
==== Front
Cureus
Cureus
2168-8184
Cureus
2168-8184
Cureus Palo Alto (CA)

10.7759/cureus.67238
Endocrinology/Diabetes/Metabolism
Nephrology
Short-Term Outcomes of Infection-Related Glomerulonephritis in Diabetes Mellitus
Muacevic Alexander
Adler John R
T S Arjunlal 1
Kaliaperumal Thirumalvalavan 1
Fernando Edwin 1
D Srinivasaprasad N 1
Surendran Sujith 2
Annadurai Poongodi 2
Kurian Anila A 3
1 Nephrology, Stanley Medical College, Chennai, IND
2 Nephrology, Government Stanley Medical College and Hospital, Chennai, IND
3 Renopathology, Renopath Center for Renal and Urological Pathology Pvt. Ltd., Chennai, IND
Arjunlal T S drarjunlalts@gmail.com
19 8 2024
8 2024
16 8 e6723819 8 2024
Copyright © 2024, T S et al.
2024
T S et al.
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article is available from https://www.cureus.com/articles/275270-short-term-outcomes-of-infection-related-glomerulonephritis-in-diabetes-mellitus
Background and objective

Infection-related glomerulonephritis (IRGN) in adults, particularly the diabetic population, has a grave prognosis with many patients progressing to dialysis-dependent renal failure. Indian data on this entity are very scarce. This study attempts to correlate the clinicopathological factors related to diabetic IRGN and its short-term outcomes.

Subjects and methods

A retrospective analysis of all diabetic patients with biopsy-proven IRGN between January 2017 and August 2021 was conducted. Factors affecting outcomes such as clinical characteristics, urine examination, complete blood count, serum biochemistry, renal biopsy, and follow-up data were obtained and analyzed to determine the risk of progression to chronic kidney disease (CKD)/end-stage renal disease (ESRD). Univariate/multivariate analysis and receiver operating characteristic (ROC) curve were performed to identify independent risk factors affecting outcomes.

Results

A total of 40 diabetic patients with IRGN was included in the study, with a mean age of 53.08 ± 10 years, comprising predominantly males (60%). Infective foci were occult in majority (37.5%). Isolated low C3 levels were documented in the majority, while three patients (7.5%) had normal complement levels. Complete renal recovery was noted in 15 patients (37.5%), while 12 patients (30%) progressed to ESRD. Anuria or uremia at presentation, glomerulosclerosis >28.6%, interstitial fibrosis with tubular atrophy (IFTA) >17.5%, and diabetic nephropathy correlated to poor renal recovery. No correlation was observed between endocapillary proliferation, the pattern of deposits, the prevalence of crescents, and complement levels with the outcome.

Conclusion

IRGN is a common immune-mediated clinical entity among diabetics and often requires renal replacement therapy. Anuria or uremia at presentation, diabetic nephropathy, elevated glomerulosclerosis, and IFTA were associated with poor renal recovery. Complement levels and crescents had no impact on the outcome.

irgn
diabetes mellitus
kidney
glomerulonephritis
infection
==== Body
pmcIntroduction

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD) in India [1]. The epidemiology and outcomes of infection-related glomerulonephritis (IRGN), the most common and perhaps the most serious renal event with short- and long-term repercussions, are influenced largely by the geographical, sociocultural, economic, genetic, and practice patterns of a country. In adults with IRGN, significant dissimilarities have been observed between renal outcomes within the population of a confined region [1-4]. Various factors play confounding roles in renal recovery such as pre-existing comorbidities (e.g., DM, hypertension, analgesic abuse, to name a few). Globally, studies from Italy and the United States have documented an increased incidence of IRGN in the diabetic subpopulation [4,5]. Studies also have noted that diabetic patients have lower renal recovery rates following acute insult [1-3]. Since the central acute kidney injury (AKI) registry in our country is in its infancy, a scarcity of data exists on the epidemiology and outcomes of IRGN. Existing literature from our country has inherent limitations including, but not limited to, single-centre data, under-reporting, under-recognition, retrospective design, and varied definitions [6-8]. At our centre, we noted that 60% (n = 72) of patients with biopsy-proven IRGN over the past five years had DM as a comorbidity.

Though the short-term morbidity and mortality of IRGN are better recognised, a critical knowledge gap exists regarding the long-term consequences in IRGN survivors, which have clinical and public health implications. The conventional ideology of benign outcomes in IRGN survivors has been recently challenged by observational studies. It is well established that any acute insult relates to an increased risk of development of de novo CKD, or progression of existing CKD, to such extent that AKI and CKD are now recognised as mutually interconnected syndromes facilitating one another [9,10]. Additionally, in a recent single-centre study from South India, 30% of IRGN among adults progressed to end-stage renal disease (ESRD) [1]. Available regional data suggest the incidence of IRGN in diabetics with rapidly progressive renal failure was over six times that of the nondiabetic adult rapidly progressive renal failure (RPRF) population [11]. Hence, IRGN survivors represent a high-risk population imparting a significant burden on the patient and public health resources, calling for risk stratification and mitigation measures.

This study aims to analyse the etiology and short‑term (90 days) outcomes in patients with IRGN among the diabetic mellitus subpopulation in a tertiary care centre. Further, the study intends to identify the risk factors associated with CKD development or progression and mortality in these patients.

Materials and methods

Subjects and methods

This study was a retrospective, observational study conducted in our tertiary care hospital between January 2017 and August 2021.

Patient selection and data collection

Adult patients (age ≥ 18 years) with DM and a biopsy-proven IRGN were included in the study. As no single clinical or pathological finding is pathognomic for IRGN, the diagnosis was based on the criteria put forth by Nasr et al. [12]. At least three of the following five criteria are required: (i) clinical or laboratory evidence of infection preceding or at the onset of glomerulonephritis; (ii) depressed serum complement; (iii) endocapillary proliferative and exudative glomerulonephritis; (iv) C3-dominant or co-dominant glomerular immunofluorescence staining; and (v) hump-shaped subepithelial deposits on electron microscopy (EM). Data on demographic characteristics, etiology, clinical features, comorbidities, and biochemical parameters including but not limited to urine routine examination, complete blood count, serum biochemistry, body fluid cultures, fasting, and post-prandial blood sugars, as well as C3 and C4 levels, were taken; histopathology, treatment provided, renal replacement therapy, and outcomes were retrieved from patient case records using a standardized data form. An extensive search for any active focus of infection was done in every patient with an emphasis not to miss any occult active infection. The sepsis screen included evaluation of the ear, nose, throat, and oral cavity including teeth; dermatology evaluation; echocardiography to rule out infective endocarditis; chest X-ray; and ultrasound abdomen. Laboratory parameters were measured at admission, serially, and at the discharge or before death as deemed required. Patient status was followed up for a period of up to 90 days to determine prognosis.

Outcome

The data were analysed regarding the demographic features, etiology, laboratory parameters, histopathology, and renal replacement therapy (RRT) against 90-day outcomes. The primary outcome was a composite of de novo CKD (defined by eGFR < 60 mL/min/1.73 m2) or CKD progression (decline in eGFR category to any higher stage) in patients with baseline CKD, at 90 days. The composite outcome of de novo CKD (defined by eGFR < 60 mL/min/1.73 m2) or CKD progression (decline in eGFR category to any higher stage) to ESRD warranting RRT or death at 90 days was studied as the secondary outcome.

Statistical methods

To describe the data, descriptive statistics, frequency analysis, and percentage analysis were used for categorical variables, and mean with standard deviation (SD) or median with interquartile range (IQR) were used for continuous variables. The association between qualitative variables was evaluated with the X2 test (chi-square) or Fisher's exact test. Quantitative variables were summarized in their mean ± SD or median and IQR. The quantitative variables were analysed using Student’s t-test (in comparisons of one variable with two categories) and/or the analysis of variance (ANOVA). Univariate and multivariable logistic analyses were used to explore the risk factors associated with in-hospital death. The risk factors with p < 0.05 for primary and secondary outcomes identified with univariate analysis using the chi-square test were further assessed using binary regression analysis. Co-linearity was analysed between the covariates. Statistical significance was considered at a p < 0.05, and an odds ratio with a 95% confidence interval was also calculated. Statistical analysis was done using IBM SPSS statistics (version 23.0) software.

Results

Within the predefined study period, 40 patients were diagnosed to have had DM and biopsy-proven IRGN in our centre and were included in the final analysis.

Socio-demographic and clinical characteristics and etiology

The group comprised predominantly males (n = 24, 60%) rather than females (n = 16, 40%), with more female patients warranting RRT at presentation than males (Table 1). The mean age of our study population was 53.08 ± 10 years, with no significant age difference between both genders (p = 0.001). Of the patients included in the study, 12.55% had newly diagnosed DM at admission. In the remaining 35 patients, the mean duration was DM was 6.75 ± 4.07 years, with only 45.7% on regular treatment. History of nonsteroidal anti-inflammatory drug (NSAID) abuse was noted in three patients (7.5%), while smoking and alcoholism were present in 55% and 42.5%, respectively. Oliguria (87.5%) with features of volume overload (92.5%) predominated at clinical presentation, while new onset hypertension and uremia were observed in 60% and 45%, respectively. All seven patients who had anuria at presentation showed endocapillary proliferation, while crescents were evident in four patients. A total of 22 (55%) patients warranted haemodialysis at presentation.

Table 1 Patient clinical characteristics

NSAID - Non-Steroidal Anti-Inflammatory Drugs, RRT - Renal Replacement Therapy, HIV - Human Immunodeficiency Virus, SD - Standard Deviation

Parameter	Total (n=40)	Fully Resolved (n=15)	Non-RRT Dependent (n=13)	RRT Dependent (n=12)	p value	
n (%)	Male	24 (60)	9 (37.5)	7 (29.2)	8 (33.3)	0.808	
Female	16	6 (37.5)	6 (37.5)	4 (25)	
Age [years, (Mean ± SD)]	53.08 ± 10	49.07 ± 2.75	56.92 ± 3.00	53.92 ± 2.43	0.129	
Comorbidities	Hypertension (n, %)	24 (60)	3 (18.8)	8 (50)	5 (31.3)	0.081	
Chronic Liver Disease (n, %)	1 (2.5)	0 (0)	1 (100)	0 (0)	-	
Diabetic Nephropathy (n, %)	9 (22.5)	0 (0)	3 (33.3)	6 (66.7)	0.008	
Hypothyroidism (n, %)	1 (2.5)	0 (0)	1 (100)	0 (0)	-	
Malignancy (n, %)	1 (2.5)	0 (0)	1 (100)	0 (0)	-	
Psoriasis (n, %)	1 (2.5)	1 (100)	0 (0)	0 (0)	-	
Pulmonary Tuberculosis (n, %)	1 (2.5)	0 (0)	1 (100)	0 (0)	-	
Smoking (n, %)	22 (55)	8 (36.4)	5 (22.7)	9 (40.9)	0.183	
Alcohol (n, %)	17 (42.5)	6 (35.3)	4 (23.5)	7 (41.2)	0.368	
Duration of Diabetes Mellitus [years, (Mean ± SD)]	6.75 ± 4.07	5.58 ± 1.20	62.3 ± 1.25	8.85 ± 1.09	0.196	
Newly detected Diabetes Mellitus (n, %)	5 (12.5)	3 (60)	2 (40)	0 (0)	0.275	
Diabetes Mellitus treatment compliance (n, %)	19 (54.3)	4 (21.1)	6 (31.6)	9 (47.4)	0.123	
History of Acute Kidney Injury (n, %)	0 (0)	0 (0)	0 (0)	0 (0)	-	
History of NSAID abuse (n, %)	3 (7.5)	2 (66.7)	0 (0)	1 (8.3)	0.406	
Newly detected hypertension (n, %)	24 (60)	12 (50)	5 (20.8)	7 (29.2)	0.081	
Fever (n, %)	13 (32.5)	4 (30.8)	5 (38.5)	4 (30.8)	0.800	
Duration of fever [days, (Mean ± SD)]	2.35 ± 4.15	0.86 ± 0.41	4.08 ± 1.64	2.33 ± 1.05	0.124	
HIV infection (n, %)	1 (2.5)	0 (0)	1 (100)	0 (0)	0.345	
Oliguria (n, %)	35 (87.5)	11 (31.4)	13 (37.1)	11 (31.4)	0.091	
Duration of oliguria [days, (Mean ± SD)]	6.13 ± 4.02	5.00 ± 1.15	8.85 ± 1.04	4.50 ± 0.67	0.008	
Anuria (n, %)	7 (17.5)	1 (14.3)	1 (14.3)	5 (71.4)	0.031	
Duration of anuria [days, (Mean ± SD)]	2.57 ± .079	2 ± 0	2 ± 0	2.80 ± 0.37	0.568	
Fluid volume overload (n, %)	37 (92.5)	13 (35.1)	13 (35.1)	11 (29.7)	0.406	
Uremia (n, %)	18 (45)	2 (11.1)	7 (38.9)	9 (50)	0.004	
Mean interval to presentation	7.97 ± 4.48	8.27 ± 1.51	9.62 ± 0.96	5.83 ± 0.74	0.101	
Infective Foci	Diabetic foot ulcer (n, %)	14 (35)	2 (14.3)	6 (42.9)	6 (42.9)	0.346	
Skin infection (n, %)	8 (20)	5 (62.5)	2 (25)	1 (12.5)	
Dental caries (n, %)	1 (2.5)	1 (100)	0 (0)	0 (0)	
Lung infection (n, %)	2 (5)	0 (0)	1 (50)	1 (50)	
Unidentified (n, %)	15 (37.5)	7 (46.7)	4 (26.7)	4 (26.7)	
Diabetic Neuropathy (n, %)	14 (35)	2 (14.3)	6 (42.9)	6 (42.9)	0.082	
Diabetic Retinopathy (n, %)	26 (65)	6 (23.1)	10 (38.5)	10 (38.5)	0.035	
Peripheral Vascular Disease (n, %)	10 (25)	2 (20)	6 (60)	2 (20)	0.098	
Need for RRT (n, %)	22 (55)	2 (37.5)	8 (36.4)	12 (54.5)	<0.001	
Mean Duration of Hospital Stay (days)	17.28 ± 8.03	12.93 ± 1.53	19.85 ± 2.95	19.92 ± 1.27	0.025	

The mean interval to presentation to our centre was 7.9 ± 4.8 days from onset of symptoms. Microscopic hematuria was uniformly present, but proteinuria was variable. Diabetic foot ulcers (35%) and skin infections (20%) were identified as predominant infective triggers, while no infective foci could be identified in the majority of the study group (37.5%).

Laboratory parameters and histopathology

The mean C3 and C4 complement levels were 53.6 ± 19.0 mg/dL and 19.15 ± 2.42 mg/dL, respectively, while normal complement levels were observed in three (7.5%) patients (Table 2). Endocapillary proliferation was universal, while capillary lumen obliteration was found only in one-third of cases (Figure 1). It was also noticed that a significant proportion of patients (42.5%) have had concomitant crescentic glomerulonephritis, while acute tubular injury (ATI) was identified in 24 (60%) patients. Coexisting diabetic nephropathy on histopathology was noted in nine patients, among which six patients progressed to ESRD.

Table 2 Patient laboratory parameters

Parameter	Total (n=40)	Fully Resolved (n=15)	Non-RRT Dependent (n=13)	RRT Dependent (n=12)	p value	
Urine exam (n, %)	Blood	40 (100)	15 (37.5)	13 (32.5)	12 (30)	0.598	
Protein > 300 mg/dL	27 (67.5)	12 (44.4)	9 (33.3)	6 (22.2)	0.251	
Leucocyte esterase positive	0 (0)	0 (0)	0 (0)	0 (0)	-	
Nitrate positive	0 (0)	0 (0)	0 (0)	0 (0)	-	
RBC cast	7 (17.5)	2 (28.6)	3 (42.9)	2 (28.6)	0.792	
WBC cast	0 (0)	0 (0)	0 (0)	0 (0)	-	
Nephrotic range proteinuria (n, %)	4 (10)	4 (100)	0 (0)	0 (0)	0.025	
Haemoglobin (g/dL)	10.38 ±0.73	10.6 ± 0.20	10.39 ± 0.21	10.11 ± 0.18	0.214	
Total leucocyte count (cells/cumm)	14632 ± 3486	12026 ± 623	15692 ± 1014	16741 ± 686	<0.001	
Serum creatinine	Admission	6.28 ± 4.06	4.62 ± 1.43	7.00 ± 0.76	7.58 ± 0.66	0.125	
Discharge	3.53 ± 2.69	1.21 ± 0.41	3.05 ± 0.43	6.95 ± 0.47	-	
Serum complement level (mg/dL)	C3	53.6 ± 19.0	58.73 ± 4.69	47.77 ± 4.89	53.5 ± 6.11	0.322	
C4	19.15 ± 2.42	19.2 ± 0.34	19.23 ± 0.48	19 ± 1.10	0.969	
Low C3 alone (n, %)	36 (90)	14 (38.9)	12 (33.3)	10 (27.8)	0.655	
Low C4 alone (n, %)	0 (0)	0 (0)	0 (0)	0 (0)	
Low C3 and C4 (n, %)	1 (2.5)	0 (0)	0 (0)	1 (100)	
Normal complement levels (n, %)	3 (7.5)	1 (33.3)	1 (33.3)	1 (33.3)	

Figure 1 Hematoxylin and eosin staining of glomeruli showing an exudative pattern of the glomerular injury

Immunofluorescence showed predominant C3 deposits over IgG in 70%, while a codominant and IgG predominant pattern was noted only in 5% each. We also observed co-staining c1q, IgA, and IgM staining in 10%, 5%, and 5% of patients, respectively (Table 3). An IgA-dominant IRGN pattern was found in two patients, and both progressed to ESRD.

Table 3 Patient histopathological parameters (40 patients)

RBC - Red Blood Cell, IFTA - Interstitial Fibrosis and Tubular Atrophy, RPS - Renal Pathology Society, IgG - Immunoglobin G, IgA - Immunoglobin A

Light Microscopy	Total (n=40)	Fully Resolved (n=15)	Non-RRT Dependent (n=13)	RRT Dependent (n=12)	p value	
Glomeruli	Viable (%)	79.87 ± 21.66	96.16 ± 2.85	67.85 ± 7.32	54.67 ± 6.05	<0.001	
Glomerulosclerosis (%)	20.13 ± 21.66	3.83 ± 2.85	32.15 ± 7.32	45.32 ± 6.04	<0.001	
Glomerulosclerosis > 30% (n, %)	15 (37.5)	(1 (6.7)	6 (40)	8 (53.3)	0.004	
Necrotising lesion (n, %)	0 (0)	0 (0)	0 (0)	0 (0)	-	
Enlarged & hypercellular (n, %)	22 (55)	11 (50)	6 (27.3)	5 (22.7)	0.191	
Mesangial matrix expansion (n, %)	9 (22.5)	3 (33.3)	3 (33.3)	3 (33.3)	0.952	
Endocapillary proliferation (n, %)	40 (100)	15 (37.5)	13 (32.5)	12 (30)	-	
Obliteration of capillary lumen (n, %)	30 (75)	12 (36.8)	8 (34.2)	10 (28.9)	0.387	
Double contours and spikes (n, %)	2 (5)	1 (50)	0 (0)	1 (50)	0.591	
Kimmelstiel Wilson lesions (n, %)	3 (7.5)	0 (0)	1 (33.3)	2 (66.7)	0.263	
Capsular drops (n, %)	0 (0)	0 (0)	0 (0)	0 (0)	-	
Hyaline caps (n, %)	1 (2.5)	0 (0)	0 (0)	1 (100)	0.302	
Podocyte hyperplasia (n, %)	0 (0)	0 (0)	0 (0)	0 (0)	-	
Capillary microaneurysms (n, %)	1 (2.5)	0 (0)	0 (0)	1 (100)	0.302	
Crescents (n, %)	17 (42.5)	5 (29.4)	5 (9.4)	7 (41.2)	0.400	
Cellular crescents (n, %)	12 (70.6)	5 (41.7)	2 (16.7)	5 (41.7)	0.138	
Fibro-cellular crescents (n, %)	4 (23.5)	0 (0)	3 (75)	1 (25)	
Fibrous crescents (n, %)	1 (5.9)	0 (0)	0 (0)	1 (100)	
Tubules	Acute tubular injury (n, %)	24 (60)	9 (37.5)	9 (37.5)	6 (25)	0.618	
Cytoplasmic vacuoles in tubular epithelial cells (n, %)	16 (40)	5 (31.3)	6 (37.5)	5 (31.3)	0.780	
RBC cast (n, %)	8 (20)	5 (62.5)	1 (12.5)	2 (25)	0.225	
Interstitium	Interstitial edema (n, %)	27 (67.5)	10 (37)	6 (22.2)	11 (40.7)	0.052	
Nil inflammation (n, %)	29 (72.5)	15 (51.7)	11 (37.9)	3 (10.3)	0.002	
Mild inflammation (n, %)	7 (17.5)	0 (0)	1 (14.3)	6 (85.7)	
Moderate inflammation (n, %)	4 (10%)	0 (0)	1 (25)	3 (75)	
Severe inflammation (n, %)	0 (0)	0 (0)	1 (25)	3 (75)	
IFTA (%)	12.75 ± 18.19	2.2 ± 1.70	15 ± 5.93	30 ± 7.79	<0.001	
IFTA > 30%	8 (20)	0 (0)	2 (25)	6 (75)	0.005	
Vascular	Arterial fibro-intimal proliferation (n, %)	16 (43.2)	4 (25)	6 (37.5)	6 (37.5)	0.218	
Arteriolar hyalinosis (n, %)	17 (43.6)	1 (5.9)	7 (41.2)	9 (52.9)	<0.001	
Diabetic nephropathy (n =9)	RPS I (n, %)	0 (0)	0 (0)	0 (0)	0 (0)	0.276	
RPS IIa (n, %)	1 (11.1)	1 (100)	0 (0)	0 (0)	
RPS IIb (n, %)	7 (77.8)	2 (28.6)	0 (0)	5 (71.4)	
RPS III (n, %)	1 (11.1)	0 (0)	0 (0)	1 (100)	
RPS IV (n, %)	0 (0)	0 (0)	0 (0)	0 (0)	
Immunofluorescence	 	
Pattern of immune complex deposition	Granular over capillary loops (n, %)	28 (70)	10 (35.7)	13 (46.4)	5 (17.9)	0.100	
Granular over capillary loops and mesangium (n, %)	11 (27.5)	3 (27.3)	2 (18.2)	6 (54.5)	
Linear over capillary loops (n, %)	1 (2.5)	0 (0)	0 (0)	1 (100)	
Immune complex staining	C3 only	2 (5)	0 (0)	0 (0)	2 (100)	0.198	
IgG more than C3	2 (5)	1 (50)	0 (0)	1 (50)	
C3 more than IgG	32 (80)	11 (33.6)	14 (45.4)	7 (20.8)	
Co-dominant IgG and C3 deposition	2 (5)	1 (50)	1 (50)	0 (0)	
IgA dominant	2 (5)	0 (0)	0 (0)	2 (100)	

Outcome

Of 40 patients included in the study, haemodialysis was employed as an RRT modality in 22 (55%). At 90 days, only 15 patients (37.5%) had complete renal recovery defined as GFR > 90 mL/min/1.73m2 and absence of proteinuria (Table 4). Of the remaining 62.5% of patients, 13 (32.5%) patients progressed to CKD and another 12 (30%) patients culminated in ESRD on RRT, respectively. We did not observe any mortality during the study period.

Table 4 90-day outcomes of the study population

LR - Likelihood Ratio, NSAID - Non-steroidal Anti-Inflammatory Drugs, # - Endocapillary Proliferation is a constant in both groups.

90-Day Outcomes	Total [n (%)]	
N	40 (100)	
Lost to follow up	0 (0)	
n (after excluding loss to follow up)	40 (100)	
Fully recovered	15 (37.5)	
Primary outcome (de novo CKD (eGFR < 60 mL/min/1.73 m2) or CKD progression (decline in eGFR category to any higher stage) in patients with baseline CKD)	25 (62.5%)	
Mortality	0 (0)	
Secondary outcome (de novo CKD (eGFR < 60 mL/min/1.73 m2) or CKD progression (decline in eGFR category to any higher stage) in patients with baseline CKD or death)	25 (62.5%)	
RRT dependency	12 (30)	
Factors influencing RRT dependency at 90 days	LR	p value	
Fever	0.005	0.941	
Oliguria	0.291	0.590	
Anuria	6.388	0.011	
Fluid overload	0.017	0.897	
Uremia	6.390	0.011	
Male gender	0.322	0.571	
Diabetic nephropathy	6.950	0.008	
Diabetic retinopathy	2.739	0.098	
Diabetic neuropathy	1.657	0.198	
RRT warranted at admission	11.553	<0.001	
Peripheral vascular disease	0.670	0.413	
Crescents	1.749	0.186	
Arteriolar hyalinosis	9.489	0.002	
Interstitial edema	5.320	0.021	
Acute tubular injury	0.707	0.400	
Endocapillary proliferation	#	#	
Obliteration of capillary lumen	0.670	0.413	
History of hypertension	0.020	0.888	
NSAID abuse	0.017	0.897	
Alcohol	1.749	0.186	
Smoking	2.882	0.090	
New-onset hypertension	0.020	0.888	
Newly detected DM	3.865	0.049	
DM drug incompliance	3.274	0.070	
Low complement levels	0.017	0.897	

Risk factors associated with primary and secondary outcomes

In multivariate analysis anuria or uremia at presentation, coexisting diabetic retinopathy, intense inflammatory infiltration of interstitium, interstitial edema, arterial hyalinosis, coexisting IgG deposition over tubular basement membrane, and intensity IgG deposition (> 2+) over capillaries were observed more frequently in those with poor renal outcomes. Both glomerulosclerosis and IFTA on microscopy showed a positive correlation with incomplete renal recovery (Spearman’s rho = 0.001). Receiver operating characteristic (ROC) analysis of glomerulosclerosis > 28.6% (sensitivity of 66.7% and specificity of 82.1%) and IFTA > 17.5% (sensitivity of 75% and specificity of 92.9%) in biopsy revealed a correlation with poor renal recovery and progressing to CKD/ESRD (Figure 2). However, we did not observe any relation between endocapillary proliferation causing obliteration of the lumen, the pattern of immunoglobulin deposit, prevalence/type crescents, or complement levels with the final renal outcome.

Figure 2 ROC curve depicting glomerulosclerosis and IFTA on microscopy showing a positive correlation with incomplete renal recovery (Spearman’s rho = 0.001)

ROC - Receiver Operating Characteristic; IFTA - Interstitial Fibrosis and Tubular Atrophy

Discussion

Accumulating evidence on the adverse long-term consequences of IRGN in diabetics has changed our perception of this disease, generally considered to have a benign outcome. The development and validation of histopathological and immunohistochemical staining patterns, apart from use in epidemiologic studies and trials, has increased our understanding of the short- and long-term outcomes of IRGN.

More than half of our study population were males. However, we noted that, among the 22 (55%) who warranted haemodialysis upon presentation, the majority were females (odds ratio: 2.14). At our tertiary care centre, we noticed delayed presentation of patients despite one week or more since disease onset, reasons being delayed recognition, inadequate management of the precipitating cause, difficulty in health care access, resorting to alternate medicine, and delayed referral including in-hospital nephrology referral. The mean age of 53.08 ± 10 years and the mean diabetic duration of 6.75 ± 4.07 years were comparable to most of the similar studies, though some studies have reported considerably lesser and greater mean age than ours [12-15]. A significant proportion of patients had undiagnosed DM at admission and have been excluded while calculating the average duration of the said illness. Regardless, a longer duration of DM was found to correlate with poor renal outcomes in our study population. Compared to data from developed countries, IRGN is approximately 10 times more prevalent in the Indian population [1,13,15]. Males were represented more than females (1.5:1) in our study, as has been observed in other studies, which may be related to more healthcare access for males [6,16].

Infectious foci triggering the inflammatory cascade could not be identified in the majority of the cases (37.5%). In those for whom evident focus was identified, diabetic foot ulcer was the leading cause (35%), followed by cutaneous infections (20%) viz. cellulitis, boils, lower respiratory tract infections (5%), and dental caries (25%). This pattern is attributed to the wider prevalence of DM in the elderly Indian subpopulation [17,18]. Among the different sites, skin and soft tissue was the most common sepsis source in our cohort, which could have been largely prevented if they had been managed appropriately early. In a recent study by Priyamvada et al., skin and soft tissue was the most common foci, whereas other studies have cited the urogenital system, lung, or abdomen as the predominant site [1,19,20].

In our current study, 55% of patients needed renal replacement therapy, which was preferably provided as intermittent haemodialysis in the majority, while most other related studies showed a slightly lower requirement of renal replacement therapy [1,21]. At 90 days, only 15 patients showed complete renal recovery, with the remaining 25 (62.5%) patients progressing to CKD. This was significantly higher than other studies on IRGN in the general population [1,2]. This finding may be partially explained by co-existing diabetic kidney disease as evidenced by biopsy in nine patients, though their baseline GFR prior to the current renal insult was unknown. However, a total of six patients with coexisting diabetic nephropathy progressed to ESRD and continued to be on RRT at the end of 90 days. Sixteen patients (40%) with IRGN without baseline CKD developed de novo CKD at 90 days, with six patients culminating in ESRD warranting RRT. Experimental models have shown maladaptive repair or disordered regeneration or both, due to renin-angiotensin activation, tubular G2/M arrest, inflammation, epigenetic changes, and mitochondrial dysfunction among others, culminating in vascular drop-out and resulting in glomerulosclerosis and interstitial fibrosis with tubular atrophy, each of which contributes to progressive renal dysfunction by perpetuating injury and hampering repair [9,22]. AKI progresses to CKD through at least two distinct pathways, either non-recovering AKI progressing to CKD being the most established trajectory or after an ‘apparent’ recovery following AKI; a serial decline of normal renal function is hastened, which is being frequently noted in recent times [23]. In our study, we have assessed only the first pathway of non-recovering AKI progressing to CKD. Another caveat with apparent ‘complete’ recovery is that it resorts to creatinine level as a primary marker of renal recovery, which is drastically confounded by factors, such as muscle mass loss, changes in volume of distribution, and hyperfiltration [9,24]. The race is already afoot in search of biomarkers to identify ongoing renal injury, which may help in risk-stratifying patients for intervention [9,22]. We observed very low mortality in our 90-day study period, which may be partially influenced by the exclusion of patients with haemodynamic instability from the study population as they were unfit to undergo renal biopsy mandated in the inclusion criteria. In view of the scarcity of data regarding the same, no patients received oral or IV corticosteroids during their hospital stay. Regardless, in general, all studies quoted here have not documented any serious mortality risk.

Various studies across the globe show AKI to CKD progression in 8-54% of patients with IRGN [8,25-29]. In a similar study from the same region, Arivazhagan et al.'s prognosis of 45 patients with IRGN among adults in the general population was studied, and they noted that 33.3% progressed to ESRD at the end of 90 days [1]. The predominant risk factors for poor outcomes were identified to be age > 40 years, alcohol intake, peak creatinine > 1.5 mg/dL, a requirement for dialysis at presentation, and the presence of moderate-to-severe interstitial fibrosis with tubular atrophy (IFTA). These results are concurrent with our study outcomes as well, except for the higher ERSD rates in our study. Our study population comprised predominantly elderly population (age > 45 years) and coexisting diabetic nephropathy 22.5% cases may be the reason that we noted higher CKD rates.

On analysing the risk factors associated with 90-day outcomes, advanced age, anuria or uremia at presentation, diabetic retinopathy, baseline diabetic kidney disease (DKD), need for RRT, intense inflammatory infiltration of interstitium, interstitial edema alongside features of chronicity such as arterial hyalinosis, and coexisting IgG deposition over the tubular basement membrane were observed more frequently in those with poor renal outcomes. Light microscopy revealed glomerulosclerosis > 28.6% (sensitivity of 66.7% and specificity of 82.1%) and IFTA > 17.5% (sensitivity of 75% and specificity of 92.9%) in biopsy revealed a correlation with de novo CKD or progressing to CKD/ESRD. We did not observe any correlation between alcohol intake, smoking, immunoglobulin deposition pattern, serum complement levels, and crescentic transformation to renal outcome. IgA-dominant IRGN has been already established to have poor outcomes [29], which were noted in two patients in our study. The sample size was not sufficient to make any relevant remarks on the impact of NSAID abuse on renal recovery.

Despite accumulating evidence on poor long-term outcomes of IRGN among adults, barriers and knowledge gaps exist about interventions to improve outcomes. Considering the increasing incidence of IRGN in diabetics and its progression to ESRD, care provided during the admission warrants revamping to include a follow-up period, which is amenable to interventions to forestall the development of CKD and or to secure early permanent vascular access for RRT, which is often difficult in the DM patients. In the Western world, apart from a Brazilian study that showed 8% ESRD risk in IRGN, most other studies on IRGN were primarily based on children, and hence even in developed countries, follow-up care is lacking [26-29]. Another study from East India also concluded that IRGN should no longer be considered a benign disease considering its higher risk of progression to ESRD [29]. Post-IRGN risk stratification, improved processes of care including regular monitoring of blood pressure, glycemic control, proteinuria and renal function, and medication reconciliation are strategies to improve long-term outcomes for these patients down the lane.

The primary strength of our study is that we focused on diabetic patients as our study population and that we conducted an extensive search for occult infectious triggers and looked into the impact of histopathological aspects on biopsy. Our study did have a few limitations, including retrospective study design, single-centre study, small sample size, exclusion of hemodynamically unstable patients or those without renal biopsy, being a tertiary care centre, and a study population that may not be representative of the general population.

Conclusions

The survival after IRGN in the DM subpopulation is now increasingly regarded as being a portent of adverse long-term events. Knowledge of the epidemiology and outcomes are essential to frame policies to overcome the barriers and care gaps to improve outcomes. The present study has thrown light on the epidemiological factors for IRGN and the impact of diabetes on recovery in the adult diabetes population. The severity of IRGN at presentation as marked by anuria or uremia at presentation, need for RRT, alongside other features of severe renal insult such as intense inflammatory infiltration of interstitium, interstitial edema, arterial hyalinosis, moderate-to-severe glomerulosclerosis or IFTA, and additional presence of coexisting diabetic retinopathy or nephropathy were as red flags in the development or progression of CKD in our study, while classical markers of active inflammation such as serum complement levels and presence crescents have shown to be less impactful. A longer follow-up of ‘apparently’ recovered patients is warranted to better delineate the impact of IRGN in the diabetic population.

Disclosures

Author Contributions

Human subjects: Consent was obtained or waived by all participants in this study.

Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Concept and design:  Arjunlal T S, Edwin Fernando, Thirumalvalavan Kaliaperumal, Srinivasaprasad N. D, Sujith Surendran, Poongodi Annadurai, Anila A. Kurian

Acquisition, analysis, or interpretation of data:  Arjunlal T S

Drafting of the manuscript:  Arjunlal T S, Edwin Fernando, Thirumalvalavan Kaliaperumal, Poongodi Annadurai

Critical review of the manuscript for important intellectual content:  Arjunlal T S, Edwin Fernando, Thirumalvalavan Kaliaperumal, Srinivasaprasad N. D, Sujith Surendran, Anila A. Kurian

Supervision:  Thirumalvalavan Kaliaperumal
==== Refs
References

1 Clinicopathological profile and outcome of adult infection-related glomerulonephritis: a prospective follow-up study Natl Med J India Arivazhagan S Rajasekar D Gopalakrishnan N 260 264 33 2020 34213450
2 The contrasting characteristics of acute kidney injury in developed and developing countries Nat Clin Pract Nephrol Cerdá J Bagga A Kher V Chakravarthi RM 138 153 4 2008 18212780
3 A study of infection-related glomerulonephritis (IRGN) from a tier-2 city in Southern Tamilnadu J Med Sci Clin Res Balamurugan S 542 546 6 2018
4 Novel insights into acute kidney injury-chronic kidney disease continuum and the role of renin-angiotensin system J Formos Med Assoc Chou YH Huang TM Chu TS 652 659 116 2017 28615146
5 IgA-dominant infection-related glomerulonephritis in India: a single-center experience Indian J Nephrol Dhanapriya J Balasubramaniyan T Maharajan SP Dineshkumar T Sakthirajan R Gopalakrishnan N Nagarajan M 435 439 27 2017 29217879
6 Spectrum of acute kidney injury in critically ill patients: a single center study from South India Indian J Nephrol Eswarappa M Gireesh MS Ravi V Kumar D Dev G 280 285 24 2014 25249716
7 The Italian experience of the national registry of renal biopsies Kidney Int Gesualdo L Di Palma AM Morrone LF Strippoli GF Schena FP 890 894 66 2004 15327376
8 Incidental healed postinfectious glomerulonephritis: a study of 1012 renal biopsy specimens examined by electron microscopy Hum Pathol Haas M 3 10 34 2003 12605360
9 Long-term prognosis in acute glomerulonephritis. The predictive value of early clinical and pathological features observed in 65 patients Am J Med Hinglais N Garcia-Torres R Kleinknecht D 52 60 56 1974 4588640
10 Changing epidemiology of acute post-streptococcal glomerulonephritis in Northeast Florida: a comparative study Pediatr Nephrol Ilyas M Tolaymat A 1101 1106 23 2008 18373105
11 Long-term outcomes of acute kidney injury and strategies for improved care Nat Rev Nephrol James MT Bhatt M Pannu N Tonelli M 193 205 16 2020 32051567
12 Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature Medicine (Baltimore) Nasr SH Markowitz GS Stokes MB Said SM Valeri AM D'Agati VD 21 32 87 2008 18204367
13 Clinicopathologic features of IgA-dominant postinfectious glomerulonephritis Korean J Pathol Koo TY Kim GH Park MH 105 114 46 2012 23109989
14 Infection-related glomerulonephritis is the most common finding in renal biopsies in the very elderly in India Clin Kidney J Kurien AA Prema KS Gopalakrishnan N 454 456 14 2019 33564457
15 Different patterns of renal damage in type 2 diabetes mellitus: a multicentric study on 393 biopsies Am J Kidney Dis Mazzucco G Bertani T Fortunato M Bernardi M Leutner M Boldorini R Monga G 713 720 39 2002 11920336
16 Rapidly progressive renal failure in type 2 diabetes in the tropical environment: a clinico-pathological study Ren Fail Moger V Kumar SK Sakhuja V 595 600 27 2005 16152999
17 Management of acute kidney injury: core curriculum 2018 Am J Kidney Dis Moore PK Hsu RK Liu KD 136 148 72 2018 29478864
18 Long-term prognosis of diffuse proliferative glomerulonephritis associated with infection in adults Nephrol Dial Transplant Moroni G Pozzi C Quaglini S 1204 1211 17 2002 12105242
19 Bacterial infection-related glomerulonephritis in adults Kidney Int Nasr SH Radhakrishnan J D'Agati VD 792 803 83 2013 23302723
20 Ten-year follow-up of patients with epidemic post infectious glomerulonephritis PLoS One Pinto SW Mastroianni-Kirsztajn G Sesso R 0 10 2015
21 Prevalence of type 2 diabetes and its complications in India and economic costs to the nation Eur J Clin Nutr Pradeepa R Mohan V 816 824 71 2017 28422124
22 Changing epidemiology of community-acquired acute kidney injury in developing countries: analysis of 2405 cases in 26 years from eastern India Clin Kidney J Prakash J Singh TB Ghosh B 150 155 6 2013 26019843
23 IgA dominant postinfectious glomerulonephritis: report of two cases Indian J Nephrol Rajakumar V Mohamed SA Kurien AA Fernando ME 181 184 24 2014 25120298
24 The current state of poststreptococcal glomerulonephritis J Am Soc Nephrol Rodriguez-Iturbe B Musser JM 1855 1864 19 2008 18667731
25 Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition Diabetes Res Clin Pract Saeedi P Petersohn I Salpea P 107843 157 2019 31518657
26 Post-discharge kidney function is associated with subsequent ten-year renal progression risk among survivors of acute kidney injury Kidney Int Sawhney S Marks A Fluck N Levin A McLernon D Prescott G Black C 440 452 92 2017 28416224
27 Five-year follow-up of patients with epidemic glomerulonephritis due to Streptococcus zooepidemicus Nephrol Dial Transplant Sesso R Pinto SW 1808 1812 20 2005 15919694
28 The epidemiology, clinical features, and outcome of infection-related glomerulonephritis from East India: a single center experience Indian J Nephrol Trivedi M Pasari A Chowdhury AR Kurien AA Pandey R 307 312 27 2017 28761234
29 Long-term prognosis for endocapillary glomerulonephritis of poststreptococcal type in children and adults Nephron Vogl W Renke M Mayer-Eichberger D Schmitt H Bohle A 58 65 44 1986 3748251
