DISEASEOF THE MONTH Immunoglobulin A Nephropathy: A Clinical Perspective JAMES V. DONADIO, JR.* and JOSEPH P. GRANDEt *Dit,isio,t of Nephrology and Internal Medicine and t/te tDepartment of Laboraton’ Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. First described in 1968 by Berger and Hinglais (1), idiopathic patient selection bias, but also by a conservative approach immunoglobulin A nephropathy (IgAN) is now recognized as taken by nephrologists in our country in recommending renal the most common primary glomerulonephritis in the world biopsy in patients who have only an asymptomatic, abnormal (2,3). Also, we now appreciate as did Berger that renal failure urine sediment. It is common practice for patients presenting can develop in a substantial number of patients with IgAN with isolated hematuria or mild proteinuria not to receive a (initially thought to be a totally benign process) over variable renal tissue diagnosis, the renal biopsy being reserved for those periods of time (4-9). IgAN is an immune complex-mediated people who develop increasing amounts of urine protein or a glomerulonephritis defined morphologically by the constant rising serum creatinine concentration, or both. This practice presence of predominant or codominant mesangial deposits of has bearing on comparative outcome studies and recommen- IgA accompanied by a variety of histopathologic lesions (9- dations for treatment to be discussed later. 1 1 ). The etiology is unknown in that no consistent environ- mental or infectious agent has been shown to be antigenic with Clinical Features an IgA antibody response. Since the original description of the IgAN occurs at all ages, with the usual age of clinical onset glomerulopathy, idiopathic IgAN has received the bulk of in the second and third decade of life (2,7,8, 1 1 ). There is a attention in the medical literature, but many diseases have been usual male sex predilection ranging from less than 2: 1 in reported that are sporadically associated with mesangial IgA Japanese patients to as high as 6: 1 in Caucasian patients in deposition (Table 1). Sch#{246}nlein-Henoch purpura, a multisys- northern Europe and the United States. IgAN has a predilection temic disease, is the most common and arguably considered a for whites and Asians and is less common in blacks. part of the spectrum of idiopathic IgAN. The association of IgAN must be highly suspected in any patient in whom there many of the secondary disorders may be coincidental because may be one of two common presentations: (1) episodic, mac- of the high prevalence of IgAN that is usually a long-term and roscopic hematuria, often coincident with an upper respiratory chronic disease. This review offers a perspective on the epi- tract infection, less often a gastroentenitis; or (2) asymptomatic demiology, clinical features, and diagnosis, pathology, out- with findings on urinalysis of an abnormal urine sediment come, and management of patients with idiopathic IgAN. containing erythrocytes (RBC) and RBC casts and proteinuria in patients in whom the urinalysis was performed as part of an Epidemiology examination for other purposes. Loin pain will accompany Population epidemiologic studies concerning the incidence macroscopic hematuria in approximately one-third of the of IgAN are meager; most reports relate prevalence rates cases. The presenting illness of episodic, grossly visible hema- expressed as a percentage of primary glomerulonephritis or of turia is more common in younger people, whereas that of an a total biopsy series originating in referral-based cohort studies abnormal urine sediment is more frequent in older individuals. (2,7, 1 1). For example, IgAN accounts for 7 to 52% of patients For example, in a recently completed, randomized clinical trial with glomerulonephnitis, which ranges from 4 to 44% of total of fish oil involving 106 proteinuric patients, a history of biopsy series, as reported in a recent comprehensive review by macroscopic hematuria was obtained only in patients under 34 Ibels and Gyory (7). The high-end prevalence rates are found yr old, the median age of the study cohort (12). in Singapore, Japan, Australia, Hong Kong, Finland, and Unfortunately, abnormalities found on urinalysis may be southern Europe, and the lower prevalence rates are reported overlooked or purposely not acted on by further testing until from the United Kingdom, Canada, and the United States, with renal function impairment becomes evident. It is imperative to the exception of Native Americans living in New Mexico (2,7). pursue urine sediment changes when first detected so as not to The low prevalence rate reported from the United States is delay making an accurate diagnosis. By definition, a diagnosis influenced not only by the fact that all published series from of IgAN requires renal biopsy, including immunofluorescence the United States are from referral centers in which there is a microscopy. This again raises the controversial issue among nephrolo- gists of performing a renal biopsy under the circumstances of Correspondence to Dr. James V. Donadio. Jr., Division of Nephrology, Mayo Clinic, 200 First Street, SW, Rochester. MN 55905. the above-cited presentations without renal function impair- ment or nephrotic-range proteinuria because of the perception l()46-6673/0808- I 324$03.00/0 Journal of the American Society of Nephrology that specific treatment is not available. The approach of pro- Copyright 0 1997 by the American Society of Nephrology spectively evaluating an asymptomatic patient was an accept- IgA Nephropathy I 325 Table 1. Classification of diseases associated with casts and dysmorphic RBC accompanying either macroscopic predominant mesangial IgA deposition or microscopic hematuria clearly indicate to the clinician that bleeding in the urinary tract is glomerular in origin, and this Idiopathic IgA nephropathy (Berger disease) should spare the patient from having to undergo urologic Secondary procedures such as cystoscopy and retrograde pyelography. Sch#{246}nlein-Henoch purpura-most common; a distinct Qualitative proteinuria can be assessed further by measuring entity or a multisystemic extension of IgA nephropathy 24-h total urine protein or by semiquantitative protein/osmo- Diseases of the lality or protein/creatinine ratios on first morning, voided urine liver: alcoholic, cryptogenic and primary biliary samples (16). Also, adults over 50 yr old who are first discov- cirrhosis; hepatitis B (endemic areas); chronic ered to have proteinuria in the nephrotic range (protein excre- schistosomiasis tion of 3.5 g or more per 24 h) should be screened for Bence intestine: celiac disease; chronic ulcerative colitis; Jones proteinuria by the sulfosalicylic precipitation method and Crohn’s disease examination by immunofixation electrophoresis to detect skin: dermatitis herpetiformis; psoriasis monoclonal light chains and immunoglobulins even in very bronchus/lung : idiopathic pulmonary hemosiderosis; low concentrations. cystic fibrosis, sarcoidosis The presence of an abnormal urine sediment and proteinuria Neoplasia: carcinoma of lung, larynx, and pancreas; require measurement of renal function, preferably by a clear- mycosis fungoides; IgA monoclonal gammopathy ance technique, to estimate GFR. Serial measurement of renal Infection: human immunodeficiency virus; leprosy; function is essential in the long-term follow-up of patients with toxoplasmosis IgAN. Other systemic/immunologic disorders: systemic lupus A small group of patients with IgAN will present with severe erythematosus; cryoglobulinemia; rheumatoid arthritis; azotemia, some even requiring dialysis, obviously representing psoriatic arthritis; ankylosing spondylitis; Sjogren’s the most aggressive form of the disease. The late referral of a syndrome; antineutrophil cytoplasmic antibody- previously undiagnosed patient is also not unusual. associated vasculitis; familial immune Likewise, on immunofluorescence there may be the rarely thrombocytopenia reported, coexistent nephrotic syndrome and IgAN marked by IgA mesangial deposits associated with focal and segmental mesangial expansion and minimal or no cellular proliferation. able practice until recently, in that rational therapeutic inter- There is no consensus about whether this clinicopathologic ventions can now be offered to patients who are at risk for combination represents a variant of one or other of the two developing progressive renal disease based on recently re- conditions, or of two different coexisting disorders. Prompt ported treatment studies (12-15). remission of the nephrotic syndrome after steroid treatment, or It is the rule for microscopic hematuria and proteinuria to spontaneously, suggests the phenotypic expression of minimal persist in variable amounts throughout the course of the dis- change disease (17). ease, even in those patients whose presenting illness is mac- There are other laboratory variables, including elevated se- roscopic hematuria. Complete and prolonged remission of all rum IgA levels, C3 fragments, IgA-fibronectin aggregates, and clinical signs is uncommon (approximately 4%). To illustrate the presence of circulating IgA-containing immune complexes, the importance of direct urine sediment examination, Ibels and which are found in patients with IgAN, but none can replace Gyory (7) showed a positive correlation between the quantity the renal biopsy for the firm establishment of a diagnosis (1 1). of RBC per milliliter of urine and the number of hyaline casts and progressive