Workshop on the Use of Renal Biopsy in Research on Diabetic Nephropathy: A Summary Report

Workshop on the Use of Renal Biopsy in Research on Diabetic Nephropathy: A Summary Report Richard J. Glassock, MD, Gladys H. Hirschman, MD, and Gary E. Striker, MD INDEX WORDS: Diabetic nephropathy; kidney biopsy; research studies.

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ANY GAPS EXIST in our understanding of the kidney disease that develops as a result oflong-standing diabetes mellitus. The importance of closing these gaps is self-evident, since the magnitude of the problem of progressive renal failure secondary to the kidney disease of diabetes mellitus (KDDM) is now well appreciated. While analysis of kidney function and glomerular perm selectivity has undoubtedly contributed to our ability to detect kidney disease in diabetic patients at earlier stages of evolution, remarkable alterations in kidney structure may occur even in the absence of significant alterations in kidney function. Careful analysis of structural changes, particularly in the earliest phases of the evolution of KDDM, could provide better insights into fundamental pathogenetic mechanisms, lead to a more refined approach to prognosis, and/or facilitate the development of better end-points with which to judge the effectiveness of therapeutic interventions. There are significant differences between insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). Yet, the final structural result appears to be the same in the kidney; namely, diffuse or nodular intercapillary glomerulosclerosis, arteriolonephrosclerosis, chronic interstitial fibrosis, and tubular atrophy. Nevertheless, kidney diseases unrelated to diabetes mellitus can and do occur in patients with diabetes mellitus, particularly NIDDM. Often, renal biopsies are the only means of identifying these kidney diseases in, but not of, diabetes mellitus. Percutaneous renal biopsy is a time-honored approach to the study of kidney disease; yet, current conventional practice has relegated renal biopsy to a rather limited role in the care of patients with diabetes mellitus. Perhaps this is justified from a clinical perspective in patients who present with classical overt signs of diabetic nephropathy in a setting of well-developed extrarenal manifestations of microvascular disease secondary to diabetes mellitus, eg, proliferative retinopathy or other complications of diabetes mellitus, including peripheral neuropathy. However, because of

the great advances in techniques of cell and molecular biology, which can now be applied to the tiny fragments of renal tissue removed by renal biopsy, and because of the limitations of a purely functional approach to the study ofKDDM, there is a need for the evaluation of the possible contributions of renal biopsy to research into the origins and evolution of KDDM. Accordingly, a Workshop to review the role of renal biopsy for future research in diabetic nephropathy was convened on November 7 and 8, 1990, at the National Institutes of Health. The charge to the Workshop was to evaluate the general rationale and to develop guidelines for the use of renal biopsies as a research tool in patients with diabetes mellitus. From these discussions emerged a consensus view that renal biopsies are appropriate and sometimes integral parts of wellplanned investigational studies of patients with diabetes mellitus, even in the absence of overt functional disorders suggesting the presence of KDDM under the following strict conditions: • When renal biopsies are performed by experienced and knowledgeable physicians, in centers with appropriate expertise, and under conFrom the National Institutes o/Diabetes and Digestive and Kidney Diseases, National Institutes o/Health. workshop held in Bethesda, MD, November 7-8, 1990. Program Chairman: Richard J. Glassock. Workshop Participants: Clive O. Callendar, Washington, DC; Russell W. Chesney, Memphis, TN; Daniel Cordonnier, Grenoble, France; William G. Couser, Seattle, WA; Chester M. Edelmann, Jr, Bronx, NY; William L. Freeman, Tuczon, AZ; Richard J. Glassock, Torrance, CA; Gladys H. Hirschman, Bethesda, MD; Michael K. Hise, Baltimore, MD; Harry R. Jacobson, Nashville, TN; Pedro A. Jose, Washington, DC; Saulo Klahr, St Louis, MO; Robert G. Luke, Cincinnati, OH; S. Michael Mauer, Minneapolis, MN; Emil Paganini, Cleveland, OH; Elsa P. Paulsen, Charlottesville, VA; Carlo Pesce, Bethesda, MD; Philip Raskin, Dallas, TX; Peter A. Singer, Toronto, Canada; Liliane J. Striker, Bethesda, MD; Gary E. Striker, Bethesda, MD. Address reprint requests to Gladys H. Hirschman, MD, National Institutes 0/ Health, Federal Building, Room 102, Bethesda, MD 20892. © 1991 by the National Kidney Foundation, Inc. 0272-6386/91/1805-0009$3.00;0

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ditions that optimize patient informed consent and safety. • When research protocols are designed to ensure the most complete evaluation of the removed tissue. • When the human subjects freely give fully informed consent. Depending on the specific hypothesis or questions being addressed, renal structural information could be viewed as helpful, but not essential, strongly encouraged, but not mandatory or central and necessary to the question being examined. Studies of the effect of specific interventions on the natural history of disease may not only warrant an entry level renal biopsy, but a repeat biopsy at a well-defined interval(s) would also be reasonable in some circumstances. The biopsy interval would need to represent anticipated rates of change in the parameter(s) being investigated. Thus, although the Workshop adopted a position of enhanced permissiveness with respect to the use of renal biopsy as a research tool in KDDM, it is mindful of the absolute necessity to protect the safety and dignity of the individual human volunteer and the need to empower the human subjects with truly free and informed choice, in an environment of unfettered and careful communication regarding potential risks and tangible benefits to the individual, as well as potential benefits to all patients afflicted with diabetes mellitus. RENAL BIOPSY IN RESEARCH ON DIABETES MELLITUS: GOALS AND OBJECTIVES

In its deliberations, the Workshop considered the why, when, how, and what of research renal biopsies in diabetes mellitus. For example, why does one need to consider renal biopsy as a research tool in diabetes mellitus? When is a biopsy clinically indicated? When is a renal biopsy clinically contraindicated? When is a renal biopsy useful for research purposes only? How should renal biopsies be performed in order to minimize risks and maximize informational content? What type of research studies should be conducted? In what groups of patients should renal biopsy be considered? What are the risks and benefits of renal biopsies in diabetes mellitus? What type of administrative and organizational arrangement would be necessary to maximize the utility of renal biopsy material obtained from diabetic patients? In considering these questions, the Work-

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shop attempted to carefully distinguish between 100M (type I diabetes) and NIDDM (type II diabetes), between adults and children, between the general population and potentially vulnerable and accessible subgroups such as African Americans and Native Americans, and between initial and serial renal biopsies. The Workshop was also cognizant of the possible applicability of studies involving renal biopsies to other areas such as essential hypertension. The Workshop concluded that the goals and objectives underlying the performance of a renal biopsy in patients with diabetes mellitus, for research purposes would be: • To characterize in precise morphologic and biologic terms the factors responsible for the kidney disease of, not in, diabetes mellitus. • To define the value of morphologic parameters as prognostic tools. • To acquire in the most efficient, safe, and ethically defensible manner a body of morphologic information related to clinical and laboratory features that would assist clinicians in the prevention or management ofKDDM. The goal would be to eliminate dependence on the performance of a renal biopsy to make optimal clinical decisions. • To provide a tool that could supply rational end-points for intervention trials in patients with diabetes mellitus at well-defined risk points, and that would provide data on efficacy and safety of the therapeutic intervention in the most efficient manner. • To establish a renal biopsy database and a central renal biopsy repository to provide the tools and information necessary for the development of standard objective criteria for nomenclature and procedures on which to base the analysis of structure and function in KDDM. SPECIFIC PROTOCOLS FOR RESEARCH INVOLVING RENAL BIOPSIES IN PATIENTS WITH DIABETES MELLITUS

Having reached general agreement on the broad goals and objectives for research involving renal biopsies in patients with diabetes mellitus, the Workshop then moved to a consideration of specific research protocols. The following represents a summary of these deliberations: • A research protocol involving renal biopsies must clearly distinguish between the kidney disease of diabetes mellitus (KDDM) and kidney

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RECOMMENDATIONS ON KIDNEY BIOPSY IN DIABETICS

disease in diabetes mellitus. The current lack of clinical and laboratory parameters that can reliably separate these two subsets of kidney disease makes renal biopsy a vital tool in study design, particularly in studies of NIDDM. • Based on available information, it appears highly desirable that studies involving renal biopsies be conducted early in the course of KDDM during the clinically silent or incipient phases and that these studies be extended serially over specified time intervals. It was believed that renal biopsies obtained after the onset of overt diabetic nephropathy were not likely to provide useful information. • Tissue obtained for investigative purposes by renal biopsy must be analyzed using state of the art methodology and must ensure the optimum use of such tissue. To the extent possible, these analyses must be quantitative and reproducible, and result in outcomes with acceptable levels of precision through the use of well-standardized reagents, methods, and interpretation. • All research studies involving renal biopsies must include a design that will help to define the natural history of the disease· and to establish correlations between structure and function. Furthermore, they must include appropriate simultaneous and concurrent assessment of variables that may impact the severity of disease. These studies should ensure the inclusion of a wide variety of racial and ethnic subgroups. Such studies would be particularly important in defining the hallmarks of "slow-track" and "fast-track" patients with KDDM. In this context, slow-track and fast-track could refer to the rates at which clinical progression occurs or at which structural changes occur. • A great need exists for the development of new approaches to the analysis of renal biopsy material that incorporate modern techniques of molecular and cell biology. The development of new tools and protocols should be validated in animal research before application to human biopsy material. • To ensure maximum usefulness of protocols involving renal biopsies, collaborative arrangements for research and a data bank that includes biopsy tissue should be established. • Normal standards and variations of renal morphology with respect to age, sex, type of diabetes, and staging of the renal disease need to

be established. This will be required for the development of standard nomenclature. CLINICAL AND RESEARCH INDICATIONS FOR RENAL BIOPSY IN PATIENTS WITH DIABETES MELLITUS

The Workshop reached a consensus on the indications for clinical and indications for research renal biopsy and the relative contraindications to renal biopsy. A clinically indicated renal biopsy is one performed in the anticipation that the information provided will have direct clinical usefulness in a given patient, either for a decision regarding institution or avoidance of a specific therapeutic intervention, for diagnosis or prognosis, or for genetic and family counseling. A research-indicated renal biopsy is one performed to obtain information deemed necessary or highly desirable for the conduct of a study of pathogenesis or natural history or as a part of an interventional trial. The anticipated direct benefit to the patient is not a necessary element of such a renal biopsy; in some instances, there may be no anticipated direct benefit. Of course, a research protocol may also involve renal biopsies that are clinically indicated. The relative contraindications to renal biopsy are those clinical or laboratory features that when present, are associated with a definite increase in the risk of complications, either minor or major (eg, a bleeding diathesis, severe uncontrolled hypertension, uncooperative patient). Among patients with diabetes mellitus and overt clinical manifestations of kidney disease, percutaneous renal biopsies should be given serious consideration on clinical grounds alone in two settings: (1) the patient with IDDM of less than 10 years' duration who develops clinical evidence of renal disease regardless of age, sex, race, or ethnicity; and (2) the patient with NIDDM who develops clinical renal disease in the absence of background or, of proliferative retinopathy, regardless of the known duration of diabetes mellitus. In patients who do not meet these fundamental criteria, renal biopsy could be considered when one or more of the following findings are present: (1) the rate of decline of glomerular filtration rate or the rate of worsening of proteinuria falls significantly outside established norms for patients with proven KDDM. This would include the sudden onset of nephrotic syndrome or the development of acute renal failure of unknown

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origin in a patient with diabetes mellitus regardless of subtype; (2) when clinical or laboratory findings are present that indicate the likelihood of another primary or secondary renal disease (such as significant glomerular hematuria and/or erythrocyte casts); (3) in patients with 100M who develop clinical renal disease after 10 or more years' duration of diabetes when a multisystem disease may be present and causing the renal disease (eg, systemic lupus erythematosus). Patients with diabetes mellitus regardless of the presence or absence of overt manifestations of kidney disease could be appropriately considered for research renal biopsies for the following reasons, given in descending order of benefit to risk ratio to the specific patient: (1) to study the influence of therapeutic interventions of unproven efficacy or safety in relationship to specific morphologic parameters or end-points; (2) to study the natural history of glomerular, tubular, interstitial, or vascular disease in defined groups of patients in association with appropriate clinical-pathologic correlations, in order to move toward an individualized risk profile based on morphology, and/or to elucidate reliable clinical surrogates for morphologic parameters of prognosis; and (3) to study basic pathogenetic mechanisms ofKDOM. These reasons for research renal biopsies are not necessarily mutually exclusive in anyone study. The risk for renal biopsies performed primarily for research purposes when conducted by experienced physicians under optimal conditions are not precisely known for patients with diabetes mellitus of varying ages or stages of disease. However, the Workshop concluded that the risks are likely to be less than that published for adults undergoing renal biopsies, since these studies included patients with different clinical indications and were conducted in a variety of clinical settings. More data are needed regarding the risks of renal biopsies when performed in patients with diabetes mellitus. The true risks of renal biopsy are importantly influenced by the experience of the operator, the general condition of the patient, the method used, and the stage of disease in the patient. The consensus was that percutaneous renal biopsies performed with ultrasound guidance by experienced operators on otherwise healthy and cooperative diabetic patients who are nonhypertensive or have well-controlled hypertension, and in whom there are no specific con-

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traindications to renal biopsies, would have only a minor additional risk over that which is considered minimal risk. Second or follow-up renal biopsies in randomized trials must be ethically justified as legitimate end-points when compared with other surrogate, noninvasive end-points. This justification must be entirely separate from that used for the initial renal biopsies, used primarily for entry of patients into the specific study. It is advisable that the institutional review of investigational protocols involving such a procedure should include the recommendations of an expert knowledgeable in this field, but with no direct interest in the particular research project. ANALYSIS OF DATA AND INFORMED CONSENT

The Workshop expressed concern about bias, which could creep into intervention studies where only a fraction of patients agreed to renal biopsy. Analysis of data on the basis of intent-to-biopsy should be given proper consideration, just as therapeutic trials are analyzed on an intent-totreat basis. Newer interpretation of the human subjects review process has emphasized the importance of informed consent and the quality of the information provided by the investigator to putative volunteer subjects. Explicit risks, if not extreme in relationship to anticipated benefits, would be permitted when the informed consent process is carefully conducted to respect the human subjects and their autonomy. Also, research involving individual human subjects from vulnerable but easily accessible populations is justified when, even though that population will benefit from such research, the autonomy of individual human subjects from those communities is yet fully protected. Risks and benefits are not necessarily contemporaneous. Renal biopsy risks are shortterm, finite, and experienced by the human subject. Benefits of research renal biopsies are longterm, imprecise, and experienced by society. Since research renal biopsies are not viewed as necessarily entailing extreme patient risks in relationship to putative benefits, research protocols of KDOM that involve renal biopsies should strongly emphasize informed consent, the quality of the information provided to the patient, and the assurance that such information is understood by each human subject.