Correspondence
IgA Nephropathy
N Engl J Med 2003; 348:79-81January 2, 2003
- Article
To the Editor:
In their review article, Donadio and Grande (Sept. 5 issue)1 emphasize the favorable effects of corticosteroids and n – 3 fatty acids on the progression of renal insufficiency in IgA nephropathy. Unfortunately, a considerable number of cases of IgA nephropathy remain undiagnosed until an irreversible decline in renal function has occurred. As pointed out by the authors, IgA nephropathy typically becomes symptomatic when there is an episode of macroscopic hematuria, often accompanied by loin pain. To most general physicians, hematuria with loin pain in a patient suggests the presence of nephrolithiasis. The patient will be referred to a urologist and will undergo studies to rule out severe urologic diseases. The patient will be falsely reassured of the supposedly benign nature of the hematuria.
Hematuria in IgA nephropathy (glomerular hematuria) can easily be distinguished from nonglomerular bleeding (as in nephrolithiasis) by microscopical urinalysis. We previously reported that the presence of acanthocytes (erythrocytes with vesicle-shaped protrusions) is strongly associated with glomerular bleeding.2 In a comparison of 93 patients with hematuria and either biopsy-proven IgA nephropathy or nephrolithiasis, we found that the proportion of acanthocytes in the urine was 2 percent or more in 20 of 24 patients with IgA nephropathy but in only 3 of 69 patients with nephrolithiasis.2 Therefore, in patients who present with new-onset hematuria, even in the presence of loin pain, the morphologic features of the urinary erythrocytes should be determined as the first diagnostic step in order to distinguish glomerular from nonglomerular bleeding.
2 ReferencesGunnar Heine, M.D.
Urban Sester, M.D.
Hans Kohler, M.D.
University of Saarland, 66424 Homburg, Germany
inhkoe@uniklinik-saarland.de 1
Donadio JV ,Grande JP . IgA nephropathy. N Engl J Med 2002;347:738-748
Full Text | Web of Science | Medline2
Kohler H ,Wandel E ,Brunck B . Acanthocyturia -- a characteristic marker for glomerular bleeding. Kidney Int 1991;40:115-120
CrossRef | Web of Science | Medline
To the Editor:
Certain issues are overlooked in the review of IgA nephropathy by Donadio and Grande. There is, for instance, a relevant reaction to Haemophilus parainfluenzae in patients with IgA nephropathy,1 making one wonder why biopsies of the tonsils and respiratory tract are not contemplated more often. VδT cells recognize small antigens of carbohydrate or protein from bacteria, but mucosal T cells isolated from patients with IgA nephropathy may show a decrease in the expression of the genes that encode Vγ3 and Vδ3. Such a deficiency of VδT cells in the duodenum can be misleading, because T cells can shift to other lymphoid areas.2 Tonsillar reactions to bacteria that express phosphorylcholine (known to induce type 2 helper T [Th2] cells) may influence the bone marrow and splenic antibody responses. The production of mucosal IgA is independent of T cells,3 but the renal circulation is exposed to aberrantly glycosylated systemic IgA1. Furthermore, Chintalacharuvu et al.4 have shown that Th2 cell cytokines can cause this aberration of IgA glycosylation.
Trials of fish-oil therapy for IgA nephropathy have bypassed antithromboxanes.5 If trials of treatment for glomerulonephritis are conducted along with measurements of thromboxane activity and other relevant molecules (e.g., urinary thromboxanes, monocyte chemotactic protein, tumor necrosis factor α, and tumor necrosis factor β), then we might soon learn whether such therapy works or not. If the results of long-term, formal trials generate only equivocal results, we might better understand why, if these molecules are measured. In reports on trials of fish oil, urinary thromboxanes and related molecules were not measured.
5 ReferencesE. Nigel Wardle, M.D.
21 Common Rd., Oxford OX29 6RD, United Kingdom1
Suzuki S ,Fujieda S ,Sunaga H , et al. Immune response of tonsillar lymphocytes to Haemophilus parainfluenzae in patients with IgA nephropathy. Clin Exp Immunol 2000;119:328-332
CrossRef | Web of Science | Medline2
Buck KS ,Foster EM ,Watson D , et al. Expression of T cell receptor variable region families by bone marrow gammadelta T cells in patients with IgA nephropathy. Clin Exp Immunol 2002;127:527-532
CrossRef | Web of Science | Medline3
Macpherson AJ ,Gatto D ,Sainbury E ,Harriman GR ,Hentgartner H ,Zinkernagel RM . A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 2000;288:2222-2226
CrossRef | Web of Science | Medline4
Chintalacharuvu SR ,Nagy NU ,Sigmund N ,Nedrud JG ,Amm ME ,Emancipator SN . T cell cytokines determine the severity of experimental IgA nephropathy by regulating IgA glycosylation. Clin Exp Immunol 2001;126:326-333
CrossRef | Web of Science | Medline5
Wardle EN . Thromboxanes in glomerulonephritis: what about therapy? Am J Ther 1999;6:111-114
CrossRef | Medline
To the Editor:
The statement that “no study has shown that angiotensin-converting–enzyme [ACE] inhibitors preserve renal function in patients with IgA nephropathy” overlooks at least two studies that have shown such an effect.1,2 In a small study by Kanno et al.,1 a relatively minor decrease in blood pressure from below 140/85 mm Hg to below 130/70 mm Hg was associated with significantly better creatinine clearance after three years. Many patients with IgA nephropathy may further benefit from blood-pressure reduction with ACE inhibitors because of the presence of concomitant cardiovascular risk factors. ACE inhibitors have fewer side effects than many other treatments recommended for IgA nephropathy and should perhaps be used, with care, more frequently. Unfortunately, these agents are underused by many physicians.3
3 ReferencesMartin Sedlacek, M.D.
Uniklinikum, 60590 Frankfurt am Main, Germany
sedlam@web.de 1
Kanno Y ,Okada H ,Saruta T ,Suzuki H . Blood pressure reduction associated with preservation of renal function in hypertensive patients with IgA nephropathy: a 3-year follow-up. Clin Nephrol 2000;54:360-365
Web of Science | Medline2
Rekola S ,Bergstrand A ,Bucht H . Deterioration rate in hypertensive IgA nephropathy: comparison of a converting enzyme inhibitor and β-blocking agents. Nephron 1991;59:57-60
CrossRef | Medline3
Dissmann W ,de Ridder M . The soft science of German cardiology. Lancet 2002;359:2027-2029
CrossRef | Web of Science | Medline
Author/Editor Response
We agree with Heine et al. that when hematuria develops, the first clue in making a proper diagnosis of glomerular bleeding comes from careful urinalysis done on a first-morning, freshly voided urine sample; evidence of glomerular bleeding can prevent unnecessary urologic intervention. In the hands of a trained observer, positive-phase microscopy of uncentrifuged urine is highly specific and very sensitive in differentiating glomerular bleeding from bleeding involving urinary erythrocytes originating from nonglomerular sites, as in papillary necrosis, tumors, and calculi.1 Erythrocytes arising from glomeruli vary markedly in size, shape (as in the case of acanthocytes, or dysmorphic red blood cells), and hemoglobin content. We emphasize that a comprehensive examination of the urine sediment is essential to determine whether a renal biopsy is indicated.2 As originally advocated by Birch et al.,1 the finding of dysmorphic erythrocytes on urinalysis provides strong support that a renal biopsy is necessary.
In response to Wardle: in our review, we mention that abnormal glycosylation of IgA, irrespective of the source, may play a major part in the pathogenesis of IgA nephropathy.2 In a murine model of IgA nephropathy, a relative or absolute increase in Th2 cytokine production in response to mucosal infection appeared to regulate glycosylation of IgA (as documented by Chintalacharuvu et al. in the report Wardle cites in his letter). Although abnormalities in Th2 responses have been identified in stimulated lymphocytes from patients with IgA nephropathy,3 it remains to be established whether this abnormal Th2 response leads to abnormal IgA glycosylation in humans.
Studies have shown that cytokine expression may reflect disease activity in IgA nephropathy.4 Analysis of these mediators may be useful in explaining the lack of response in some patients to n – 3 fatty acids or other therapies.
In response to Sedlacek: ACE inhibitors are the current drugs of choice for hypertensive patients with IgA nephropathy. A meta-analysis of ACE inhibitors in 240 adults with IgA nephropathy found that in seven trials (three short-term, one randomized prospective, and three retrospective trials) in hypertensive subjects, these drugs lowered proteinuria; however, the decrease was significant in only four of the seven trials.5 Some renoprotective effects of ACE inhibitors were noted, but the authors of the meta-analysis concluded that differences in control therapies and study designs prevented them from drawing firm conclusions about the benefits of treatment with ACE inhibitors in patients with IgA nephropathy and that a prospective, controlled trial was needed.5
5 ReferencesJames V. Donadio, M.D.
Joseph P. Grande, M.D., Ph.D.
Mayo Clinic, Rochester, MN 55905
donadio.james@mayo. edu 1
Birch DF ,Fairley KF ,Whitworth JA , et al. Urinary erythrocyte morphology in the diagnosis of glomerular hematuria. Clin Nephrol 1983;20:78-84
Web of Science | Medline2
Donadio JV ,Grande JP . IgA nephropathy. N Engl J Med 2002;347:738-748
Full Text | Web of Science | Medline3
Ebihara I ,Hirayama K ,Yamamoto S ,Muro K ,Yamagata K ,Koyama A . Th2 predominance at the single-cell level in patients with IgA nephropathy. Nephrol Dial Transplant 2001;16:1783-1789
CrossRef | Web of Science | Medline4
Yano N ,Endoh M ,Nomoto Y ,Sakai H ,Fadden K ,Rifai A . Phenotypic characterization of cytokine expression in patients with IgA nephropathy. J Clin Immunol 1997;17:396-403
CrossRef | Web of Science | Medline5
Dillon JJ . ACE inhibitor therapy for IgA nephropathy: a meta-analysis. J Am Soc Nephrol 1998;9:86A-86A abstract.
