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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM ASIA-AFRICA  
Year : 2021  |  Volume : 32  |  Issue : 6  |  Page : 1727-1735
Clinical Presentation, Histology, and Outcomes of Immunoglobulin A Nephropathy: A Single-Center Experience from Pakistan


Department of Medicine, Section of Nephrology, Aga Khan University Hospital, Karachi, Pakistan

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Date of Web Publication27-Jul-2022
 

   Abstract 


Clinical presentation, kidney biopsy findings, and clinical outcomes of immunoglobulin A nephropathy (IgAN) are highly variable. The objective of this study is to study the clinical presentation, histologic patterns, and outcomes of IgAN in the Pakistani population, as no significant data are available in international literature from this part of the world. A retrospective chart review was conducted of all patients with biopsy-proven IgAN between January 2007 and December 2017. Of a total of 977 renal biopsies, 50 patients had biopsy-proven IgAN (5.1%). The median age at the time of biopsy was 34 years (27-42); 92% of patients were between 18 and 40 years. Thirty-eight (76%) were male. Ninety-two percent of patients had significant proteinuria of >1 g/day, with 32% having nephrotic range proteinuria. The mean estimated glomerular filtration rate (eGFR) at presentation was 46.58 mL/min/1.73 m2. Seventy-eight percent of patients were hypertensive at the time of presentation and most of them had uncontrolled hypertension (HTN). The most common lesion on light microscopy was focal necrotizing glomerulonephritis (26%), followed by mesangial expansion with segmental/global glomerulosclerosis (22%). Crescents were seen in 38% of cases. Of 50 patients, a follow-up of at least six months was available for 32 patients. Most of the patients who had an eGFR of <30 mL/min at presentation progressed to kidney failure at six-month follow-up period. IgAN usually presents in young male adults in the age range of 18-40 years, with most patients having severe clinical presentation characterized by nephrotic-range proteinuria, HTN, renal insufficiency, and severe histological stages.

How to cite this article:
Yaqub S, Jasmine A, Awan S, Razzaque MA, Tareen HU. Clinical Presentation, Histology, and Outcomes of Immunoglobulin A Nephropathy: A Single-Center Experience from Pakistan. Saudi J Kidney Dis Transpl 2021;32:1727-35

How to cite this URL:
Yaqub S, Jasmine A, Awan S, Razzaque MA, Tareen HU. Clinical Presentation, Histology, and Outcomes of Immunoglobulin A Nephropathy: A Single-Center Experience from Pakistan. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Sep 25];32:1727-35. Available from: https://www.sjkdt.org/text.asp?2021/32/6/1727/352435



   Introduction Top


Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis (GN) worldwide and the most common cause of the end-stage renal disease (ESRD) due to primary GN.[1],[2] IgAN usually presents in the second or third decades of life.The clinical presentation is highly variable, ranging from asymptomatic urinary findings like microscopic hematuria with or without proteinuria to clinically overt abnormalities such as gross hematuria and nephrotic syndrome, or rapidly progressive GN. Biopsy and organ replacement registries exhibit geographical variation in disease burden, ranging from 2% to 52%, with a higher incidence in Pacific Asian regions.[3] The reported prevalence from various parts of Pakistan varies from as low as 2.5% to as high as 20.8%.[4],[5],[6],[7],[8],[9] A variety of factors affect prognosis, especially the presence of hypertension (HTN), proteinuria, and estimated glomerular filtration rate (eGFR) at diagnosis.[10] It has been reported that nearly 50% of patients develop ESRD within 20 years of diagnosis.[11]

Although some studies have been conducted to study the prevalence, histological pattern, and clinical presentation of IgAN in Pakistan, most of these data are from the northern part of the country and is based on observational studies on a small population. Data encompassing clinical presentation, histological picture, and outcomes of IgAN in a bigger population group are lacking, especially from the southern part of Pakistan.


   Material and Methods Top


We performed a retrospective review of 977 native renal biopsies performed at our tertiary care center, Aga Khan University Hospital (AKUH), from January 2007 to December 2017. The study was approved by the institutional ethics review committee. We included all patients of either gender, aged 18 years or older, with biopsy-proven IgAN. All patients with inadequate/inconclusive biopsy specimen and graft biopsies after renal transplant were excluded. We also excluded patients who had undergone a biopsy for diagnosis outside AKUH.

All kidney biopsy specimens were processed for light microscopy (LM) and immunofluorescence (IF) and interpreted by the consultant histopathologist at our hospital. Electron microscopy was not performed as unfortunately, the facility is currently not available at our hospital. The biopsies were performed using real-time ultrasonography and automated percutaneous devices by either a consultant radiologist or a nephrologist with 16- or 18- gauge needles. Two cores of tissue were obtained and were processed separately for LM and IF. All patients had given written consent for biopsy and were observed for a period of 24 h after the procedure.

Medical charts and electronic laboratory data were reviewed, and the following details were recorded in the pro forma: demographics, serum creatinine, and eGFR at presentation as well as at follow-up, presenting symptoms, urinalysis, protein quantification as measured by 24 h urinary protein (g/day) or spot protein creatinine ratio wherever available, histological lesions, and management strategies. Follow-up laboratory data were also recorded where available.

Descriptive statistical analysis of continuous variables was expressed as mean ± standard deviation and was carried out using IBM SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, USA).


   Results Top


Between January 2007 and December 2017, a total of 977 renal biopsies were performed. A total of 50 patients had biopsy-proven IgAN (5.1%) and were included in the study. The median age at the time of biopsy was 34 years (27-42); 92% of patients were between 18 and 40 years. Seventy-six percent were male. Most of them had microscopic hematuria at presentation; macroscopic or gross hematuria was present in only 6% of the cases [Figure 1]. Median proteinuria was 2.4 g/day (1.7-4.3 g/day) [Figure 2]. The median serum creatinine was 2.1 mg/dL. Eight percent of the patients had a positive family history of IgA nephropathy. Seventy-eight percent of the patients were hypertensive at the time of presentation, and most of them had uncontrolled HTN. The most common lesion on LM was focal necrotizing GN (26%) followed by mesangial expansion with segmental glomerulosclerosis (22%) [Figure 3]. Crescents were seen in 38% of cases. On IF, the most common deposits were IgA plus C3 positive in 34% of the patients [Figure 4]. The mean eGFR at presentation was 46.58 mL/min/1.73 m2 [Figure 5]. Of 50, a follow-up of at least 6 months was available for 32 patients. Most of the patients who had an eGFR of less than 30 mL/min at presentation progressed to kidney failure at six-month follow-up period [Table 1]. A higher frequency of IgAN was seen over the years [Figure 6].
Figure 1. Clinical features at presentation

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Figure 2. Degree of proteinuria (g/d) at presentation.

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Figure 3. Light microscopy findings.
TIN: Tubulointerstitial nephritis, MPGN: Membranoproliferative glomerulonephritis, FNGN: Focal necrotizing glomerulonephritis.


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Figure 4. Pattern of immunofluorescence findings.

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Figure 5. Estimated glomerular filtration rate (mL/min) at the time of presentation.

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Figure 6. Trend of immunoglobulin A nephropathy on renal biopsies from 2007 to 2017.

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Table 1. Estimated glomerular filtration rate (mL/min) at baseline and at 6-month follow-up ( n =32).
eGFR: Estimated glomerular filtration rate.


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   Discussion Top


Previously, research has been done to study the clinical and histopathologic presentation of the disease, but none from Pakistan has reported outcomes. This is the first study encompassing clinical presentations, histologic findings, and outcomes of IgAN from Pakistan.

IgAN prevalence shows distinct geographic and racial variation. Differences in the indications of renal biopsy may also account for the varying prevalence reported globally. The frequency of IgAN in our study was found to be 5.1% which is much lower than that reported from countries such as Japan (31.0%),[12] China (36.6%),[13] and Singapore (43.2%)[14] but similar to those reported from India (6.3%)[15] and Bangladesh (6.9%).[16] The prevalence from various parts of Pakistan also varies from as low as 2.5% to as high as 20.8%.[4],[5],[6],[7],[9] It is of note that most of the studies reporting a higher frequency had smaller sample sizes. The most recent study by Arshi et al reported a sample size of 1658 biopsies and IgAN was diagnosed in 8.6% of cases, which is similar to our findings.[4]

Although IgAN has been reported in all age groups, the peak incidence is found to be in the second and third decades of life with male preponderance. A similar pattern was observed in our study, with 92% of the patients being between the ages of 18 and 40 years, with a mean age of 36.6 years. This is consistent with findings reported in literature, both in the region and internationally.[4],[5],[6],[7],[8],[9],[16],[17],[18]

The male-to-female ratio in our study was 3.2:1. Previously, studies had shown that in North American cohorts, the male-to-female ratio is about 2:1 for children and adults, whereas, in Asian populations, the ratio is 1:1.[19],[20],[21] Our findings are consistent with recent literature from our region, which reports a male preponderance (male-to-female ratio of more than 1:1).[7],[8],[10],[11],[22] Variations in the gender distribution of IgAN may reflect differences in biopsy indications in different regions and could also be due to the diversity of genetic backgrounds and access to healthcare facilities. Deng et al from China reported that male IgAN patients presented with worse clinicopathologic features than female patients; however, no significant differences were observed in long-term renal survival between male and female patients.[23] However, in our series, we did not find any gender-based significant differences in clinical presentation as well as in the progression of disease to kidney failure.

Clinical presentation of IgAN is variable. Episodic (one or recurrent) macroscopic hematuria, usually after an upper respiratory infection, is believed to be the most common clinical presentation (40%−50%).[24] Other presentation includes asymptomatic microscopic hematuria and mild proteinuria in 30%−40% of cases, and <10% present with either nephrotic syndrome or acute rapidly progressive GN.[24],[25].We found that while most of our patients had microscopic hematuria (82.4%), only 5.9% of patients presented with gross hematuria [Figure 1]. Ninety-two percent of patients had significant proteinuria of >1 g/day, with 32% having nephrotic range proteinuria [Figure 2]. Other studies from the region have also reported that nephrotic range proteinuria is the most common presentation and our findings are consistent with them.[26],[27] However, the frequency of gross hematuria on presentation is quite low in our study as opposed to described elsewhere in the literature.[28],[29].We feel that probably owing to smaller sample sizes in studies from various regions of Pakistan, there might have been an overrepresentation of gross hematuria. Our finding, however, is in accordance with that by Das et al from India that macroscopic hematuria is a rare presentation (5.2% cases only).[26] One can speculate a possible change in the epidemiology of IgAN in this region in recent years. However, both ours and Das et al’s studies are single-center studies and may not be a true representative of the entire region.

IgAN may present with a wide variety of histologic patterns on renal biopsy, ranging from a minimal lesion to a diffuse proliferative GN to crescentic GN. Mesangioproliferative GN is the main histopathological finding worldwide. Literature search reveals that necrotizing lesions like the disruption of the capillary wall, mesangiolysis, leukocytic infiltration, nuclear fragmentation, fibrinous deposits, and cellular crescents are seen in only about 10% of IgAN patients.[22] The presence of crescents and necrotizing lesions is associated with a rapid decline in renal function and poor outcome. In our study, the most common lesion on LM was focal necrotizing/crescentic GN with (26%) and mesangial expansion with focal segmental glomerulosclerosis (22%), both lesions constituting almost half of the renal biopsies [Figure 3]. Studies from India have also found a high incidence of crescentic GN, which is rarely observed in studies from elsewhere.[15],[26] We found that another 28% of patients had focal necrotizing or crescentic GN progressing to chronic phase exhibiting sclerosis of glomeruli, tubular atrophic changes, and moderate-to-severe interstitial fibrosis [Figure 3]. This finding is in agreement with that described in a multicenter study by Masood et al from the northern part of the country.[6]

The pathognomonic histologic finding in IgAN is observed on IF microscopy, which demonstrates prominent, globular deposits of IgA (often accompanied by C3 and IgG) in the mesangium and, to a lesser degree, along the glomerular capillary wall. Deposits of IgA with C3 is the most common finding in the present series, which is comparable with the largest study from the country as well as with those from the region [Figure 4].[4],[26],[30],[31],[32],[33] The role of the complement system in the pathogenesis of IgA nephropathy is controversial. While IgA antibodies cannot activate complement through the classic pathway, studies have shown that complement can be activated by the alternate pathway.

IgAN is believed to be a slowly progressive disease, and it has been reported that even in patients who develop overt proteinuria and/or an elevated serum creatinine concentration, progression to ESRD is approximately 15%- 25% at 10 years and 20%-30% at 20 years. As in other GNs, elevated serum creatinine concentration, uncontrolled HTN (>140/90 mm Hg), and persistent proteinuria above 1000 mg/day are clinical predictors of more severe disease and hence worse outcomes in IgAN.[34],[35] Patients who have little or no proteinuria (<500−1000 mg/day) have a low risk of progression, at least in the short term. Besides the clinical markers, certain histologic findings have been associated with an increased risk of progressive diseases such as crescent formation and immune deposits in the capillary loops in addition to the mesangial deposits that are present in all patients, and the presence of glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular disease.[32],[34] In the present study, more than 90% of patients had significant proteinuria (>1000 mg/d) at the time of presentation and more than two-third of patients had uncontrolled HTN. Besides, the great majority of patients had crescents and necrotizing lesions on biopsy and hence the poor outcomes. Almost all patients who had an eGFR <30 mL/min at presentation did not respond to treatment and went on to develop kidney failure within six months [Table 1]. Taken together, our data suggest severe clinical features of IgAN in our population at the time of presentation. Studies from India are in agreement with the existence of aggressive clinical features and advanced histological changes at presentation in IgAN patients in the region as opposed to the rest of the world.[26],[30],[31],[33] Moreover, a rapid progression to ESRD has also been reported from the region.[26],[30],[31],[33] The difference may be accounted for by the absence of routine screening programs in the schools and at workplace in this part of the world as well as by a variation in practices and threshold for performing kidney biopsy.

According to the yearly distribution of cases, we observed a higher frequency from 2015 onward. We speculate that the surge may be accounted for partly by an increase in referrals and/or a lower threshold of renal biopsies by nephrologists.


   Limitations Top


First, since it was a retrospective study, follow-up data for all patients were not available. Second, the histologic findings were not categorized according to the Oxford classification owing to the retrospective study design. Third, even though we reviewed a total of 977 biopsies done at our center, 50 patients were found to have IgAN. Therefore, the sample size of our study was not big enough for the results to be generalizable to the population. Finally, it was a single-center study conducted at a tertiary care hospital; hence, the results might not reflect the true clinical, histological, and prognostic picture of the disease.


   Conclusion Top


We conclude that our study revealed severe clinical presentation of IgAN characterized by nephrotic-range proteinuria, HTN, renal insufficiency, and severe histological patterns with a rapid progression to kidney failure. We propose that larger prospective observational studies need to be conducted, especially in our part of the world, to assess the effectiveness of treatment modalities in terms of hard outcomes such as the development of kidney failure, morbidity, and mortality. The prevalence reported from studies conducted in Pakistan might be an underestimation of the true picture because there is a wide variation, from clinician to clinician, of the indications and threshold of performing renal biopsy, especially in patient population with mild proteinuria and/or asymptomatic microscopic hematuria. Prevalence may therefore appear to be higher in countries with an active urinetesting program and a low threshold for the performance of renal biopsy in patients with isolated asymptomatic hematuria, such as Japan, where testing is routinely performed in schools and in the workplace. In the presence of asymptomatic persistent microscopic hematuria and/or mild proteinuria, the clinicians should not underestimate the symptoms and must refer the patient to a nephrologist. Furthermore, nephrologists could include the clinical pattern of persistent microscopic hematuria and/or mild proteinuria in the indications for a kidney biopsy so that prompt intervention and management can delay progression to kidney failure.

Conflict of interest: None declared .



 
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Correspondence Address:
Sonia Yaqub
Department of Medicine, Section of Nephrology, Aga Khan University Hospital, Karachi, Pakistan.
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.352435

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