8% of the patients, sufficient tissue was obtained to make a reliable histopathologic diagnosis.
When combined with real-time US technology, there are several advantages to using the fully automatic biopsy guns. For example, the depth of the biopsy is controlled precisely and can be selected for a particular clinical situation. In the case of one of the most commonly used instruments
(Biopty, Bard Urological Division, C.R. Bard, Covington, GA), the long-throw device has a depth of 2.3 cm, yielding a specimen with a potential length of up to 1.7 cm. The shortthrow device has a depth of 1.15 cm and a potential specimen length of 0.9 cm.64 Fully automatic biopsy guns can be triggered with one hand, thus leaving the operator with a free hand to control the US probe if necessary. Instruction in the use of the biopsy gun is also easier. Many also believe that there is less discomfort with use of the biopsy gun.21,53,54,60 Some studies have found decreased bleeding with automated biopsy devices,65 whereas others have not.60 The use of automated renal biopsy devices has almost completely replaced the use of manual devices.
(Biopty, Bard Urological Division, C.R. Bard, Covington, GA), the long-throw device has a depth of 2.3 cm, yielding a specimen with a potential length of up to 1.7 cm. The shortthrow device has a depth of 1.15 cm and a potential specimen length of 0.9 cm.64 Fully automatic biopsy guns can be triggered with one hand, thus leaving the operator with a free hand to control the US probe if necessary. Instruction in the use of the biopsy gun is also easier. Many also believe that there is less discomfort with use of the biopsy gun.21,53,54,60 Some studies have found decreased bleeding with automated biopsy devices,65 whereas others have not.60 The use of automated renal biopsy devices has almost completely replaced the use of manual devices.
Currently, there is no universal agreement on the optimum size of the needle that should be used with the various biopsy guns. Many favor the 18-gauge needle, which retrieves almost as many glomeruli per specimen as larger gauge needles.41,42,43,44,45,46,47,48,49,50,51,52,53,54 This is due, in part, to the fact that the individual specimens have cleaner, sharper edges with less crush artifact. Certainly, in pediatric patients, the 18-gauge needle has been found to be quite adequate.49,50,52,63 We favor use of a 15- or 16-gauge needle for biopsies in adult patients.
An alternative technique for performing the renal biopsy involves the transjugular approach. In this technique, a guide wire is inserted through the right internal jugular vein, through the vena cava, into the right renal vein, and is then wedged into the lower pole of the right kidney. A transvenous biopsy needle, similar to those used for transjugular hepatic biopsies, is then inserted over the guide wire, advanced into the kidney, and samples are taken. The first description of the procedure is generally attributed to Mal et al.,66 who reported its use in 50 consecutive patients. All were patients in whom conventional percutaneous renal biopsy was felt to be clinically contraindicated, because of a need for simultaneous hepatic and renal biopsies, severe clotting disorders, respiratory insufficiency, uncontrolled hypertension, morbid obesity, or a solitary kidney. Renal tissue was obtained in 88% of patients, and glomeruli were present in 76% of the samples. Since this initial description, the procedure has become available and is used in a large number of centers. Typically, because of the increased technical difficulty and the cost of the procedure, the transjugular renal biopsy is reserved for patients with contraindications to a percutaneous renal biopsy. Subsequent studies that followed this initial report have confirmed its usefulness in patients in whom a conventional percutaneous approach is contraindicated. In general, adequate tissue is obtained in 85% to 95% of procedures.67,68,69,70,71,72 The reported complications include capsular perforation, collecting system puncture, hematuria or loin pain, sufficient bleeding that blood transfusion is necessary, and hypovolemic hemorrhagic shock.67,68,69,70,71,73,74 Because of the risk of postprocedure complications, most patients should be observed overnight after the procedure. The presence of an underlying clotting disorder is associated with an increased risk of complications,74 but morbid obesity is not.70 Thus, the transjugular renal biopsy provides an approach to the renal biopsy in patients in whom a conventional percutaneous approach is contraindicated. The risk of complications, although not inconsequential, is generally considered acceptable if the result of a renal biopsy is important in the patient’s management.
Because decreased glomerular filtration rate can lead to platelet dysfunction, which may increase the risk of bleeding, efforts have been made to determine whether specific prebiopsy testing can decrease the risk of clinically significant postrenal biopsy bleeding. Traditional coagulation tests, such as partial thromboplastin time (PTT), prothrombin time (PT), and the International Normalized Ratio (INR), assess coagulation factor-mediated clotting, which is not altered with renal disease. Therefore, such tests are not good predictors of bleeding after a renal biopsy. The bleeding time, sometimes termed the template bleeding time, is more specific for assessing platelet function. Many authors feel that the bleeding time should be a routine component of the pretransplant evaluation,75,76 whereas others disagree and have instead suggested that failing to measure the bleeding time does not expose the patient to an increased risk of bleeding.77 Our personal practice is to assess the bleeding time, particularly in individuals with an increased blood urea nitrogen (BUN), in whom the risk of uremic platelet dysfunction is greater.
There are a number of treatment options in patients with uremic platelet dysfunction. Desmopressin (deamino-8-Darginine vasopressin) rapidly decreases the bleeding time in patients with uremic platelet dysfunction,78 and can be used to treat patients with a prolonged bleeding time.75 A recent prospective, randomized clinical trial suggested that the routine use of desmopressin in patients with a serum creatinine less than 1.6 mg per deciliter and normal coagulation parameters, irrespective of bleeding time, decreases both the likelihood of postbiopsy bleeding (treated, 13.7% versus control, 30.5%) and, in those with bleeding, decreases both the size of the hematoma and the duration of hospital stay.79 Although very intriguing, it is our current belief that confirmatory studies are necessary before adopting routine desmopressin treatment for all renal biopsies. Uremic platelet dysfunction can also be treated either with renal replacement therapy, such as hemodialysis,80 or with oral estrogen therapy.81,82 These alternative therapies take longer to improve the bleeding time than is required for desmopressin, and therefore are not routinely used.
INDICATIONS
There is no universal agreement on the precise indications for use of the percutaneous renal biopsy despite almost 60 years of experience with the technique by the nephrology community. The present section describes several clinical situations in which this technique is either routinely or frequently employed to aid in the evaluation and management of a patient with undiagnosed kidney disease.
Acute Kidney Injury
There are many occasions when the etiology of acute kidney injury secondary to intrinsic renal disease is not evident despite a carefully performed history and physical examination and the availability of information gained from various laboratory studies. A biopsy can be very useful in establishing the diagnosis, determining the approach to management, and defining the prognosis in this clinical setting. Retrospective studies from several centers have revealed that the diagnosis of acute tubular necrosis (ATN) cannot be established clinically76,83,84,85 in 10% to 25% of patients who present with acute kidney injury. A biopsy in this population can be important because other causes of acute kidney injury are revealed, such as crescentic proliferative glomerulonephritis, interstitial nephritis, Wegener granulomatosis, polyarteritis nodosa, multiple myeloma, amyloidosis, endocapillary proliferative glomerulonephritis, cortical necrosis, hemolytic-uremic syndrome (HUS), systemic lupus erythematosus (SLE), and thrombotic thrombocytopenic purpura, to list just a few. These diseases usually require an approach to management that is different than that normally employed in uncomplicated cases of ATN.
Occasionally, a biopsy can provide helpful clinical information in patients who appear to have ATN on clinical grounds at initial presentation, but who do not regain renal function after 2 to 3 weeks of supportive therapy, including dialysis. The diagnostic possibilities generally are the same as those listed in the preceding paragraph. A careful evaluation of the clinical situation is deemed prudent before a renal biopsy is initiated because this procedure carries a higher risk in the patient with acute uremia.86
Nephrotic Syndrome
A renal biopsy in the clinical setting of an acute nephrotic syndrome not associated with systemic disease is influenced greatly by the age of the patient. It is common practice to treat children initially with high-dose corticosteroids, because most younger children have minimal change nephrotic syndrome (MCNS) on a biopsy. The presence of a selective proteinuria and normal renal function and the absence of hypertension strengthen the clinical diagnosis. In children, a biopsy is usually reserved for patients with no response to corticosteroid therapy or in whom the clinical and laboratory features of the illness at the time of initial presentation are distinctly atypical for MCNS. These features would include hypertension, azotemia in the absence of volume depletion, nonselective proteinuria, a highly active urine sediment including red cell casts, and involvement of other organ systems.
Most nephrologists believe that the adult nephrotic patient without signs of systemic disease should undergo a biopsy before therapy is initiated because the majority of these patients, including elderly persons,87 have a renal disease other than MCNS.10 The most frequent cause of the nephrotic syndrome in adults is idiopathic membranous glomerulonephritis10,88; other frequent causes include focal segmental glomerular sclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), proliferative glomerulonephritis, immunoglobulin A (IgA) nephropathy, and amyloidosis. Because the optimal treatment differs in different conditions, a renal biopsy can provide helpful clinical information. Moreover, fewer than one-third of adult patients have MCNS. Thus, if the physician elects to administer a short course of high-dose corticosteroid therapy equivalent to that employed in pediatric patients, approximately two-thirds of the patients would not be expected to respond favorably. Despite suggestions to the contrary,25 we believe the risks associated with the use of corticosteroids or other immunosuppressive agents, such as azathioprine, chlorambucil, cyclosporine A, mycophenolate mofetil, and cyclophosphamide, in this population are too great to justify their use in the absence of a specific histologic diagnosis.
Isolated Proteinuria
Isolated nonnephrotic proteinuria of 1 g or less per 24 hours without hematuria or pyuria in an otherwise asymptomatic patient who does not have diabetes mellitus is a relatively common clinical problem. Often, the proteinuria is first detected during a routine physical examination required for participation in school athletics, during a preemployment examination, or at the time of application for life insurance. In young adults, orthostatic proteinuria is commonly identified in this presentation, carries a benign prognosis, and does not require a renal biopsy89 Otherwise, unless the patient requests a kidney biopsy for purposes of reassurance, it is currently our policy to merely monitor the clinical course of such patients at periodic intervals of 6 months to 1 year. There is little evidence to suggest that these patients will progress to renal failure or that they are candidates for any type of specific medical therapy in the absence of impaired renal function.90 If there is any evidence during follow-up of functional deterioration or the development of additional clinical signs or symptoms suggesting the presence of a primary renal disease or kidney involvement secondary to systemic disease, the patient is thoroughly reevaluated and is often advised to undergo a kidney biopsy for diagnosis and possible therapeutic intervention.
In asymptomatic patients who do not have diabetes mellitus and who remain nonnephrotic but persistently excrete more than 1 g of protein per 24 hours, we advise a renal biopsy. It is this group of patients who are more likely to have an underlying renal abnormality. Some of the more common diagnostic possibilities include early idiopathic membranous glomerulonephritis, FSGS, and IgA nephropathy. Patients with urinary abnormalities such as hyaline and granular casts are even more likely to have an underlying glomerular abnormality91
Hematuria with or without Proteinuria
Asymptomatic hematuria, especially in children and young adults, is a frequent cause of referral to nephrologists. It is important that causes of hematuria due to neoplasms in either
the upper or lower collecting system or due to either cystitis or pyelonephritis be excluded before one considers a renal biopsy. In general, the diagnostic value of a renal biopsy in the setting of idiopathic microscopic hematuria relates directly to the extent of associated clinical and laboratory findings. For example, in a series of 76 pediatric patients with isolated hematuria, Trachtman et al.92 found that almost three-quarters of all biopsy specimens obtained in patients who had either a first-degree relative with hematuria or a history of at least one episode of gross hematuria were abnormal histologically IgA nephropathy and Alport syndrome were the two most common findings. Schröder et al.93 performed renal biopsies in 65 children with isolated hematuria of at least a 1-year duration. Of the group, 95% had histologic abnormalities that included IgA nephropathy (16 patients), Alport syndrome (8 patients), thin glomerular basement membrane (33 patients), and nonspecific mesangial abnormalities (5 patients). In a later report, Topham et al.94 evaluated 165 children and adults with isolated hematuria using cystourethroscopy and renal biopsy. All had a normal intravenous pyelogram, were normotensive with a normal serum creatinine, and were free of both proteinuria and a urinary tract infection. In this group, 47% had significant histologic findings, including IgA nephropathy in 49 patients, whereas only 5 abnormalities were identified on a cystourethroscopy. Renal biopsy abnormalities were most common among patients under 20 years of age (69%), prompting these investigators to conclude that a renal biopsy should replace a cystoscopy in younger patients as the next step in evaluation if renal imaging yielded normal results. Furthermore, because renal histologic abnormalities are quite frequent in the clinical setting of isolated hematuria, these investigators recommended a kidney biopsy in patients over 45 years of age in whom findings at renal imaging and cystoscopy are normal.
the upper or lower collecting system or due to either cystitis or pyelonephritis be excluded before one considers a renal biopsy. In general, the diagnostic value of a renal biopsy in the setting of idiopathic microscopic hematuria relates directly to the extent of associated clinical and laboratory findings. For example, in a series of 76 pediatric patients with isolated hematuria, Trachtman et al.92 found that almost three-quarters of all biopsy specimens obtained in patients who had either a first-degree relative with hematuria or a history of at least one episode of gross hematuria were abnormal histologically IgA nephropathy and Alport syndrome were the two most common findings. Schröder et al.93 performed renal biopsies in 65 children with isolated hematuria of at least a 1-year duration. Of the group, 95% had histologic abnormalities that included IgA nephropathy (16 patients), Alport syndrome (8 patients), thin glomerular basement membrane (33 patients), and nonspecific mesangial abnormalities (5 patients). In a later report, Topham et al.94 evaluated 165 children and adults with isolated hematuria using cystourethroscopy and renal biopsy. All had a normal intravenous pyelogram, were normotensive with a normal serum creatinine, and were free of both proteinuria and a urinary tract infection. In this group, 47% had significant histologic findings, including IgA nephropathy in 49 patients, whereas only 5 abnormalities were identified on a cystourethroscopy. Renal biopsy abnormalities were most common among patients under 20 years of age (69%), prompting these investigators to conclude that a renal biopsy should replace a cystoscopy in younger patients as the next step in evaluation if renal imaging yielded normal results. Furthermore, because renal histologic abnormalities are quite frequent in the clinical setting of isolated hematuria, these investigators recommended a kidney biopsy in patients over 45 years of age in whom findings at renal imaging and cystoscopy are normal.
The likelihood of identifying significant glomerular pathology is considerably higher when hematuria is accompanied by proteinuria, with or without an abnormal urine sediment that includes red blood cell, granular, hyaline, or white blood cell casts. We believe it is important to establish the histologic diagnosis of the renal lesion in this clinical setting; although admittedly, a biopsy is not required to identify the source of hematuria. Primary renal diseases that can be seen include IgA nephropathy, acute or resolving postinfectious glomerulonephritis, MPGN, and an occasional example of interstitial nephritis. Heredofamilial and multisystem diseases that may be seen include Fabry disease, sickle cell trait and disease, polyarteritis nodosa, Wegener granulomatosis, diabetes mellitus, SLE, and Henoch-Schönlein disease. Many of these systemic diseases may be evident on clinical grounds if a careful prebiopsy evaluation is undertaken, as discussed in the next section.
Systemic Disease
There are many systemic diseases that involve the kidney, although the extent and frequency of involvement varies considerably in different conditions. Patients often undergo a renal biopsy for diagnosis and management on the basis of either the frequency or severity of the renal lesion. These diseases include SLE, Henoch-Schönlein purpura, polyarteritis nodosa, Goodpasture syndrome, Wegener granulomatosis, and various gammopathies.
In approximately 40% to 50% of all patients with type I insulin-requiring diabetes mellitus and comparable percentages with type II adult-onset diabetes mellitus, renal failure develops during the course of the disease.95,96 The natural history of renal disease in both types of diabetes mellitus has been well studied and is reasonably predictable96; thus, in most patients, a renal biopsy is seldom indicated for a diagnosis or management. However, a biopsy can be helpful in patients whose course may be complicated by the sudden development of renal failure, proteinuria, or nephrotic syndrome, or who have serologic evidence of other causes of renal disease.
Although nephrotic syndrome is observed in approximately 10% of all patients with diabetes, its sudden appearance, especially in the young diabetic without previous evidence of functional renal impairment, should not be ascribed automatically to diabetic nephropathy. This point is well illustrated by the experience of Urizar et al.97 who described five young diabetic patients with nephrotic syndrome in whom the renal disease was not distinguishable histologically from MCNS. Nephrotic syndrome appeared either simultaneously or shortly after the recognized onset of diabetes in three of the children. Treatment with corticosteroids in four patients resulted in a prompt response, with loss of edema, cessation of proteinuria, and normalization of all serum abnormalities. No patient had abnormalities suggestive of diabetic nephropathy. Other investigators have reported similar experiences.98,99
Other types of renal disease also can be seen in association with diabetes mellitus, often in the clinical setting of the nephrotic syndrome. Couser et al.100 reported the coexistence of dense deposits within the glomerular and tubular basement membranes, resembling those seen in type 2 MPGN and lesions typical of diabetic nephropathy in a 24-year-old nephrotic man with type I diabetes mellitus. Other examples of well recognized renal diseases that have been reported to occur in patients with diabetes mellitus in either the presence or absence of diabetic nephropathy include acute postinfectious proliferative glomerulonephritis,101,102 crescentic proliferative glomerulonephritis,101 and membranous glomerulonephritis.103,104,105
The renal biopsy is central to the management of SLE with renal involvement (i.e., lupus nephritis). At present, it is our practice to biopsy all patients who present with clinical evidence of active lupus nephritis unless a medical contraindication exists. Border106 has suggested that patients with more than six red blood cells (RBCs)/high-power field, a urine protein excretion greater than 200 mg per 24 hours, or an abnormal serum creatinine value are candidates for a biopsy. There is no other way to establish the type of renal lesion that is present, and the management of lupus nephritis varies considerably depending on the specific histologic lesion.
The value of renal biopsy in predicting a prognosis has been debated. The results of earlier studies suggested that the biopsy classification of lupus nephritis was useful in predicting the clinical course107,108 and this issue was challenged109,110,111 from a prognostic standpoint but reaffirmed subsequently.112,113,114,115,116 Correspondingly, we believe it is important to establish as precise a histologic diagnosis as possible because, in general, patients with diffuse proliferative lupus nephritis with signs of disease activity, such as increased cellularity, segmental necrosis, fibrinoid deposits, and crescents in the glomeruli, have a poorer prognosis than individuals with mesangiopathic, focal proliferative, or membranous lupus nephritis.
Controversy also exists concerning the value of renal biopsy in patients with clinically silent lupus nephritis. In 1977, Mahajan et al.117 described 12 patients with diffuse lupus nephritis but without clinical or laboratory evidence of renal involvement at the time of renal biopsy. A later report, in which 10 of the original 12 patients were followed from 5 to 11 years, revealed deterioration of renal function in 3 years, with one death as the result of renal failure.118 All patients received prednisone alone or in combination with azathioprine. These investigators concluded that the prognosis for the preservation of renal function appeared better in patients with clinically silent diffuse proliferative nephropathy as opposed to those with clinically active disease, and recommended a biopsy in patients with SLE even in the absence of overt clinical renal involvement.118 Woolf et al.119 described eight patients ranging in age from 6 to 26 years, with clinically silent lupus nephritis, who on biopsy had a variety of histologic lesions indicative of active renal involvement. Although no consensus exists regarding the use of a renal biopsy in patients with SLE who are without clinical evidence of renal involvement, it is currently our policy to withhold a biopsy in this group of patients.
Renal biopsy can often aid the clinician in selecting an appropriate therapy for the treatment of vasculitis when renal involvement is present. Polyarteritis nodosa and Wegener granulomatosis require aggressive combination therapy with cyclophosphamide and prednisone. The prognostic value of crescents in antiglomerular basement membrane (GBM) disease and other conditions is discussed in later paragraphs. Other systemic diseases that often exhibit renal involvement and, therefore, can be diagnosed with the aid of a renal biopsy when other diagnostic tests have failed or have not been employed include multiple myelomas, kappa light-chain disease,120 amyloidosis,121 fibrillary glomerulonephritis, and mixed cryoglobulinemia with renal failure.85,122
Transplant Kidney
Renal biopsies are a valuable diagnostic tool in the management of the transplant recipient. A biopsy of an allograft represents the major clinical exception to avoidance of a percutaneous biopsy of a single functioning kidney. Numerous studies confirm the value and relative safety of a renal biopsy in this setting.41,42,43,44,45,46,47,48,123,124 A biopsy is the most accurate means of determining the presence of lesions, such as cellular or humoral rejection, ATN, drug-induced or viral (especially BK virus) interstitial nephritis, hemorrhagic infarction, calcineurin inhibitor toxicity, and de novo or recurrent glomerulonephritis in the allograft. There are several clinical settings in which a biopsy of the allograft is often indicated. These include failure of the graft to function within the initial 7 to 10 days after surgery, a rapid deterioration in function of unknown etiology after the initial good function, an absence of a response to an adequate antirejection therapy within a reasonable period of time, and an unexplained nephrotic syndrome or nephrotic-range proteinuria.
A large number of cadaveric kidneys are engrafted, and ischemia-reperfusion injury is a frequent complication. Failure to achieve improved renal function within 7 to 10 days after surgery raises the possibility of a more severe form of renal injury, such as an infarction or a superimposed episode of acute rejection. A biopsy is often invaluable in determining the etiology of the renal failure, in guiding subsequent therapy, and in establishing a prognosis. For example, Kiaer et al.125 reported a 100% graft loss when infarction, capillary thrombosis, and arterial or arteriolar thrombosis were found either singly or in combination on a biopsy. Thus, the presence of these lesions in the clinical setting of an acute kidney injury would obviate the necessity for the continued use of antirejection therapy.
The incidence of acute rejection, characterized by a sudden decrease in renal function, is greatest during the first 6 months after transplantation. In most instances, the suspicion of acute rejection can be made on clinical grounds. However, acute rejection often occurs in the absence of clinical features, such as graft tenderness or fever, and a patient believed to have acute rejection may not respond to a reasonable course of antirejection therapy. It may be desired to tailor the antirejection therapy to vascular versus tubulointerstitial rejection or antibody versus cellular rejection. A biopsy can be extremely helpful at this juncture in the patient’s therapy. In particular, the presence of peritubular C4d deposition suggests the presence of acute humoral rejection, whereas its absence is typical in cell-mediated rejection.126,127 A confirmation of acute humoral rejection involves the demonstration of morphologic evidence of acute tissue injury in combination with circulating antibodies to either donor human leukocyte antigen (HLA) or to other antidonor endothelial antigens.128 Other complications, such as ATN, drug-induced nephrotoxicity, or overt renal infarction may be diagnosed.
As noted previously, C4d staining of biopsies has been a valuable tool. C4d is produced by the activation of the classic and lectin complement pathways. Thus, ischemia reperfusion (I/R), necrosis, lupus nephritis, and other conditions may exhibit C4d staining and must be considered in a biopsy interpretation.129,130,131,132,133 Current guidelines recommend the exclusion of loci of I/R, necrosis, and fibrosis when using C4d staining to evaluate for possible humoral rejection.128,134,135
The occurrence of the nephrotic syndrome or nephrotic-range proteinuria in a transplant recipient suggests the possibility of either recurrent or de novo glomerulonephritis.136,137 Those forms of disease that are most likely to recur in the transplant kidney include MPGN, FSGS, diabetic nephropathy, and IgA nephropathy.136,137 To date, the most common de novo disease reported is membranous glomerulonephritis.136 Although some would take exception, we believe it is worthwhile to establish the lesion that is responsible for proteinuria, especially if the proteinuria is associated with a decrease in renal function.
Renal Mass or Neoplasm
In addition to a percutaneous kidney biopsy for traditional medical indications, as introduced previously, the past decade has seen renewed interest in percutaneous (core) biopsies for renal masses and other neoplasms. The technique fell into disfavor in previous decades because of bleeding, false-negative results, and other less common complications.138 Regardless, there is a driving force for tissue diagnosis because 50% of renal neoplasms are now identified as incidental to abnormal imaging for other reasons. A percutaneous renal mass biopsy is often performed to evaluate for a possible lymphoma, a renal abscess, or metastatic disease due to a known extrarenal malignancy. It may also be performed to confirm the diagnosis of a primary renal neoplasm in a patient with known disseminated disease or an unresectable retroperitoneal tumor in whom surgical treatment is contraindicated.138,139,140,141,142,143,144 Although there was initial concern regarding the potential for seeding the biopsy tract with malignant cells, only a total of six cases have been reported, and multiple case series published since 1999 have reported no such events.145
CONTRAINDICATIONS
Both the relative and the absolute contraindications for a renal biopsy vary among nephrologists. However, most agree that the risk of complications increases in the presence of severe uncontrolled hypertension, sepsis, known or suspected renal parenchymal infection, a hemorrhagic diathesis, a solitary ectopic or horseshoe kidney (except in the case of a transplanted kidney), or when the patient is unable to cooperate during the procedure.
In 1958, Kark et al.146 published the results from their initial 500 percutaneous renal biopsies and listed 11 contraindications. These included an uncooperative patient, large cysts, a renal neoplasm, a renal artery aneurysm, marked calcific arteriosclerosis, a hemorrhagic diathesis, a single kidney, a perinephric abscess, hydronephrosis or pyonephrosis, a terminal state of illness, and a rising blood nonprotein nitrogen level greater than 100 mg per deciliter. Hypertension was viewed as a relative contraindication, depending on the importance of the biopsy and the skill of the operator.
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