Podocyte infolding glomerulopathy (PIG) is a newly recognized rare glomerular injury. The clinical significance and mechanism of this injury pattern remains unclear.

We conducted a retrospective study of renal biopsies from January 2018 to December 2020 in Kingmed Diagnostics. The renal biopsy features and clinical data were reviewed. Laser scanning microdissection and mass spectrometry (LMD/MS) was conducted to analyze the potential mechanism.

A total of 116 (0.092%) out of 126,086 biopsies were diagnosed as PIG during the period. Of these, 89 (76.7%) cases were found to have PIG coexisting with immune-complex associated glomerulonephritis (IC-PIG) whereas 27 (23.3%) were identified as isolated PIG without immunoglobulin or complement deposition. Systemic lupus erythematosus (SLE), especially with membranous lupus nephritis (LN), was diagnosed in most (70.8%) IC-PIG cases. Of the isolated PIG cases, 51.9% had no known underlying conditions; however, a relatively high positive rate (42.1%) of antinuclear antibody (ANA) was detected. Nearly half (47.5%) of the patients presented with nephrotic syndrome (NS). PIG grade was associated with proteinuria in isolated PIG (P = 0.035). LMD/MS revealed dysregulated cytoskeletal protein α-actinin4 (ACTN4) and tubulin beta-4 chain in PIG compared with normal donor kidney and minimal change disease (MCD). The displacement of ACTN4 into the glomerular basement membrane (GBM) was confirmed by the confocal microscope.

PIG is a rare podocyte injury that can exist alone without underlying disease or be concurrent with various diseases, especially SLE. Podocyte cytoskeletal protein ACTN4 and tubulin beta-4 chain were dysregulated, which may be involved in the mechanism of PIG.

Podocyte infolding glomerulopathy (PIG) is a peculiar and very rare manifestation in renal pathology. Its underlying pathogenesis mechanism and clinical characteristics remain unclear due to sparse reports.

To further elucidate the clinical profile of PIG by carefully reporting our four cases and a comprehensive review of cases in the literature.

This study retrospectively reviewed four cases of PIG from 2010 to 2022 in our centre. Clinical and pathological profiles were reported. PIG cases in the literature were searched in the MEDLINE database and analysed together with our cases.

Four cases of PIG identified from our centre and 40 cases from the current literature were reported. The pooled analysis of these 44 cases indicated 79.5% (35/44) were females, 93.2% (41/44) were East Asians, and 63.6% (28/44) were reported in Japan. The average age was 42.0 ± 12.5 years old. The average amount of proteinuria at the time of renal biopsy was 3.06 ± 3.2 g/day. The most reported comorbidities were connective tissue diseases, mainly systemic lupus erythematosus, and 20.5% (9/44) of the cases did not have any contaminant disease. Most of the cases (81.8%, 36/44) had been treated with immunosuppressants, of which a combination of corticosteroids and one other type of immunosuppressant was most commonly reported. In addition, 45.4% (20/44) and 34.1% (15/44) of the cases had achieved complete response and partial response, respectively, after treatment. Whole exosome sequencing indicated mutations in the INF2 gene.

PIG is a rare condition and seen in relatively younger populations, often associated with connective tissue diseases clinically and one or two other glomerulopathies histologically. The outcomes following immunosuppressive treatment are relatively good. Mutations in INF2 might be involved in the development of PIG; however, the implications of these results need to be investigated.

Rare cases of membranous glomerulopathy (MGN) with subepithelial deposits consisting of microspherular structures identified by electron microscopy have been described in the literature as either MGN with spherules or podocyte infolding glomerulopathy (PIG). The paucity of available studies shows a strong association with underlying autoimmune disease. To further understand the significance of subepithelial microspherular deposits, we retrospectively identified native kidney biopsies from 10 patients diagnosed as MGN with subepithelial microspherular structures identified by ultrastructural examination at the University of Rochester Medical Center (URMC) during an 11-year period. The majority were Caucasian (80%) with a mean age of 51.3 (±12.9) years. 50% had an autoimmune disorder, of which 80% were SLE. Two SLE cases had concomitant rheumatoid arthritis and Sjogren's syndrome. One additional case had antiphospholipid syndrome and showed lupus-like features on biopsy. 40% were idiopathic and negative for PLA2R, NELL1, and THSD7A. MGN with subepithelial microspherular structures is frequently associated with an underlying autoimmune disease. The majority are negative for markers of primary MGN (PLA2R, THSD7A, and NELL1) and show features suggestive of secondary MGN.

Podocyte infolding glomerulopathy (PIG) is a newly described condition with only 37 cases reported worldwide. Due to its rarity, the pathogenesis and evolution of this disease is unclear. This case report contributes to our collective knowledge about the clinical and histological progression of this disease.

Over the course of a year, a 52-year-old Malaysian woman with no known prior medical history developed progressively worsening edema and other findings consistent with nephrotic syndrome.

Unlike most patients with PIG, this patient did not have any autoimmune disease. She was Hepatitis B core antibody positive with a Hepatitis B surface antibody >1000, suggesting prior Hepatitis B infection with immunity. A renal biopsy was performed which was consistent with PIG. A second renal biopsy was done 2 years later which again showed characteristic findings of PIG with worsened podocyte effacement but no interval change in chronicity.

The patient was treated with blood pressure control and renin-angiotensin-aldosterone system (RAAS) blockade with irbesartan and spironolactone. She was also treated with prednisone at 1 mg/kg for 2 months followed by a taper for a total of 7 months of prednisone treatment.

The patient had a partial response to a course of prednisone. However, since stopping steroids, her proteinuria and renal function has been gradually worsening.

PIG is mostly found in patients of East Asian descent. It presents as proteinuria and is often associated with autoimmune disease but can be idiopathic. It is characterized on renal biopsy by infolding or protrusion of podocyte cytoplasm into glomerular basement membrane, as well as intramembranous cytoplasmic microspherules or microtubules. Atypical membranous nephropathy should be ruled out prior to diagnosis. Unlike membranous nephropathy, PIG usually responds at least partially to steroid monotherapy. To our knowledge, this is the first reported case of PIG from North America. Furthermore, it is the first case of PIG with repeat biopsy showing interval worsening of PIG rather than either resolution of PIG or transformation of PIG to a different diagnosis.