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ORIGINAL ARTICLE
Crescentic glomerulonephritis in children
Ulrike Mayer1 & Jessica Schmitz2 & Jan Hinrich Bräsen2 & Lars Pape1
Received: 12 October 2019 /Revised: 21 November 2019 /Accepted: 25 November 2019 # The Author(s) 2020
Abstract Background To date, there is insufficient knowledge about crescentic glomerulonephritis (cGN), the most frequent immunologic cause of acute kidney injury in children. Methods Over a period of 16 years, we retrospectively analyzed kidney biopsy results, the clinical course, and laboratory data in 60 pediatric patients diagnosed with cGN. Results The underlying diseases were immune complex GN (n = 45/60, 75%), including IgA nephropathy (n = 19/45, 42%), lupus nephritis (n = 10/45, 22%), Henoch-Schoenlein purpura nephritis (n = 7/45, 16%) and post-infectious GN (n = 7/45, 16%), ANCA-associated pauci-immune GN (n = 10/60, 17%), and anti-glomerular basement-membrane GN (n = 1/60, 2%). Patient CKD stages at time of diagnosis and at a median of 362 days (range 237–425) were CKD I: n = 13/n = 29, CKD II: n = 15/n = 9, CKD III: n = 16/n = 7, CKD IV: n = 3/n = 3, CKD V: n = 13/n = 5. Course of cGN was different according to class of cGN, duration of disease from first clinical signs to diagnosis of cGN by biopsy, percentage of crescentic glomeruli, amount of tubular atrophy/interstitial fibrosis and necrosis on renal biopsy, gender, age, nephrotic syndrome, arterial hypertension, dialysis at presentation, and relapse. Forty-eight/60 children were treated with ≥ 5 (methyl-) prednisolone pulses and 53 patients received oral prednis(ol)one in combination with mycophenolate mofetil (n = 20), cyclosporine A (n = 20), and/or cyclophosphamide (n = 6), rituximab (n = 5), azathioprine (n = 2), tacrolimus (n = 1), and plasmapheresis/immunoadsorption (n = 5). Conclusions The treatment success of cGN is dependent on early diagnosis and aggressive therapy, as well as on the percentage of crescentic glomeruli on renal biopsy and on the underlying type of cGN. CsA and MMF seem to be effective alternatives to cyclophosphamide.
Keywords Glomerulonephritis . Acute kidney injury . Prednisolone . Dialysis . Kidney biopsy . Children
Introduction
Crescentic glomerulonephritis (cGN) is not a single disease entity but a pattern that can occur in a variety of glomerular diseases [1]. Caused by different pathomechanisms lesions and necrosis develop in glomerular capillaries in the case of systemic and kidney-restricted diseases. Ruptures of the glo- merular basement membrane lead to fibrin exudation as well as cellular and humoral components of inflammation in the Bowman’s capsule. Parietal epithelial cells proliferate. This
leads to the so-called extracapillary proliferations that narrow the remaining space in the capsule and appear as crescents on renal biopsy [1–3] (Fig. 1). Because of the ongoing inflamma- tion, this process can lead to renal scarring. cGN is frequently associated with fast deterioration of kidney function and there- fore often referred to as rapidly progressive glomerulonephri- tis (RPGN) [4]. Depending on the clinical context, the wide- spread definition of “crescentic GN” as a process involving > 50% of glomeruli [3] can be misleading, as there may be major diagnostic and clinical significance in the finding of even one fresh crescent.
The clinical course of cGN is dependent on the severity of the histopathological findings, i.e., by the percentage of glo- meruli with crescents [5], but in adult series also on the un- derlying disease. In proliferative lupus nephritis, for example, the outcome is much worse than in post-streptococcal GN even if the percentage of glomeruli with crescents is similar at 25% [1]. An additional parameter for the prognosis is the severity of acute kidney injury at the time of diagnosis [2, 5].
* Lars Pape [email protected]
1 Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
2 Department of Pathology, Nephropathology Unit, Hannover Medical School, Hannover, Germany
https://doi.org/10.1007/s00467-019-04436-y Pediatric Nephrology (2020) 35:829–842
/Published online: 12 2020February
The primary signs of cGN are hematuria, albuminuria, ne- phritic sediment, decreasing glomerular filtration rate (GFR), and oliguria. These renal symptoms might be associated with other organ manifestations in the case of an underlying sys- temic disease [3]. cGN is classified by different subtypes: Type I: anti-glomerular basement-membrane (anti-GBM) dis- ease; Type II: GN caused by deposition of immune complexes (i.e., in IgA nephropathy (IgAN), lupus nephritis, post- infectious GN (PIGN), Henoch-Schoenlein purpura nephritis (HSPN)) and Type III: pauci-immune GN (i.e., caused by ANCA-vasculitis) [3]. In contrast to older patients in whom Type III predominates, Type II is the most common disease in the pediatric setting. Early induction therapy with intravenous (IV) steroids and/or cyclophosphamide is recommended in cGN, and in adults, plasmapheresis is sometimes used in ad- dition [2]. In children, no such recommendations exist and adult guidelines are therefore used. However, the use of cy- clophosphamide is declining, especially in children, because of long-term side effects such as infertility and carcinogenic- ity. Therefore, newer immunosuppressants such as cyclospor- ine A (CsA), mycophenolate mofetil (MMF), or rituximab have been evaluated [3]. Despite these general recommenda- tions, the underlying disease has to be treated according to the disease-specific guidelines. As the 2012 Kidney Disease: Improving Global Outcomes (KIDGO) Guidelines are partly outdated and not child-specific, other published pediatric con- sensuses have to be followed.
Unfortunately, to date, only one publication on the clinical course and treatment of cGN has been published, nearly 30 years ago [6]. A more recent review of newer treatments and outcomes is therefore warranted. Consequently, we assessed the clinical course and morphological parameters of pediatric patients with biopsy-proven cGN in our center in order to determine diagnostic parameters for development of estimated glomerular filtration rate (eGFR) and dialysis-free survival.
Patients and methods
Eight hundred eighty kidney biopsies performed in native and transplanted kidneys of children at Hannover Medical School between 1999 and 2015 were investigated, with crescents de- tected in 61/808 patients. Disease duration was defined as the time between first symptoms of the underlying disease and diagnoses of cGN on renal biopsy. For definition of crescents (cellular, fibrocellular and fibrous), the Oxford IgA classifica- tion was used [7]. A crescent was defined as extracapillary proliferation of more than two cell layers of any size (regard- ing the glomerular circumference); a cellular crescent was defined as > 50% of the proliferation occupied by cells, a fibrocellular crescent by < 50% of the lesion occupied by cells, and < 90% by matrix. Fibrous crescents (defined as > 90% of the lesion occupied by matrix) were not taken into
a
c d
b
Fig. 1 Histology of pediatric crescentic glomerulonephritis (cGN): a Granulomatosis with polyangiitis (GPA), female 16 years, arrow depicts cellular crescent. b ANCA-negative pauci-immune glomerulonephritis (GN), male 7 years; arrow points out cellular crescent and arrowhead fibrinoid necrosis. c Lupus nephritis revealing mesangiocapillary (arrowhead) and crescentic (arrow) proliferation (insert illustrates positive
IgG immunohistochemistry (brown, DAB)), female 16 years. d Mesangioproliferative IgA nephropathy (insert shows glomerular positiv- ity for IgA (brown, DAB), male 12 years. a, d H&E, b, c Jones methe- namine counterstained with H&E. Bars represent 50 μm in a, b, and 100 μm in c, d.
Pediatr Nephrol (2020) 35:829–842830
account. Each patient with a minimum of one crescent in a biopsy was included in this analysis. A median of 20 glo- meruli per biopsy (range 5 to 107) was evaluated. One 17- year-old patient was excluded because no follow-up data were available as he was treated in an adult nephrology unit, leaving 60 patients for analyses. All 60 kidney biop- sies were re-evaluated by the same experienced nephropathologist (JHB) for this work using light, immu- nohistochemical, and electron microscopy. The pathologist was blinded to the patient’s data 12-month outcome. Clinical signs of GN, such as macrohematuria, edema, oliguria, arterial hypertension (defined by the Kinder- und Jugendgesundheitssurvey [Health Interview and Examination Survey for Children and Adolescents] (KiGGS) criteria [8]), non-renal signs and demographic parameters including age, gender, and duration of symp- toms at presentation, were evaluated. Renal volume was measured by ultrasound (Ellipsoid formula) at time of di- agnosis. At time of disease onset and at 1 week and after 1, 3, 6, and 12 months, the following laboratory values were documented: serum levels for creatinine, urea, albumin, electrolytes, hemoglobin, WBC, and eGFR as determined by the 2009 Schwartz bedside formula [9]. Arterial hyper- tension was defined as office blood pressures above the gender- and height-matched 95th percentile. End-stage re- nal disease (ESRD) was defined as need for renal- replacement therapy (dialysis, transplantation).
At time of diagnosis (time of renal biopsy), the following examinations and immunological parameters were deter- mined: p-ANCA, c-ANCA, MPO-antibody (Ab) PR3-Ab,
ANA, double-stranded-DNA Ab (anti-DNS), C3, C4, anti- streptolysin, IgA serum-level and glomerular basement- membrane Ab (anti-GMB) (Table 1(a)). As data evaluation was performed retrospectively, time ranges were used instead of exact time points and data was not available for each patient at each timepoint (Table 1(b)).
Data were documented using Microsoft Excel 365 (Microsoft Cooperation, Seattle, WA, USA). Time of disease duration was defined as the time between first clinical symp- toms and kidney biopsy. Statistical analyses were performed with GraphPad Prism 5.0 (GraphPad, San Diego, CA, USA). Exploratory data analyses were primarily performed. All data was negatively tested for normal distribution. Therefore, me- dian values between different groups were compared using the Mann-Whitney U test for pre-defined subgroups as gender, age, nephrotic syndrome, and arterial hypertension. Paired data was compared by Wilcoxon signed-rank test. Logistic regression analyses were performed to evaluate the relation- ship between one dependent binary variable and one or more nominal or ordinal independent variables. Kaplan Meier anal- yses were done to determine survival. p < 0.05 was considered as statistically significant. We have not based the analyses on the three categories of cGN, as there was only one patient in group I and as we could observe large differences between the underlying diagnoses in groups II and III in relation to outcome.
All patients have agreed with their hospital treatment con- tract that their data can be used for research in anonymized matter. The Ethics Committee of Hannover Medical School has agreed to this policy.
Table 1 Clinical tests performed and time points of evaluation (a)
Laboratory chemical tests
Serological investigations: Creatinine, urea, albumin, protein
Immunological investigations: P-ANCA, c-ANCA, MPO-Antibody (Ab) PR3-Ab, ANA, double-stranded-DNA Ab, C3, C4, anti-streptolysin, IgA serum-level and glomerular basement-membrane Ab.
Urine analysis: Red blood cells and protein in urinary dipstick investigation, creatinine and albumin in spot urine.
Clinical investigations
Gender, age, weight, body length, blood pressure, disease duration, edema, oliguria, macrohematuria, treatment, relapse of disease during observation time..
Renal ultrasound
Measurement of kidney volume.
Renal biopsy
Light, immunohistochemical and electron microscopy.
(b)
Time point T1 T2 T3 T4 T5 T6
Median time after kidney biopsy [days] 0 7 38 96 187 362
Range [days] 4–15 27–57 74–135 140–255 237–425
N 60 54 54 55 52 53
Pediatr Nephrol (2020) 35:829–842 831
Results
The 60 patients (median age 13 years, range 3–18, 31 male) could be subclassified into three groups of cGN and, further, by the underlying disease as demonstrated in the flow chart in Table 2 (which also gives the number of patients with data available 1 year after diagnosis). Interestingly, there was no gender difference overall. Figure 2 a shows the number of newly diagnosed diseases associated with cGN within the time period of the study. eGFR at time of diagnosis and courses of s-creatinine (serum-creatinine) in the disease groups are shown in Fig. 2b, c.
Glomerular filtration rate
The median eGFR increased from 55 (range 4–161) from time of diagnosis to 92 ml/min/1.73m2 (range 5–175), p < 0.001, 1 year later, with differences in the three subgroups.
The patient with cGN type I presented with terminal renal failure which did not significantly improve (eGFR 8 to 14 ml/ min/1.73m2 at presentation and 1 year later, respectively). In children with cGN type II, median eGFR increased from 65 ml/min/1.73m2 (range 9–161) to 100 ml/min/1.73m2
(range 5–175), p < 0.001. In patients with cGN type III, me- dian eGFR increased from 28 ml/min/1.73m2 (range 8–94) to 60 ml/min/1.73m2 (range 37–113), p = 0.013. Patients with a renal disease not classifiable by clinical and histopathological techniques had an initial median eGFR of 9 ml/min/1.73m2
(range 6–46) and a final median eGFR of 10 ml/min/1.73 m2
(range 5–54), p > 0.999 (Fig. 3a, b). Patients with a fulminant progressive course of disease,
defined as less than 30 days between time of first clinical symptoms and kidney biopsy (short disease duration) experi- enced a fast deterioration of kidney function (median eGFR ≤ 30 days 20 ml/min/1.73 m2 [range 8–115] and > 30 days 64 ml/min/1.73 m2 [range 6–161], p = 0.001) (Fig. 2d). They also presented with the highest urea values (median urea ≤ 30 days 20 mmol/l [range 4–40] and > 30 days 8 mmol/l [range 3–40], p < 0.001). GFR increased significantly during the observation time only in children with a disease course > 30 days (median eGFR disease course ≤ 30 days 57 ml/min/ 1.73m2 [range 5–151], p = 0.07 and disease course >30 days 94 ml/min/1.73 m2 [range 6–175], p = 0.003).
Disease duration
The median duration time of the underlying disease before cGN was diagnosed in renal biopsy and therapy started was 60 days (range 3–1806). Patients with ANCA-negative pauci- immune GN demonstrated the shortest periods between diag- nosis and therapy (3 to 5 days) as did the patients with micro- scopic polyangiitis and renal-limited vasculitis (MPA/RLV), PIGN, and dense-deposit disease (DDD). Patients with IgAN presented with a large variety in time between first symptoms and when biopsy was performed (range 22–1806 days) (Fig. 2e).
Table 2 Subtyping and number of follow up of the patients with crescentic glomerulonephritis (cGN)
Median observation time 362 days (R 237-425)
n = 53
ANCA neg. GN
n = 2 m
Age: 8 and 17
Anti-GBM GN
n = 1
Unknown
n = 4
MPA/RLV
n = 3; 1 child was kidney transplantated
DDD
n = 1 m
Age: 4
IgAN
n = 16
PSHN
n = 6
LN
n = 10
DDD
n = 1
MWS
n = 1
ANCA neg. GN
n = 2
GPA
n = 4
Crescentic Glomerulonephritis At time of diagnosis: n = 60 (29 f, 31m)
Median age 13 years (R 3–18)
Anti-GBM GN
n = 1 m
Age: 17
LN
n = 10 (9 f, 1 m)
Median age: 13 (R 10-17)
IgAN
n = 19 (5 f, 14 m)
Median age: 13 (R 6–17)
PSHN
n = 7 (3 f, 4 m)
Median age: 15 (R 7-18)
PIGN
n = 7 (3 f, 4 m)
Median age: 7 (R 3–12)
GPA
n = 4 f
Median age: 11 (R 9-17)
MPA/RLV
n = 4 (3 f, 1 m)
Median age: 15 (R 9–17)
MWS
n = 1 f
Age: 9
Unknown
n = 4 (1 f, 3 m)
Median age: 13 (R 7-17)
Undetermined
n = 4 (1 f , 3 m)
PIGN
n = 5
Type II
n = 45 (21 f, 24 m)
Type I
n = 1 m
Type III
n = 10 (7 f, 3 m)
DDD dense-deposit disease, GBM glomerular basement-membrane, GPA granulomatosis with polyangiitis, IgAN IgA nephropathy, LN lupus nephritis, MPA/RLV microscopic polyangiitis and renal-limited vasculitis, MWS Muckle-Wells syndrome, PIGN post-infectious glomerulonephritis, PSHN Henoch-Schoenlein purpura nephritis
Pediatr Nephrol (2020) 35:829–842832
Dialysis
Twelve children received initial dialysis (Table 3), with five remaining on dialysis during the observation period, one of whom received a kidney transplant. One patient required di- alysis during the observation time without the need of dialysis at presentation. The need for primary dialysis was associated with a significantly worse outcome of kidney function: medi- an eGFR primary dialysis 16 ml/min/1.73 m2 (range 5–134) versus no primary dialysis 93ml/min/1.73 m2 (range 21–175), p < 0.001 (Fig. 4a).
Clinical factors
There was no difference between initial eGFR between chil- dren > 12 years and younger patients. However, gain of func- tion (eGFR) was lower in the older children: median GFR > 12 years 72 ml/min/1.73 m2 (range 6–151) compared to < 12 years 107 ml/min/1.73m2 (range 5–175), p = 0.020 (Fig. 4b).
Male gender was associated with worse outcome despite gender-independent eGFR at timepoint of diagnosis: median eGFR at last visit was 66 ml/min/1.73m2 (range 5–175) in
Fig. 2 Number of crescentic glomerulonephritis (cGN) diagnosis per year and subclassification (a). Initial estimated glomerular filtration rate (eGFR) in the subgroups (b). Course of s-creatinine over the observation time (c). Initial eGFR depending on time of disease duration (d). Time of disease duration in the subgroups (e). Abbreviations: DDD, dense-deposit
disease; GBM, glomerular basement-membrane; GPA, granulomatosis with polyangiitis; IgAN, IgA nephropathy; LN, lupus nephritis; MPA/ RLV, microscopic polyangiitis and renal-limited vasculitis; MWS, Muckle-Wells Syndrome; PIGN, post-infectious glomerulonephritis; PSHN, Henoch-Schoenlein purpura nephritis
Pediatr Nephrol (2020) 35:829–842 833
19 99 20
00 20
01 20
02 20
03 20
04 20
05 20
06 20
07 20
08 20
09 20
10 20
11 20
12 20
13 20
14 20
15 0 1 2 3 4 5 6 7 8 9
10
Year
N um
be r o
f p at
ie nt
s (n
=6 0)
a
0 - 15
16 -
30
31 -
91
92 -
36 5
> 3 65
0 2 4 6 8
10 12 14 16 18 20
N um
be r o
f p at
ie nt
s (n
= 60
)
Time of disease duration [days]
e
0 4
- 1 5
27 -
57
74 -
13 6
14 0 -
25 6
23 7 -
42 5
100
20
250
500 750
50
1103
S -C
re at
in in
e [µ
m ol
/l]
Time points of evaluation after diagnosis [days]
c
< 15
15 -
29
30 -
59
60 -
89 >
90 0 2 4 6 8
10 12 14 16 18 20
Initial eGFR [ml/min/1.73 m 2]
N um
be r
of p
at ie
nt s
(n =6
0)
b
0 - 1
5
16 -
30
31 -
91
92 - 3
65 >
36 5
0
25
50
75
100
125
150
175
In iti
al e
G F
R [
m l/m
in /1
.7 3m
2 ]
Time of disease duration [days]
d p=0.001
Anti-GBM GN IgAN PSHN
PIGN LN DDD
MWS
ANCA-neg. GN
GPA MPA/RLV
Main diseases highlighted:
Undetermined
boys and 100 ml/min/1.73 m2 (range 37–151) in girls, respec- tively p = 0.039 (Fig. 4b).
We also observed that initially nephrotic children showed reduced recovery of kidney function compared to the remain- der of the cohort although the initial eGFR of both groups was not significantly different: median eGFR of initially nephrotic and initially non-nephrotic children at last visit was 63 ml/ min/1.73 m2 (range 5–151) and 92 ml/min/1.73 m2 (range 6–151), respectively, p = 0.045 (Fig. 4c).
Forty-five percent of patients had arterial hypertension at the time of diagnosis. Arterial hypertension at the time of diagnosis was another independent risk factor of having poorer kidney function after 1 year: median eGFR of patients having initial arterial hypertension was 62 ml/min/1.73 m2
(range 5–128) compared to children with no initial arterial hypertension, 100 ml/min/1.73 m2 (range 5–175), p = 0.006 (Fig. 4c).
Recurrence
Eleven patients developed a recurrence of underlying disease during the observation period. The increase of eGFR was significantly lower in this group with a me- dian eGFR of 63 ml/min/1.73m2 (range 25–163) com- pared to the non-relapsing children 92 ml/min/1.73m2
(range 5–175), p = 0.298 (Fig. 4a).
Clinical signs
Dialysis-free survival of the native kidney was different in Kaplan Meier analysis between those patients with a short (≤ 30 days) or longer period (> 30 days) of time from first documented symptom to biopsy (p = 0.006, Fig. 4d), between the different underlying diagnoses (p < 0.001, Fig. 4e), as well
as between patients with greater or fewer than 50% of glomer- uli with crescents (p = 0.002, Fig. 4f). At time of diagnosis, all children presented with hematuria, 55%with macrohematuria. Fifty/52 patients had proteinuria, with 58% being nephrotic. The albumin-to-creatinine-ratio (ACR) varied significantly between the patients regardless of the underlying disease (Table 3) and decreased from 266 g/mol (range 8–6541) at time of diagnosis to 8 g/mol (range 1–679), p < 0.001, 1 year later. At time of diagnosis, the patients with an eGFR less than 90 ml/min/1.73 m2 (median ACR 277 g/mol, range 15–6541) had a higher ACR than those with an eGFR > 90 ml/min/ 1.73 m2 (median ACR 83 g/mol, range 8–601), p = 0.045.
Serum IgA was determined in 47 of the patients. Twenty- nine children presented with normal IgA values, 12 of them with IgAN and two with PSHN. From 18 children with in- creased IgA, two suffered from HSPN, six from IgAN and ten from other underlying diseases. Complement factor C3 was normal in 68% of cases. All children with lupus GN and DDD had decreased C3. P-ANCA and c-ANCA could be detected in ten and two children, respectively.
ANAs were negative in 27 patients and positive in all lupus nephritis children, whereas all lupus patients were also posi- tive for anti-DNS. Anti-GBM-Ab was only positive in the single patient with anti-GBM GN. The anti-streptolysin titer was positive in 4/6 children with PIGN and in 11 children with other underlying diseases.
At time of diagnosis, renal ultrasound was only document- ed or available in 33/60 children. This is possibly due to the fact that many patients were not primarily seen at our center but transferred. Seventy percent presented with an elevated (> 95th percentile) and 18% with a borderline elevated (90-95th percentile) renal volume as compared to weight-matched nor- mal values. Nephrotic range proteinuria was defined as a uri- nary albumin/creatinine ratio > 220 mg/mmol in spot urine.
All
An ti-G
BM GN IgA
N PS HN
PIG N LN DD
D MW
S
AN CA -ne
g. GN GP
A
MP A/R
LV
Un de ter mi ne d
25
50
75
100
125
150
175
15
eG FR
[m l/m
in /1 .7 3m
2 ]
a
All
An ti-G
BM GN IgA
N PS HN
PIG N LN DD
D MW
S
AN CA -ne
g. GN GP
A
MP A/R
LV
Un de ter mi ne d
25
50
75
100
125
150
175
15
eG FR
[m l/m
in /1 .7 3 m
2 ]
b p<0.001
Fig. 3 Course of estimated glomerular filtration rate (eGFR) during ob- servation period dependent on underlying disease at time of diagnosis (a) and 1 year later (b). Abbreviations: DDD, dense-deposit disease; GBM GN, glomerular basement-membrane glomerulonephritis; GPA,
granulomatosis with polyangiitis; IgAN, IgA nephropathy; LN, lupus nephritis; MPA/RLV, microscopic polyangiitis and renal-limited vasculi- tis; MWS,Muckle-Wells Syndrome; PIGN, post-infectious glomerulone- phritis; PSHN, Henoch-Schoenlein purpura nephritis
Pediatr Nephrol (2020) 35:829–842834
Ta bl e 3
C lin
ic al da ta of
th e to ta lc oh or t
P at .I D
eG FR
[m l/m
in /
1. 73
m 2 ]
U ri na ry
di ps tic k
an al ys is
A lb um
in -t o-
cr ea tin
in e
ra tio
[g /m
ol ]
G lo m er ul i
w ith
cr es ce nt s
[% of
al lg lo m er ul i]
D is ea se
du ra tio
n [d ay s]
M et hy l- /p re dn is ol on e
pu ls e th er ap y
(n :i ni tia l+
du ri ng
th e
co ur se
of ob se rv at io n)
P re dn is o- (l o) ne
(n :i ni tia l+
du ri ng
th e co ur se
of ob se rv at io n)
A dd iti on al
im m un os up pr es si ve
th er ap y (i ni tia l+
du ri ng
th e co ur se
of ob se rv at io n)
H em
od ia ly si s (H
D ),
pe ri to ne al di al ys is (P D ),
pl as m a ex ch an ge
(P E ),
im m un oa ds or pt io n (I A )
(i ni tia l+
du ri ng
th e
co ur se
of ob se rv at io n)
Fi rs t
vi si t
L as t
vi si t
R B C
[/ μ l]
Pr ot ei n
[m g/ dl ]
F ir st
vi si t
L as t
vi si t
A nt i- G B M
gl om
er ul on ep hr iti s
1 8
H D
14 25 0
N eg .
15 A nu ri a
10 0
48 Y es
(5 )
Y es
(c a. 50 )
C Y C 14
da ys
p. o. + 1×
R T X
H D ,P
E :3
+ 6
Ig A ne ph ro pa th y
10 38
58 25 0
50 0
39 2
4 42
41 Y es
(6 + 2)
Y es
(2 19 )
M M F
N o
13 47
95 25 0
10 0
21 1
23 89
70 Y es
(6 )
Y es
(4 2)
N o
N o
14 11 5
15 1
20 0
30 0
59 9
1 42
12 Y es
(6 )
Y es
(7 1)
C sA
N o
18 68
a 4 9
N B D
N B D
70 9
a 3 13
17 Y es
(6 )
Y es
(> 18 6)
M M F + C sA
on to p
N o
25 91
95 20 0
10 0
86 3
22 42
N o
Y es
(1 84 )
+ C sA
N o
27 10 0
15 1
20 0
> 30 0
80 18
8 24 4
N o
N o
N o
N o
28 71
13 0
20 0
> 30 0
25 16
10 17 66
Y es
(6 )
Y es
(5 6)
N o
N o
30 11
14 0
25 0
N eg .
N B D
1 8
42 3
Y es
(6 )
Y es
(6 )
N o
N o
36 66
64 20 0
> 30 0
52 1
14 50
18 06
Y es
(6 )
N o
M M F
N o
40 47
67 20 0
> 30 0
16 2
7 36 2
Y es
(6 )
Y es
(2 78 )
M M F
N o
44 10 4
N B D
80 > 30 0
60 1
N B D
6 19 4
Y es
(6 )
Y es
(u nk no w n)
C sA
N o
47 29
92 20 0
> 30 0
77 4
31 30 9
Y es
(5 )
Y es
(5 6)
C sA
N o
50 10 7
12 3
25 0
30 67
23 20
97 N o
N o
N o
N o
52 63
a 6 6
20 0
> 30 0
61 1
a 3 77
28 33
Y es
(6 )
Y es
(u nk no w n)
C sA
N o
59 79
92 25 0
10 0
84 1
18 34
Y es
(6 )
Y es
(6 9)
C sA
N o
63 13 5
12 7
10 10 0
N B D
9 4
11 6
N o
Y es
(1 32 )
N o
N o
67 61
21 20 0
> 30 0
27 6
67 9
25 13 19
Y es
(6 + 5 be fo re
N B x)
Y es
(4 3)
C sA
(f or
3 ye ar s) + M M F
on to p
N o
68 62
56 50
50 0
91 8
81 71
20 3
Y es
(6 )
Y es
(5 5)
TA C (L iv er -T x)
N o
69 10 3
13 6
20 0
> 30 0
36 7
14 4
6 30 5
N o
N o
N o
N o
M ed ia n ra ng e
68 11 –1 35
95 21 –1 51
20 0
> 30 0
27 6
12 20 4– 89
19 4
12 –1 80 6
Y: 14 ; N : 5
Y: 15 ; N : 4
C sA : 6 + 2;
M M F :4
+ 1;
TA C : 1;
N on e:
7
N o
H en oc h- Sc ho en le in
Pu rp ur a ne ph ri tis
24 55
61 20 0
> 30 0
21 93
1 10
22 Y es
(6 )
Y es
(1 22 )
C sA
W ith
re cu rr en ce :P
E :5
an d H D :6
29 92
N B D
> 20 0
10 0
13 6
N B D
12 83 6
Y es
(5 be fo re
N B x)
Y es
(u nk no w n)
C sA
N o
33 74
10 8
20 0
> 30 0
27 7
15 42
42 Y es
(3 )
Y es
(1 13 )
N o
N o
48 70
63 N B D
N B D
21 4
8 31
36 Y es
(6 + 6)
Y es
(u nk no w n)
C Y C 3 M o p. o. + C sA
N o
53 73
17 5
20 0
> 30 0
57 8
N B D
33 70
Y es
(3 )
Y es
(1 08 )
N o
N o
57 14
17 20 0
> 30 0
32 8
7 83
78 4
Y es
(6 )
Y es
(8 5)
C sA
H D fo r 2 m on th s
62 47
72 20 0
10 0
16 7
5 65
11 7
Y es
(6 )
Y es
(1 07 )
C sA
N o
M ed ia n ra ng e
70 14 –9 2
68 17 –1 75
20 0
> 30 0
27 7
7 33 10 –8 3
70 22 –8 36
Y: 7
Y: 7
C sA : 4 + 1,
C YC
:1 N on e:
2
P E :1
; H D :2
Po st -i nf ec tio
us gl om
er ul on ep hr iti s
8 52
12 9
20 0
> 30 0
24 6
4 13
8 N o
N o
N o
N o
11 49
94 20 0
> 30 0
24 2
2 50
10 1
N o
Y es
(1 49 )
W ith
re cu rr en ce C sA
N o
Pediatr Nephrol (2020) 35:829–842 835
T ab
le 3
(c on tin
ue d)
P at .I D
eG FR
[m l/m
in /
1. 73
m 2 ]
U ri na ry
di ps tic k
an al ys is
A lb um
in -t o-
cr ea tin
in e
ra tio
[g /m
ol ]
G lo m er ul i
w ith
cr es ce nt s
[% of
al lg lo m er ul i]
D is ea se
du ra tio
n [d ay s]
M et hy l- /p re dn is ol on e
pu ls e th er ap y
(n :i ni tia l+
du ri ng
th e
co ur se
of ob se rv at io n)
P re dn is o- (l o) ne
(n :i ni tia l+
du ri ng
th e co ur se
of ob se rv at io n)
A dd iti on al
im m un os up pr es si ve
th er ap y (i ni tia l+
du ri ng
th e co ur se
of ob se rv at io n)
H em
od ia ly si s (H
D ),
pe ri to ne al di al ys is (P D ),
pl as m a ex ch an ge
(P E ),
im m un oa ds or pt io n (I A )
(i ni tia l+
du ri ng
th e
co ur se
of ob se rv at io n)
Fi rs t
vi si t
L as t
vi si t
R B C
[/ μ l]
Pr ot ei n
[m g/ dl ]
F ir st
vi si t
L as t
vi si t
16 9
13 4
N B D
N B D
88 2
74 9
Y es
(6 )
Y es
(6 0)
M M F
PD 9 d
22 33
12 2
20 0
> 30 0
36 1
3 50
25 Y es
(3 + 2)
Y es
(7 8)
N o
N o
23 59
12 3
20 0
> 30 0
73 6
12 8
67 32
Y es
(6 + 11 –1 3)
Y es
(u nk no w n)
N o
N o
32 24
92 50
50 0
96 9
N B D
21 20
Y es
(6 )
Y es
(u nk no w n)
N o
PD 4 d
58 11
PD 5
25 0
50 0
N B D
A nu ri a
10 0
17 Y es
(5 + 6)
Y es
(6 3)
N o
PD
M ed ia n ra ng e
33 9– 59
12 2
5– 12 9
20 0
> 30 0
24 6
3 50 13 –1 00
20 8– 10 1
Y: 5;
N : 2
Y: 6;
N :1
C sA : + 1; M M F : 1;
N on e:
5 P D : 3
L up us
ne ph ri tis
7 65
92 20 0
> 30 0
54 2
5 59
17 5
Y es
(6 )
Y es
(2 91 )
C sA
N o
26 61
10 0
20 0
30 0
28 2
7 27
37 Y es
(+ 6)
Y es
(2 48 )
C Y C 4×
IV + C sA
N o
34 91
12 8
80 > 30 0
74 1
9 10 2
N o
Y es
(> 36 5)
M M F
N o
41 9
92 25 0
30 21 4
77 97
27 Y es
(6 )
Y es
(1 61 )
M M F
+ 1×
R T X
N o
46 82
91 80
> 30 0
N B D
25 17
12 3
Y es
(6 )
Y es
(1 93 )
M M F
N o
49 16 1
10 5
80 30
7, 9
1 7
43 N o
Y es
(2 78 )
M M F
N o
55 11 4
10 0
20 0
> 30 0
53 9
11 29
19 2
Y es
(6 )
Y es
(2 80 )
C sA
N o
56 47
10 0
25 0
50 0
48 1
5 18
40 Y es
(6 )
Y es
(2 22 )
M M F
N o
65 11 5
10 7
20 0
> 30 0
75 1
9 17 3
Y es
(6 )
Y es
(> 36 5)
C sA
N o
66 38
10 6
20 0
> 30 0
91 5
40 63
74 N o
Y es
(> 36 5)
C Y C 6x
IV N o
M ed ia n ra ng e
74 9– 16 1
10 0
91 –1 28
20 0
> 30 0
28 2
6 23 7– 97
88 27 –1 92
Y: 6 + 1;
N : 3
Y: 10
C sA : 3 + 1;
M M F :5
; C YC
:2 ;
R TX
: + 1
N o
D en se -d ep os it di se as e
39 79
PD 25
N B D
N B D
65 41
N B D
94 23
Y es
(6 + 6)
Y es
(6 3 + 89 )
C sA
+ H D th en
PD
M uc kl e- W el ls sy nd ro m e
42 89
13 6
20 0
> 30 0
14 1
8 28
38 1
Y es
(6 )
Y es
(1 61 )
Il ar is
N o
A N C A -n eg at iv e va sc ul iti s w ith
pa uc i- im
m un e gl om
er ul on ep hr iti s
35 10
11 3
20 0
> 30 0
23 8
2 10 0
5 Y es
(6 )
Y es
(> 36 5)
M M F
H D :2
;I A :5
51 14
66 > 20 0
10 0
38 1
50 3
Y es
(6 )
Y es
(8 0)
M M F
PE :6
G ra nu lo m at os is w ith
po ly an gi iti s w ith
pa uc i- im
m un e gl om
er ul on ep hr iti s
4 50
52 10
> 30 0
38 7
a 4 9
50 33 0
Y es
(4 be fo re
N B x)
Y es
(u nk no w n)
C Y C p. o. (b ef or e N B x) ;A
Z A
N o
6 13
60 25 0
30 84
16 3
76 50
Y es
(6 )
Y es
(> 36 5)
M M F, 3 × R T X
PE :3
;P D in iti al ;+
H D
4 da ys
9 8
37 25 0
30 24 4
95 77
4 Y es
(6 + 6 + un kn ow
n) Y es
(> 36 5)
+ C Y C 1×
IV ,M
M F,
1× R T X
PD 9 da ys
61 94
85 N B D
N B D
20 9
7 52 1
Y es
(6 + 3 + 2)
Y es
(u nk no w n)
M M F
+ 4×
R T X ,A
Z A
N o
Pediatr Nephrol (2020) 35:829–842836
T ab
le 3
(c on tin
ue d)
P at .I D
eG FR
[m l/m
in /
1. 73
m 2 ]
U ri na ry
di ps tic k
an al ys is
A lb um
in -t o-
cr ea tin
in e
ra tio
[g /m
ol ]
G lo m er ul i
w ith
cr es ce nt s
[% of
al lg lo m er ul i]
D is ea se
du ra tio
n [d ay s]
M et hy l- /p re dn is ol on e
pu ls e th er ap y
(n :i ni tia l+
du ri ng
th e
co ur se
of ob se rv at io n)
P re dn is o- (l o) ne
(n :i ni tia l+
du ri ng
th e co ur se
of ob se rv at io n)
A dd iti on al
im m un os up pr es si ve
th er ap y (i ni tia l+
du ri ng
th e co ur se
of ob se rv at io n)
H em
od ia ly si s (H
D ),
pe ri to ne al di al ys is (P D ),
pl as m a ex ch an ge
(P E ),
im m un oa ds or pt io n (I A )
(i ni tia l+
du ri ng
th e
co ur se
of ob se rv at io n)
Fi rs t
vi si t
L as t
vi si t
R B C
[/ μ l]
Pr ot ei n
[m g/ dl ]
F ir st
vi si t
L as t
vi si t
M ed ia n ra ng e
32 8– 94
56 37 –8 5
25 0
30 16 4
95 63 7– 77
19 0
4– 52 1
Y: 3 + 1
Y: 4
M M F :2
+ 1;
C YC
: 1 + 1;
R TX
: 1 + 2;
A ZA
:1 + 1
P E :1
; P D :2
; H D :+
1
M ic ro sc op ic po ly an gi iti s an d re na l- lim
ite d va sc ul iti s w ith
pa uc i- im
m un e gl om
er ul on ep hr iti s
5 40
52 N B D
N B D
N B D
13 88
26 Y es
(6 )
Y es
(2 59 )
M M F
N o
43 51
52 20 0
10 0
16 7
a 1 6
20 15
N o
Y es
(1 82 )
M M F
N o
54 55
76 N B D
N B D
76 4
64 36 3
Y es
(6 )
Y es
(9 9)
M M F
N o
60 15
P D
a 5 N B D
N B D
33 1
N B D
10 0
18 Y es
(3 be fo re
N B x)
Y es
(9 6)
N o
H D th en
PD ;N
T x
M ed ia n
R an ge
46 15 –5 5
a 5 2
5– 76
20 0
10 0
16 7
9 76 20 –1 00
22 15 –3 63
Y: 2 + 1;
N :1
Y: 4
M M F :3
; N on e:
1 H D : 1;
P D : + 1:
N Tx : 1
U nd et er m in ed
2 10
14 20 0
> 30 0
68 3
N B D
10 0
14 Y es
(6 + 3)
Y es
(c a. 16 3)
M M F in te rm
itt en t
H D :1 1 da ys
21 8
PD 5
20 0
> 30 0
43 2
A nu ri a
10 0
5 Y es
(6 )
N o
N o
PD 37
46 54
80 > 30 0
26 6
21 46
23 0
Y es
(4 )
Y es
(u nk no w n)
C sA
N o
64 6
H D 6
20 0
> 30 0
10 54
A nu ri a
80 98
N o
N o
N o
H D
M ed ia n ra ng e
9 6– 46
10 5– 54
20 0
> 30 0
55 8
21 90 46 –1 00
56 5– 23 0
Y: 3;
N : 1
Y: 2;
N :2
C sA : 1;
M M F :1
; N on e:
2
H D : 2;
P D : 1
A ZA
az at hi op ri ne ,C
sA cy cl os po ri ne
A ,C
YC cy cl op ho sp ha m id e, G B M
gl om
er ul ar ba se m en t- m em
br an e, eG
F R es tim
at ed
gl om
er ul ar fi ltr at io n ra te ,I V in tr av en ou s, N B D no td et er m in ed ,M
M F m yc op he -
no la te m of et il,
N no ., N B x ki dn ey
bi op sy ,N
eg .n eg at iv e, N Tx
ki dn ey
tr an sp la nt at io n, P at .I D pa tie nt
ID ,p .o .p er
or al ,R
B C re d bl oo d ce ll,
R TX
ri tu xi m ab ,T A C ta cr ol im
us ,T
x tr an sp la nt at io n, Y ye s
a L as tv
al ue
co lle ct ed
in ca se
no 1 ye ar
da ta w as
av ai la bl e
Pediatr Nephrol (2020) 35:829–842 837
Pathology
Table 3 shows the results of the proportion of glomeruli with crescents (extracapillary proliferation) relating to the number of non-sclerotic glomeruli (median 38%, range 4 to 100). Fibrocellular crescents were found in only 21 patients, and they accounted for 19% of the total amount (80 fibrocellular versus 333 cellular crescents). In 26/60 patients, crescents were detected in ≥ 50% of the glomeruli. This criterion was fulfilled by 100% of the children with anti-GBM GN, DDD, and ANCA-negative pauci-immune GN, as well as in 75% of patients with systemic granulomatosis with polyangiitis (GPA), MPA/RLV, or unknown GN, and in 71% of children with PIGN. Only 16% of children with IgAN and 29% with HSPN had more than 50% crescents. This subgroup presented with a lower initial median eGFR (24 ml/min/1.73m2, range
6–79) compared to the patients with crescents in < 50% of glomeruli (74 ml/min/1.73 m2, range 11–161), p < 0.001. In addition, the improvement of eGFR was better for children with crescents in > 50% of the glomeruli (24 to 62 ml/min/ 1.73m2, range 5–123) compared to the other patients (74 to 100 ml/min/1.73m2, range 21–175), p < 0.001. In this context, it is important to refer to the 12 children with extracapillary proliferations in > 80% of glomeruli, as seven of these chil- dren developed ESRD, with initial median eGFR 11 ml/min/ 1.73 m2 (range 6–79) and final eGFR 17 ml/min/1.73 m2
(range 5–113), respectively, p = 0.3875. Nevertheless, three of the patients with extracapillary proliferations in > 80% of glomeruli, who initially experienced moderately impaired kid- ney function or kidney failure, had a normalization of eGFR within the observation period. It is also noticeable in this group that median duration of disease was 25 days (range 5–
0
50
100
150
15
75
125
175
eG F
R [
m l/m
in /1
.7 3m
2 ]
firs t v
isi t
p=0.129 p=0.039 p=0.465 p=0.020
Female
Male
Younger than 12 years
Older than 12 years
las t v
isi t
firs t v
isi t
las t v
isi t
0
50
100
150
15
75
125
175
eG F
R [
m l/m
in /1
.7 3m
2 ]
p=0.622 p=0.045 p=0.624 p=0.007
Nephrotic syndrome
No nephrotic syndrome
Arterial hypertension
No arterial hypertension
firs t v
isi t
las t v
isi t
firs t v
isi t
las t v
isi t
0 4-
15 27
-57
74 -1
35
14 0-
25 5
23 7-
42 5
0
20
40
60
80
100
Time [days]
D ia
ly si
s- fre
e su
rv iv
al [%
] < 50% (n=29)
Extracapillary proliferations:
50% (n=25)
Log-rank p-value = 0.002
0
50
100
150
15
75
125
175
eG F
R [
m l/m
in /1
.7 3m
2 ] p=0.767 p = 0.298 p<0.001 p<0.001
Relapse of disease during observation time
No relapse
Dialysis at presentation
No dialysis at presentation
firs t v
isi t
las t v
isi t
firs t v
isi t
las t v
isi t
0 4-
15 27
-5 7
74 -1
35
14 0-
25 5
23 7-
42 5
0
20
40
60
80
100
Time [days]
D ia
ly si
s- fre
e su
rv iv
al [%
] cGN Typ I (n=1)
cGN Typ II (n=39)
cGN Typ III (n=10)
Undetermined (n=4)
Log-rank p-value < 0.001
Classification:
0 4-
15 27
-57
74 -1
35
14 0-
25 5
23 7-
42 5
0
20
40
60
80
100
Time [days] D
ia ly
si s-
fre e
su rv
iv al
[% ] 30 d (n=15)
> 30 d (n=39)
Disease Duration:
Log-rank p-value = 0.006
b
c
f
a
e
d
Fig. 4 Factors influencing the course of estimated glomerular filtration rate (eGFR) during observation time. Disease relapse and dialysis at first visit (a), gender and age at time of disease onset (b), and nephrotic syn- drome and arterial hypertension at time of disease onset (c). Kaplan-
Meier curves of dialysis-free survival depending on disease duration (d), the classification of crescentic glomerulonephritis (cGN) (e), and the percentage of crescents (f)
Pediatr Nephrol (2020) 35:829–842838
Table 4 Additional renal biopsy findings of patients
Median eGFR [ml/min/1.73 m2] (range)
First visit Last visit
Tubular atrophy/interstitial fibrosis < 20% (n = 50) 55 (8–161) 94 (5–175)
≥ 20% (n = 10) 56 (6–91) 54 (5–128)
p value p = 0.425 p = 0.021
Glomeruli with necrosis < 20% (n = 49) 62 (6–161) 95 (5–175)
≥ 20% (n = 11) 11 (8–70) 62 (5–113)
p value p < 0.001 p = 0.022
Tubulointerstitial inflammation < 50% (n = 41) 65 (8–161) 95 (14–175)
≥ 50% (n = 18) 24 (6–115) 58 (5–151)
p value p < 0.001 p = 0.009
Tubulointerstitial inflammation [Intensity 0–3]
0 (n = 1) 135 125
1 (n = 20) 69 (9–161) 92 (21–151)
2 (n = 28) 54 (8–115) 95 (5–175)
3 (n = 10) 26 (6–82) 66 (5–123)
RBC casts [Intensity 0–3]
0 (n = 13) 50 (6–161) 85 (5–151)
1 (n = 26) 64 (10–135) 100 (14–175)
2 (n = 9) 70 (13–115) 67 (25–130)
3 (n = 10) 11 (8–47) 92 (5–140)
Thrombi within glomeruli Yes (n = 7) 13 (8–114) 78 (5–140)
No (n = 51) 55 (6–161) 92 (5–175)
p value p = 0.486 p = 0.62
ATI severity score [Intensity 1–3]
1 (n = 7) 73 (47–161) 99 (52–175)
2 (n = 32) 65 (6–115) 100 (6–151)
3 (n = 21) 38 (8–82) 56 (5–113)
IgA [Intensity 0–3]
< 1 (n = 15) 50 (9–94) 66 (5–136)
1 (n = 13) 63 (8–115) 92 (14–175)
2 (n = 9) 59 (6–161) 99 (6–151)
3 (n = 18) 70 (11–135) 100 (56–140)
IgG [Intensity 0–3]
< 1 (n = 15) 47 (6–135) 81 (6–151)
1 (n = 23) 51 (9–115) 67 (5–175)
2 (n = 12) 68 (9–114) 104 (21–129)
3 (n = 5) 65 (47–161) 100 (92–105)
IgM [Intensity 0–3]
0 (n = 4) 32 (14–89) 59 (17–136)
1 (n = 24) 67 (9–115) 98 (5–151)
2 (n = 22) 57 (6–161) 60 (6–175)
3 (n = 4) 47 (15–61) 100 (72–100)
C1q [Intensity 0–3]
0 (n = 5) 55 (13–94) 76 (60–136)
1 (n = 15) 50 (9–115) 95 (5–151)
2 (n = 19) 55 (8–107) 60 (17–175)
3 (n = 18) 67 (6–161) 100 (6–128)
C3c [Intensity 0–3]
< 1 (n = 6) 53 (13–103) 71 (52–136)
1 (n = 10) 70 (14–135) 92 (17–127)
2 (n = 24) 64 (9–161) 92 (14–175)
3 (n = 16) 50 (6–100) 107 (5–151)
Mesangial hypercellularity overall ≤ 50% of glomeruli (n = 23) 51 (8–103) 76 (5–136)
> 50% of glomeruli (n = 32) 64 (6–161) 100 (6–175)
p value p = 0.05 p = 0.09
Pediatr Nephrol (2020) 35:829–842 839
784) shorter than in the patients with extracapillary prolifera- tions in < 80% of glomeruli. In regression analysis, the per- centage of crescents correlated negatively with the eGFR at the end of observation time (R2 = 31%, p < 0.001) with more crescents leading to a lower eGFR.
Table 4 shows the additional renal biopsy findings from patients. Tubular atrophy and interstitial fibrosis of ≥ 20% and tubulointerstitial inflammation in ≥ 50% of the tubulointerstitium, as well as necrosis in ≥ 20% of glomeruli, were associated with a worse eGFR at last visit.
Treatment
Eighty percent of patients were treated with 5–6 (methyl-)- prednisolone pulses with a median prednisolone dose of 309 mg/m2 body surface area (BSA) (range 281–513) if BSAwas < 1.67 m2. The remaining patients were treated with 500 mg per day. The median dose for methylprednisolone was 561 mg/m2 BSA (range 275–708). In addition, 53 patients were treated with oral prednis(ol)one with a median duration of 151 days (range 6–> 365). Seventy-two percent of the total cohort was additionally treated with other immunosuppres- sants: MMF (n = 20), CsA (n = 20), cyclophosphamide (n = 6), azathioprine (n = 2), and rituximab (n = 5). One liver- transplanted patient continued with tacrolimus, and the patient the Muckle-Wells syndrome was additionally treated with canakinumab. Table 3 shows the mono- or combination ther- apy immunosuppressive treatments used in association with the underlying disease. Depending on the underlying disease, four patients received therapeutic plasmapheresis or immunoadsorption at time of disease manifestation. One pa- tient with a relapse was treated with plasmapheresis as rescue therapy (Table 3).
Discussion
This analysis of pediatric patients with cGN in our cohort revealed a wide inter-individual variability in initial kidney function which was independent of the underlying disease. An early treatment with IV(methyl-)prednisolone followed by oral steroids in combination with other immunosuppres- sants was most often successful. Outcome was dependent on percentage of glomerular crescents, disease duration, and the underlying type of cGN. No patient died during the observa- tion time.
The frequency of underlying diagnoses is in accordance with the published literature [10], with the highest prevalence of immune complex crescentic GN. Regarding the percentage of crescents, the highest incidence in the total cohort was for IgAN. PIGN was most frequently associated with crescents in more than 50% of glomeruli.
Our results confirm other studies demonstrating that the percentage of glomeruli with crescents correlates with the se- verity of cGN [3, 5]. All of our seven patients who progressed to ESRD had crescents in more than 80% of the glomeruli, in most cases, a short disease duration and nearly all presented with acute kidney failure. However, even in the majority of patients with a high number of crescents, our results suggest that intensive immunosuppressive treatment has a good chance of success. However, our retrospective data analysis does not allow us to build a predictive model based on these factors. Only one patient required dialysis during the observation time. Another prognostic factor is the time of disease duration: those patients with a faster, more fulminant course of disease showed minor improvement in renal function and resulted in a higher percentage of ESRD. The term “rapid progressive glomerulo- nephritis”—though not clearly defined in the literature—can be used to describe this latter group. On the other hand, some
Table 4 (continued)
Median eGFR [ml/min/1.73 m2] (range)
First visit Last visit
Mesangial hypercellularity global ≤ 50% of glomeruli (n = 29) 52 (8–161) 85 (5–136)
> 50% of glomeruli (n = 26) 62 (6–135) 100 (6–175)
p value p = 0.27 p = 0.18
Mesangial hypercellularity segmental ≤ 50% of glomeruli (n = 53) 59 (6–135) 92 (5–175)
> 50% of glomeruli (n = 2) 92 + 161 105
Intracapillary hypercellularity Yes (n = 54) 57 (6–161) 92 (5–175)
No (n = 2) 9 + 94 92 + 85
Intracapillary hypercellularity ≤ 50% of glomeruli (n = 35) 61 (8–161) 74 (5–175)
> 50% of glomeruli (n = 21) 55 (6–115) 103 (6–151)
p value p = 0.93 p = 0.16
eGFR estimated glomerular filtration rate, RBC red blood cells, ATI acute tubular injury
Pediatr Nephrol (2020) 35:829–842840
patients (i.e., with IgA Nephropathy) had a long time between primary diagnosis of their underlying disease and detection of cGNon renal biopsy. For those patients, continuous, closemon- itoring of renal function seems to be important so that a sudden deterioration of their kidney function can be diagnosed early enough for successful intervention.
Interestingly, in addition to children with initial dialysis or disease relapse during observation, male patients, children with arterial hypertension or nephrotic syndrome at presenta- tion, and those older than 12 years had a worse outcome. Further renal damage factors, such as tubular atrophy and interstitial fibrosis, glomerular fibrinoid necrosis, or tubulointerstitial inflammation, were associated with worse kidney function outcome.
Our results show that high kidney volume seems to be a good non-invasive surrogate parameter for the diagnosis of cGN, especially in combination with high blood pressure and urinary dipstick analysis positive for erythrocytes and protein.
Serum IgA did not prove itself as a marker for IgAN in our cohort, due to its low positive predictive value [11], which contradicts results published elsewhere [12]. The same is true for ASL-titer. In contrast, a decreased serum C3 was a good marker for lupus GN or DDD. On the other hand, as shown before, the anti-DNS titer did not correlate with disease sever- ity of lupus GN [13].
MPO antibodies (p-ANCA) were detectable in all children with MPA/RLV, whereas in children with GPA, the detection of PR3 antibodies (c-ANCA) dominated, which broadly cor- responds to the literature [14].
Historically, despite steroids, the primary immunosuppres- sant administered in cGN has been cyclophosphamide [13, 15–17]. As cyclophosphamide therapy is associated with a long-term risk for infertility and has a pro-oncogenic charac- ter, other immunosuppressive therapies such as CsA, MMF, and rituximab have been administered in many patients with good results (although treatment is obviously dependent on the underlying disease). This is especially important in chil- dren who have a long life expectancy. However, a detailed disease-based analysis of the efficacy of different immunosup- pressive therapies is not possible in our cohort because of its heterogeneous, retrospective nature and the small number of patients in each group. The CD20 antibody rituximab has been shown to be effective in children with recurrence; how- ever, we could not analyze the effect of rituximab in detail because of the large differences between the five rituximab patients in underlying diagnosis and disease course. In severe, antibody-based cGN, plasma exchange, or immunoadsorption were effectively used for induction therapy or in the case of a relapse.
Our analysis has several limitations. Because of the retro- spective character of the analysis, patient clinical data were not documented in a standardized fashion. There are only a
few uniformly accepted treatment recommendations for subdiagnoses of cGN in children, and over the long inclusion time of our analysis, these have changed. According to the high number of different underlying diagnoses, an analysis for differences in the relationship of all subdiagnoses and eGFR development was not statistically possible. Also, the influence of additional treatment strategies for the underlying diseases could not completely be analyzed. The same is true for side effects of medications, as the retrospective nature of this study did not allow a complete documentation of adverse events, especially when patients were seen by other physi- cians. The initial pathological evaluations on which therapeu- tic interventions were based were performed by different pa- thologists. Moreover, classifications and classification criteria have changed during the study period. Aiming at harmoniza- tion of morphological analyses, all histologies have been re- evaluated using accepted criteria by the same pathologist. Some patients had biopsies with fewer glomeruli than required by the Oxford Classification (8 glomeruli) or the HSPN criteria (10 glomeruli) [7, 17]. Interestingly, treatment of cGN in our center did not really change during the long ob- servation time of our study. Steroid pulse therapy was conse- quently used over the whole period. Rituximab was intro- duced in our center for children as early as 2005. An exception was the use of cyclophosphamide, only administered in the earlier period until 2006 for some cases of lupus nephritis, GPA, and anti-GBM nephritis, according to older recommen- dations. Despite these mentioned limitations, this is the first analysis of a large group of children with cGN using a stan- dardized pathological assessment by the same pathologist. Although some of the morphological data confirm published results of smaller collectives, a comprehensive morphological workup proves to be valuable in assessment of disease sever- ity and therapeutic strategy planning.
We conclude that early detection and immediate aggressive treatment of cGN in children leads to stable remissions in the majority of patients and should therefore be implemented in most cases. To further determine more detailed therapy rec- ommendations (including new, emerging therapies for cGN, such as mifepristone, budesonide or erlotinib [18–20] not yet used in children), improved cGN classification should be de- veloped, including documentation of comprehensive clinical data in an international registry. Due to the small, heteroge- neous group of patients, randomized, controlled trials do not appear to be feasible.
Acknowledgments None.
Authors’ contributions L.P. and U.M. initiated the study, collected clini- cal data, and analyzed data. J.H.B. and J.S. conducted the pathological analyses. U.M. performed statistical analyses. The original manuscript draft was prepared by U.M. and L.P., J.H.B. and J.S. prepared critical revisions. All the authors contributed to the interpretation and discussion of results and reviewed and edited the manuscript.
Pediatr Nephrol (2020) 35:829–842 841
Funding Information Open Access funding provided by Projekt DEAL.
Compliance with ethical standards The Ethics Committee of Hannover Medical School has agreed to this policy.
Conflict of interest The authors declare that they have no conflict of interest.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adap- tation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, pro- vide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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- Crescentic glomerulonephritis in children
- Abstract
- Abstract
- Abstract
- Abstract
- Abstract
- Introduction
- Patients and methods
- Results
- Glomerular filtration rate
- Disease duration
- Dialysis
- Clinical factors
- Recurrence
- Clinical signs
- Pathology
- Treatment
- Discussion
- References
