Con: Kidney biopsy: an irreplaceable tool for patient management in nephrology

It is ironic that this defense of renal biopsy as a vital clinical tool in the management of kidney disease is being written so soon after the death of Claus Brun (at age 100 years) [1]. Professor Brun is rightly credited (along with his close associate in Copenhagen, Professor Poul Iverson) with the introduction of percutaneous biopsy of the kidney into clinical medicine in 1951, more than six decades ago [2]. Early adopters of the technique, especially Robert Kark, Robert Muehrcke and Conrad Pirani in the USA [3], made major contributions to establishing its clinical value. While the technique of kidney biopsy has evolved (position used, localization method, needles employed, performance site, training of proceduralists) over the intervening years, its value in diagnosis, prognosis and therapeutic decision-making has increased enormously [4, 5]. This evolution has been aided especially by the appearance of new methods of analyzing the tissue obtained (such as immunofluorescence [6] and electron microscopy [7])—a process which continues even in the present time, as exemplified by such techniques as laser-capture mass spectrometry [8] and transcriptomic analysis [9] of renal tissue. Advances in treatment modalities for many renal diseases have only heightened the value of kidney biopsy, especially in the field of glomerular diseases. The discipline of renal pathology, originally dependent on the autopsy, has now blossomed into a vibrant branch of knowledge, with its own set of standards and many artful practitioners [4, 5, 10]. Who knows how many renal biopsies have been performed throughout the world since the epoch-making year of 1951—perhaps millions! Curiosity combined with the renal biopsy procedure has led to the delineation of many new disease entities in the past 50 years or so; such as, IgA nephropathy (IgA N), membranous nephropathy, IgM nephropathy, C1q nephropathy, C3 glomerulopathy, lipoprotein glomerulopathy and thin basement membrane nephropathy, to name a few. Extension of the procedure from biopsy of the native organ to that of the transplanted organ has contributed to a better understanding of allograft rejection and its morphological classification [11]. Systematic reviews and analyses of data gleaned from renal biopsies have generated new disease classifications, having prognostic utility, for native kidney diseases as well. This has occurred most notably in nephrotic syndrome due to focal and segmental glomerulosclerosis [12], lupus nephritis [13], IgA nephropathy [14], vasculitis [15] and diabetes [16]. Although percutaneous kidney biopsy is an invasive procedure, in experienced hands whilst avoiding obvious contra-indications (e.g. an active bleeding disorder), it has proven to be remarkably safe in a broad array of clinical settings and patient ages. In four recent publications involving ∼15 000 biopsies in adults, mortal complications occurred in only one subject (death from post-biopsy bleeding) and major complications developed in ∼2.2% (0.2–6.6%) of subjects (mainly a need for blood transfusion or surgical intervention) [17–20]. It is not easy to quantify the clinical utility of renal biopsy when compared with its research value, but renal biopsies result in a change in diagnosis in ∼60% and an alteration in treatment approach in ∼35% of instances [21]. Unexpected findings can also be found in renal biopsy of diabetic patients presenting with manifestations of kidney disease and in selected patients with acute kidney injury (AKI). However, except in cases suspected of having underlying glomerulonephritis, vasculitis or tubulo-interstitial nephritis renal biopsy is not commonly used to evaluate the cause of AKI. In addition, certain common diseases can only be diagnosed (presently) by kidney biopsy; such as IgA nephropathy, thin basement membrane nephropathy, C3 glomerulopathy as examples. Appropriate planning for treatment and identifying futility of interventions can be greatly aided by renal biopsy in systemic lupus erythematosus (SLE), vasculitis and IgA nephropathy. To be sure, renal biopsy has its limitations. Inadequate sampling of representative renal tissue confounded by errors of identifying focal lesions (such as focal and segmental glomerulosclerosis and crescentic glomerulonephritis), poor availability of necessary evaluation tools like immunofluorescence and electron microscopy on a global scale, excessive inter-observer disagreement on interpretation continue to hamper the utility of renal biopsy. Nevertheless, over more than six decades percutaneous kidney biopsy has transformed from an experimental procedure to an indispensable tool in the diagnostic, prognostic and therapeutic decision-making armamentarium of the clinical nephrologist [4, 5]. But this is history—the real question posed by this Polar Views discussion is embedded in the uncertainties about the future role of renal biopsies in clinical medicine. Specifically, whether new molecular ‘biomarkers’, assayed in serum or urine, will supplant renal biopsy for disease discovery, diagnosis, prognosis or therapeutic decision-making in the near-term (say the next decade). It seems highly unlikely that such a biomarker-catalyzed revolution can ever replace renal biopsy for discovery of new disease entities, as any new, heretofore uncharacterized biomarker signature will have to be morphologically confirmed. Then, the issue is narrowed to the power of ‘biomarker’ technology to provide answers to questions concerning diagnosis, prognosis and treatment of existing disease entities or lesions at a level of precision and reliability that makes renal biopsy redundant or unnecessary. This is not a trivial issue. From the very beginning, renal biopsy has been a ‘snapshot’ tool, incapable of accurately revealing the evolution of a disease in an individual patient except by comparison to a population of clinically similar (but not identical) patients with what is believed to be the same disease. This ‘camera analogy’ deficiency of renal biopsy can be overcome to some extent by repeated renal biopsy (by indication or in a protocolized fashion), such as has been advanced to considerable benefit in the post-kidney transplant period [11] and which is beginning to emerge in management of lupus nephritis [22]. But even with the development of a systematic approach to repeat renal biopsy, there are practical (and safety) limits imposed upon a purely morphological approach to examining the evolution of disease in individual subjects, in order to foster more personalized care of illness. Consensus classification systems based on analysis of real prospective data (such as in the Oxford system for IgA N [14] and the Banff system for allograft rejection [23]) also aid in relating findings in single renal biopsy samples to the course of a disease over time. Can biomarkers be developed and validated to authentically reveal the morphological evolution of disease and thus ultimately replace renal biopsy? This may be feasible in kidney transplants as early work, such as urinary cell mRNA profiles, shows great promise [24]. However, much remains to be done in native kidney disease to prospectively examine the separate or added value of these approaches compared with ‘gold standard’ tissue diagnosis and evaluation by consensus scoring methods. Because of the wide availability of serial renal biopsy samples coupled with a consensus system for evaluation of renal morphology, I suspect that the shift to a biomarker-based standard for evaluation of renal transplants will proceed with greater alacrity than with native kidney disease. Nevertheless, as recurrence of the original disease (e.g. glomerulonephritis, monoclonal gammopathy or diabetic nephropathy) becomes a more important cause of graft failure in the future [25], such a biomarker-based strategy will not likely soon (if ever) completely replace transplant renal biopsy for evaluation of disorders of allograft function. Native kidney disease, especially when it occurs in adults without any obvious cause (e.g. ‘idiopathic’) or in connection with a well-defined but potentially treatable disease (such as SLE or Vasculitis), is considered a valid reason for performance of a kidney biopsy. This is based on the widely perceived incremental value of a morphological evaluation to aid in diagnosis, prognosis and therapeutic decision-making (both usefulness and futility). To what extent will a biomarker-based strategy replace each of these functions of a renal biopsy? For diagnosis, such biomarkers need to be evaluated for sensitivity, specificity, positive and negative predictive value against a ‘gold standard’ renal biopsy interpretation utilizing ‘real-life’ comparisons. It makes no sense at all to evaluate the capacity of a biomarker-based strategy to identify a disease compared with normal subjects but it makes eminent good sense to assess the capacity of a biomarker-based strategy to correctly identify a specific disease among patients with similar clinical manifestations (e.g. distinguishing IgA N from thin basement membrane nephropathy in a patient with hematuria and mild proteinuria or diagnosing membranous nephropathy in a subject with apparently ‘idiopathic’ nephrotic syndrome). In both of these exemplary situations, a biomarker-based diagnostic strategy is already suggested. Studies of galactose-deficient (gd) IgA1 and/or IgG/IgA anti-IgG/IgA auto-antibodies to gdIgA1a in serum of subjects suspected as having IgA N [26, 27] have shown real diagnostic potential but have yet to be examined in ‘real-life’ situations. Furthermore, at present they have levels of sensitivity and specificity lower than that required for confidence in replacing them for a renal biopsy in an individual patient. The value of testing for serum auto-antibody to M-type phospholipase A2 receptor (PLA2R) protein in patients with nephrotic syndrome suspected to have underlying membranous nephropathy has already shown great value as a biomarker as a ‘positive’ test virtually assures the finding of a membranous nephropathy lesion on renal biopsy [28], but additional testing of a renal biopsy specimen is needed to help differentiate primary from a secondary membranous nephropathy lesion, so anti-PLA2R auto-antibody testing alone cannot replace renal biopsy in such patients (except perhaps in patients with some relative contra-indication to biopsy performance, such as solitary kidney or an iatrogenic bleeding disorder). Other serum assays for endogenous proteins (such as serum soluble urokinase plasminogen activator receptor protein; suPAR) as diagnostic tests for specific lesions in patients with nephrotic syndrome, such as minimal change disease or focal and segmental glomerulosclerosis have thus far proven disappointing [29]. Testing of urine or plasma for monoclonal proteins (free light chains, ‘M’ spike on protein electrophoresis or immunofixation) has time-honored utility as biomarkers for diagnosis of the monoclonal immunoglobulin deposition disease [30], but a confirmatory renal biopsy is most often needed to determine the precise type of renal morphology (e.g. amyloid, non-amyloid or mixed patterns). Other biomarkers, such as micro-RNA moieties or clustering of urine or plasma proteomic patterns, have been suggested as candidates for diagnostic testing [31, 32], but none have yet shown test-characteristics compatible as a replacement for renal biopsy. Perhaps multiple biomarker panels will be required to optimize diagnostic accuracy, but this is more ‘hope’ than ‘reality’ at the present time [33]. The use of biomarkers for estimating prognosis or making treatment decisions (value and futility), independent of or as a supplement to renal biopsy findings has a rich history and variable degrees of success. ‘Traditional’ biomarkers, including urine protein (or albumin) excretion rates, serum creatinine levels and estimated glomerular filtration rate (eGFR—calculated by any of several formulas) have been shown to have prognostic value in populations [34], but the applicable thresholds vary widely according to biopsy diagnosis [35] and can show a poor correlation with biopsy findings in individuals suffering from many disease states, including diabetic nephropathy [36]. Examining the specific composition of urine proteins (such as fractional excretion of IgG, Beta-2 microglobulin excretion, or proteomic patterns) as biomarkers of prognosis or treatment responsiveness might be of value, but so far these have been tested mainly in biopsy-proven disease entities only [37]. As stated above, limitations placed on repeated renal biopsy, enhance the potential utility of biomarkers for identifying specific aspects of renal pathology having prognostic and therapeutic importance, such as interstitial fibrosis and tubular atrophy, arteriolar hyalinosis or thrombotic micro-angiopathy [38]. The potential value of these ‘non-traditional’ biomarkers as substitutes for renal biopsy has great appeal but they must withstand close comparison to ‘traditional’ biomarkers using appropriate study design and statistical analysis, including the Net Reclassification Index (NRI) or Relative Integrated Discrimination Index (RIDI), applying decision analytical weighted versions, as stressed by Vickers and Pepe, in a critique of statistical methods for assessing the predictive value of biomarkers [39]. Already, selected immunological biomarkers are showing great promise as adjuncts to but not as replacements for renal biopsy in such diseases as primary membranous nephropathy and IgA N, leading to the possibility of greater accuracy of prognosis and optimization of treatment of these conditions in individual patients [28, 40]. In summary, after more than six decades of ever growing and global use, thousands of publications, broadening applications, refinements in technique, study and interpretation, percutaneous renal biopsy is firmly, and I think irrevocably, embedded in the science and practice of nephrology. In many circumstances, most notably in chronic kidney diseases, it remains as the ‘gold standard’ for morphological diagnosis and classification, for evaluating prognosis and for assisting in rational but often empiric treatment decisions (including futility). By virtue of its invasive nature and due to variations in the obtained tissue sample as a proxy for the kidneys as a whole, renal biopsy has its own unique limitations as a clinical tool. Nevertheless, renal biopsy has amassed a good track record of safety and utility. It seems highly unlikely that the surge in biomarker technology development will lead to abandonment of renal biopsy as a useful clinical (and research) tool. It seems far more likely that such biomarker development will focus on areas where renal biopsy poses serious risks or limitations, such as in longitudinal evaluation of prognosis and response to treatment in biopsy-defined disease. It is also likely that the field of renal pathology, so uniquely dependent upon the renal biopsy procedure itself, will continue to evolve, in particular through the incorporation of refinements in immuno-pathological analysis and characterization of the molecular and genetic pathways involved in tissue injury. Poul Iverson and Claus Brun can be justly proud of their historic contribution to the fields of nephrology and pathology. Their legacy will continue to enjoy wide use in clinical care and research for the foreseeable future, in my opinion. The contents of this paper have not been previously published in whole or in part. (See related article by Mischak. Pro: Urine proteomics as a liquid kidney biopsy: no more kidney punctures! Nephrol Dial Transplant 2015; 30: 532–537; See related article by Floege. Moderator's view: Will ‘modern’ urine proteomics replace ‘old-fashioned’ renal biopsy? Nephrol Dial Transplant 2015; 30: 538–540.) The author greatly appreciates the helpful review and comments for an early draft of this paper by Fernando Fervenza, MD of the Mayo Clinic.