Clinicopathological characteristics and predictors of renal outcomes in diffuse crescentic glomerulonephritis : a retrospective single-center study from Western China study

doi:10.21203/rs.3.rs-3888109/v1

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Clinicopathological characteristics and predictors of renal outcomes in diffuse crescentic glomerulonephritis : a retrospective single-center study from Western China study

https://doi.org/10.21203/rs.3.rs-3888109/v1

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Aim: To investigate the clinicopathological characteristics and prognosis among various types of diffuse crescentic glomerulonephritis(DCGN) and especially type II DCGN and to identify predictive factors for renal outcomes in these patients.

Methods: This study retrospectively examined 107 patients diagnosed with diffuse crescentic glomerulonephritis through biopsy at the Sichuan Provincial People's Hospital, spanning from January 2012 to July 2022. The investigation primarily aimed to identify the occurrence of end-stage kidney disease (ESKD) as the primary endpoint. Analytical methods included Cox regression models and Kaplan-Meier survival analysis to assess the data.

Results: Among the 107 enrolled patients, 12 (11.2%) patients had Type I diffuse crescentic glomerulonephritis, 70 (65.4%) patients had Type II (including immunoglobulin A [IgA] nephropathy, 40%; lupus nephritis, 38.6%), and 25 (23.4%) patients had Type III. Thirty-seven (34.6%) patients received kidney replacement therapy (KRT) at presentation, while 17 (15.9%) received plasmapheresis. In the follow-up cohort, 46 (47%) patients progressed to ESKD. For patients with diffuse crescentic glomerulonephritis (DCGN), the 5-year cumulative renal survival rates were markedly different across the three types: Type I had a rate of 0%, Type II had a rate of 57.5%, and Type III had a rate of 18.6%. Furthermore, among Type II patients, IgA nephropathy emerged as the most prevalent condition. The cumulative 5-year kidney survival rates were 50% for patients with IgA nephropathy, 64% for lupus nephritis, and 70% for Henoch-Schönlein purpura nephritis. A significant association between the risk of ESKD development and several factors was revealed by a multivariate Cox regression analysis: baseline serum creatinine level (P=0.001), initial kidney replacement therapy (KRT) at presentation (P=0.003), interstitial inflammation (P=0.023), global glomerulosclerosis (P=0.009), and the presence of fibrous crescents over 50% (P=0.033).

Conclusion: Type II diffuse crescentic glomerulonephritis was the most prevalent type in DCGN, and favors better renal prognosis than type I and III DCGN, in which IgA nephropathy was the most common entity of Type II DCGN in western China. The prognosis for IgA nephropathy was worse than that for patients with lupus nephritis or Henoch-Schönlein purpura nephritis. Additionally, baseline serum creatinine level, initial KRT at presentation, interstitial inflammation, global glomerulosclerosis, and fibrous crescents >50% were identified as predictors of renal outcomes in diffuse crescentic glomerulonephritis .

Health sciences/Diseases

Health sciences/Nephrology

Health sciences/Risk factors

Health sciences/Urology

Crescentic glomerulonephritis

clinical pathology

End stage kidney disease

prognosis

risk factors

kidney survival

Characterized by a swift and progressive decline in kidney function, diffuse crescentic glomerulonephritis (DCGN) is recognized as a severe renal disease. The hallmark pathological feature of DCGN is the formation of crescents in over 50% of the glomeruli[1]. The primary immunopathological classifications of DCGN encompass anti-glomerular basement membrane antibody-mediated glomerulonephritis, immune complex-mediated glomerulonephritis, and pauci-immune glomerulonephritis[2]. These three types have different clinical and pathological features as well as outcomes[1–5]. The etiology of DCGN patients varies in different geographical regions worldwide. In regions such as North China[6], East China[3], the United States[7], and Spain[8], pauci-immune glomerulonephritis was predominant. Conversely, in Southern China[2], India[4, 9], South Asia[10], Turkey[11], Germany[12], Saudi Arabia[13], and Egypt[14], there was a relatively higher incidence of glomerulonephritis mediated by immune complexes, with lupus nephritis being the most common type within immune complex-mediated glomerulonephritis[1, 2, 10, 13, 14]. A study from Hunan, China reported an equal occurrence rate of type II (39%) and type III (39%) DCGN[5]. Furthermore, while the majority of past studies indicated that type I patients had the poorest renal prognosis[2–4, 6, 10, 15], a few studies suggested that type II[16] or III patients[5, 9, 11] may have had the worst prognosis. The prognosis of different types of DCGN still remains controversial. Some research indicated that elevated serum creatinine levels, Severe-to-extreme interstitial fibrosis and tubular atrophy, and oliguria/anuria could predict adverse kidney outcomes[4]. Other studies reported that the severity of clinical conditions reflected by the need for dialysis during initial hospitalization was more associated with lower short-term kidney survival rates[3]. However, the risk factors and long-term prognosis that affect the renal survival rate of DCGN are still unclear. In addition, there is no literature reporting the clinical manifestations and prognosis of the three most common diseases among type II patients: IgA nephropathy, lupus nephritis, and purpura nephritis. Therefore, this retrospective study aims to evaluate the clinical and pathological features of patients with diffuse crescentic glomerulonephritis (DCGN), with a particular emphasis on Type II DCGN. Additionally, the study endeavors to identify risk factors that may have an impact on the overall prognosis of these patients.

Study Design and Patients

This retrospective study included a total of 107 patients with biopsy-proven diffuse crescentic glomerulonephritis (DCGN) from January 2012 to July 2022. These patients were admitted to the Sichuan Provincial People's Hospital. Inclusion criteria for the study encompassed the following: (1) age ≥ 14 years; (2) over 50% of the renal histologic tissue showing crescents formation in each glomerulus[1]; (3) at least eight glomeruli per biopsy section. The following criteria were used for exclusion: (1) insufficient medical records; (2) patients who had less than 6 months of follow-up in the follow-up cohort. The follow-up cutoff date was February 15, 2023.

Clinical and Laboratory Variables

The baseline data comprised information on sex, age, blood pressure, serum creatinine levels, albumin levels, eGFR, 24-hour urine protein excretion, and urine erythrocyte count.

Renal Histopathology and outcomes

Based on immunofluorescence staining, the patients were categorized into three types: Type I was characterized by the linear deposition of immunoglobulin along the glomerular basement membrane; Type II showed significant accumulation of immune complexes in the glomeruli; Type III exhibited minimal presence of immune complexes in the glomeruli. Two experienced nephropathologists independently evaluated all pathological sections, ensuring their blindness to the clinical data.

The primary outcome, known as end-stage renal disease (ESRD), was determined by an eGFR < 15 mL/min/1.73m² or the onset of renal replacement therapy, which encompasses hemodialysis, peritoneal dialysis, or kidney transplantation.

Statistical analysis

We utilized SPSS 27.0 software for data analysis. Normally distributed variables were expressed as mean ± standard deviation and compared using t-tests or analysis of variance (ANOVA) as appropriate. The non-parametric variables were presented as median (interquartile range) and compared using the Mann-Whitney U test. Categorical variables were presented as frequencies (percentages) and compared using the chi-square test. Kaplan-Meier survival analysis was used to evaluate renal survival rate. To assess the independent risk factors associated with renal survival, both univariate and multivariate Cox regression analyses were conducted. The results were presented as hazard ratios (HR) along with their corresponding 95% confidence intervals (95% CI). A p-value < 0.05 was considered statistically significant.

Etiology

This retrospective study recorded a total of 107 eligible patients with biopsy-proven diffuse crescentic glomerulonephritis (DCGN) from January 2012 to July 2022 at the Sichuan Provincial People's Hospita. The disease distribution of DCGN was as follows: 12 (11.2%) patients were diagnosed as type Ⅰ DCGN, 70 (65.4%) as type Ⅱ and 25 (23.4%) as type Ⅲ. In type Ⅱ DCGN, 27 patients were diagnosed with lupus nephritis, 28 with IgA nephropathy, 11 with Henoch-Schönlein purpura nephritis, 3 with idiopathic cases, 1 with hepatitis B virus–associated nephritis. The flow chart of this retrospective study was displayed in Fig. 1. The number of newly diagnosed diseases by DCGN during the study period is shown in Fig. 2a.

Baseline Demographic data and Kidney Manifestation.

Among the 107 patients diagnosed with DCGN, 46 (43%) were male and 61 (57%) were female, and the average age at biopsy was 41.2 ± 17.9 years (Table 1). A higher proportion of females was observed among patients with type II and type III, while type I was equally distributed between the sexes. The eGFR in each disease group was shown in Fig. 2c. The initial eGFRs did not differ significantly between different time periods of disease progression (Fig. 2d). The mean duration between the onset of clinical symptoms and renal biopsy was 1.3 (0.7-3) months. The disease course was relatively shorter for type I patients. There was a large difference in time from the onset of symptoms to renal biopsy for type II and III patients (range 6-1200 days) (Fig. 2b). All the patients with DCGN had hematuria. Patients with type I had a higher prevalence of anemia and elevated serum creatinine levels. Type II patients had higher prevalence of females, higher proteinuria and more severe hypoproteinemia. Type III patients were mostly seen in middle aged and elderly people.

Table 1

The baseline demographic characteristics and renal/extra-renal manifestations of the study population.
Characteristic	Type Ⅰ(n = 12)	Type Ⅱ(n = 70)					Type Ⅲ(n = 25)	P value
Characteristic	Type Ⅰ(n = 12)	Total(n = 70)	IgAN(n = 28)	LN(n = 27)	HSPN(n = 11)	P value	Type Ⅲ(n = 25)	P value
Age(years,mean ± SD)	38.1 ± 17.5	37.3 ± 17.1	38.3 ± 18.4	34.8 ± 14.1	36.6 ± 20.7	0.756	53.7 ± 15.0	<0.001^b,c
Gender(male:female (ratio))	6:6(1.00)	31:39(0.79)	18: 10(1.8)	5: 22(0.23)	8: 3(2.7)	<0.001^d,f	9:16(0.56)	0.675
Duration of disease,mo	0.9(0.4,1)	1.4(0.7,3.2)	2.1(1.0,3.4)	1.0(0.7,5.0)	1.0(0.7,2.0)	0.234	2.0(1.0,3.0)	0.060
BMI,kg/m²	22.8 ± 3.1	22.7 ± 3.3	22.9 ± 2.6	22.7 ± 3.4	21.6 ± 4.2	0.537	22.4 ± 3.2	0.886
MAP,mmHg	108.1 ± 17.7	105.2 ± 18.7	104.5 ± 19.7	111.9 ± 18.4	92.8 ± 12.4	0.016^f	109.9 ± 16.1	0.514
Albumin,g/L	32.4 ± 2.9	26.0 ± 5.7	28.0 ± 5.7	24.6 ± 4.4	23.3 ± 6.4	0.018^d	30.2 ± 4.9	<0.001^a,c
Globulin,g/L	26.4 ± 6.7	25.1 ± 6.5	24.6 ± 5.8	26.0 ± 6.7	21.7 ± 6.9	0.185	30.4 ± 5.6	0.002^c
Neutrophil	5.9(4.6,9.9)	5.6(4.1,8.2)	5.8(4.1,7.3)	4.4(3.4,7.7)	9.3(5.8,15.7)	0.004^e,f	7.4(4.6,11.6)	0.540
Lymphocyte	1.0(0.9,1.2)	1.3(0.9,1.9)	1.9(1.0,2.4)	1.0(0.5,1.3)	1.5(1.4,2.5)	<0.001^d,f	1.1(0.8,1.5)	0.243
CRP	5.1(0.5,15.1)	3.0(1.0,10.0)	2.1(1.0,7.2)	4.0(1.0,10.8)	5.5(1.8,11.5)	0.369	11.0(2.2,32.6)	0.111
UA,µmol/L	483.2 ± 96.8	421.0 ± 125.1	376.8 ± 112.0	498.3 ± 116.2	360.0 ± 91.1	<0.001^d,f	412.9 ± 102.7	0.200
BUN,mmol/L	21.0 ± 6.4	13.8 ± 8.9	11.4 ± 6.4	16.8 ± 11.3	11.5 ± 7.6	<0.001^d	19.3 ± 9.9	0.004^a,c
Scr,µmol/L	789.6 ± 440.5	253.2 ± 227.4	252.2 ± 246.6	239.7 ± 211	183.2 ± 140.6	0.632	420.5 ± 249.8	<0.001^a,c
Proteinuria,g/d	2.0(0.7,2.9)	5.2(3.2,8.1)	4.2(2.8,8.2)	5.3(3.8,6.7)	6.4(3.7,8.4)	0.617	2.5(1.0,3.5)	<0.001^a,c
Urine RBC count,×10⁴/mL	1315(85,2000)	363(181,1884)	671(304,3267)	268(73,501)	287(198,2372)	0.009^d	993(253,2501)	0.516
eGFR,mL/min/1.73m²	6.7(5.2,9.2)	34(18,75)	43(16,94)	34.4(21.9,47.3)	34(25,117)	0.413	13.8(8.1,20.0)	<0.001^a,c
≥ 90,n(%)	0	15(21.4)	8(28.6)	3(11.1)	4(36.4)		1(4)
60–89,n(%)	0	4(5.7)	3(10.7)	0	1(9.1)		1(4)
30–59,n(%)	0	24(34.3)	6(21.4)	14(51.9)	3(27.3)		2(8)
15–29,n(%)	1(8.3)	13(18.6)	5(17.9)	6(22.2)	2(18.2)		7(28)
<15,n(%)	11(91.7)	14(20)	6(21.4)	4(14.8)	1(9.1)		14(56)
Skin rash,n(%)	0	17(24.3)	0	9(33.3)	11(100)	<0.001^d,e,f	1(4)	0.017^c
Arthritis,n(%)	2(16.7)	12(17.1)	1(3.6)	9(33.3)	2(18.2)	0.017^d	3(12)	0.831
Pulmonary,n(%)	8(66.7)	27(38.6)	12(42.9)	8(29.6)	4(36.4)	0.595	18(72)	0.007^c
Cardiovascular,n(%)	0	3(4.3)	2(7.1)	1(3.7)	0	0.606	5(20)	0.022^c
Gastrointestinal symptoms,n(%)	4(33.3)	20(28.6)	11(39.3)	2(7.4)	4(36.4)	0.018^d,f	4(16)	0.393
Note:Values for categorical variables are given as number(percentage);values for continuous variables, as mean ± standard deviation or median [interquartile range]. Abbreviations: eGFR,estimated glomerular filtration rate;RBC,red blood cell;Scr,serum creatinine;BMI,Body Mass Index;MAP,mean arterial pressure;CRP,C-reactive protein;UA,uric acid;BUN,blood urea nitrogen;IgAN,IgA nephropathy;LN,lupus nephritis;HSPN,Henoch-Schönlein purpura nephritis. a:P<0.05 between typesⅠand Ⅱ; b:P<0.05 between typesⅠand Ⅲ; c:P<0.05 between types Ⅱ and Ⅲ. d:P<0.05 between IgAN and LN; e:between IgAN and HSPN; f:between LN and HSPN.

Among the three most common diseases in type II patients, IgA nephropathy (IgAN) showed more severe hematuria. Lupus nephritis (LN) had a higher prevalence in females, with higher rates of hypertension and anemia. Henoch-Schönlein purpura nephritis (HSPN) patients exhibited higher levels of proteinuria (Table 1).

Laboratory and Serologic Data.

Table 2 showed the serologic features of diffuse crescentic glomerulonephritis. Type II patients exhibited lower serum complement levels compared to both type I and type III patients.

Table 2

Laboratory and Serologic Data of the study population.
Characteristic	Type Ⅰ(n = 12)	Type Ⅱ(n = 70)					Type Ⅲ(n = 25)	P value
Characteristic	Type Ⅰ(n = 12)	Total(n = 70)	IgAN(n = 28)	LN(n = 27)	HSPN(n = 11)	P value	Type Ⅲ(n = 25)	P value
Hb,g/L	83.9 ± 18.4	101.1 ± 24.6	114.8 ± 22.7	84.6 ± 16.6	108.3 ± 22.4	<0.001^d,f	85.0 ± 19.1	0.003^c
Low C3,n/N(%)	5/11(45.5)	36/68(52.9)	5/28(17.9)	27/27(100)	2/11(18.2)	<0.001^d,f	12/23(52.2)	0.953
Low C4,n/N(%)	0	16/68(23.5)	0	16/27(59.3)	0	<0.001^d,f	1/23(4.3)	0.031^c
IgA,g/L	2.0(1.4,3.1)	2.3(1.8,3.3)	2.2(1.8,3.1)	2.3(1.7,3.2)	2.7(1.9,3.3)	0.523	2.8(2.1,3.7)	0.259
IgG,g/L	12.7 ± 5.9	9.6 ± 5.6	6.9 ± 3.3	12.9 ± 6.0	6.3 ± 2.5	<0.001^d,f	15.0 ± 4.3	0.001^c
IgM,g/L	1.1(0.7,1.5)	0.9(0.7,1.4)	1.0(0.8,1.6)	0.9(0.7,1.0)	0.7(0.6,1.5)	0.310	1.1(0.8,1.6)	0.324
ANA positive	3(25)	25(35.7)	0	25/27(92.6)	0	<0.001^d,f	11(44)	0.519
Anti-dsDNA positive	0	20(28.6)	0	20/27(74.1)	0	<0.001^d,f	1(4)	0.005^c
ANCA positive	3(25)	6(8.6)	0	5/27(18.5)	0		22(88)	<0.001^b,c
MPO-ANCA positive	3(25)	6(8.6)	0	5/27(18.5)	0		21(84)	<0.001^b,c
PR3-ANCA positive	0	0	0	0	0		1(4)	0.346
Anti-GBM positive	10(83.3)	0	0	0	0		0	<0.001^a,b
Note:Values for categorical variables are given as number(percentage);values for continuous variables, as mean ± standard deviation or median [interquartile range]. Abbreviations:ANCA,antineutrophil cytoplasmic antibody;C3, complement 3;C4, complement 4;GBM,glomerular basement membrane;MPO,myeloperoxidase;PR3,proteinase3;ANCA:antineutrophil cytoplasmic antibody;IgAN,IgA nephropathy;LN,lupus nephritis;HSPN,Henoch-Schönlein purpura nephritis. a:P<0.05 between typesⅠand Ⅱ; b:P<0.05 between typesⅠand Ⅲ; c:P<0.05 between types Ⅱ and Ⅲ. d:P<0.05 between IgAN and LN; e:between IgAN and HSPN; f:between LN and HSPN.

Only five patients with LN were positive for ANCA in type II patients, and patients were not positive for anti-GBM antibodies. Compared to the other two groups, LN had lower serum complement levels and relatively higher IgG levels (p < 0.001).

Pathological features.

Table 3 showed the pathologic features of diffuse crescentic glomerulonephritis. Type I patients had the highest percentage of crescents in glomeruli (70.8%). A higher percentage of type I patients had ruptured Bowman's capsule and severe interstitial inflammation compared to other groups. In type II patients, there was a lower incidence of balloon sclerosis and milder interstitial inflammation. In type III patients, there was a higher occurrence of glomerular fibrinoid necrosis.

Table 3

Pathological features.
Characteristic	Type Ⅰ(n = 12)	Type Ⅱ(n = 70)					Type Ⅲ(n = 25)	P value
Characteristic	Type Ⅰ(n = 12)	Total(n = 70)	IgAN(n = 28)	LN(n = 27)	HSPN(n = 11)	P value	Type Ⅲ(n = 25)	P value
Histological characteristics
Number of glomeruli	11(9,14)	13(11,16)	12(10,14)	13(12,17)	15(10,21)	0.131	12(9,15)	0.183
Crescents(%)	71(57,83)	62.5(54.5,72.9)	63(55,69)	66.7(54.5,75.0)	60.0(52.0,72.2)	0.523	66.7(51.7,75.0)	0.153
Cellular crescents(%)	17(10,49)	26.1(11.6,50.0)	22(13,36)	37.5(7.7,52.4)	28.6(13.3,46.7)	0.340	15.8(0.0,29.7)	0.028^c
Fibrocellular crescent(%)	28.15 ± 15.09	25.07 ± 15.51	25.5 ± 16.1	25.8 ± 15.7	22.1 ± 15.6	0.792	29.61 ± 10.60	0.373
Fibrous crescents(%)	13(0,26)	0.0(0.0,18.75)	3.3(0,21.1)	0(0,11.1)	0(0,27.3)	0.552	20.0(11.1,29.2)	0.004^c
Fibrinoid necrosis,n(%)	2(16.7)	17(24.3)	5(17.9)	8(29.6)	4(36.3)	0.412	13(52)	0.019^c
Bowman’s capsule rupture,n%	8(66.7)	0	0	0	0		1(4)	<0.001^a,b
Global glomerulosclerosis(%)	10.8(1.4,30.6)	0(0,11.5)	3.1(0,12.5)	0(0,11.1)	0	0.200	13.3(0,21.6)	0.007^c
Interstitial inflammation,n(%) 0.180 0.038^a
Absent	0(0)	2(2.9)	0	1(3.7)	1(9.1)		0(0)
<25%	4(33.3)	56(80)	22(78.6)	20(74.1)	10(90.9)		18(72)
25–50%	7(58.3)	11(15.7)	5(17.9)	6(22.2)	0		6(24)
>50%	1(8.3)	1(1.4)	1(3.6)	0	0		1(4)
Immunofluorescence pattern,n(%)
C3 Number of negative	1(8.3)	1(1.4)	0	0	1(9.1)	0.041^f	4(16.7)	<0.001^a,c
Number of 1+	6(50)	16(22.9)	6(21.4)	4(14.8)	5(45.5)		11(45.8)
Number ≥ 2+	5(41.7)	53(75.7)	22(78.6)	23(85.2)	5(45.5)		9(37.5)
IgA Number of negative	7(58.3)	4(5.7)	0	3(11.1)	0	0.004^d	19(79.2)	<0.001^a,c
Number of 1+	3(25)	12(17.1)	0	8(29.6)	2(18.2)		3(12.5)
Number ≥ 2+	2(16.7)	54(77.1)	28(100)	16(59.3)	9(81.8)		2(8.3)
IgG Number of negative	4(33.3)	39(55.7)	25(89.3)	3(11.1)	10(90.9)	<0.001^{d, e, f}	17(70.8)	0.079
Number of 1+	5(41.7)	21(30.0)	3(10.7)	17(63)	1(9.1)		7(29.2)
Number ≥ 2+	3(25)	10(14.3)	0	7(25.9)	1(9.1)		0(0)
IgM Number of negative	8(66.7)	15(21.4)	5(17.9)	2(7.4)	5(45.5)	0.064	12(50)	0.006^a,c
Number of 1+	4(33.3)	38(54.3)	18(64.3)	16(59.3)	4(36.4)		8(33.3)
Number ≥ 2+	0(0)	17(24.3)	5(17.9)	9(33.3)	2(18.2)		4(16.7)
Note:Values for categorical variables are given as number(percentage);values for continuous variables, as mean ± standard deviation or median [interquartile range]. Abbreviations:IgAN,IgA nephropathy;LN,lupus nephritis;HSPN,Henoch-Schönlein purpura nephritis. a:P<0.05 between typesⅠand Ⅱ; b:P<0.05 between typesⅠand Ⅲ; c:P<0.05 between types Ⅱ and Ⅲ. d:P<0.05 between IgAN and LN; e:between IgAN and HSPN; f:between LN and HSPN.

IgAN had a higher proportion of chronic glomerular lesions compared to LN and HSPN, including the percentage of fibrocellular crescents and mesangial sclerosis.

Figure 3 showed the fluorescence, light microscopy, and electron microscopy findings of different types of crescentic glomerulonephritis. Immunofluorescence staining showed that IgG was deposited along the glomerular basement membrane in Type I Diffuse Crescentic Glomerulonephritis, with disorganized arrangement of crescent cells and possible Bowman's capsule rupture. Type II Diffuse Crescentic Glomerulonephritis commonly exhibited mesangial or intracapillary proliferation, with more orderly arrangement of crescent cells and deposition of immune complexes in the mesangial area, often accompanied by significant infiltration of inflammatory cells. Type III Diffuse Crescentic Glomerulonephritis could present weak C3 deposition and was frequently associated with focal segmental fibrinoid necrosis.

Extrarenal Manifestations.

Patients with different types of DCGN exhibited distinct extrarenal manifestations. Type I patients had a higher frequency of pulmonary involvement (66.7%) and gastrointestinal symptoms (33.3%). Patients with type II had a greater prevalence of skin rash (24.3%) and arthritis (17.1%). Type III patients had a higher frequency of pulmonary infections (72%) and cardiovascular diseases (20%) (Table 1).

IgAN was dominated by upper respiratory (42.9%) and gastrointestinal (39.3%) symptoms. Arthritis (33.3%) was more frequent in LN. Rash (100%) predominated in HSPN.

Treatment and outcomes of follow-up queue patients.

Treatment and follow-up data were presented in Table 4. Among the 37 cases (34.6%) of patients, dialysis was required during hospitalization, especially for type I (83.3%) and type III (48%) patients. Only 17 patients (15.9%) received plasma exchange therapy, while the majority of patients (78.5%) received GC + CTX treatment. Over the follow-up period, 46 DCGN patients (46.9%) progressed to ESKD. This included 9 instances (75%) of type I, 21 occurrences (33.3%) of type II, and 16 occurrences (69.6%) of type III. According to Fig. 4, the kidney survival rate in type II patients was significantly greater than that of the other two groups (P < 0.001). Type I and type III DCGN patients did not show significant improvement in eGFR at the end of follow-up. In type II DCGN patients, the eGFR increased from 34 (18,75) ml/min/1.73m² to 62 (13,95) ml/min/1.73m², P = 0.042 (Fig. 2e, Fig. 2f).

Table 4

Treatment and outcomes of follow-up queue patients.
Item	Type Ⅰ(n = 12)	Type Ⅱ(n = 63)					Type Ⅲ(n = 23)	P value
Item	Type Ⅰ(n = 12)	Total(n = 63)	IgAN(n = 26)	LN(n = 25 )	HSPN(n = 8)	P value	Type Ⅲ(n = 23)	P value
In-hospital dialysis,n(%)	10(83.3)	15(23.8)	3(11.5)	8(32)	1(12.5)	0.162	12(52.2)	<0.001^a,c
Plasma exchange,n(%)	8(66.7)	5(7.9)	0	4(16)	0	0.054	3(13.0)	<0.001^a,b
GC + CTX	11(91.7)	49(77.8)	19(73.1)	21(84)	6(75)		20(87.0)
GC + MMF	0	6(9.5)	2(7.7)	3(12)	1(12.5)		1(4.3)
GC + LEF	0	2(3.2)	1(3.8)	0	1(12.5)		0
GC	1(8.3)	4(6.3)	4(15.4)	0	0		2(8.7)
Follow-up(months,means ± SD)	28.8 ± 31.1	41.2 ± 36.3	36.6 ± 34.0	37.9 ± 33.3	67.4 ± 43.4	0.085	25.1 ± 23.3	0.107
Status at last follow-up
Scr,µmol/L	524(367,949)	105(73,503)	108(75,346)	86(73,572)	95(68,418)	0.819	451(313,522)	<0.001^a,c
eGFR,mL/min/1.73m²	8(5,17)	62(13,95)	63(15,98)	79(9,94)	73(21,129)	0.720	10(8,16)	<0.001^a,c
dialysis,n(%)	9(75)	21(33.3)	10(38.5)	7(28)	2(25)		17(73.9)	<0.001^a,c
6 months renal survival rate	33.3 ± 13.6	84.1 ± 4.6	84.6 ± 7.1	88.0 ± 6.5	87.5 ± 11.7	0.966	52.2 ± 10.4	<0.001^a,c
3-year renal survival rate	33.3 ± 13.6	70.2 ± 6.2	65.6 ± 10.1	72.1 ± 9.9	87.5 ± 11.7	0.552	27.9 ± 10.8	<0.001^a,c
5-year renal survival rate	0	57.5 ± 7.7	51.6 ± 11.9	64.1 ± 11.6	70.0 ± 18.2	0.600	18.6 ± 10.4	<0.001^a,c
Note:Values for categorical variables are given as number(percentage);values for continuous variables, as mean ± standard deviation or median [interquartile range]. Abbreviations:GC,Glucocorticoid;CTX,Cyclophosphamide;MMF,Mycophenolate Mofetil;LEF,Leflunomide;eGFR,estimated glomerular filtration rate;Scr,serum creatinine;IgAN,IgA nephropathy;LN,lupus nephritis;HSPN,Henoch-Schönlein purpura nephritis. a:P<0.05 between typesⅠand Ⅱ; b:P<0.05 between typesⅠand Ⅲ; c:P<0.05 between types Ⅱ and Ⅲ. d:P<0.05 between IgAN and LN; e:between IgAN and HSPN; f:between LN and HSPN.

At the end of follow-up, ESKD was achieved in 10 (38.5%), 7 (28%), and 2 (25%) patients with IgAN, LN, and HSPN, respectively (Table 4). 5-year cumulative renal survival was 52%, 64%, and 70%, respectively (Fig. 4).

Predictors of Renal Survival in DCGN.

Kaplan-Meier survival analysis (Supplementary Fig. 1) showed that global glomerulosclerosis (P = 0.008), initial renal replacement therapy (KRT) (P < 0.001), fibrous crescents > 50% (P = 0.004), serum creatinine ≥ 290 µmol/L (P < 0.001), and moderate to severe interstitial inflammation (P = 0.002) were linked to the advancement to ESKD.

After correcting for baseline clinicopathologic parameters, including serum creatinine, mean arterial blood pressure, Initial KRT, hemoglobin, urinary erythrocyte count, tubular atrophy and interstitial fibrosis, interstitial inflammation, Global glomerulosclerosis, crescent percentage, and fibrous crescent percentage, multifactorial Cox regression analyses indicated that baseline serum creatinine level (P = 0.001), initial KRT at presentation (P = 0.003), interstitial inflammation (P = 0.023), global glomerulosclerosis (P = 0.009), and fibrous crescents > 50% (P = 0.033) were significantly linked to the risk of patients progressing to ESRD (Table 5).

Table 5

Potential prognostic factors for kidney outcome by multivariate Cox’s regression analyses.
Variables	Univariate		Multivaria Analysis
Variables	HR (95% CI)	P value	HR (95% CI)	P value
Serum creatinine(µmol/L)	1.002(1.001–1.002)	<0.001	1.002(1.001–1.003)	0.001
MAP(mmHg)	1.015(0.999–1.031)	0.074	1.000(0.977–1.024)	0.991
Initial KRT	7.904(4.056–15.403)	<0.001	3.951(1.601–9.750)	0.003
Hemoglobin, < 90g/L	1.774(0.990–3.179)	0.054	1.029(0.475–2.229)	0.943
Proteinuria,g/d	1.010(0.938–1.088)	0.793	1.035(0.964–1.110)	0.342
Urine RBC count,×104/mL	1.000(1.000–1.000)	0.093	1.000(1.000–1.000)	0.168
TAIF,moderate to severe	1.903(1.051–3.447)	0.034	1.158(0.521–2.572)	0.719
Interstitial inflammation, moderate to severe	2.525(1.373–4.644)	0.003	2.682(1.145–6.281)	0.023
Global glomerulosclerosis(%)	1.046(1.027–1.065)	<0.001	1.034(1.009–1.060)	0.009
Crescents(%)	1.033(1.012–1.055)	0.002	1.017(0.984–1.052)	0.305
Fibrous crescent, >50%	2.371(1.291–4.356)	0.005	2.340(1.071–5.115)	0.033
Abbreviations:TAIF: Tubular Atrophy and Interstitial Fibrosis; KRT: kidney replacement therapy;MAP, mean arterial pressure;

The incidence of patients with diffuse crescentic glomerulonephritis is increasing year by year[2], and defining its clinicopathologic features and prognosis is important for treatment decisions. This study provided detailed data of diffuse crescentic glomerulonephritis(DCGN) and especially type II DCGN from western China. This study found that type II diffuse mesangial proliferative glomerulonephritis (DCGN) was the most common and had the best prognosis among DCGN types. Among them, the most common condition observed was IgA nephropathy, with lupus nephritis following closely behind. Among the three most common diseases in type II patients, IgA nephropathy had the lowest five-year kidney survival rate, followed by lupus nephritis and Henoch-Schönlein purpura nephritis.

The epidemiological characteristics of diffuse crescentic glomerulonephritis (DCGN) vary significantly in different regions. It has been found that lupus nephritis is the main type in southern China[2], Saudi Arabia[13], and Egypt[14], while minimal change disease is the main pathological type in India[4], northern China[6], the United States[7], Spain[8], and Shanxi province in China[5]. However, in our cohort, IgA nephropathy was the most common, which had been rarely mentioned in previous studies. In this retrospective study, the patients' age was lower compared to Shanxi province in China[5] and the United States[7], but similar to southern China[2] and India[4]. In our cohort, the average serum creatinine concentration was lower compared to studies conducted in southern China[2], India[4], and Shanxi province in China[5], while the average urine protein level was higher than in previous research[2, 4, 5]. Our crescent proportion was similar to that of India[4] but lower than that of Shanxi province in China[2].

There is no literature reporting the clinical manifestations and prognosis of different diseases in type II patients. In this study, we analyzed the three most common diseases in type II patients and discovered that the 5-year kidney survival rate was lower in IgA nephropathy compared to Henoch-Schönlein purpura nephritis and lupus nephritis. The baseline creatinine and proportion of fibrous crescents were higher in IgA nephropathy compared to the other two diseases. We attribute this to the presence of extrarenal diseases, which makes the diagnosis of Henoch-Schönlein purpura nephritis and lupus nephritis easier in the early stages, allowing for earlier treatment[17]. In contrast, IgA nephropathy patients have no clinical symptoms, and kidney biopsies are performed at any stage of disease progression. This can explain the poorer renal function at the time of diagnosis. Therefore, our study supports early kidney biopsy for patients with abnormal kidney function to establish a definitive diagnosis.

The study's findings suggested a significant correlation between DCGN classification and renal prognosis, with patients diagnosed with Type II diffuse crescentic glomerulonephritis (DCGN) exhibiting the highest kidney survival rates, and those with Type I DCGN experiencing the lowest kidney survival rates. However, there are discrepancies in the prognosis of different types of DCGN among different studies. The results from studies conducted in southern China and India are similar to ours[2, 10]. However, a study by Su et al., which included 109 cases of crescentic glomerulonephritis, demonstrated that Type II had the best renal prognosis, while Type III had the poorest prognosis[5]. On the other hand, Wu et al. proposed that Type III had the best renal prognosis, while Type I had the poorest prognosis[15]. Further confirmation of these comparisons may require larger research cohorts in the future. Furthermore, our current study shows that 46 patients (46.9%) developed end-stage kidney disease (ESKD) at the end of follow-up. The poor renal prognosis in the enrolled patients may be associated with higher creatinine levels and crescent proportions at the time of presentation. A study with similar findings to ours reported that 89 patients (45%) in an Indian population developed ESKD within a median follow-up of 9.4 months[10]. Another study involving 72 patients from Saudi Arabia showed that 26% of patients required dialysis at the end of follow-up[13]. In contrast, Su et al.'s study revealed that 67% of patients died or developed ESKD during long-term follow-up, indicating severe kidney involvement as a characteristic of their patient cohort[5].

Low renal survival was associated with high serum creatinine level, proportion of fibrous crescents > 50%, and initial KRT at presentation, as demonstrated by the results of this study. As reported in most of the previous studies, high serum creatinine level was considered as a predictor of low renal survival in patients with diffuse crescentic nephritis. However, our study found that the proportion of fibrous crescents > 50% and initial KRT were also significant risk factors for poor renal survival, which was rarely mentioned in previous studies.

Historically, the severity of glomerular inflammation was often reflected by the high proportion of crescents observed. Recently, Su et al. analyzed 109 patients with crescentic glomerulonephritis and observed that all patients with a crescent proportion over 90% reached the primary outcome[5]. However, to date, there is a relatively limited investigation on the impact of crescent type on kidney survival rates. Our study included patients with a fibrocellular crescent proportion greater than 50% and found it to have higher predictive value. Our study adds to the literature and emphasizes the importance of performing renal biopsies for definitive diagnosis and early treatment for improving patient prognosis. During 2022, Ge et al. conducted a prognostic analysis involving 76 patients with antiglomerular basement membrane nephritis and determined that the initial KRT could function as an indicator of an unfavorable renal outcome in these patients[18]. In contrast, the correlation between initial KRT and renal survival was not investigated in other studies involving patients with diffuse crescentic nephritis. Therefore, the current study contributes to the limited body of research by confirming the association between initial KRT and renal prognosis. This study provides evidence that renal function recovery is challenging for patients undergoing initial kidney replacement therapy (KRT).

Plasma exchange therapy has been proven beneficial for patients with ANCA-associated vasculitis or crescentic glomerulonephritis caused by anti-GBM antibodies[19, 20]. However, Wang et al. suggested that plasma exchange therapy does not improve the prognosis of patients with crescentic IgA nephropathy on top of conventional immunosuppressive therapy[21]. Within our follow-up cohort, a total of 16 patients underwent combination therapy involving plasma exchange, glucocorticoids, and cyclophosphamide. At the conclusion of the follow-up period, 11 patients (69%) had progressed to end-stage kidney disease. Therefore, we believe that for Type I diffuse crescentic glomerulonephritis patients, occasional recovery of renal function may occur with combination therapy, while plasma exchange therapy seems to have limited benefits for Type II and Type III patients. Additionally, the presence of crescents has been widely recognized as an indicative factor for the severity of glomerular inflammation over a significant period of time. In our cohort, all patients with 100% involvement of crescents in the glomeruli reached ESKD, while only 10 cases with more than 75% crescents in the glomeruli had any remaining viable glomeruli, despite receiving glucocorticoids and immunosuppressive therapy. In summary, for patients with more than 75% crescentic involvement in the glomeruli, the value of intensified treatment is extremely limited[5].

This study report has several limitations that should be acknowledged. To begin with, This retrospective study was conducted at a single center, potentially leading to selection bias. Secondly, because of the compromised renal function in patients with Type I diffuse crescentic glomerulonephritis at the time of presentation, renal biopsies were not conducted, leading to a relatively small number of cases included in the study. Lastly, the sample size in this study was limited, and the follow-up duration was insufficient. Additionally, certain types of Type II patients were not included (e.g., C3 nephropathy, membranous nephropathy). Future studies with larger sample sizes are expected to be conducted, aiming to provide further validation of these findings.

In conclusion, our study showed that type II diffuse crescentic glomerulonephritis was the most prevalent type in DCGN, and favors better renal prognosis than type I and III DCGN. IgA nephropathy exhibited the highest incidence in Type II and had a less favorable prognosis compared to lupus nephritis and purpura nephropathy. In addition, serum creatinine, initial KRT, interstitial inflammation, global glomerulosclerosis and fibrous crescent > 50% were predictive factors for ESKD in DCGN.

Ethics Approval and Consent to Participate

The study obtained approval from the Human Ethics Committee of Sichuan Provincial People's Hospital, and written informed consent was obtained from all participating patients. The study was conducted in accordance with relevant guidelines and regulations.

Author Contributions

Data collection was conducted by S.W., S.C., P.Z., Y.L., and W.W. The study design was developed by S.W., S.C., W.W., and G.L. Statistical analyses were performed by S.W., S.C., and W.W. The writing of the manuscript was completed by S.W., S.C., and W.W. All authors have reviewed and approved the final version of the manuscript for publication.

Funding

The National Natural Science Foundation of Sichuan Province provided support for this study (No. 23NSFSC0600).

Declaration of Competing Interest

The authors state that they have no known financial interests or personal relationships that could potentially influence the work reported in this paper.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to ethical restrictions.

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No competing interests reported.

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Clinicopathological characteristics and predictors of renal outcomes in diffuse crescentic glomerulonephritis : a retrospective single-center study from Western China study

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BACKGROUND

METHODS

Study Design and Patients

Clinical and Laboratory Variables

Renal Histopathology and outcomes

Statistical analysis

RESULTS

Etiology

DISCUSSION

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