Incidence, demographic, biochemical, and clinicopathological profile of primary IgAN in a tertiary care center from Northern India

Primary IgA nephropathy (IgAN) has variable distribution and clinicopathological spectrum throughout the world. We report the incidence, demographic, and clinicopathological profile of primary IgAN from a tertiary care center in Northern India. This is a single-center, prospective, observational study conducted at Sheri- Kashmir Institute of Medical Sciences, J&K, India, from January 2015 to December 2018. The study was approved by the hospital ethical committee. A total of 106 patients were included in this study, accounting for 19% (106/558) of all native kidney biopsies done during the period from January 2015 till December 2018. Males and females accounted for 60.4% (64/106) and 39.6% (42/106), respectively, with a ratio of 1.5:1. The mean age was 31.37±11.60 years. Edema and hypertension were the most common presenting symptoms and signs, seen in 69 (65.1%) and 72 (67.9%) patients, respectively. The baseline 24-h urine protein excretion was 2.32 ±1.34 g, Nephrotic range proteinuria (≥3.5g/day) was seen in 23/106 (21.7%). Average serum creatinine was 1.6±0.80 mg/dl and estimated glomerular filtration rate using CKD-EPI was <60 ml/min/1.73 m2 in 48.1% of patients (51/106). In patients with < 1 g proteinuria, 36.8% had E1, 78.9% had S1, 36.8% had T1, and 42.1% had T2 lesions. IgAN is common in North India and has a more severe histopathological presentation, characterized by extensive sclerosis and tubulointerstitial fibrosis. Renal dysfunction and nephrotic range proteinuria are common. Hypertension, low eGFR, and proteinuria correlate with the presence of segmental scarring, endocapillary hypercellularity, and IFTA. Screening of asymptomatic individuals might help in early diagnosis and long-term preservation of renal function.


Introduction
First described by Berger and Hinglais in 1968, IgA nephropathy is the most prevalent pattern of glomerular diseases in most countries where renal biopsy is widely used as an investigative tool. IgAN is an immune-complex mediated disease defined by the presence of either dominant or co-dominant deposits of IgA, predominantly in the glomerular mesangium. The distribution and clinicopathological spectrum of IgA nephropathy vary in different regions throughout the world [1]. The bulk of the disease burden is borne by Asians and Caucasians [2,3]. IgAN is reported in 10 to 15% of all kidney biopsies in India with a high proportion of nephrotic syndrome and renal dysfunction at presentation [4][5][6][7][8][9]. Indian patients seem to manifest the disease a decade earlier than Caucasian and East Asian patients [10,11]. It is unclear whether

Open Access
The Egyptian Journal of Internal Medicine *Correspondence: dsry81@gmail.com 2 Bahrain Specialist Hospital, PO.Box 10588, Jufair Manama, Kingdom of Bahrain Full list of author information is available at the end of the article Results A total of 106 patients were included, accounting for 19% (106/558) of all native kidney biopsies done during the study period. The male-to-female ratio was 1.5:1 (64/42). The mean age at presentation was 31.4±11.6 (range 15-64) years. Ninety-one (86%) patients were in the age group between 15 and 45 years. Sixty patients (56.6%) were in the age group of 15-30 years and 31 (29.2%) patients in the age group of 30-45 years. Edema was the most common presenting complaint, seen in 69 (65.1%) patients. Twelve patients (11.3%) presented with gross hematuria. Hypertension was present in 72 (67.9%) patients. Stage 2 hypertension was present in 65 (61.3%) patients. The mean 24-h urine protein at the time of biopsy was 2.32 ±1.34 (range 0.5-6.5) g. Nephrotic range proteinuria (≥3.5 g/day) was seen in 23 (21.7)% of patients. Sixty-four (60.4%) patients had proteinuria in the range of 1.0 to 3.49 g per day. Mean creatinine at the time of biopsy was 1.6±0.8 (range 0.7-4.40) mg/dl. Estimated glomerular filtration rate (CKD-EPI eGFR) less than 60 ml/min/1.73m 2 was seen in 48.1% (51/106). Mesangial hypercellularity score was > 0.5 (M1) in 57 (53.8%), endocapillary hypercellularity (E1) was present in 75 (70.8%), segmental glomerulosclerosis (S1) was present in 87 (82.1%) patients, and interstitial fibrosis with tubular atrophy (IFTA) involving 26-50% (T1), and > 50% (T2) of cortical area was seen in 46 (43.4%) and 34 (32.1%), respectively. C3 was co-deposited in 83 (78.3%) cases. Co-deposition of IgM and IgG was seen in 18 (16.9%) and 9 (8.45%) respectively. Out of 72 patients with hypertension, C3 was deposited in 59, p value 0.19. Twenty-four-hour urine protein and serum creatinine were significantly higher in patients with mean arterial pressure (MAP) ≥ 104 mmHg, p value <0.05. Patients with eGFR <30ml/min/1.73m 2 were significantly older than patients with eGFR > 60ml/min/1.73m 2 , p value 0.01. There was an increased incidence of systolic, diastolic, and MAP with decreased glomerular filtration rate, p value <0.05. Mean arterial pressure in patients with 24-h urine protein >3.0 g per day was significantly higher as compared to patients with 24-h urine protein of <1.0 g per day, p value <0.05. MAP, and mean proteinuria were significantly higher in patients with E1 compared to E0, p value <0.05. MAP and mean proteinuria were higher and mean eGFR was lower in patients with S1 compared to S0, p value <0.001. There is a significant decrease in eGFR across T0 to T2, p value <0.05. The results are summarized in Tables 1, 2, 3, and 4.

Discussion
IgAN has a wide geographical variation around the globe with incidence varying from 2 to 52%. Our study incidence of 19% is like the 16.2% incidence reported by Vanikar et al. from Western India [12]. The striking geographic variation across the world might be due to the presence of particular gene alleles that alter the susceptibility for the development of IgAN or may be related to environmental factors, or the different threshold for kidney biopsy in different centers. Most of our patients were men similar to what was reported by Chacko et al. [13] and Chandrika et al. [14]. Few studies using east Asian cohorts report either equal incidence in men and women or even an increased frequency in females [15][16][17][18]. One reason for male predominance in our study can be ascribed to the fact that more males consent for kidney biopsy than females. However, the role of hormonal factors cannot be ruled out with certainty. Mean age of onset, mean serum creatinine, mean systolic, mean diastolic, and MAP were lesser in females compared to men, but they did not reach statistical significance. Similar findings were reported from China [16]. The most common age of presentation in our cohort is the 2nd to 3rd decade of life which correlates with other studies [5,9,19]. The most common presenting symptom in our study is bilateral lower extremity edema, present in 65.1% of our cohort. An incidence of 46.5% is reported in a study from South India [19]. There was an increase in the incidence of edema with increasing proteinuria; however, it did not reach statistical significance. Hypertension is the most common sign present in 67.9% of patients. In another study from North India, hypertension was found in 78.8% of patients. This high lightens the increased prevalence of hypertension in IgAN patients [8]. At baseline, higher MAP (≥ 104mmHg) was associated with significantly higher proteinuria and lower eGFR. Similar findings were seen in the GRACE-IgANI cohort. Gross hematuria was presenting manifestation in 12% of our patients. A similar incidence (10%) was present in the GRACE-IgANI cohort from South India [19]. Clinicopathological correlations were analyzed at the time of biopsy with clinical variables like the amount of proteinuria, blood pressure, and eGFR. Endocapillary hypercellularity was found to correlate with the degree of hypertension and proteinuria. This is consistent with studies from Europe and China [20,21]. Presence of sclerosis was found to associate with high MAP, proteinuria, and low eGFR. IFTA score of T1 and T2 was found to be associated with low eGFR. The presence or absence of mesangial hypercellularity was not found to correlate with MAP, eGFR, or proteinuria at the time of renal biopsy. This is consistent with studies from Germany [21], France [22], and North America [23]. None of the biopsies in our cohort showed a crescent or any evidence of acute /active or chronic thrombotic microangiopathy. Significant proteinuria of > 1 g per day was present in 82% of cases. Proteinuria of <1 g per day was seen in 19 (17.9%) patients.
In this group, despite having low-grade proteinuria, there were already signs of significant kidney disease with 36.8% having E1, and 78.9% having S1. T1 and T2 lesions were seen in 36.8 and 42.1% of patients respectively. Even in patients with <1 g proteinuria per day and eGFR > 60 ml/ min/1.73m 2 . E1, S1, T1, and T2 lesions were present in 38 (69.1%), 40 (72.7%), 26 (47.3%), and 5 (9.1%), respectively. So, despite relatively preserved eGFR and low-grade proteinuria, there were signs of significant chronicity in kidney biopsy suggestive of delay in diagnosis. Nephrotic range proteinuria is uncommon in Caucasians [24,25] but was seen in 23 (21.7%) patients in our cohort. Higher incidence (34%) was found in the GRACE-IgANI cohort likely because of the lower threshold used for the definition of nephrotic range proteinuria (3 g/day). As expected, 23 (100%) patients had E1 and S1 lesions. T1 and T2 lesions were seen respectively in 12 (52.2%) and 5 (21.7%) patients. Even in patients with nephrotic range proteinuria and eGFR > 60 ml/min/1.73 m 2 E1, and S1 lesions were seen in 13 (100%) patients. T1 and T2 lesions were present in 7 (53.8%) and 0%, respectively. It has been postulated that there may be a podocytopathic variant of IgAN marked by predominant podocyte injury [26][27][28][29]. Podocyte hypertrophy and tip variant have been described in IgAN and are associated with greater baseline proteinuria. The lack of electron microscopy in our cohort does limit podocyte evaluation. There is a disproportionate over-representation of segmental sclerosing lesions and   tubulointerstitial fibrosis at presentation even with relatively well-preserved eGFR and low levels of proteinuria. This contrasts with studies from the east Asian population where predominant features at presentation are active glomerular lesions with little background scarring [20,30]. It is unclear why our cohort has such advanced fibrotic lesions so early in the clinical course. This might be related to low nephron number consequent to poor maternal health and nutritional status owing to the poor socio-economic status with subsequent hyperfiltration injury resulting in an increased risk of hypertension and CKD. However, this would need confirmation from larger studies and further evaluation. The overall incidence, demographic, biochemical, and clinicopathological profile of primary IgAN from our center in Northern India is very similar to the rest of the country. The main limitation of the present study is that being a hospital-based single-center study, it does not represent the true burden of the disease, since only the patients who presented to the hospital were biopsied. The study also lacks long-term follow-up data.

Conclusions
IgAN is common in North India and has more severe histopathological presentation, characterized by extensive sclerosis and tubulointerstitial fibrosis at diagnosis. Renal dysfunction and nephrotic range proteinuria are common. The presence of hypertension, low eGFR, and significant proteinuria correlate with the presence of segmental scarring, endocapillary hypercellularity, and IFTA on renal biopsy. Screening of asymptomatic individuals might help in early diagnosis and long-term preservation of renal functions.

Funding
The study is not funded.

Availability of data and materials
Data and material will be available on request.

Declarations Ethics approval and consent to participate
The study is approved by the institutional ethics committee of Sheri-Kashmir Institute of Medical Sciences under Reference no. SIMS/377/241/2014/332 dated 16 th December 2014. Since this is an observational study, the consent to participate has been waived off by the ethics committee of Sheri-Kashmir Institute of Medical Sciences Consent for publication Not applicable.