Prognostic value of the MEST-C score in long-term outcomes of immunoglobulin A nephropathy patients: Insights from a developing country

Abstract

BACKGROUND

Immunoglobulin A nephropathy is a leading cause of primary glomerulonephritis globally. Predicting disease progression using clinical markers alone is often inadequate. Integrating the Oxford classification may enhance kidney survival predictions, though its relevance in Pakistan remains unexplored.

AIM

To determine the correlation between MEST-C scores and clinical parameters, as well as their utility in predicting long-term kidney outcomes.

METHODS

A retrospective analysis was conducted on biopsy-confirmed immunoglobulin A nephropathy cases diagnosed from 1998 to 2019 at the Sindh Institute of Urology and Transplantation, with a minimum follow-up of 12 months.

RESULTS

Among 118 patients (mean age: 29.03 ± 10.58 years), median proteinuria was 2.13 g/day, and mean estimated glomerular filtration rate (eGFR) was 67.82 ± 44.60 mL/minute/1.73 m². Upon admission, 26.4% required kidney replacement therapy. Oxford classification components (E1, T1/T2, C1/C2) were significantly linked to proteinuria and eGFR decline (P = 0.00). Remission rates were 79.6%, 77.9%, 77.1%, 49.3%, and 33.3% at 6 months, and at 1 year, 2 years, 5 years, and 10 years, respectively. End-stage kidney disease progression increased over time, reaching 20.3%, 22%, 22.8%, 31.3%, and 33.8% at 6 months, 1 year, 2 years, 5 years, and 10 years, respectively. Three (2.5%) patients died. The median follow-up was 3.5 years; kidney survival rates were 79.6%, 77.9%, 77.1%, 49.3% and 33.3% at 6 months and at 1 year, 2 years, 5 years, and 10 years, respectively. Higher MEST-C scores and lower baseline eGFR were associated with poorer kidney survival (log-rank P = 0.00), while no significant correlation was observed with the degree of proteinuria (log-rank P = 0.26).

CONCLUSION

The E1, T1/2, and C1/C2 components of the MEST-C score showed strong correlations with baseline clinical markers. Delayed diagnosis has led to poor long-term kidney outcomes.

Key Words: Estimated glomerular filtration rate; End-stage kidney disease; Immunoglobulin A nephropathy; Kidney replacement therapy; MEST-C

Core Tip: This study highlights the prognostic significance of the Oxford MEST-C score classification in immunoglobulin A nephropathy patients in Pakistan. Among 118 biopsy-confirmed cases, higher MEST-C scores - particularly E1, T1/2, and C1/C2 lesions - correlated with worse clinical parameters like proteinuria and estimated glomerular filtration rate, and predicted poor kidney survival. Remission rates declined, and end-stage kidney disease rates increased over time, with only 33.3% kidney survival at 10 years. These findings emphasize the value of integrating histopathological scoring with clinical data for early risk stratification. Delayed diagnosis contributed to adverse outcomes, underscoring the need for timely recognition and intervention in immunoglobulin A nephropathy management.

INTRODUCTION

Immunoglobulin A nephropathy (IgAN) is recognized as the most prevalent form of primary glomerulonephritis worldwide[1]. Its diagnosis hinges upon identifying immunoglobulin A (IgA)-dominant immune complex deposits within the mesangium, as observed in kidney histopathological examination and immunofluorescence (IF) studies[2]. The prevalence of IgAN varies significantly across regions, with developed nations in Asia such as Singapore (43.2%) and Japan (31%) reporting the highest rates, followed by Western countries (10%-30%)[3]. Despite its high prevalence in Asia, a very low prevalence has been reported from Pakistan[4-7]. This disparity may stem from the disease’s diverse clinical manifestations, ranging from asymptomatic urinary abnormalities and hypertension to nephrotic syndrome and rapidly progressive glomerulonephritis[8,9]. No early diagnostic protocols currently exist for IgAN, and the absence of systematic screening programs makes it challenging to pinpoint disease onset. As a result, many cases remain undetected until significant symptoms and kidney dysfunction emerge[10].

While IgAN is often associated with a benign clinical course, approximately 20%-30% of cases advance to end-stage kidney disease (ESKD) within a decade[11]. This progression is influenced by factors such as demographic characteristics, ethnic background, and therapeutic interventions. Although there is no targeted treatment for IgAN, optimal supportive care remains the cornerstone of management, while the effectiveness of systemic immunosuppressive therapy continues to be debated[12].

Several clinical risk factors have been firmly established for predicting poor outcomes in IgAN, including reduced glomerular filtration rate at diagnosis, severe proteinuria, and hypertension[13]. However, clinical markers alone often fail to accurately predict disease progression. Patients can develop ESKD after years of stable kidney function[14,15]. To better identify high-risk individuals, predictive tools have been devised, incorporating known clinical and histological factors to estimate the likelihood of ESKD in individual patients[16]. The Oxford classification system, developed by the International IgA Nephropathy Network and the Renal Pathology Society, stands as the most widely adopted framework for categorizing histological lesions in IgAN. It utilizes four independent histological variables, mesangial hypercellularity (M), segmental glomerulosclerosis (S), endocapillary hypercellularity (E), and tubular atrophy/interstitial fibrosis (T), to predict kidney outcomes. Later, the inclusion of crescent formation (C) as a prognostic factor expanded the scoring system to the MEST-C score[17]. This classification has undergone validation in various population cohorts[18].

To date, only a single study conducted in Pakistan has explored short-term kidney outcomes in IgAN patients, albeit with a very limited sample size[19]. The long-term kidney outcomes in Pakistani patients, particularly in relation to the Oxford classification, remain inadequately studied. This study aims to determine the correlation between MEST-C scores and clinical parameters, as well as their utility in predicting long-term kidney outcomes.

MATERIALS AND METHODS

Ethics statement

This study received approval from the Institutional Review Board of the Sindh Institute of Urology and Transplantation (approval No. SIUT-ERC-2025/A-551). All research activities were conducted in strict adherence to the ethical principles outlined in the Declaration of Helsinki.

Study population

This study retrospectively analyzed the medical records of adults aged 18 years and older who were referred to the Kidney Division of the Sindh Institute of Urology and Transplantation, Karachi, Pakistan. These referrals spanned from January 1998 to December 2019, specifically for native kidney biopsies. Eligible patients were those with a histopathological diagnosis of IgAN who had been monitored at the kidney clinic for a minimum of 12 months following their biopsy.

Data collection

Patient medical records were thoroughly examined, encompassing clinical, biochemical, serological, and histopathological findings both at the time of biopsy and during subsequent follow-ups. Clinical data included factors such as age, gender, the rationale for conducting the biopsy, presence of hypertension, administered treatment protocols, the necessity for kidney replacement therapy (KRT), and follow-up details. Laboratory investigations recorded serum creatinine and albumin levels upon admission and at subsequent intervals, along with complement levels (complement component 3 and complement component 4) categorized as either normal or reduced. Additionally, a comprehensive urinalysis was conducted, including the urine protein-to-creatinine ratio at baseline and during follow-ups, as well as 24-hour urinary protein measurements, where available. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula[20].

Histopathology

The histopathological assessment comprised a detailed analysis of the total number of glomeruli, including those exhibiting sclerosis. It also evaluated the proportion of glomeruli displaying C categorized as cellular, fibrocellular, or fibrous, along with mesangial and E, which was noted as either diffuse or focal. Additional features such as capillary wall double contours and the extent of tubular atrophy and interstitial fibrosis were graded into four categories: None (0%-5%), mild (6%-25%), moderate (26%-50%), or severe (> 50%). IF results demonstrated positivity for IgA, IgG, IgM, complement component 3, complement component C1q, κ, and λ, with staining patterns and intensities rated on a scale ranging from 0 to 3 +. In addition, pathological variables were scored using the 2016 revised Oxford classification MEST-C criteria[21], encompassing M0/M1, E0/E1, S0/S1, tubular T0/T1/T2, and C0/C1/C2.

Outcomes

In the absence of established guidelines for determining remission in IgAN, we applied criteria typically used for proliferative lupus nephritis and classified patients into three distinct groups[22].

Complete remission: Characterized by a normal urinalysis, indicated by a dipstick result that is either negative or shows trace amounts of protein and blood. Serum albumin levels > 3.5 g/dL, along with an eGFR > 90 mL/minute/1.73 m².

Partial remission: Denoted by an abnormal urinalysis, which may reveal microscopic hematuria or proteinuria ≥ 1. Serum albumin levels remain < 3.5 g/dL, while the eGFR falls within the range of 60 mL/minute/1.73 m² to 90 mL/minute/1.73 m².

No remission: Defined as persistent proteinuria > 3 g/day or a progressive decline in kidney function.

Kidney survival: Refers to the duration from the initial kidney biopsy to the earliest instance of initiating dialysis, undergoing a kidney transplant, or a reduction in eGFR to < 15 mL/minute/1.73 m², with no subsequent recovery to levels above 15 mL/minute/1.73 m² during the follow-up period.

Kidney flare: Describes a recurrence or exacerbation, evidenced by a dipstick result turning positive after previously being negative, or an increase in proteinuria identified either through dipstick analysis or elevated urine protein-to-creatinine ratio levels in patients previously achieving complete remission (CR) or partial remission (PR)[23].

Study endpoints: The primary endpoint was defined as kidney survival without the onset of ESKD or death. The secondary endpoint focused on the proportion of patients achieving CR or PR during the follow-up period.

Statistical analysis

The statistical analysis was performed using version 22.0 of the SPSS software (IBM Corp, Armonk, NY, United States). Continuous variables were presented as either mean ± SD or median with interquartile range. Categorical data were reported as frequencies and percentages, while discrete variables were expressed in terms of proportions. Kaplan-Meier methodology was employed to construct the overall survival curve. P > 0.05 was regarded as indicative of statistical significance.

RESULTS

Patient demographics and clinical characteristics

Table 1 summarizes the demographic, clinical, and serological characteristics of patients with IgAN. The mean age at diagnosis was 29.03 ± 10.58 years, with the cohort consisting of 73 males (61.9%) and 45 females (38.1%). One-fifth of the patients, 24 (20.3%), were asymptomatic and diagnosed incidentally. Among the remaining patients, 66 patients (55.1%) presented with edema, and the median 24-hour proteinuria was 2.13 g/day (range: 1.08-3.74 g/day). 18 patients (15.3%) had nephrotic-range proteinuria (> 3.5 g/day), accompanied by microscopic hematuria. Hypertension was observed in 44 patients (37.3%), while 23 patients (19.49%) exhibited macroscopic hematuria.

Table 1 Baseline demographic and clinical characteristics of patients with immunoglobulin A nephropathy, n (%)/mean ± SD.

	n = 118
Age at biopsy (years)	29.03 ± 10.58
Gender
Male	73 (61.9)
Female	45 (38.1)
Weight (kg)	65.62 ± 15.14
HTN	44 (37.3)
Presence of edema	65 (55.1)
Evidence of recent infection	26 (22)
Asymptomatic	24 (20.3)
Urinary abnormality	14 (11.9)
Abnormal creatinine	5 (4.2)
Newly diagnosed HTN	5 (4.2)
Symptomatic	94 (79.7)
Nephrotic syndrome	26 (22)
Nephritic syndrome	45 (38.1)
Gross hematuria	23 (19.49)
Proteinuria (dipstick)
Trace	5 (4.2)
+1	11 (9.3)
+2	25 (21.2)
+3	59 (50)
+4	18 (15.3)
Microscopic hematuria
Trace	11 (9.3)
+1	20 (16.9)
+2	21 (17.8)
+3	52 (44.1)
+4	14 (11.9)
Serum creatinine (mg/dL), median (IQR)	1.4 (0.85-2.45)
eGFR (mL/minute/1.73 m2)	67.82 ± 44.60
Serum albumin (g/dL)	3.19 ± 0.81
Spot PCR (mg/dL) or 24-hour proteinuria (g/24 hours), median (IQR)	2.13 (1.08-3.74)
Spot PCR (mg/dL) or 24-hour proteinuria (g/24 hours)
Proteinuria < 1 g	5 (4.2)
Proteinuria 1-3 g	95 (80.5)
Proteinuria > 3 g	18 (15.3)
Serum C3 levels
Low (< 0.8 g/L)	7 (5.93)
Normal (> 0.8 g/L)	111 (94.06)
Serum C4 levels
Low (< 0.16 g/L)	3 (2.54)
Normal (> 0.16 g/L)	115 (97.45)
Required KRT (%)	43 (26.4)
Antiproteinuric treatment	102 (86.4)
Immunosuppressive treatment	73 (61.9)
Steroid alone	43 (36.4)
Combination treatment	30 (25.4)

HTN: Hypertension; IQR: Interquartile rang; eGFR: Estimated glomerular filtration rate; PCR: Protein-to-creatinine ratio; C: Crescent formation; KRT: Kidney replacement therapy.

Complement levels were within normal ranges in over 95% of cases at the time of presentation. The median serum creatinine concentration was 1.4 mg/dL (range: 0.85-2.45 mg/dL), while the mean eGFR was 67.82 ± 44.60 mL/minute/1.73 m². Additionally, 43 patients (26.4%) required KRT upon admission. A total of 102 patients (86.4%) were treated with renin-angiotensin-aldosterone system inhibitors. Of the 118 patients, 73 patients (61.9%) underwent immunosuppressive therapy. Among them, 43 patients (36.4%) received steroid monotherapy, while the remaining 30 patients (25.4%) were treated with combination therapy. For the combined immunosuppressive regimens, the majority of patients received steroids plus cyclophosphamide 20 (16.9%), followed by steroids plus azathioprine 15 (12.7%), steroids plus mycophenolate mofetil 3 (2.5%), and steroids plus calcineurin inhibitors 2 (1.6%).

Kidney histopathological characteristics

The histopathological features of the kidneys in patients with IgAN are summarized in Table 2. The mean number of glomeruli observed was 14.86 ± 7.02, while the mean number of globally sclerotic glomeruli was 2.99 ± 3.73. Using the Oxford classification for assessment, 70.3% of patients exhibited M1, while E1 was present in 11.9%. S1 affected 44.1% of patients, and 57.7% demonstrated T1/T2 in at least 25% of the cortical area. Additionally, C1/C2 were identified in 36.6% of patients. 96 (81.35%) patients demonstrated a MEST-C score of 3 or lower. In terms of IF findings, mesangial complement component 3 staining was observed in varying intensities: Mild in 36.4% and moderate to intense in another 36.4% of patients. Isolated IgA deposits were present in 42 cases (35.6%), whereas most patients displayed co-deposition of IgM or IgG (52.5% vs 11.9%, respectively).

Table 2 Biopsy findings of immunoglobulin A nephropathy patients categorized by MEST-C score, n (%)/mean ± SD.

	n = 118
Total glomeruli	14.86 ± 7.02
Globally sclerosed	2.99 ± 3.73
Mesangial hypercellularity
M0	35 (29.7)
M1	83 (70.3)
Endocapillary hypercellularity
E0	104 (88.1)
E1	14 (11.9)
Segmental glomerular sclerosis
S0	66 (55.9)
S1	52 (44.1)
IFTA (T)
T0	50 (42.4)
T1	56 (47.5)
T2	12 (10.2)
Cellular crescents
C0	76 (64.4)
C1	27 (22.9)
C2	15 (12.7)
C3 staining on IF
Negative	32 (27.1)
+1	43 (36.4)
+2	38 (32.2)
+3	4 (4.2)
IgA staining on IF
Alone	42 (35.6)
IgA + IgG co-deposition	14 (11.9)
IgA + IgM co-deposition	62 (52.5)
MEST-C score
1	30 (25.4)
2	31 (26.3)
3	35 (29.7)
4	16 (13.6)
5	5 (4.2)
6	1 (0.80)
7	0

IFTA: Tubular atrophy/interstitial fibrosis; C3: Complement component 3; IF: Immunofluorescence; Ig: Immunoglobulin.

Comparison of clinical characteristics at kidney biopsy in relation to MEST-C indices

Table 3 illustrates the correlation between baseline clinical parameters and the Oxford MEST-C scores. Among the indices, M1 and S1 displayed no significant association with clinical features such as hypertension, proteinuria, or reduced eGFR at presentation. Conversely, the E1 score was notably linked to nephrotic-range proteinuria (P = 0.002) and a decreased eGFR at kidney biopsy (< 48 mL/minute/1.73 m²) (P = 0.04). Additionally, the T1 and T2 scores demonstrated a positive association with hypertension (P = 0.01) and significantly reduced eGFR (< 50 mL/minute/1.73 m²) at biopsy (P = 0.00). Similarly, the cellular C1-C2 scores were also strongly correlated with nephrotic-range proteinuria (P = 0.02) and markedly lowered eGFR (< 45 mL/minute/1.73 m²) at biopsy (P = 0.00).

Table 3 Comparison of clinical characteristics at kidney biopsy in correlation with MEST-C scores, n (%)/mean ± SD.

	HTN	P value	Proteinuria (g/24 hours)	P value	eGFR (mL/minute/1.73 m2)	P value
Mesangial hypercellularity
M0	15 (42.8)	0.53	2.90 ± 1.78	0.57	63.74 ± 50.09	0.55
M1	29 (34.9)		2.63 ± 2.48		69.56 ± 42.26
Endocapillary hypercellularity
E0	38 (36.5)	0.77	2.46 ± 2.01	0.002	70.61 ± 44.87	0.04
E1	6 (42.8)		4.95 ± 3.37		47.28 ± 37.91
Segmental glomerular sclerosis
S0	21 (31.8)	0.18	2.86 ± 2.85	0.56	65.70 ± 47.36	0.56
S1	23 (44.2)		2.57 ± 1.60		70.46 ± 41.20
IFTA (T)
T0	12 (24)	0.01	2.48 ± 2.24	0.34	92.77 ± 37.34	0.00
T1-T2	32 (47)		2.94 ± 2.33		49.83 ± 40.77
Cellular crescents
C0	31 (40.7)	0.32	2.31 ± 1.96	0.02	81.20 ± 39.56	0.00
C1-C2	13 (30.9)		3.78 ± 2.76		43.92 ± 43.50

HTN: Hypertension; eGFR: Estimated glomerular filtration rate; IFTA: Tubular atrophy/interstitial fibrosis.

Impact of the MEST-C score and clinical characteristics at kidney biopsy on kidney outcomes

Table 4 highlights kidney function metrics and all-cause mortality over a 10-year follow-up period in patients with IgAN, grouped by MEST-C score categories. Out of the entire cohort, 94 patients (79.6%) achieved remission within six months. Among these, 58 patients (49%) attained CR, while 36 patients (30.5%) achieved PR. However, remission rates declined progressively over time, falling to 77.9%, 77.1%, 49.3%, and 33.3% at the 1-year, 2-year, 5-year, and 10-year marks, respectively. Conversely, the progression to ESKD rose gradually, involving 24 patients (20.3%) at 6 months and increasing to 22%, 22.8%, 31.3%, and 33.8% at 1 year, 2 years, 5 years, and 10 years, respectively. The MEST-C score was a key determinant, as lower grades corresponded with better remission outcomes, while intermediate grades exhibited mixed results. Patients with higher MEST-C grades demonstrated greater deterioration in kidney function and an accelerated progression to ESKD (P < 0.05).

Table 4 Comparison of kidney outcomes with MEST-C score of immunoglobulin A nephropathy at 6 months, 1 year, 2 years, 5 years and 10 years, n (%).

	MEST-C score
	Overall (n = 118)	1 (n = 30)	2 (n = 31)	3 (n = 35)	4 (n = 16)	5 (n = 5)	6 (n = 1)	P value
At 6 months
CR	58 (49.1)	27 (90)	17 (54.8)	11 (31.4)	2 (12.5)	1 (20)	0	0.00
PR	36 (30.5)	3 (10)	14 (45.1)	9 (25.7)	6 (37.5)	4 (80)	0
ESKD	24 (20.3)	0	0	15 (42.8)	8 (50)	0	1 (100)
At 1 year
CR	55 (46.6)	26 (86.6)	15 (48.3)	11 (31.4)	2 (12.5)	1 (20)	0	0.00
PR	37 (31.3)	4 (13.3)	15 (48.3)	8 (22.8)	6 (37.5)	4 (80)	0
ESKD	26 (22.0)	0	1	16 (45.7)	8 (50)	0	1 (100)
At 2 years
CR	54 (45.7)	27 (90)	16 (51.6)	9 (25.7)	2 (12.5)	0	0	0.00
PR	37 (31.3)	3 (10)	14 (45.1)	9 (25.7)	6 (37.5)	5 (100)	0
ESKD	27 (22.8)	0	1 (3.2)	17 (48.5)	8 (50)	0	1 (100)
At 3 years
CR	22 (18.6)	8 (26.6)	10 (32.2)	3 (8.5)	1 (6.2)	0	0	0.00
PR	21 (17.7)	1 (3.3)	7 (22.5)	9 (25.7)	3 (18.7)	1 (20)	0
ESKD	36 (30.5)	0	5 (16.1)	17 (48.5)	10 (62.5)	3 (60)	1 (100)
Lost-to-F/U	39 (33.0)	21 (70)	9 (29.0)	6 (17.1)	2 (12.5)	1 (20)	0
At 5 years
CR	17 (14.4)	6 (20)	8 (25.8)	2 (5.7)	1 (6.2)	0	0	0.00
PR	19 (16.1)	2 (6.6)	7 (22.5)	8 (22.8)	1 (6.2)	1 (20)	0
ESKD	37 (31.3)	0	6 (19.3)	17 (48.5)	10 (62.5)	3 (60)	1 (100)
Lost-to-F/U	45 (38.1)	22 (73.3)	10 (32.2)	8 (22.8)	4 (25)	1 (20)	0
At 10 years
CR	8 (6.7)	3 (10)	4 (12.9)	0	1 (6.2)	0	0	0.00
PR	12 (10.1)	3 (10)	4 (12.9)	5 (14.2)	0	0	0
ESKD	40 (33.8)	0	6 (19.3)	18 (51.4)	12 (75)	3 (60)	1 (100)
Lost-to-F/U	58 (49.1)	24 (80)	17 (19.3)	12 (34.2)	3 (18.7)	2 (40)	0

CR: Complete remission; PR: Partial remission; ESKD: End stage kidney disease; F/U: Follow-up.

The mortality rate included three patients (2.5%) who succumbed to sepsis. Additionally, the loss-to-follow-up rates stood at 38.1% and 49.1% at the 5-year and 10-year milestones, respectively. Over a median follow-up duration of 3.5 years (ranging from 2.3 years to 19 years), kidney survival rates were recorded at 79.6%, 77.9%, 77.1%, 49.3%, and 33.3% at 6 months, 1 year, 2 years, 5 years and 10 years, respectively. Lower MEST-C scores at the time of initial evaluation were associated with significantly better kidney survival rates (log-rank P = 0.00) (Figure 1A).

Figure 1 Kaplan-Meier survival analysis. A: Immunoglobulin A nephropathy (IgAN) patients during follow-up stratified by MEST-C score at presentation; B: IgAN patients during follow-up, stratified by the degree of proteinuria at presentation; C: IgAN patients during follow-up, stratified by estimated glomerular filtration rate at presentation. eGFR: Estimated glomerular filtration rate.

Upon correlating baseline clinical parameters, specifically the degree of proteinuria and eGFR at presentation, with kidney outcomes, we observed that patients with proteinuria < 1 g/day at presentation demonstrated better kidney survival compared to those with proteinuria levels of 1-3 g/day and > 3 g/day. However, this difference did not reach statistical significance (log-rank P = 0.26) (Figure 1B). In contrast, when evaluating eGFR at presentation, we found a significantly poorer kidney survival associated with decreasing eGFR levels (log-rank P = 0.00) (Figure 1C).

DISCUSSION

IgAN is a complex and diverse disease characterized by varying clinical manifestations, morphological differences, long-term kidney deterioration, and distinct regional prevalence. This study examines a group of kidney biopsies from a single center in Pakistan, a country where research on IgAN has been scarce, despite its widespread occurrence across Asia. The Oxford classification has been applied rigorously, ensuring precise evaluation. While the findings stem from a single-center analysis, they are highly significant as one of the pioneering efforts to thoroughly explore the relationship between MEST-C scores and clinical indicators. Additionally, they demonstrate the value of these scores in forecasting long-term kidney health, contributing meaningful insights into the Pakistani population.

In this study, an analysis of baseline clinical and laboratory parameters revealed that the mean age of participants was 29.03 ± 10.58 years. This aligns with findings from other studies conducted in Pakistan[4-7] as well as globally, where reported mean ages range from 28 years to 38 years[24,25]. Notably, the younger age at diagnosis, despite the absence of a nationwide urinary screening program, underscores the high prevalence of the condition in this region compared to officially documented data. The male-to-female ratio in this study was 1.62:1, which is consistent with reports from Western cohorts demonstrating a male predominance[26,27]. However, in Asia, the ratio is closer to 1:1[28,29], suggesting potential variations in underlying pathogenic mechanisms. Interestingly, only 35% of patients in this study exhibited isolated IgA deposition on IF, while the remaining cases displayed co-deposition with either IgG or IgM, further highlighting the heterogeneity of disease manifestation.

IgAN is a condition characterized primarily by mesangial IgA deposits, yet no single defining factor unifies its presentation across different regions[2]. Many experts propose that IgAN may not represent a singular disease entity but rather a spectrum of disorders with varying manifestations worldwide. In IgAN, activated mesangial cells release mediators that contribute to kidney damage by affecting podocytes and proximal tubule epithelial cells, increasing glomerular permeability, and causing scarring in both glomerular and interstitial compartments. These pathological changes culminate in hypertension, proteinuria, hematuria, and impaired renal clearance[30,31]. Hypertension prevalence among IgAN patients varies significantly across studies, with rates ranging from 6% to 65% in the validation study of the Oxford classification of IgAN cohort[24]. In our study, 37.3% of patients were hypertensive. High-grade proteinuria (> 1.0 g/24 hours) and arterial hypertension have been identified as independent risk factors for kidney disease progression[32,33]. However, this association lacks consistency, as demonstrated by Tan et al[34], who reported normotensive patients with mild proteinuria yet significant kidney impairment at the time of IgAN diagnosis in a Chinese cohort. Similarly, our study found that 84.7% of patients exhibited non-nephrotic range proteinuria despite considerable kidney dysfunction, and no significant correlation was observed with the degree of proteinuria. This observation aligns with findings by Mittal et al[35], where 77% of patients presented with non-nephrotic range proteinuria, contrasting with other studies in which nephrotic-range proteinuria was more predominant[36,37].

Based on clinical indicators, this study found that 92 patients (77.9%) achieved remission within 1 year, a considerably lower rate compared to other reports from Asia. For instance, Thapa and Sigdel[21] documented a total remission rate of 90.38% at 1 year in a Nepalese cohort. This discrepancy, along with the poor kidney outcomes observed, may be attributed to the fact that 26.4% of patients required KRT at the time of presentation, and a significant correlation was found with the eGFR at presentation. The remission rates progressively declined over time, dropping to 77.9%, 77.1%, 49.3%, and 33.3% at the 1-year, 2-year, 5-year, and 10-year marks, respectively. Likewise, disease progression to ESKD was identified in 24 patients (20.3%) at 6 months, increasing steadily to 22%, 22.8%, 31.3%, and 33.8% at 1 year, 2 years, 5 years and 10 years, respectively. These figures exhibit significant variation when compared to previously published data from both Asian and Western populations[38-40]. This disparity underscores the issue of late disease presentation in this region, largely due to the absence of government-led screening programs. The failure to identify high-risk IgAN patients early prevents timely intervention, which could potentially alter their long-term kidney prognosis. Additionally, the younger age at presentation reflects the aggressive nature of the disease in this cohort. Furthermore, a substantial proportion of patients, 50%, were lost to follow-up by the 10-year mark, presenting a considerable limitation that impacts long-term outcome assessments.

Existing literature suggests that incorporating the MEST-C score into clinical data at the time of biopsy enhances the prediction of composite kidney outcomes[25,26]. The prognostic value of this score is contingent on the presence of various histopathological features, as well as the overall MEST-C classification. Studies have reported variable associations, with higher scores at initial evaluation being linked to poorer kidney survival. A systematic review and meta-analysis conducted by Lv et al[41] in China demonstrated a strong correlation between ESKD and the S1 and T1/T2 subgroups, whereas no significant association was observed with the E1 subgroup. Similarly, Haaskjold et al[42] found a robust relationship between the MEST-C score and kidney outcomes. Schimpf et al[43] reported that the M1 subgroup was associated with an unfavorable prognosis, while ESKD was more frequently observed in the T1/T2 category. Additionally, the C1/C2 subgroups were linked to poorer outcomes, but only in cases where corticosteroids were not administered. In line with these findings, the present study identified strong correlations between the E1 and C1/C2 subgroups and nephrotic-range proteinuria. Moreover, alongside T1/T2, these variables exhibited a significant association with kidney survival. However, no meaningful relationship was observed with the M1 and S1 subgroups. Additionally, our data reaffirmed that higher MEST-C scores at presentation were predictive of worse long-term kidney prognosis.

The current Oxford classification does not provide a framework for treatment stratification, as it is primarily centered on clinical markers such as persistent proteinuria and eGFR. In our study, we similarly found no significant correlation between treatment response and the MEST-C score. Despite 62% of patients receiving immunosuppressive therapy, with one-fourth undergoing combination treatment alongside steroids, kidney outcomes remained poor. Our findings align with those of Itami et al[44] and Coppo et al[45], both of whom failed to establish a meaningful association between the MEST-C score and treatment response to corticosteroids. These results further highlight the complexity of IgAN management and the need for additional research to refine therapeutic approaches.

Strengths and limitations of the study

This study possesses several notable strengths. Foremost, it stands as one of the most extensive investigations conducted on an adult cohort of biopsy-confirmed IgAN cases in a developing South Asian country, offering a fair representation of the Pakistani population. In the context of scarce existing research, it bridges a crucial knowledge gap by providing the first published dataset on the long-term renal outcomes of IgAN patients. Furthermore, rigorous patient follow-up until the study’s completion enabled a thorough assessment of treatment efficacy, facilitating comparisons between various MEST-C scores and long-term prognosis. Importantly, the study presents valuable data on ESKD incidence and mortality rates, contributing significant insights into disease progression and prognosis.

Despite these strengths, certain limitations should be acknowledged. Firstly, as a retrospective study, it is prone to missing data, which may affect the reliability of the final conclusions. Additionally, the inherent constraints of retrospective analysis hinder comprehensive adjustments for all potential confounding variables. Secondly, the study’s single-center design limits the generalizability of its findings, restricting their broader applicability. Thirdly, the absence of electron microscopy evaluations for all cases may have narrowed the scope of pathological insights. Lastly, the lack of standardized treatment protocols introduces variability in patient outcomes, potentially influencing the study’s overall conclusions.

CONCLUSION

Our findings suggest that initial clinical characteristics are closely linked to the E1, T1/2, and C1/C2 components of the MEST-C score, with higher scores predicting poorer long-term kidney survival. Future prospective studies are essential to explore this further. Due to delayed diagnosis, kidney prognosis in our population has been unfavorable, highlighting the urgent need for a nationwide screening program for early detection and intervention.

ACKNOWLEDGEMENTS

We extend our sincere gratitude to the Department of Electronic Health Record System for their invaluable contributions in facilitating this work. We also wish to express our heartfelt appreciation to all colleagues and collaborators for their support throughout this endeavor.