Immunoglobulin G4-related disease (IgG4-RD) is a rare chronic immune-mediated multisystem disease with renal manifestations of tubulointerstitial nephritis (IgG4-TIN) and membranous nephropathy (IgG4-MN). IgG4-RD and its sequelae are treated with immunosuppressive therapy, including steroids and rituximab (RTX), which have demonstrated high efficacy in achieving disease remission. We describe a patient who was diagnosed with pancreatitis secondary to IgG4-RD through laboratory and imaging studies. Despite being on RTX, he developed acute kidney injury (AKI) and was diagnosed with IgG4-TIN via kidney biopsy. He was treated with prednisone and RTX, and his symptoms and renal function improved. Despite RTX reaching peak efficacy 6 months after administration, our patient had a breakthrough IgG4-TIN during this period. This case highlights the importance of maintaining a high index of suspicion for renal involvement (IgG4-TIN or IgG4-MN) in patients with AKI superimposed on IgG4-RD, and that maintenance therapy with RTX retreatment was associated with longer relapse-free survival at 12 months of follow-up. Our patient had no severe infections or hypogammaglobulinemia (≤5 g/l) with RTX, confirming RTX's safety and efficacy in maintenance remission therapy for recurrent IgG4-TIN.

Kidney disease is a major global public health problem that affects 15-20% of adults globally. Increasing evidence shows that kidney injury results in intestinal barrier dysfunction, microbial dysbiosis, and microbial-derived metabolite disorder. Microbial-derived metabolites are recognized as multi-kingdom intermediates. The alterations of the gut microbiota lead to the reductions of short-chain fatty acids including acetate, butyrate, and propionate, while excessive accumulation of uremic toxins, including indoxyl sulfate, indole-3-acetic acid, trimethylamine-N-oxide, and p-cresyl sulphate that involved in renal disease. Various effects are moderated by regulating aryl hydrocarbon receptor, G-protein-coupled receptor 43, Toll-like receptor 4, domain-like receptor family protein 3, phosphatidylinositol-3 kinase, inhibitor of kappa B /nuclear factor kappa B and kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathways via gut microbiota-derived metabolites. Among them, tryptophan metabolites are considered pivotal in the communication between gut microbiota and kidneys. This review summarizes current understanding of the role of gut microbial-derived metabolites in acute kidney injury and chronic kidney disease including diabetic kidney disease, immunoglobulin A nephropathy and membranous nephropathy, explain the underlying pathophysiology of these associations and pinpoint potential targets for the future precision-based modulation of therapies. This review also explores therapeutic options, such as natural products, prebiotics, probiotics, and renal replacement therapy, for targeting gut microbiota dysbiosis and their metabolites in patients with kidney diseases to provide a more concept-driven and precise therapy strategy.

Secondary membranous nephropathy (MN) is an increasingly recognized manifestation of immunoglobulin G4 (IgG4)-related disease (IgG4-RD). It is typically seen alongside tubulointerstitial nephritis but may occur independently. In this study, we discuss the case of a 65-year-old man who was initially investigated for steatorrhea and marked weight loss. He was diagnosed with idiopathic chronic pancreatitis, which spontaneously resolved with conservative management. He later represented with profound nephrotic syndrome, lymphadenopathy, and cutaneous lesions. There were no detectable antiphospholipase A2 receptor antibodies in the blood, but he was found to have elevated serum IgG4 levels. A kidney biopsy demonstrated antiphospholipase A2 receptor-negative MN with no evidence of tubulointerstitial inflammation. He was investigated for secondary causes of MN with a positron emission tomography-computed tomography scan, which showed increased uptake in the gastric mucosa and thoracic lymph nodes. An endobronchial lymph node biopsy showed reactive changes only; the diagnosis of multisystem IgG4-RD was made on a gastric biopsy, which detected marked polyclonal infiltration with IgG4+ plasma cells. He showed an excellent clinical and radiological response to induction therapy, with a tapering course of prednisolone followed by rituximab. This case adds to the limited body of evidence reporting MN without tubulointerstitial inflammation in the context of pancreatic IgG4-RD.

Anti-glomerular basement membrane (GBM) disease is the most severe form of autoimmune glomerulonephritis following assaults on kidney and alveolar basement membranes by pathogenic anti-GBM antibodies. Typically, anti-GBM disease is characterized by rapidly progressive glomerulonephritis and an increased risk of lung hemorrhage, with kidney biopsy revealing ominous crescent formation. Although patient survival has improved with standard of care including plasma exchange and intensive immunosuppression in the recent decade, kidney survival still remains poor because of delayed recognition and tardy initiation of standard therapy. With the increasing understanding of the disease in clinical practice, several variant forms have been recognized. We here propose to group these forms into 4 categories according to their immunologic properties and clinical presentations: overlapping autoimmune syndromes (anti-GBM disease with combined antineutrophil cytoplasmic antibody, concurrent membranous nephropathy, or IgA nephropathy), immunologic distinct forms (Alport post-transplant anti-GBM disease and seronegative anti-GBM disease), clinical phenotypic variant forms (recurrent anti-GBM disease in native kidney, anti-GBM disease in elderly individuals, or with normal kidney function), and medication-associated anti-GBM disease. These patients have different features in terms of clinical manifestations, pathologic findings, or prognosis compared with patients with classical anti-GBM disease. In this review, we discuss these variant forms with emphasis on their phenotypes and underlying mechanisms. An enhanced understanding of pathophysiology of anti-GBM disease variant forms can pave the way for personalized therapies tailored to patients with different presentations of the disease.

Primary adult glomerular diseases (GDs), including immunoglobulin A nephropathy, membranous nephropathy, and focal segmental glomerulosclerosis, are important causes of chronic kidney disease and may progress to kidney failure. Nonimmunosuppressive foundation drug therapy for primary adult GD focuses on renin-angiotensin-aldosterone system inhibition to reduce proteinuria, alleviate hypertension, and reduce the risk of kidney disease progression. Additional agents with a distinct mechanism of action may be added or substituted in patients with a high progression risk or who are intolerant to renin-angiotensin-aldosterone system inhibitors. This review highlights the role of lifestyle optimization as well as summarizing the currently nonimmunosuppressive pharmacologic treatment options, for the management of primary adult GDs. We also provide an overview of the key pathophysiologic processes contributing to disease progression. Given the safety concerns associated with immunosuppressive therapies, we discuss the future role of newer nonimmunosuppressive agents including finerenone (a nonsteroidal mineralocorticoid receptor antagonist), sparsentan (a dual endothelin-angiotensin II receptor antagonist), atrasentan (an endothelin receptor antagonist), and iptacopan (complement inhibitor), which are currently Food and Drug Administration approved or are under investigation in clinical trials for primary GDs. These and other agents may expand the currently limited treatment landscape for patients with primary adult GD. Plain-Language Summary Each kidney contains about 1 million tiny functional units called nephrons, and each nephron has a filter called a glomerulus. The glomeruli filter waste products and remove excess fluids from the blood, which exit the body through urine. When the glomeruli are damaged, there is loss of protein through the urine. This can result in a condition called glomerular disease (GD). Treatments for GD include eating a diet that is low in sodium, potassium, and protein because eating these in excess can make GD worse. People with GD may also be advised to exercise, stop smoking, and aim for an ideal target weight. Drug medicines are also an important part of treatment for GD. A type of drug called a renin-angiotensin-aldosterone system (RAAS) inhibitor helps to reduce the amount of damage to the glomeruli and also helps to reduce blood pressure in people who also have high blood pressure (called hypertension). If a person is taking a RAAS inhibitor drug (or an appropriate alternative) but their GD does not improve, then they are at a high risk of kidney disease progression. In this scenario, the person will be offered an additional drug (to take alongside their RAAS inhibitor drug) or an alternative drug that targets their GD in a different way. Some of these work by inhibiting parts of the immune system (called immunosuppressive drugs), whereas others do not do this (called nonimmunosuppressive drugs). Our review focuses on nonimmunosuppressive drugs for GD. We consider nonimmunosuppressive drugs already available for treating GD, ones that have only recently been made available, and drugs that are being tested in large clinical trials involving people with GD.