- Email: [email protected]
To the Editor
210
LETIERS TO THE EDITOR
REFERENCES
TO THE EDITOR
1. Twardowski ZJ, Nolph KD , McGary TJ, et al: Insulin binding to plastic bags: A methodologic study. Am J Hosp Pharm 40:575-579, 1983 2. Twardowski ZJ, Nolph KD , McGary TJ , et al: Nature of insulin binding to plastic bags . Am J Hosp Pham 40:579-582, 1983 3 . Twardowski ZJ , Nolph KD , McGary TJ , et aI: Influence of temperature and time on insulin adsorption to plastic bags . Am J Hosp Pharm 40:583-586, 1983 4. Twardowski ZJ : Insulin adsorption to peritoneal dialysis bags. Peritoneal Dial Bull 3: 113-115, 1983
In a recent paper in the American Journal of Kidney Diseases, a patient with IgA glomerulonephritis (IgA GN) and the nephrotic syndrome was described in whom the nephrosis remitted rapidly after the addition of cyclophosphamide to corticosteroid therapy. I We wish to report a patient with IgA GN with steroiddependent nephrotic syndrome who has been in long-standing clinical remission during therapy with chlorambucil.
REPLY Dr Twardowski and associates have raised important methodologic concerns regarding the binding of insulin. Close examination of their cited work reveals, for the most part, striking similarity to the methods employed in our study. To avoid binding of insulin to intermediate containers, syringes containing the samples were placed directly into the gamma counter. Likewise, the concentration of labeled insulin was kept similar in all solutions (0.5 }lCi). The amount of insulin added to each container was calculated in a manner similar to that used by Twardowski: amount (counts) injected = counts per minute in syringe (before injection) - counts remaining in syringe (after injection). The amount of unbound insulin and the percent of insulin lost to the surface of each container also were calculated in a manner similar to that used by Twardowski. Following injection of the insulin into the containers, each container was gently mixed by inversion and squeezing. Foaming of the solutions did not occur. This procedure appears to be similar to what was described in Twardowski's papers. We remain unconvinced that the diffe·rences in adsorption seen at one minute and later sampling times as reported in our study can be explained by inadequate sample mixing. In the study by Twardowski, the solutions were transferred repeatedly between bags. The effect of transferring and the accompanying agitation of the fluid on insulin adsorption is unknown. To address the issue of sample geometry, we conducted a brief experiment using noninsulin , 125I-containing solutions. Samples of varying dimensions were counted. As indicated by Twardowski and associates, the geometry of the samples does influence the isotope counts recorded. The extent to which this factor contributed to our results is unknown . We agree , however, that the differences observed in the studies may be partially explained by this observation. We thank Twardowski et al for their comments and suggestions.
Curtis A. Johnson, PharmD Gordon Amidon, PhD James E. Reichert, MS William R. Porter, PhD School of Pharmacy University of Wisconsin 425 N Charter St Madison, WI 53706
Case Report After a febrile infection in January 1980, a 57-year-old man had noticed peripheral swellings, for which he came to Tampere University Central Hospital. On physical examination, there was edema on the legs, hands, and face, and the BP was 125/90 mm Hg. Laboratory tests showed normal blood count. Serum creatinine was 1.2 mg/dL, serum protein 4.6 g/dL, and serum albumin 1.5 g/dL. Serum cholesterol was 1140 mg/dL. The serum ASO titer was not elevated, there were no cryoglobulins, and the ANA test was negative. The serum C3 and C4 concentrations were normal. Serum IgA level was elevated, ie, 675 mg/dL (normally 70 to 370 mg/dL) . Urinalysis showed 3+ protein; there were no RBCs. Urine protein excretion was 12.5 g/24 h. Renal biopsy was performed, and the specimens were processed as described previously.2 Light microscopic study showed minimal increase in mesangial matrix. On immunofluorescence, heavy mesangial deposits of IgA and smaller amounts of C3 were observed in a diffuse and granular pattern. Ultrastructural examination disclosed large mesangial electrondense deposits and a few subendothelial deposits, as well as widely spread foot process fusion. Methylprednisolone (MP) 48 mg/d was started, and a rapid response was noticed; urine protein levels became normal and swellings disappeared. The first relapse of the nephrotic state was noticed in June 1980 during a gastroenteritis caused by Salmonella typhimurium. The patient was treated with MP, and because he now did not rapidly respond to MP, cyclophosphamide (150 mg/d) was added to the therapy. After that, the nephrotic syndrome remitted. One month later, cyclophosphamide was discontinued because of dysuria and microscopic hematuria. Subsequently, hematuria has not been observed, and the patient has had three relapses during 2 years. In all the thr.ee cases, a rapid response has been obtained with an increasect dosage of MP. The longest period that the patient has been free of MP has been 2 months . Because of the elevated blood glucose level (222 mg %) during the high dose of MP, chlorambucil (IO mg/d) was started in October 1982. During a follow-up of 17 months there have been no recurrences of the nephrotic syndrome, and the regimen of the patient is presently chlorambucil 5 mg/d and MP 8 mg every two days. The renal function and BP have been normal.
Comment This case report agrees with the concept that the nephrotic syndrome in IgA GN may be responsive to immunosuppressive
211
LETTERS TO THE EDITOR
therapy.' In our patient, as in that of Abreo and Wen,' the addition of cyclophosphamide to corticosteroid therapy seemed to cause the disappearance of the nephrosis . Further, in our case, the patient has been in long-standing clinical remission during the therapy with chlorambucil. The beneficial effect of corticosteroid therapy on the nephrotic syndrome in IgA nephropathy patients has recently been described in a few cases.'·3 In all the patients of these reports, light microscopic study has shown minimal mesangial alterations. The absence of hematuria also seems to correlate with favorable therapeutic and prognostic features. In these histologic and clinical aspects, these patients with IgA GN closely resemble those with minimal change nephrotic syndrome. Of interest is a recent report of patients who initially had minimal change glomerulonephritis but in whom control renal biopsies disclosed typical findings of IgA GN. 4 The authors suggest that the association of IgA GN and minimal change GN may indicate common predisposing factor to these glomerular disorders.4 Jukka Mustonen, MD Amos Pasternack Professor of Medicine Department of Clinical Sciences University of Tampere Teiskontie 35 SF-33520 Tampere 52 Finland
REFERENCES I. Abreo K, Wen S-F: A case of IgA nephropathy with an unusual response to corticosteroid and immunosuppressive therapy. Am J Kidney Dis 3:54-57, 1983 2. Mustonen J, Pasternack A, Rantala I: The nephrotic syndrome in IgA glomerulonephritis: Response to corticosteroid therapy. Clin Nephrol 20:172-176, 1983 3. Saint-Andre Jp, Simard CL, Spiesser R , et al: Syndrome nephrotique de renfant alesions glomerulaires minimes, avec depots mesangiaux d'IgA . Nouv Presse Med 9:531-532, 1980 4. Hogg R, Silva F: Development of IgA nephropathy (IgAN) in 4 children with long-standing steroid-responsive nephrotic syndrome (SRINS). American Society of Nephrology, 16th Annual Meeting, Washington, DC, 1983, P30A
REPLY Heavy proteinuria associated with IgA nephropathy has generally been thought to occur only in the advanced stage of the disease and most commonly indicates a poor prognosis. 1.2 On rare occasions, however, IgA nephropathy may present with nephrotic syndrome without microscopic hematuria or hypertension and may resemble minimal change disease in its responsiveness to steroids and immunosuppressive medications. J.> The report by Mustonen and Pasternack in their letter
further confirms the existence of such an entity, which is distinctly different from the conventional IgA nephropathy. The question of whether these cases represent a variant of IgA nephropathy or, alternatively, the steroid-dependent, minimal change nephrotic syndrome is superimposed on a preexisting, subclinical IgA nephropathy remains unresolved. The report by Hogg and Silva· of the development of IgA nephropathy in children with steroid-responsive nephrotic syndrome may suggest some relationship between the two diseases, but in view of the high incidence of IgA nephropathy in certain populations,7.8 their coexistence may also be purely coincidental. Clinical implication of these reports is clear. IgA nephropathy presenting as nephrotic syndrome with minimal glomerular changes should not be considered to be invariably resistant to steroid or immunosuppressive therapy. A trial of such treatment should frequently bring about a dramatic clearing of nephrotic syndrome. Although the long-term prognosis of these cases is still unknown, it appears to be more favorable than that of the conventional IgA nephropathy complicated by nephrotic syndrome. Sung-Feng Wen, MD Professor of Medicine Nephrology Section University of Wisconsin Medical School 600 Highland Ave , H4/51O Madison, WI 53792
REFERENCES 1. Hood SA, Velosa JA , Holley KE, et al: IgA-IgG nephropathy: Predictive indices of progressive disease. Clin Nephrol 16:55-62, 1981 2. Kincaid-Smith P, Nicholls K: MesangiallgA nephropathy. Am J Kidney Dis 3:90-102, 1983 3. Abreo K,Wen S-F: A case of IgA nephropathy with an unusual response to corticosteroid and immunosuppressive therapy. Am J Kidney Dis 3:54-57, 1983 4. Mustonen J, Pasternack A, Rantala I: The nephrotic syndrome in IgA glomerulonephritis: Response to corticosteroid therapy. Clin Nephrol 20: 172-176, 1983 5. Saint-Andre Jp, Simard CL, Spiesser R, et al: Syndrome nephrotique de l'enfanta lesions glomerulaires minimes, avec depots mesangiaux d 'lgA. Nouv Presse Med 9:531-532, 1980 6. Hogg R, Silva F: Development of IgA nephropathy (IgAN) in 4 children with long-standing steroid-responsive nephrotic syndrome (SRINS). American Society of Nephrology, 16th Annual Meeting , Washington, DC , 1983, P 30A 7. Sinniah R, Pwee HS , Lim CH: Glomerular lesions in asymptomatic microscopic hematuria discovered on routine medical examination. Clin Nephrol 5:216-228 , 1976 8. Shirai T, Tomino Y, Sato M, et al: IgA nephropathy: Clinicopathology and immunopathology. Contrib Nephrol 9:88-100, 1978
LETIERS TO THE EDITOR
REFERENCES
TO THE EDITOR
1. Twardowski ZJ, Nolph KD , McGary TJ, et al: Insulin binding to plastic bags: A methodologic study. Am J Hosp Pharm 40:575-579, 1983 2. Twardowski ZJ, Nolph KD , McGary TJ , et al: Nature of insulin binding to plastic bags . Am J Hosp Pham 40:579-582, 1983 3 . Twardowski ZJ , Nolph KD , McGary TJ , et aI: Influence of temperature and time on insulin adsorption to plastic bags . Am J Hosp Pharm 40:583-586, 1983 4. Twardowski ZJ : Insulin adsorption to peritoneal dialysis bags. Peritoneal Dial Bull 3: 113-115, 1983
In a recent paper in the American Journal of Kidney Diseases, a patient with IgA glomerulonephritis (IgA GN) and the nephrotic syndrome was described in whom the nephrosis remitted rapidly after the addition of cyclophosphamide to corticosteroid therapy. I We wish to report a patient with IgA GN with steroiddependent nephrotic syndrome who has been in long-standing clinical remission during therapy with chlorambucil.
REPLY Dr Twardowski and associates have raised important methodologic concerns regarding the binding of insulin. Close examination of their cited work reveals, for the most part, striking similarity to the methods employed in our study. To avoid binding of insulin to intermediate containers, syringes containing the samples were placed directly into the gamma counter. Likewise, the concentration of labeled insulin was kept similar in all solutions (0.5 }lCi). The amount of insulin added to each container was calculated in a manner similar to that used by Twardowski: amount (counts) injected = counts per minute in syringe (before injection) - counts remaining in syringe (after injection). The amount of unbound insulin and the percent of insulin lost to the surface of each container also were calculated in a manner similar to that used by Twardowski. Following injection of the insulin into the containers, each container was gently mixed by inversion and squeezing. Foaming of the solutions did not occur. This procedure appears to be similar to what was described in Twardowski's papers. We remain unconvinced that the diffe·rences in adsorption seen at one minute and later sampling times as reported in our study can be explained by inadequate sample mixing. In the study by Twardowski, the solutions were transferred repeatedly between bags. The effect of transferring and the accompanying agitation of the fluid on insulin adsorption is unknown. To address the issue of sample geometry, we conducted a brief experiment using noninsulin , 125I-containing solutions. Samples of varying dimensions were counted. As indicated by Twardowski and associates, the geometry of the samples does influence the isotope counts recorded. The extent to which this factor contributed to our results is unknown . We agree , however, that the differences observed in the studies may be partially explained by this observation. We thank Twardowski et al for their comments and suggestions.
Curtis A. Johnson, PharmD Gordon Amidon, PhD James E. Reichert, MS William R. Porter, PhD School of Pharmacy University of Wisconsin 425 N Charter St Madison, WI 53706
Case Report After a febrile infection in January 1980, a 57-year-old man had noticed peripheral swellings, for which he came to Tampere University Central Hospital. On physical examination, there was edema on the legs, hands, and face, and the BP was 125/90 mm Hg. Laboratory tests showed normal blood count. Serum creatinine was 1.2 mg/dL, serum protein 4.6 g/dL, and serum albumin 1.5 g/dL. Serum cholesterol was 1140 mg/dL. The serum ASO titer was not elevated, there were no cryoglobulins, and the ANA test was negative. The serum C3 and C4 concentrations were normal. Serum IgA level was elevated, ie, 675 mg/dL (normally 70 to 370 mg/dL) . Urinalysis showed 3+ protein; there were no RBCs. Urine protein excretion was 12.5 g/24 h. Renal biopsy was performed, and the specimens were processed as described previously.2 Light microscopic study showed minimal increase in mesangial matrix. On immunofluorescence, heavy mesangial deposits of IgA and smaller amounts of C3 were observed in a diffuse and granular pattern. Ultrastructural examination disclosed large mesangial electrondense deposits and a few subendothelial deposits, as well as widely spread foot process fusion. Methylprednisolone (MP) 48 mg/d was started, and a rapid response was noticed; urine protein levels became normal and swellings disappeared. The first relapse of the nephrotic state was noticed in June 1980 during a gastroenteritis caused by Salmonella typhimurium. The patient was treated with MP, and because he now did not rapidly respond to MP, cyclophosphamide (150 mg/d) was added to the therapy. After that, the nephrotic syndrome remitted. One month later, cyclophosphamide was discontinued because of dysuria and microscopic hematuria. Subsequently, hematuria has not been observed, and the patient has had three relapses during 2 years. In all the thr.ee cases, a rapid response has been obtained with an increasect dosage of MP. The longest period that the patient has been free of MP has been 2 months . Because of the elevated blood glucose level (222 mg %) during the high dose of MP, chlorambucil (IO mg/d) was started in October 1982. During a follow-up of 17 months there have been no recurrences of the nephrotic syndrome, and the regimen of the patient is presently chlorambucil 5 mg/d and MP 8 mg every two days. The renal function and BP have been normal.
Comment This case report agrees with the concept that the nephrotic syndrome in IgA GN may be responsive to immunosuppressive
211
LETTERS TO THE EDITOR
therapy.' In our patient, as in that of Abreo and Wen,' the addition of cyclophosphamide to corticosteroid therapy seemed to cause the disappearance of the nephrosis . Further, in our case, the patient has been in long-standing clinical remission during the therapy with chlorambucil. The beneficial effect of corticosteroid therapy on the nephrotic syndrome in IgA nephropathy patients has recently been described in a few cases.'·3 In all the patients of these reports, light microscopic study has shown minimal mesangial alterations. The absence of hematuria also seems to correlate with favorable therapeutic and prognostic features. In these histologic and clinical aspects, these patients with IgA GN closely resemble those with minimal change nephrotic syndrome. Of interest is a recent report of patients who initially had minimal change glomerulonephritis but in whom control renal biopsies disclosed typical findings of IgA GN. 4 The authors suggest that the association of IgA GN and minimal change GN may indicate common predisposing factor to these glomerular disorders.4 Jukka Mustonen, MD Amos Pasternack Professor of Medicine Department of Clinical Sciences University of Tampere Teiskontie 35 SF-33520 Tampere 52 Finland
REFERENCES I. Abreo K, Wen S-F: A case of IgA nephropathy with an unusual response to corticosteroid and immunosuppressive therapy. Am J Kidney Dis 3:54-57, 1983 2. Mustonen J, Pasternack A, Rantala I: The nephrotic syndrome in IgA glomerulonephritis: Response to corticosteroid therapy. Clin Nephrol 20:172-176, 1983 3. Saint-Andre Jp, Simard CL, Spiesser R , et al: Syndrome nephrotique de renfant alesions glomerulaires minimes, avec depots mesangiaux d'IgA . Nouv Presse Med 9:531-532, 1980 4. Hogg R, Silva F: Development of IgA nephropathy (IgAN) in 4 children with long-standing steroid-responsive nephrotic syndrome (SRINS). American Society of Nephrology, 16th Annual Meeting, Washington, DC, 1983, P30A
REPLY Heavy proteinuria associated with IgA nephropathy has generally been thought to occur only in the advanced stage of the disease and most commonly indicates a poor prognosis. 1.2 On rare occasions, however, IgA nephropathy may present with nephrotic syndrome without microscopic hematuria or hypertension and may resemble minimal change disease in its responsiveness to steroids and immunosuppressive medications. J.> The report by Mustonen and Pasternack in their letter
further confirms the existence of such an entity, which is distinctly different from the conventional IgA nephropathy. The question of whether these cases represent a variant of IgA nephropathy or, alternatively, the steroid-dependent, minimal change nephrotic syndrome is superimposed on a preexisting, subclinical IgA nephropathy remains unresolved. The report by Hogg and Silva· of the development of IgA nephropathy in children with steroid-responsive nephrotic syndrome may suggest some relationship between the two diseases, but in view of the high incidence of IgA nephropathy in certain populations,7.8 their coexistence may also be purely coincidental. Clinical implication of these reports is clear. IgA nephropathy presenting as nephrotic syndrome with minimal glomerular changes should not be considered to be invariably resistant to steroid or immunosuppressive therapy. A trial of such treatment should frequently bring about a dramatic clearing of nephrotic syndrome. Although the long-term prognosis of these cases is still unknown, it appears to be more favorable than that of the conventional IgA nephropathy complicated by nephrotic syndrome. Sung-Feng Wen, MD Professor of Medicine Nephrology Section University of Wisconsin Medical School 600 Highland Ave , H4/51O Madison, WI 53792
REFERENCES 1. Hood SA, Velosa JA , Holley KE, et al: IgA-IgG nephropathy: Predictive indices of progressive disease. Clin Nephrol 16:55-62, 1981 2. Kincaid-Smith P, Nicholls K: MesangiallgA nephropathy. Am J Kidney Dis 3:90-102, 1983 3. Abreo K,Wen S-F: A case of IgA nephropathy with an unusual response to corticosteroid and immunosuppressive therapy. Am J Kidney Dis 3:54-57, 1983 4. Mustonen J, Pasternack A, Rantala I: The nephrotic syndrome in IgA glomerulonephritis: Response to corticosteroid therapy. Clin Nephrol 20: 172-176, 1983 5. Saint-Andre Jp, Simard CL, Spiesser R, et al: Syndrome nephrotique de l'enfanta lesions glomerulaires minimes, avec depots mesangiaux d 'lgA. Nouv Presse Med 9:531-532, 1980 6. Hogg R, Silva F: Development of IgA nephropathy (IgAN) in 4 children with long-standing steroid-responsive nephrotic syndrome (SRINS). American Society of Nephrology, 16th Annual Meeting , Washington, DC , 1983, P 30A 7. Sinniah R, Pwee HS , Lim CH: Glomerular lesions in asymptomatic microscopic hematuria discovered on routine medical examination. Clin Nephrol 5:216-228 , 1976 8. Shirai T, Tomino Y, Sato M, et al: IgA nephropathy: Clinicopathology and immunopathology. Contrib Nephrol 9:88-100, 1978