Building the case for biopsy in IgA nephropathy
Using biopsy to track disease activity
William Check, PhD
Advances in understanding IgA nephropathy, like the disease itself, come in two classes: the slowly progressive type, which is more common, and the less common aggressive form. Consequently, recent reports on this disease contain many preliminary or "promising" findings but fewer firm conclusions.
Summarizing a clinical conference on IgA nephropathy that he co-chaired at the 2000 annual meeting of the American Society of Nephrology, J. Charles Jennette, MD, says, "The conference emphasized that there are still a lot of unresolved issues in clinical management, etiology and pathogenesis, and pathological evaluation of IgA nephropathy."
Pathogenesis is "one of the most exciting issues," says Dr. Jennette, Brinkhous Distinguished Professor and chair of pathology and laboratory medicine at the University of North Carolina at Chapel Hill. "A potentially very important observation is that there may be abnormalities in the molecular structure of circulating IgA in patients with IgA nephropathy and the closely related disease Henoch-Schönlein purpura, particularly abnormalities in galactosylation in the hinge region of IgA molecules," he adds.
In the practical sphere, one element of IgA nephropathy is clear—the role of the pathologist in diagnosing this disease and consulting on its management. "Biopsy is diagnostic," says Randy Hennigar, MD, assistant professor of pathology and director of nephropathology and electron microscopy at Emory University Hospital and Clinic, Atlanta. "You need to demonstrate IgA in the glomeruli. An astute kidney pathologist will identify aggressive features on biopsy and communicate to the nephrologist how active the disease looks."
Adds Dr. Jennette: "The renal pathologist and nephrologist must interact in making the diagnosis of IgA nephropathy, in coming to a consensus on prognosis, and in trying to decide on appropriate treatment. Person-to-person or phone consultation is probably as frequent or more frequent in renal pathology practice than in any other area of pathology."
Some clinicians, however, don’t order biopsies for patients with probable IgA nephropathy until it is in an advanced stage, because no definitive treatment has been demonstrated.
"I try to avoid that kind of fatalism," says James Tumlin, MD, associate professor of nephrology and co-director of clinical nephrology at Emory University Hospital and Clinic. "With a biopsy, we can tell patients what’s wrong with them," Dr. Tumlin says, "and we can get a prognosis."
A primary care physician might tell a typical patient with probable IgA nephropathy—someone who has an episode of gross hematuria in their 20s or 30s and for whom kidney stones have been ruled out—that he or she has about a 25 percent risk of progressing to end-stage renal disease over 10 years. "But I would submit that they can’t know that without a biopsy," says Dr. Tumlin, who is collaborating with Dr. Hennigar to study this topic. "As in lupus," he adds, "it is very difficult, if not impossible, to predict the underlying histology [in an individual patient] without actually looking at the tissue. Biopsy is essential to stage patients and to determine whether more aggressive therapy is needed." (See "Using biopsy to track disease activity," sidebar.)
Only about one-third of patients who present with asymptomatic dysmorphic hematuria have IgA nephropathy, Dr. Jennette says. One-third have some form of hereditary basement membrane nephropathy, and one-third have no identifiable lesion. "If biopsy clearly shows IgA nephropathy, we can counsel the patient about prognosis and therapeutic options," he says. "We may decide we don’t need to treat based on a knowledgeable understanding of the etiology of hematuria, as opposed to a presumptive diagnosis."
William M. Bennett, MD, director of solid organ and cellular transplantation at Legacy Good Samaritan Hospital, Portland, Ore., also favors early workup, even in the absence of therapy for the primary disease, now that ACE inhibitors have been shown to control blood pressure and urinary protein. "We need to take a leaf from other countries where they make the diagnosis early rather than late if we are ever going to have a chance of influencing disease course," he says. In today’s managed care climate, ordering renal biopsy for an asymptomatic patient can be "a tough sell," Dr. Bennett adds, although he finds "some more enlightened organizations are starting to realize that making diagnoses earlier allows the physician to better manage the patient." Dr. Tumlin’s experience has been more favorable. "I have never been questioned on biopsy, not even repeat biopsy," he says.
Lack of accepted therapy for IgA nephropathy is due in part to faulty clinical trials, says Robert J. Wyatt, MD, professor of pediatrics and preventive medicine at the University of Tennessee Health Science Center and Crippled Children’s Foundation Research Center, Memphis. "We’ve got problems in glomerulonephritis," Dr. Wyatt says. "We haven’t had the best, or even close to the best, therapeutic trials."
That may be changing. Mark Haas, MD, associate professor of pathology and director of the electron microscopy laboratory at Johns Hopkins Hospital, Baltimore, says new therapeutic approaches are being developed and some trials are underway. "Data suggest that some active and severe lesions may respond to aggressive treatment, but not those that are extensively scarred. Something everyone agrees on is that one strong predictor of progression to ESRD is the amount of tubulo-interstitial scarring on biopsy," Dr. Haas says.
Although IgA nephropathy is not common overall, some data suggest it is the most common glomerular disease in the world today. In most renal biopsy practices in the United States, IgA nephropathy accounts for five to 10 percent of native (nontransplant) renal biopsy specimens, Dr. Jennette estimates. It is more frequent in Asian countries and in persons of Asian descent.
As for pathogenesis, Dr. Tumlin says, "There appears to be a growing body of evidence that these patients have aberrant o-glycosylation of amino acids located at the hinge region of IgA molecules, particularly IgA-1" (Kidney Int. 2001;59:1077 and 60:969-973). Abnormal o-glycosylation allows IgA dimers to form; they deposit in the mesangium of the glomerulus and induce expansion of mesangial matrix proteins. A thickened mesangial space is a hallmark of this disease. "In patients with very mild disease," Dr. Tumlin says, "the main manifestation you may see on biopsy is simply mesangial expansion and deposition of IgA molecules within the mesangium on immunofluorescence. Patients with only mesangial expansion usually do pretty well, unless they have concurrent proteinuria, which can lead to scarring in the kidney and progressive tubule loss."
Immune complexes containing IgA molecules are visible on electron microscopy in the mesangium. Inflammation induced by immune complexes can lead to abnormal division and proliferation of mesangial cells, causing hypercellularity (more than five cells per mesangial stalk). Microscopic hematuria may result. When immune complex deposition becomes more intense, perhaps after viral illness or a seasonal allergic response, mesangial expansion increases and produces gross hematuria, in which bleeding through the glomerulus causes visible blood in the urine. Exactly how this happens is not clear.
With severe disease, immune complexes can accumulate in capillary loops, inducing proliferation of endocapillary cells—focal segmental endocapillary proliferation—with or without necrosis. Capillary loops are occluded by infiltrating inflammatory cells and swollen endothelial cells with loss of filterable surface area in the glomeruli, leading to decreased creatinine clearance. In some patients with endocapillary proliferation, parietal epithelial cells of Bowman’s capsule divide, forming an epithelial cell crescent. "Patients with endocapillary proliferation and crescents can have a rapid decline in renal function-in essence, an IgA-dependent, rapidly progressive glomerulonephritis," Dr. Tumlin says.
Like lupus nephritis, IgA nephropathy can present with any manifestation of glomerular disease—asymptomatic microscopic hematuria, recurrent gross hematuria with normal renal function, acute nephritis, rapidly progressive glomerulonephritis, or chronic glomerulonephritis. "In any of those situations," Dr. Jennette says, "proteinuria can be quite variable, including nephrotic range proteinuria causing overt nephrotic syndrome."
A typical presentation of IgA nephropathy is the discovery in a younger person of abnormal urinary sediment—red blood cells, usually dysmorphic, and sometimes casts—on routine examination. Proteinuria also may be present. "At this point," Dr. Bennett says, "many primary care physicians would tell the patient that they have some red blood cells in their urine, but not to worry about it. But I think abnormal urinary sediment without any other explanation should trigger further investigation, possibly including renal biopsy."
IgA nephropathy also may present with recurrent episodes of hematuria, either gross or microscopic, sometimes in conjunction with upper respiratory or gastrointestinal infections. "Patients may not say they have blood in their urine," Dr. Bennett says. "They will say their urine turned dark. I saw a case the other day where a physician saw a patient whose urine turned dark, assumed it was concentrated urine, and didn’t explore further."
Dr. Bennett advocates investigating hematuria quantitatively, not simply with a dipstick. "Even looking at a sample in the microscope to determine the number of RBCs per high-power field doesn’t tell you how many RBCs are excreted per time period," he says. A better procedure is to count the number of RBCs per milliliter of urine in a counting chamber. "Quantitating RBCs tells the amount of bleeding, which correlates with severity of the lesion and lets you follow the progress of the disease," he says.
Questions remain about exactly when to biopsy, particularly in the typical patient with asymptomatic hematuria and little or no proteinuria. "Will you identify something that will change the management of the patient?" Dr. Jennette asks. In about 90 percent of all patients with hematuria, the source is in the lower urinary tract rather than the kidney. However, cases with a source in the kidney need to be evaluated by a nephrologist, not a urologist. "Unfortunately," Dr. Jennette says, "some patients with asymptomatic hematuria with little or no proteinuria have repeat urologic procedures, when in fact they have a glomerular cause." Biopsy can distinguish a renal parenchymal cause of hematuria from urologic disease in these patients, preventing unnecessary invasive urologic procedures.
Beyond the classic presentation of IgA nephropathy are more aggressive cases, usually presenting with hematuria, increasing amounts of proteinuria, and creatinine that rises at a much faster rate than in classic IgA nephropathy. "The classic case, which is usually a chronic smoldering condition, eventually comes to end-stage renal disease over many years," says Dr. Hennigar. More aggressive cases reach ESRD in about a year. "Biopsy helps to confirm that these patients do indeed have more active disease," Dr. Hennigar says. "Much like in lupus nephritis, in aggressive IgA nephropathy we can correlate very active pathological disease, such as the finding of crescents on biopsy, with more active clinical disease."
In mild cases, deciding whether to biopsy can depend on the individual patient, Dr. Haas says. "Some strongly want to know what they have. Others fear that getting tagged with a diagnosis of a kidney disease will put them at risk of losing their health insurance, and I think with substantial reason," he says. Biopsy is required, however, in more aggressive cases: patients with hematuria plus significant proteinuria (greater than 1g per day, perhaps even greater than 0.5g per day) or abnormal serum creatinine or hypertension. "In those instances, there is a substantial potential for progressive glomerular disease," Dr. Haas says.
Dr. Haas emphasizes the overall value of biopsy for prognosis. "IgA nephropathy can be mild or severe," he says, "and that correlates greatly with histology." IgA nephropathy historically has been regarded as a relatively benign disease, with Japanese and European studies from the 1980s quoting 10-year renal survival rates of 80 to 90 percent. But, Dr. Haas says, "In Japan, they tend to be much more willing to biopsy someone who has blood in their urine with minimal protein and normal renal function, so they would have more patients with milder lesions." In the United States, patients tend not to be biopsied unless they have proteinuria or a decline in renal function, which explains the 60 percent 10-year renal survival rate in some U.S. reports.
In his own work, Dr. Haas has pushed the prognostic value of biopsy beyond glomerular findings to show that tubular atrophy and interstitial fibrosis are also important prognostic indicators and should perhaps influence how aggressively clinicians treat. Generally speaking, he says, a lesion with extensive scarring will do poorly, regardless of how active the glomerular lesion looks.
Dr. Haas devised a classification system for IgA nephropathy by adapting the World Health Organization classification for lupus nephritis. His intent was to provide a simple system that pathologists could use in daily practice. A previous report had shown that outcome in IgA nephropathy was related to glomerular cell proliferation, as in lupus nephritis. So Dr. Haas started with three classes: class I, minimal proliferation; class III, focal proliferation; and class IV, diffuse proliferation. He added class II, no proliferation but occasional segmental scarring; and class V, heavily scarred lesions.
In his study, Dr. Haas graded more than 100 biopsies and followed the patients to determine renal survival. "Overall, there was pretty good correlation between classification and outcome," he says (Am J Kidney Dis. 1997;29:829-842). Histologic class was significant in univariate analysis and after controlling for serum creatinine at biopsy.
Moreover, within classes III and IV, the presence of interstitial fibrosis and tubular atrophy correlated with worse prognosis. And among class III lesions, the presence of one or more cellular crescents predicted a worse long-term prognosis: Ten-year renal survival was nearly 80 percent in patients whose biopsies had no crescents but only 30 percent if crescents were present.
Biopsy also can be helpful in renal failure in a renal transplant recipient who had IgA nephropathy, Dr. Haas says. "If there is any evidence for clinical disease-hematuria or proteinuria-or mesangial expansion or proliferation on the transplant biopsy, it is certainly worth doing immunofluorescence, maybe with just one glomerulus, to see if the patient has recurrent IgA nephropathy," he says.
Obstacles to mounting conclusive treatment trials include the difficulty of obtaining enough patients from one institution and the fact that many U.S. patients with mild or moderate disease don’t get biopsied until they have chronic renal insufficiency. "Those aren’t the best patients for trials because they have already moved to progression," says the University of Tennessee’s Dr. Wyatt.
That is one criticism of studies on the efficacy of fish oil in IgA nephropathy conducted by James Donadio, MD, and his colleagues at the Mayo Clinic. "I don’t have any doubts about Dr. Donadio’s work being done right," Dr. Wyatt says. "But most would agree that all they have shown is that fish oil will delay progression. It does not bring down proteinuria, so it is not a treatment to use at the onset of disease in someone with normal renal function." Dr. Wyatt concedes, however, that slowing progression "would not be an insignificant accomplishment" among older IgA nephropathy patients on dialysis, who have 25 percent annual mortality.
First-line treatment for newly diagnosed IgA nephropathy is ACE inhibitors (ACEI). In future U.S. studies, all patients might be given ACEI, Dr. Wyatt conjectures. As a pediatric nephrologist, Dr. Wyatt finds it hard to get people to accept a placebo arm, even though he believes that a placebo arm is probably still appropriate. "Some people have decreased proteinuria with no treatment," he says. "But anyone with significant proteinuria—greater than 1g per 24 hours—will do better on ACE inhibitors, even without hypertension."
If proteinuria doesn’t decrease with ACEI, corticosteroids are the agents to try next. A meta-analysis demonstrated evidence of the efficacy of corticosteroids in "heavy" proteinuria—3.0g or more per 24 hours. "I flip back and forth on the value of steroids," Dr. Wyatt says. "I am fairly convinced that steroids are effective. The problem is side effects and some resistance from patients."
Drs. Wyatt and Jennette were participants in the North American IgA Nephropathy Treatment Trial, which will provide the first controlled evidence about steroids. Patients (adults under 40 and children) were randomly selected for treatment with qod prednisone, fish oil, or placebo and followed for two years. The primary endpoint is a 50 percent or 100 percent increase in serum creatinine; the secondary endpoint is proteinuria. Data are expected in about two years. Enrollment was slower than anticipated, so only 30 patients were entered into each treatment group, rather than the planned 50, before funding ran out.
"Our message is more for nephrologists than pathologists," Dr. Hennigar concludes. "Making a diagnosis of IgA nephropathy is relatively easy for kidney pathologists. What nephrologists need to recognize is that IgA nephropathy is a treatable disease. That is the new philosophy that is arising. Some cases need to be treated aggressively. And biopsy plays a vital role in identifying those cases."
William Check is a medical writer in Wilmette, Ill.