Dense Deposit Disease in Children: Prognostic Value of Clinical and Pathologic Indicators

Dense Deposit Disease in Children: Prognostic Value of Clinical and Pathologic Indicators The Southwest Pediatric Nephrology Study Group • Clinical and pathological features were examined in 16 children with dense deposit disease. The children ranged in age from 5 to 15 years (mean: 9.3 years). There were nine boys and seven girls. Semiquantitative grading of renal biopsy findings was performed in these patients and compared to clinical features at the time of presentation, and at the time of latest follow-up. Initial clinical features included hypertension and decreased glomerular filtration rate in 50% of patients, nephrotic syndrome in 69%, and gross hematuria in 73%. Serum C3 concentrations were low in nine of nine patients. All but one of the patients subsequently received steroid therapy, the dosage of which varied. Of the 16 patients, six developed progressive renal insufficiency, six have normal renal function after a period of 7 to 12 years, and four have normal renal function but have been followed for less than 6 years. When these different subgroups were compared, clinical and laboratory features were not helpful outcome indicators. By contrast, poor outcome was correlated with the following pathologic features: excessive prominence of glomerular lobules, severe mesangial hypercellularity and sclerosis, severe glomerular loop obliteration, and mesangial electron dense deposit alteration. We conclude that the course of dense deposit disease is variable and that certain pathologic features may be helpful in predicting clinical outcome. Whether alternate-day prednisone therapy may have been of benefit for the patients In this study is uncertain. © 1985 by the National Kidney Foundation, Inc. INDEX WORDS: Dense deposit disease; membranoproliferative; steroids; growth.

D

ENSE DEPOSIT DISEASE (DDD), a condition also known as membranoproliferative glomerulonephritis (MPGN), type IJI, has been associated with a poor prognosis in the majority of reported series. 1- 6 In many of these studies, an attempt has been made to evaluate clinical and renal biopsy features as outcome indicators, but the information available is incomplete. The primary goals of the present study were to describe the long-term clinical course of DDD and to identify clinical and pathologic features that might predict which patients are at greatest risk of progressive renal disease . Since most of the children in our study received steroid therapy, an attempt was also made to evaluate the effectiveness of such treatment. It will be shown that certain pathologic features might be useful outcome indicators of DDD in children, and that the remarkably good clinical status in most of our patients after a long period of follow-up may have been related to the steroid therapy received or to a more benign form of the disease, or both. MATERIALS AND METHODS Patients were considered for entry into the study on the basis of a renal biopsy diagnostic of DDD. 7 Clinical data were obtained by retrospective study of hospital records in each of the participati ng institutions . The collection of data was performed by completion of a detailed questionnaire that had been

From the Southwest Pediatric Nephrology Study Group: Ronald J. Hogg (Director); Fred S. Silva (Associate Director); Tito Cavallo, Henry R. Krous, Patrick Walker (Pathology Coordinators); Shane Roy Ill, Luther Travis, James Wenzl (Clinical Coordinators); Joan S. Reisch (Statistician); Nancy Campbell (Statistical Programmer); William Fox (Data Manager); Kaye Green (Administrative Secretary). SPNSG Centers and participants: Baylor College of Medicine , Houston (Phillip L. Berry, Edith P Hawkins , L. Leighton Hill , Sami A. Sanjad): Tulane University Medical Center, New Orleans (Frank G. Boineau. John E. Lewy, Patrick D. Walker); University of Arkansas, Little Rock (Watson C. Arnold, Edward O. Uthman); University of Colorado, Denver (Stephen 1. Guggenheim, Gary M. Lum); University of Louisiana at Shreveport (w. Frank Tenney); University of Oklahoma Medical Center, Oklahoma City (Henry R. Krous, James R. Matson , James E. Wenzl); University of Tennessee, Memphis (William M. Murphy, Shane Roy III, F. Bruder Stapleton); University of Texas Health Science Center at Dallas (Billy S. Arant, Jr. Edwin H. Eigenbrodt, Ronald J. Hogg, Mark T Houser, Ruben Meyer, H. Leslie Moore , Joan S. Reisch, Fred Silva , Arthur G. Weinberg); University of Texas Health Science Center at Houston (Eileen Brewer, Susan B. Conley, Gilbert Rose, Regina li!rani); University of Texas Medical Branch, Galveston (Ben H. Brouhard, Tito Cavallo, Alok Kalia , Srinivasan Rajaraman, Luther B. Travis); University of Texas Health Science Center at San Alllonio (Michael Foulds, Sudesh Makker, Fermin Tio , Victor Saldivar, Fred A. McCurdy). Address reprint requests to R.J. Hogg. MD, SPNSG Central Office, University of Texas Health Science Center at Dallas , 5323 Harry Hines Blvd, Dallas, TX. 75235. © /985 by the National Kidney Foundation, Inc. 0272-6386/85/0603-0005$03.00/0

American Journal of Kidney Diseases, Vol VI, No 3, September 1985

161

162

THE SOUTHWEST PEDIATRIC NEPHROLOGY STUDY GROUP Table 1.

Clinical and Pathologic Variables Studied in Patients with Dense Deposit Disease Pathologic Features

Clinical and Laboratory Features

Light Microscopic Studies

Electron Microscopic Studies

Age Sex Race Blood pressure Edema Estimate of GFR Serum ANA Serum albumin Hematuria, severity Proteinuria, semiquantitative Third component of serum complement (C3) Treatment with steroids

Glomerular enlargement Glomerular lobulation Mesangial hypercellularity Mesangial sclerosis Glomerular capillary loop obliteration Glomerular crescents

Mesangial interposition Loss of foot processes Subepithelial deposits Intramembranous deposits Glomerular basement membrane thickening Dense deposit alteration in basement membrane Dense deposit alteration in mesangia

Tubulointerstitial disease Tubular atrophy Interstitial fibrosis Inflammatory infiltration

de" eloped by members of the SPNSG. The clinical and laboratory features that are depicted in Table I were assessed in each patient on two occasions: (a) before the time of diagnostic renal biopsy and (b) at latest follow-up evaluation. Hypertension was defined as a diastolic blood pressure greater than 95 % for age based on the Pediatric Task Force recommendations,8 or a diastolic pressure equal to or greater than 90 mm Hg. Proteinuria was evaluated by dipstick estimation , by 24-hour quantitative measurement, or both. The nephrotic syndrome (NS) wa s defined as proteinuria (~ 2 + qualitative proteinuria by dipstick, or ~ 40 mg/m2/hr) , serum albumin < 2 .5 gm/dL, and edema. Hematuria was defined as positive if blood was present by dipstick or if microscopic examination of the urinary sediment showed equal to or greater than five RBC/hpf, and gross if visib le with the naked eye. Glomerular filtration rate (GFR) (mLlmin/ I. 73 m 2) was estimated as inulin, creatinine, or sodium iothalomate (Glofil. Isotex, Friendswood, Texas) , clearance when one of these procedures was carried out, but otherwise was calculated from the formula: GFR (mLlmin / I.73 m 2) = 0.55 x body length (cm)/serum creatinine (mg/dL)9 GFR was then coded for each p atie nt as normal ( > 90) ; mild reduction (60 to 90) ; mode rate reduction (30 to 60) or severe reduction « 30). End-stage renal disease (ESRD) was defined as irreversible renal failure that required dialysis. Serum concentrations of creatinine, albumin and C3 , and serum antinuclear antibody levels (A N A) were performed at each institution using local laboratory methods.

Pathologic Studies For light microscopic stud ies, the tissues had been fixed in Duboscq-Brasil , Zenker's , or 10 % buffered formalin solutions, embedded in either paraffin or plastic , and cut into thin sections (2 to 4 /lm) . The sections were stained with hematoxy lin and eosin, periodic acid-Schiff, silver methenamine, and either Gomori 's or Masson 's trichrome . Representative sections were evaluated by two patholog ists of the SPNSG without knowledge of clinical finding s or outcome. The number of glo-

meruli studied in each biopsy ranged from 6 to 50 (mean: 18). The renal biopsies were assessed with respect to the severity and distribution of a variety of pathologic features. Although a total of 34 features (15 in glomeruli , 5 in tubules, 6 in the interstitium, and 8 in vessels) were sought and assessed in light microscopic sections, only finding s that yielded some correlative information are listed in Table I. Definitions and grades of severity of pathologic features follow. Glomerular enlargement: diameter greater than 200 /lm in cross sections that included the vascular pole. Lobulatiol/: prominence of glomerular lobules. Mesangial hypercellularity: grades 1, 2 , and 3 refer to 3 to 4, 5 to 7, and 8 or more nuclei present per mesangial region , respectively. Mesangial cells contiguous to the vascular pole were not included in the assessment. Mesangial sclerosis: grades 1,2, and 3 refer to 1,2 to 3, and 4 or more sclerosed lobules , respectively. Loop obliteration: no visible residual glomerular capillary lumen ; grades 1,2, and 3 refer to < 20%,20% to 60%, or> 60 % obliteration of loops, respecti veJy. Tubular atrophy, interstirial fibrosis, and inflammatory infiltration: grades 1, 2, and 3 refer to < 20 %, 20% to 50 %, or > 50 % involvement of areas examined. For electron microscopic studies, the specimens were fixed with glutaraldehyde, Karnovsky 's fixative , or Carson 's formalin and were processed using standard laboratory techniques as detailed previously. 10 II Ultrastructural findings were compiled from photomicrographs (mean: 13 ; range : 5 to 35) and the accompanying diagnostic reports. On the average, 20 glomerular capillary loops were studied in each biopsy. The features assessed are listed in Table 1. Each feature represents the percentage of involvement rounded to the nearest 10 %. Definitions of pathologic ultrastructural features follow. Glomerular basement membrane (GBM) thi ckening: thickness at least twofold increased (about 500 to 600 nm) ; grades 1 , 2 , and 3 refer to < 20 %. 20 % to 60 %, or > 60 % involvement of loops, respectivel y. Continuous dense deposits: de nse deposit alteration involving the whole length of the GBM in a capi llary loop. Discontinllolls dense deposits: dense deposit alteration in ca pill ary loops in which portions of the GBM remained apparently uninvolved.

DENSE DEPOSITS IN CHILDREN

163

Mesangial dense deposits: dense deposit alteration involving mesangial areas. Subepithelial and intramembranous deposits: deposits of electron dense material of the variety usually encountered in immune complex disease, present in the referenced locations. All light and electron microscopic findings were assessed to reflect the average degree of involvement and are expressed as mean ± SD. Other pathologic terms are used in their common connotations. 12 For immunofluorescence studies, frozen sections were incubated with fluoresceinated monospecific antisera for human IgG, IgA, IgM, and C3. The sources of the antisera varied, but the majority of the participating institutions utilized reagents from Meloy Lab, Inc (Springfield, Va.). The findings were obtained from the renal biopsy records.

Statistical Methods Where appropriate, clinical and pathologic variables were subjected to one or more of the following statistical analyses: Student's t-test, Chi-square analysis, Fisher's exact test, and Spearman's correlation coefficient. A P value equal to or less than 0.05 was considered to be significant.

RESULTS Clinical and Laboratory Features

The major clinical and laboratory findings of the 16 patients (nine boys, seven girls) who were accepted into the study are summarized in Table 2. The mean age of the patients was 9.3 ± 2.7 years (range 5 to 15 years); 10 were white, 4 Hispanic, 1 black, and 1 oriental. None had clinical or laboratory data that suggested the presence of an associated systemic disease. Prior to the diagnostic renal biopsy procedure, 11 patients had the nephrotic syndrome, 11 had gross hematuria, seven were hypertensive, and seven had decreased renal function which was severe in one, moderate in three, and mild in three. Serum C3 concentrations were below the normal range in all nine patients in which this assay was performed.

Table 2. Dense Deposit Disease: Clinical Presentation, Length of Follow-up, Treatment Status, and Clinical Outcome Features at Presentation Patient No.

Age/Sex/Race

Group A'

2

8/F/H

5

10/FIW

8

8/M/H

9

8/MIW

15 16

9/MIW 5/M/O

Group Bt 6

7 10 11

10/FIW 111FIW 9/M/H 10/FIW

13 14

6/F/H 10/F/B

NS

GH

o

GRF Code

N

o

(BUN 10)

lU

o

o

o

1

o

Group C:f: 13/MIW 1 5/MIW 3 4 15/MIW

o o

12/MIW

o

12

BP

1

Duration of Follow-up (months)

61 (ESRD) "Pulses" then 60/d ~fter biopsy 3 (ESRD) Quintuple Rx including prednisone 19 (ESRD) 4 months Rx (12 months after presentation) 167 20 (started > 8 yrs after presentation) 38 40 100 20

N

N

N i

U 1

N i N N

N 1 N U

122 145

i i

U N

134 85

N

(BUN 10) N N

44 70 54

N

26

1

Prednisone Rx (mg/every other day)

99 121

40 40 40 20 (started 6 yrs after presentation) 60 none 80 40 120 to 50 over 3 yrs 60

Outcome Pr

Cr

GFR

C3

BP

ESRD ESRD ESRD 3

8.3

11

3 3

1.8 4.0

44 20

34 18

3 3 2 2

0.9 0.7 1.0 0.8

94

32

88 111

44 90

N N i N

2 3

0.8 0.7

105 130

27 160

N i

3

0.7 0.9 0.9

132 85 94

72 34

0.5

188

40

o o

N N

i

'Children with poor outcome. tChildren with good outcome after period of observation greater than 7 years. :f:Children with good outcome but short period of follow-up (less than 6 years). Abbreviations: W = white; H= Hispanic; B = black; 0 = other; BP = blood pressure; NS = nephrotic syndrome; GH = gross hematuria; 0 = absent; 1 = present; Pr = dipstick assessment of proteinuria (0-4 +); Cr = serum creatinine (mg/dL); C3 = serum concentration of third component of complement (mg/dL); i = elevated. Glomerular filtration rate (GFR) code: l = 60-90 mLlmin/1.73 m3 ; U = 30-60 mLlmin/1.73 m2; ltl = less than 30 mLl min/1.73 m2; N = normal.

164

THE SOUTHWEST PEDIATRIC NEPHROLOGY STUDY GROUP Table 3. Dense Deposit Disease: Semiquantitative Grading of Diagnostic Biopsies by Light Microscopy

Feature Percent large glomeruli Percent glomerular lobulation Mesangial hypercellularity (grades 2 and 3) Percent mesangial hypercellularity Mesangial sclerosis (grades 2 and 3) Percent mesangial sclerosis Loop obliteration (grades 2 and 3) Percent loop obliteration Presence of crescents

Overall Group (%) (n

=

16)

Group A' (%) (n

= 6)

Group (n

St (%) = 6)

P value;

48 ± 44 46 ± 40 75

70 ± 47 72 ± 33 100

32 ± 38 18 ± 10 67

0.15 0.01 0.46

68 ± 36

87 ± 22

43 ± 31

0.02

39

67

17

0.04

36 ± 33 50

53 ± 27 100

18 ± 21 17

0.03 0.01

48 ± 8 31

65 ± 26 67

23 ± 30

0.03 0.24

17

• Patients with evidence of progressive renal insufficiency. tPatients with no evidence of progressive renal insufficiency and follow-up period of 7 years or more. :j:Companson between groups A and B. Where standard deviations are given, the number refers to the extent of involvement (%) of the feature in patients in that group; where. sta~dard deviations are absent, the number refers to the percentage of patients in that group who demonstrate the lesion (In the severity that is indicated).

Pathologic Features

On light microscopic studies, overall, the glomeruli were enlarged, the lobules were prominent, there was an increase in mesangial sclerosis and in the number of cells in mesangial areas, the GBM were thickened, and there was variable obliteration of capillary loops . The mean percentage of glomeruli presenting the referenced features and the corresponding degree of severity are shown in Table 3. Of features assessed but not tabulated , mesangial interposition in peripheral capillary loops was present in seven of 16 biopsies but involved only a few loops; neutrophilic infiltration (more than 5 neutrophils per cross section of glomeruli) was present in three of 16 biopsies (patients 5, 15, and 16); tubular atrophy and interstitial fibrosis (2 + to 3 + ) were present in three of 16 biopsies (patients 5, 8 and 9), and was associated with interstitial lymphocytic inflammation; and vascular changes, presumably attributable to hypertension (medial hypertrophy, intimal thickening) , were present in three biopsies (patients 5, 9, and 14). On electron microscopic studies, continuous (more frequently) or discontinuous (less frequently) dense deposit alteration of the GBM were present, to a variable extent, in all biopsies . Dense deposit alteration in mesangia was present in 13 of 16 biopsies and involved 50 % or more of the me-

sangial area in 11 biopsies. Mesangial interposition was present in 12 of 16 biopsies, loss of visceral epithelial cell foot processes was present in all biopsies and involved 50% or more of the surface of capillary loops in 11; occasional subepithelial and intramembranous dense deposits of the usual variety were present in eight and six biopsies , respectively ; and thickening of the GBM was confirmed ultrastructurally in all biopsies. The mean percentage of glomerular involvement by each of the referenced features is shown in Table 4. On immunofluorescence microscopic studies, C3 was detected in 12 of 12 biopsies studied and was present in a peripheral glomerular lobular configuration in the form of short linear or short linear and mesangial granular deposits. Peripheral capillary loop deposits of IgG , IgM, and IgA were present in two of 12, nine of 12, and one of 12 biopsies, respectively. No attempt was made to establish the relative intensity of deposits because of lack of uniformity in reagents used . It was clear, however, from the reports, that in all instances , C3 was the predominant protein found in glomeruli. Pathologic Correlations

A number of the pathologic variables were found to be associated with each other. We observed that severe glomerular lobulation was asso-

165

DENSE DEPOSITS IN CHILDREN

Table 4. Dense Deposit Disease: Semiquantitative Grading of Diagnostic Biopsies by Electron Microscopy Feature

Overall Group

(n = 16)

Group A*

Group Bt (n = 6)

P value:!:

Percent mesangial interposition Percent foot process loss Presence of subepithelial deposits Presence of intramembranous deposits GBM thickening (grades 2 and 3) Percent GBM thickening Percent loops with continuous dense deposit alteration in GBM Percent of loops with discontinuous dense deposit alteration in GBM Percent of mesangial areas with dense deposit alteration

23 ± 21 66 ± 27 53 40

30 ± 24 82 ± 22 83 50

25 ± 20 57 ± 27 67 67

0.70 0.11 0.24 1.00

57

83

17

0.04

68 ± 42 61 ± 30

70 ± 39 62 ± 29

60 ± 47 55 ± 31

0.70 0.71

28 ± 25

30 ± 27

28 ± 18

0.90

59 ± 37

87 ± 16

43 ± 34

'O.02:j:

(n = 6)

• Patients with evidence of progressive renal insuffficiency. tPatients with no evidence of progressive renal insufficiency and follow-up period of 7 years or more. :j:Comparison between groups A and B. Where standard deviations are given, the number refers to the extent of involvement (%) of the feature in patients in that group; where standard deviations are absent, the number refers to the percentage of patients in that group who demonstrate the lesion.

ciated with extensive loop obliteration (P = 0.007), severe GBM thickening (P = 0.01), mesangial sclerosis (P = 0.008), and extensive loss of foot processes (P = 0.03). In addition, we noted an association between extensive mesangial sclerosis and severe degrees of both capillary loop obliteration (P = 0.007), and loss of foot processes (P = 0.03). Subsequent Clinical Course and Treatment

As shown in Table 2, steroid therapy was given to 15 of the 16 patients. This therapy was given early in the clinical course of disease to the majority of patients, the dosage being approximately 40 to 60 mg/m2 every other day, in nine of the 15 patients. This therapy has been maintained for variable periods of time but in most patients has been given consistently since the original diagnosis was made. Based on the clinical course and duration of observation, the patients are divided into three groups for subsequent analysis: group A, patients in whom progressive loss of renal function occurred; group B, patients in whom the GFR was normal at the latest assessment (mean duration of follow-up 117.6 months; range 85 to 145 months); and group C, patients with a short duration of follow-up (less than 72 months).

The relationship between steroid therapy and clinical outcome of the patients is also shown in Table 2. When the steroid therapy that was given in the subgroups of patients is compared, it is apparent that some differences are present. In group A, only one patient had steroid therapy in the dosage recommended by West et ap1.12; three other patients in this group who received steroids were started on therapy very late in their clinical course. Two of these patients (patients 5 and 8) subsequently received renal transplants and DDD recurred in both. In group B patients, steroid therapy was given along the guidelines of West et al in four of six patients. It should be noted in this group that proteinuria was present in all six patients and hypocomplementemia was present in three of five patients in the presence of normal renal function at the latest follow-up. Growth was examined in the six patients who had good function and follow-up periods exceeding 7 years. These patients showed good (4 patients) or fairly good (2 patients) maintenance of linear growth during treatment over periods of 5 to 10 years. The latter two patients fell from the 75th and 95th to the 30th and 45th percentiles, respectively. One patient (#14) had a successful pregnancy

166

THE SOUTHWEST PEDIATRIC NEPHROLOGY STUDY GROUP

that was associated with an exacerbation of her hypertension and proteinuria (2.5 gm/24 hrs) but no deterioration in renal function. It is of interest to note that this patient represents the only instance in which steroids have not been given. Outcome Indicators-Clinical and Laboratory Studies

Of the clinical and laboratory data amenable to statistical evaluation, age at presentation may be a significant factor, since five of six patients that subsequently developed renal insufficiency were younger than 10 years of age at the time of clinical onset. In addition, it was noted that gross hematuria was more frequent in younger patients (P = 0.03) . In the group of children with good outcome, by contrast, four children were 10 years of age or older at time of presentation. There was

also a greater tendency for males to develop chronic renal insufficiency (males 80%, females 30 %) although this difference did not reach statistical significance. However, no correlation was noted between clinical outcome and the presence of nephrotic syndrome, gross hematuria, hypertension, hypocomplementemia, or decreased GFR at the time of presentation. Finally, it was noted that proteinuria (3 to 4 + ) at follow-up was more common in patients with severe mesangial hypercellularity (P = 0.02) . Outcome Indicators-Pathologic Studies

Pathologic features that may serve to distinguish patients with a potentially poor outcome from those with a good outcome are illustrated in Figs 1 and 2 and shown in Tables 3 and 4. From Table 3, it can be seen that patients with DDD in whom

Fig 1. Initial biopsy from patient 15 who has had a progressive course to renal insufficiency within 38 months of follOW-Up. (A) Light microscopic appearance of an enlarged glomerulus that shows accentuation of lobules, mesangial sclerosis (and hypercellularity), obliteration of capillary loops, and thickening of basement membranes. Periodic-acid Schiff stain (original magnification: x 140). (8) Electron microscopic appearance of a glomerulus to show nearly continuous dense deposit alteration along the basement membrane (8) and mesangial (M) area. The basement membrane is thickened, and electron dense deposits of the usual variety (arrow) are seen on the epithelial side of the capillary wall. Loss of foot processes Is extensive and focal areas of detachment of the epithelium from the basement membranes (arrowheads) are seen. Note mesanglal interposition with marked obliteration of the capillary lumen. Uranyl acetate and lead citrate stain (original magnification: x 6000). (C) Fluoresence microscopic appearance of a glomerulus that shows short linear staining along the capillary loops, and granular deposits in mesangial areas. Fluoresceinated antibody to human C3 (original magnification: x 170).

DENSE DEPOSITS IN CHILDREN

167

Fig 2. Initial biopsy from patient 10 who has preserved renal function after 99 months of follow-up. (A) Light microscopic appearance of a glomerulus that shows minimal increase in mesangial matrix and slight thickening of basement membranes. There is no accentuation of lobules, and obliteration of capillary loops is minimal. Periodicacid Schiff stain (original magnification: x 140). (8) Electron microscopic appearance of a glomerulus to show discontinuous dense alteration along the basement membrane (8). Mesangial areas (M) show little or no dense deposit alteration. The basement membrane is thickened and loss of foot processes is extensive. Obliteration of the capillary lumen due to mesangial extension or interposition is less marked than in biopsy of patient 15. Uranyl acetate and lead citrate stains (original magnification: x 3600). (C) Fluorescence microscopic appearance of a glomerulus that shows faint short linear deposits along the capillary loops. Granular deposits are virtually absent from mesangial areas. Fluoresceinated antibody to human C3 (original magnification: x 170).

light microscopic studies of the glomeruli showed more extensive glomerular lobulation, mesangial hypercellularity and sclerosis, obliteration of capillary loops and severe GBM thickening had a poor outcome. Dense deposit alteration that involved 60% or more of mesangial areas distinguished, with one exception (patient 13), patients with poor from patients with good outcome. Of the eight patients that had subepithelial dense deposits, five developed renal insufficiency, but the small number of patients precluded a determination of the prognostic value of this feature. Crescents that involved 30% and 40% of the glomeruli were present in biopsies of two patients (patients 2 and 5); both developed progressive renal failure, one of them within 3 months of follow-up (Table 2). Repeat Biopsies

Repeat biopsies obtained from six patients (patients 1, 4, 5, 6, 7 and 11) were available for study.

In the repeat biopsy from patient 5 who had a rapid deterioration in renal function (Table 2), 30% of the glomeruli were sclerosed; the remaining glomeruli showed decrease in lobulation and in mesangial hypercellularity, and increases in mesangial sclerosis, loop obliteration, tubular atrophy, and interstitial fibrosis, compared to findings in the diagnostic biopsy. Other features such as GBM thickening and dense deposit alterations in GBM and mesangia did not change appreciably. The repeat biopsies in the remaining patients who have preserved renal function as of the last follow-up evaluation (Table 2), showed either unchanged features or, more often, a decrease in percentage and severity of glomeruli involved, compared to findings in the diagnostic biopsy. Overall, lobulation, mesangial hypercellularity, and mesangial sclerosis were decreased, whereas GBM thickening, loop obliteration, and dense deposit alteration in GBM and mesangia underwent little of no

168

THE SOUTHWEST PEDIATRIC NEPHROLOGY STUDY GROUP

change. Tubular atrophy and interstitial fibrosis, however, were definitely increased in two patients (patients 6 and 7). In patient 6, the biopsy specimen included only superficial cortex, and the specimen may not have been fully representative of the disease process. In patient 7, the increment in tubule atrophy and interstitial fibrosis was minimal. DISCUSSION

This study has demonstrated that the prognosis of children with DDD is not uniform and that certain renal biopsy findings, rather than clinical features, may be helpful in determining which patients are more likely to develop progressive renal insufficiency. Habib et al \,2 described clinical and pathologic features of DDD in 44 children (24 girls, 20 boys, aged from 4 years upwards) in whom 37 (84%) had the nephrotic syndrome at some stage of their disease, and 23 (52 %) had macroscopic hematuria, a feature which was most prominent during the first year of disease. Clinical features that appeared to be indicators of a poor outcome included the nephrotic syndrome, macroscopic hematuria, initial decrease in renal function, and no clinical remissions during the disease course. Lamb et al 4 also indicated that the nephrotic syndrome was a marker of poor prognosis in patients with DDD. We observed the nephrotic syndrome and gross hematuria in the majority (11 of 16) of our patients, and a decrease in renal function was evident in seven of them at the onset of the disease. Nevertheless, such features did not portend a poor prognosis (Table 2). We were not able to define the role of C3 nephritic factor in determining the clinical presentation or outcome of these patients since this assay was not performed on most of our patients. It should be noted, however, that serum C3 concentrations were depressed in the majority of patients, both at the time of presentation (100%) and at the time of follow-up (80%), regardless of the changes that occurred in GFR. While clinical features were not useful outcome indicators in this study, a number of pathologic findings appeared to be helpful. We noted, for example, that increased glomerular lobulation, capillary loop obliteration, and severity of mesangial sclerosis and hypercellularity were associated with a poor outcome, as defined by progressive reduction in GFR. Similarly, we observed that mesan-

gial dense deposit alteration was more common and more severe in patients who developed deterioration of renal function. However, since we studied only 16 patients, the predictive value of the referenced features must be taken as preliminary until confirmed in prospective studies of a larger number of patients with DDD. Nearly half of the patients described by Habib et ap·2 developed renal insufficiency: 18 progressed to end-stage renal disease (ESRD) during a period of 10 years, and 10 had a rapidly progressive course and went to ESRD within two years of their clinical onset. Klein et al 6 also reported that 56% (ten of 18) of their patients with DDD progressed to ESRD within 2.9 years of presentation. We have observed a rapid course of this type in only two of 16 patients; a third patient progressed to this stage only after a period of 5 years. Klein et al 6 observed a relatively benign course in five of 18 patients (28 %) during a period of follow-up of 11 years. We have noted a similar clinical course in ten of our 16 patients (63 %), six of whom were followed for 7 or more years (mean: 10 years). Whether the difference in outcome in our patients may be related to the use of high-dose, alternateday steroids, or to a more benign form of the disease, or both, is not clear. The role of steroid therapy in patients with DDD remains controversial. Twenty-eight of the patients in Habib's study\'2 received steroids but did not appear to respond-at least in terms of remission of proteinuria. Four of the ten patients described by Lamb et al 4 developed chronic renal failure during a period of follow-up which averaged 10 years. These authors concluded that DDD is a chronic progressive disease, largely unresponsive to conventional therapy. In contrast, the studies reported by West et aP3-15 have suggested that in MPGN type I and in DDD significant benefit may be observed when alternate-day steroids are given in dosages of 1.5 to 2.0 mg/kg body weight every other day. Reports of others, however, have not confirmed a significant benefit of steroidsl.2.45.16 in such conditions. Such discrepancy in results of therapy could reflect variations in the dosage of prednisone which has been used in different studies. 15.16 For example, West et al have recommended that the initial dose be 2.0 mg/kg body weight every other day and that, depending on the clinical course, this dose may be reduced slowly during a period of many years to a final

169

DENSE DEPOSITS IN CHILDREN

dose of 20 to 30 mg every other day. 15 This recommendation has not been adopted uniformly however, as evidenced by a recent publication,17 and by the management of three of our patients who received prednisone 20 to 30 mg every other day from onset. Although most of our patients who have maintained normal renal function for long periods of time have received alternate-day prednisone, no conclusions can be drawn regarding the efficacy of such treatment in an uncontrolled study as ours.

progressive disease; clinical features at presentation, by contrast, were not helpful in determining outcome. Finally, most patients who maintained normal renal function for prolonged periods did so in the presence of persistent hypocomplementemia and proteinuria. Therefore, some patients appear to maintain a less aggressive form of this disease with differences in the rate of deterioration of glomerular structure and function. Whether the use of corticosteroids may have influenced the outcome of renal disease in our patients is uncertain.

SUMMARY

ACKNOWLEDGMENT

This multicenter study shows that children with DDD have a variable course and may have preserved renal function for many years. Our studies suggest that certain pathologic features may be helpful to distinguish patients at risk of developing

We acknowledge support from the National Kidney Foundation of Texas, Abbott Laboratories, American Medical Products , American McGaw , B-D Drake Willock , Cutter Labs , Hoffman-LaRoche, Inc., Mead Johnson, Merck and Co., Inc., Ross Laboratories, E. R. Squibb , Southwest Airlines, Travenol Labs, and the Upjohn Company.

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