An adolescent with relapsing nephrotic syndrome: Minimal-change disease versus focal-segmental glomerulosclerosis versus C1q nephropathy

RENAL BIOPSY CASE

An Adolescent With Relapsing Nephrotic Syndrome: Minimal-Change Disease Versus Focal-Segmental Glomerulosclerosis Versus Clq Nephropathy Scott B. Shappell, INDEX ease.

WORDS:

Clq

nephropathy;

MD, PhD, Gary Myrthil, MD, and Agnes Fogo, MD

nephrotic

syndrome;

T

HE PATIENT was a 16-year-old black boy who had nephrotic-range proteinuria and trace hematuria discovered during a routine physical examination approximately 8 months before renal biopsy. Three weeks later, the urine sediment was benign with no evidence of hematuria, and the 24-hour urine protein (Uprot) level was down to 613 mg. Serologic evaluation, including antistreptolysin-0 (ASO), complement, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, and hepatitis profile, was negative. The clinical impression at that time was possible minimal-change disease with spontaneous remission. Repeat Uprot approximately 5 weeks later was 379 mg/24 hr. However, approximately 10 weeks later (3 months before biopsy), the patient was found to have a Uprot level of 5.2 g/24 hr. Laboratory evaluations showed blood urea nitrogen 9 mg/dL, serum creatinine 1.1 mg/dL, serum cholesterol 312 mg/dL, and serum albumin 2.5 mgl dL. The patient was begun on a trial of oral prednisone (40 mg/d), and 1 month later the Uprot level was down to 295 mg. Approximately 3 weeks later (1 month before biopsy), the Uprot level remained similarly reduced at 298 mg, and the patient was kept on 40 mgld prednisone for an additional 2 weeks (for a total of 8 weeks of treatment). Subsequently, he was switched to receive prednisone every other day, but 3 days later, the Uprot level was 4.2 g. At this time, laboratory evaluation showed blood urea nitrogen 16 mg/dL, serum creatinine 1.1 mg/dL, seFrom the Department of Pathology, Vanderbilt University Medical Center, Nashville, TN; and Houston Medical Center, Warner Robins, GA. Received and accepted February 27, 1997. Address reprint requests to Agnes Fogo, MD, MCN C3310, Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232. 0 1997 by the National Kidney Foundation, Inc. 0272.6386/97/2906-0022$3.00/O 966

American

Journal

focal-segmental

glomerulosclerosis;

minimal-change

dis-

rum cholesterol 362 mg/dL, and serum albumin 2.8 g/dL. A percutaneous renal biopsy was performed. The clinical differential diagnosis included minimal-change disease, focal-segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, and immunoglobulin A (IgA) nephropathy.lM5 RENAL

BIOPSY

FINDINGS

The renal biopsy specimen was a small sample of renal cortex. There were five glomeruli on the material processed for routine light microscopy. One glomerulus was globally hyalinized. Of the four remaining glomeruli, three had segmental glomerulosclerosis (Fig 1). Two of the segmental sclerotic lesions were located in peripheral portions of the respective glomeruli, and one lesion was axial in location. The sclerotic lesions contained hyalin material and were associated with adhesions of the glomerular tuft to Bowman’s capsule and visceral epithelial cell proliferation. Segmental endocapillary proliferation, necrosis, or crescents were not present. In more normalappearing portions of glomeruli, there was no appreciable increase in mesangial cellularity, and there were no basement membrane spikes or splitting on Jones’ silver stains. There was moderate tubular atrophy with associated interstitial fibrosis and a moderate mononuclear interstitial infiltrate. Sampled arterioles and interlobular arteries were unremarkable. Three glomeruli were present on frozen sections processed for immunofluorescence microscopy. There was 2-3+ (of a maximum of 4+) diffuse global staining for IgG, primarily within the mesangium, but with some evident extension into proximal capillary walls (Fig 2). There was 2+ IgA and 1 + IgM and C3 in a similar distribution. There was no staining for C4. Staining for Clq was 2-3 + in a distribution similar to that of Kidney

Diseases,

Vol 29, No 6 (June),

1997:

pp 966-970

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Fig 1. Glomerulus with segmental sclerosis and adhesion to Bowman’s capsule. (Periodic acid-Schiff stain; magnification x500.)

Fig 3. lmmunofluorescence staining of glomerulus demonstrating prominent Clq deposition in mesangium and occasional paramesangial capillary walls. (Anti-Clq; magnification x500.)

seen for IgG, with strong mesangial and some peripheral capillary staining (Fig 3). Electron microscopic examination demonstrated expansion of the mesangium, with a slight increase in mesangial cells and mesangial matrix. There were numerous medium to large electrondense deposits within the mesangium (Fig 4). Many of the deposits were concentrated beneath the mesangial basement membrane. Occasional extension of small sliver-like deposits into the paramesangial basement membrane was appreciated. The peripheral capillary basement membranes did not contain subendothelial or intramembranous deposits. No reticular aggregates were identified within capillary endothelial cells. There was focal fusion of visceral epithelial cell foot processes.

DIAGNOSIS

Fig 2. lmmunofluorescence demonstrating IgG deposition some paramesangial capillary fication X500.)

staining of glomerulus within mesangium and walls. (Anti-IgG; magni-

The diagnosis was Clq nephropathy, with segmental glomerulosclerosis. CLINICAL

COURSE

The patient has continued to have nephroticrange proteinuria, with a Uprot level of 7.2 g/24 hr approximately 6 months after the biopsy. He has not received further specific therapy, and blood urea nitrogen and serum creatinine have remained stable. DISCUSSION

The clinical differential included common causes of nephrotic syndrome in this age group (see above). Importantly, the clinicopathologic entities responsible for nephrotic syndrome in adolescents differ from those in children. In particular, minimal-change disease is much less frequent in adolescents than in younger children, constituting only approximately 30% to 40% of cases of nephrotic syndrome.‘s3 These figures have important implications regarding prognosis and possible response to treatment. Furthermore, important racial differences may exist in the incidence of specific lesions responsible for idiopathic nephrotic syndrome in younger patients. A higher incidence of FSGS and a more rapid progression to end-stage renal disease was observed in Latin and black children with idiopathic nephrotic syndrome compared with white children.496Whether this is also true for adolescent patients specifically is not established. Thus, based on light microscopic findings, a diagnosis of FSGS seems plausible and also would be consistent with

SHAPPELL,

Fig 4. Electron micrograph demonstrating prominent mesangial electron-dense deposits, located particularly beneath the basement membrane, and occasional small sliver-like deposits extending into paramesangial capillary basement membrane. (Uranyl acetate and lead citrate stain; magnification ~5,500.)

the patient’s age, race, and presentation with steroid-resistant nephrotic syndrome. However, the presence of IgG, IgA, IgM, and C3 staining indicates an immune complex-mediated process rather than FSGS. The mesangial pattern of staining excludes membranous glomernlonephritis, and the predominance of IgG deposits excludes IgA nephropathy as a diagnostic possibility. Immune complex-mediated glomerular diseases constitute an important group of disorders in young patients with nephrotic syndrome. In an analysis of 65 adolescent patients (aged 13 to 19 years at the time of biopsy) with idiopathic nephrotic syndrome, 32% were found to have a disorder other than minimal-change disease, FSGS, or membranous glomerulonephritis3 Twelve percent of the cases were due to membranoproliferative glomerulonephritis and 20% were due to other diseases, including focal and diffuse proliferative glomerulonephritis.3 Nephritis secondary to systemic lupus erythematosus (SLE) also occurs in adolescents. In our case, there was no evidence of SLE or other systemic disease process clinically, and reticular aggregates, a frequent finding in SLE, were absent. The staining with Clq in this setting is thus consistent with Clq nephropathy with segmental sclerosis. C lq nephropathy represents an important cause of nephrotic syndrome, especially in ado-

MYRTHIL,

AND

FOG0

lescents and young adults. The light microscopy varies, as described below, so that diagnosis of this entity (particularly when Clq immunostaining is not performed routinely) depends on awareness of the clinical scenario and careful consideration of immunofluorescence and electron microscopic results. Clq nephropathy is an immune complex-mediated glomerulopathy, defined by the presence of mesangial immunoglobulin and complement deposits, with Clq immunofluorescence staining intensity being greater than or equal to that of other components.7 Clq nephropathy is a disorder primarily found in children and young adults. In the description by Jennette and Hipp,7 15 patients were identified in a series of 800 consecutive renal biopsy specimens (1.9%), in which all cases were stained with Clq antisera. The patients ranged in age from 14 to 27 years, with a mean age of 17.8 years.7 Three years previously, a group of five patients with similar clinical and morphologic features was reported by Jones and Magil under the designation of nonsystemic mesangiopathic glomernlonephritis with “full house” immunofluorescence. In this series, the patients ranged in age from 19 to 38 years. In our biopsy practice (which includes both adult and pediatric patients), we identified three cases last year, comprising a percentage of native kidney biopsies similar to that reported by Jennette and Hipp.7 The ages of our patients were 16, 26, and 3 1 years. However, in a specific examination of pediatric biopsies (in patients 16 years old or younger), Iskandar et al9 identified 1.5 patients with C 1q nephropathy (with membranoproliferative glomerulonephritis and SLE excluded on morphologic and clinical grounds), constituting 16% of pediatric biopsies performed for investigation of persistent proteinuria, nephrotic syndrome, or glomerulonephritis. Although there was a slightly increased proportion of black patients in the series reported by Jennette and Hipp,7 this was not observed in the series of Iskandar et a1.9 Patients with Clq nephropathy most commonly present with proteinuria, which is frequently of nephrotic range. However, patients also may have features of glomerulonephritis, with a more active urinary sediment. In the series of Jennette and Hipp,7 all 15 patients had proteinuria and in the 14 patients with quantitation, 10

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(7 1%) had nephrotic-range proteinuria (> 3 g/ 24 hr), with a mean of 7.5 g/24 hr.7 In addition, six of 15 (40%) patients had hematuria (> 5 red blood cells/high-power field). None of the 12 patients in whom determinations were made had reduced serum complement levels.7 In the pediatric series reported by Iskandar et aL9 nine of 15 patients (60%) presented with nephrotic syndrome, one patient had nephrotic-range proteinuria and nephritic features, three had features of glomerulonephritis including red blood cell casts, and two had nonnephrotic-range proteinuria without hematuria. In the series of what now appears to be Clq nephropathy reported by Jones and Magil,’ all five patients had prominent proteinuria (two with nephrotic-range proteinuria) and four had microhematuria. Similar to the results presented above, all five patients had normal serum C3 levels.’ Hence, the clinical presentation is slightly variable, but generally includes marked proteinuria, typically with nephrotic syndrome, with or without hematuria and red blood cell casts. Although creatinine clearance may be reduced,8’9 renal failure is not a feature at presentation. In the series reported by Jennette and Hipp,7 none of the patients had a serum creatinine above 1.5 mg/dL. By light microscopy, there is a spectrum of possible glomerular alterations, including no histologic abnormalities, mesangial proliferation, focal or diffuse proliferative glomerulonephritis, or FSGS with or without associated mesangial proliferation.7,8 Cases with no histologic abnormality are essentially indistinguishable from minimal-change disease by light microscopy. The demonstration of immunoglobulin and complement deposition, including Clq, and mesangial electron-dense deposits readily distinguishes Clq nephropathy from minimal-change disease. Irmnunofluorescence microscopy typically demonstrates a “full house” pattern of immunoglobulin and complement deposition, which completely overlaps that of lupus nephritis?,* Suspicion for the much more common diagnosis of lupus nephritis increases, particularly when accompanied by a proliferative pattern on light microscopy. Distinction is made on the basis of clinical and ultrastructural features. Patients with Clq nephropathy are ANA-negative and do not fit the clinical criteria for a diagnosis of SLE.” Ultrastructurally, patients with C lq nephropathy typically have electron-dense deposits limited to

the mesangium, in contrast to the more widespread deposits seen in many forms of lupus nephritis. However, this distinction is not sufficient to have diagnostic merit. Comparison of 15 patients with Clq nephropathy with 30 patients with proliferative lupus nephritis showed that 20% of Clq patients had subendothelial dense deposits and 13% had subepithelial deposits (compared with 86% and 68%, respectively, of the lupus nephritis patients).7 The most useful ultrastructural feature for distinguishing Clq nephropathy from lupus nephritis is absence of endothelial tubuloreticular aggregates in the former. In the series by Jennette and Hipp, reticular aggregates were not identified in any of the 15 patients with Clq nephropathy, who clinically did not have SLE (all ANA negative). In contrast, reticular aggregates were present in 88% of patients with lupus nephritis (97% of whom were ANA positive).7 Hence, in a young patient with proteinuria with or without hematuria, with a mesangial proliferative glomerulonephtitis and a “full house pattern” including Clq deposits by immunofluorescence, distinction between Clq nephropathy and lupus nephritis can be made in essentially all cases. The distinction is based on ANA serology and the absence or presence of tubuloreticular aggregates. Establishing an accurate diagnosis of Clq nephropathy appears to have important implications regarding potential response to treatment. In addition, the presence of morphologic abnormalities seen by light microscopy, particularly the presence of segmental glomerular sclerotic lesions, appears to add additional prognostic information. Data available thus far indicate that Clq nephropathy is relatively resistant to standard steroid treatment regimens, as in this case. In the series reported by Jennette and Hipp,7 nine of the 15 patients received 6 to 8 weeks of oral prednisone, and none of them had a complete response, as indicated by a decrease in proteinuria. The pediatric patients reported by Iskandar et al9 also had a poor response to steroid treatment. Compared with patients with idiopathic nephrotic syndrome who have no immunofluorescence deposits, the relative risk of not responding to an initial course of steroids in the presence of Clq deposits was 1O.9 Nonresponders were treated with pulse methylprednisolone. It is important to note that patients with Clq

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deposits and focal-segmental glomerular sclerotic lesions showed a poorer response than patients whose biopsy specimens showed no histologic abnormalities,’ with one of three such patients eventually progressing to end-stage kidney disease. In the earlier series reported by Jones and Magil,” three of five patients were treated with immunosuppressive agents (azathioprine or cyclophosphamide), two of whom also received intermittent high-dose prednisone. All the patients had persistent proteinuria over a loto 58-month follow-up period.8 One patient had progression of renal disease, as reflected by a moderate increase in serum creatinine.’ Whether Clq nephropathy with focal and segmental glomerular sclerotic lesions has a different prognosis than typical idiopathic FSGS has not been established, and neither has the risk for progression in patients without sclerosis at presentation. REFERENCES 1. Schwartz MW, Hurwitz R, Comfeld D: Clinical pathological correlates in recurrently active childhood phrosis. Am J Dis Child 120:211-216, 1970 2. International Study of Kidney Disease in Children:

and neNe-

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phrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. Kidney Int 13:159-165, 1978 3. Hogg RJ, Silva FG, Berry PL, Wenz JE: Glomerular lesions in adolescents with gross hematuria or the nephrotic syndrome. Report of the Southwest Pediatric Nephrology Study Group. Pediatr Nephrol 7:27-31, 1993 4. Ingulli E, Tejani A: Racial differences in the incidence and renal outcome of idiopathic focal segmental glomerulosclerosis in children. Pediatr Nephrol 5:393-397, 1991 5. Southwest Pediatric Nephrology Study Group: A multicenter study of IgA nephropathy in children. A report of the Southwest Pediatric Nephrology Study Group. Kidney Int 221643-652, 1982 6. Ichikawa I, Fogo A: Focal segmental glomerulosclerosis. Pediatr Nephrol 10:374-391, 1996 7. Jennette JC, Hipp CG: Clq nephropathy: A distinct pathologic entity usually causing nephrotic syndrome. Am J Kidney Dis 6:103-110, 1985 8. Jones E, Magi1 A: Nonsystemic mesangiopathic glomerulonephritis with “full house” immunofluorescence. Pathologic and clinical observations in five patients. Am J Clin Path01 78:29-34, 1982 9. Iskandar SS, Browning MC, Lorentz WB: Clq nephropathy: A pediatric clinicopathologic study. Am J Kidney Dis 18:459-465, 1991 10. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Green Schaller J, Talal N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-1277, 1982