IgG4-related disease has attracted wide attention recently. It is characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive plasma cells into multiple organs, with the kidney being one representative target. Although several sets of diagnostic criteria for autoimmune pancreatitis (AIP) are available and renal lesion is recognized as an extra-pancreatic manifestation of AIP, it is difficult to differentiate IgG4-related tubulointerstitial nephritis (TIN) without AIP from other types of TIN. To clarify the entity of IgG4-related kidney disease (IgG4-RKD) and support in-depth studies, the Japanese Society of Nephrology has established a working group to prepare diagnostic criteria for IgG4-RKD.

Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been characterized. ApoE2 homozygote glomerulopathy has been found in individuals expressing homozygous apoE2/2. This was characterized histologically by glomerulosclerosis with marked infiltration of foam cells derived from macrophages, and occasionally with non-lamellated lipoprotein thrombi. Recently, several cases of apoE Toyonaka (Ser197Cys) combined with homozygous apoE2/2 have been reported, in which non-immune membranous nephropathy-like features were observed in glomeruli. Interestingly, in these cases, apoE accumulation was identified by tandem mass spectrometry. Therefore, it is speculated that these findings may arise from apoE molecules without lipids, which result from hinge damage by apoE Toyonaka and may cross the glomerular basement membrane as small molecules. LPG is primarily associated with heterozygous apoE mutations surrounding the low-density lipoprotein-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells. Recent studies have suggested that LPG can be induced by thermodynamic destabilization, hydrophobic surface exposure, and the aggregation of apoE resulting from the incompatibility of apoE mutated residues within helical regions. Additionally, apoE5 may play a supporting role in the development of LPG and in lipid-induced kidney diseases via hyperlipoproteinemia. Thus, it is interesting that many apoE mutations contribute to characteristic glomerular disorders through various mechanisms. In particular, macrophages may uptake lipoproteins into the cytoplasm and contribute to the development of apoE2 homozygote glomerulopathy as foam cells, and their dysfunction may contribute to the accumulation of lipoproteins in the glomerulus, causing lipoprotein thrombi in LPG.

Background/Aims: LDL apheresis (LDL-A) is used for drug-resistant nephrotic syndrome (NS) as an alternative therapy to induce remission by improvement of hyperlipidemia. Several clinical studies have suggested the efficacy of LDL-A for refractory NS, but the level of evidence remains insufficient. A multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was conducted to evaluate its clinical efficacy with high-level evidence. Methods: Patients with NS who showed resistance to primary medication for at least 4 weeks were prospectively recruited to the study and treated with LDL-A. The long-term outcome was evaluated based on the rate of remission of NS 2 years after treatment. Factors affecting the outcome were also examined. Results: A total of 58 refractory NS patients from 40 facilities were recruited and enrolled as subjects of the POLARIS study. Of the 44 subjects followed for 2 years, 21 (47.7%) showed remission of NS based on a urinary protein (UP) level <1.0 g/day. The UP level immediately after LDL-A and the rates of improvement of UP, serum albumin, serum creatinine, eGFR, and total and LDL cholesterol after the treatment session significantly affected the outcome. Conclusions: Almost half of the cases of drug-resistant NS showed remission 2 years after LDL-A. Improvement of nephrotic parameters at termination of the LDL-A treatment was a predictor of a favorable outcome.