Cellular Signaling and Production of Galactose-Deficient IgA1 in IgA Nephropathy, an Autoimmune Disease

Immunoglobulin A (IgA) nephropathy (IgAN), the leading cause of primary glomerulonephritis, is characterized by IgA1-containing immunodeposits in the glomeruli. IgAN is a chronic disease, with up to 40% of patients progressing to end-stage renal disease, with no disease-specific treatment. Multiple studies of the origin of the glomerular immunodeposits have linked elevated circulating levels of aberrantly glycosylated IgA1 (galactose-deficient in someO-glycans; Gd-IgA1) with formation of nephritogenic Gd-IgA1-containing immune complexes. Gd-IgA1 is recognized as an autoantigen in susceptible individuals by anti-glycan autoantibodies, resulting in immune complexes that may ultimately deposit in the kidney and induce glomerular injury. Genetic studies have revealed that an elevated level of Gd-IgA1 in the circulation of IgAN patients is a hereditable trait. Moreover, recent genome-wide association studies have identified several immunity-related loci that associated with IgAN. Production of Gd-IgA1 by IgA1-secreting cells of IgAN patients has been attributed to abnormal expression and activity of several key glycosyltransferases. Substantial evidence is emerging that abnormal signaling in IgA1-producing cells is related to the production of Gd-IgA1. As Gd-IgA1 is the key autoantigen in IgAN, understanding the genetic, biochemical, and environmental aspects of the abnormal signaling in IgA1-producing cells will provide insight into possible targets for future disease-specific therapy.

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Immunoglobulin A Nephropathy: Advances in Understanding of Pathogenesis and Treatment

American Journal of Nephrology ◽

10.1159/000481636 ◽

2018 ◽

Vol 47 (Suppl. 1) ◽

pp. 43-52 ◽

Cited By ~ 10

Author(s):

Richard A. Lafayette ◽

Ellie Kelepouris

Keyword(s):

Iga Nephropathy ◽

Association Studies ◽

Treatment Options ◽

Immunoglobulin A ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Wide Range ◽

New Treatment ◽

Stage Renal Disease ◽

End Stage

Background: Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis and has clinical associations with a wide range of inflammatory and infectious diseases. There is a substantial variation in clinical course and outcomes, with many patients not diagnosed until they present with sequelae, which may include gross hematuria, hypertension, renal insufficiency, and/or significant proteinuria. Treatment options are currently limited and directed mainly toward control of these sequelae and have limited ability to reduce the incidence of end-stage renal disease or treat the primary IgA defect. Summary: Growing knowledge about the pathogenesis of IgA nephropathy and research into its genetic basis are helping to elucidate the course of this widely variable disease. IgA accumulation in the kidneys is thought to be the result of a number of different pathways in a “multi-hit” process that includes an initial traumatic trigger (often infection related) and subsequent memory responses that are amplified in those with a genetic predisposition to the disease and lead to an inflammatory response in susceptible individuals. Genome-wide association studies are providing new insights into the genetic variance of this autoimmune disease and are yielding information that may address both its causes and consequences. Key Messages: New treatment approaches are urgently required for the management of patients with IgA nephropathy. Novel interventions based around its inflammatory nature and “multi-hit” pathogenesis are being investigated to potentially limit disease progression.

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High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1600511113 ◽

2016 ◽

Vol 113 (8) ◽

pp. 2218-2222 ◽

Cited By ~ 18

Author(s):

Catherine K. Hathaway ◽

Albert S. Chang ◽

Ruriko Grant ◽

Hyung-Suk Kim ◽

Victoria J. Madden ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Transforming Growth Factor ◽

Association Studies ◽

Lipid Peroxides ◽

Transforming Growth Factor Β1 ◽

Genome Wide Association Studies ◽

Diabetic Mice ◽

Stage Renal Disease ◽

End Stage

Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2Akita gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.

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PNPLA3 gene and kidney disease

10.37349/emed.2020.00004 ◽

2020 ◽

Vol 1 (1) ◽

pp. 42-50 ◽

Cited By ~ 1

Author(s):

Alessandro Mantovani ◽

Chiara Zusi

Keyword(s):

Kidney Disease ◽

Association Studies ◽

Liver Steatosis ◽

Kidney Injury ◽

Future Perspective ◽

Genome Wide Association Studies ◽

Alcoholic Fatty Liver ◽

Liver And Kidney ◽

Stage Renal Disease ◽

End Stage

Chronic kidney disease (CKD) is a disease regularly seen in clinical practice. At present, CKD is described as a change of kidney structure and/or function and it is classified in relation to cause, values of glomerular filtration rate and albuminuria category. Seeing that CKD is closely linked to the development of end-stage renal disease and other comorbidities, the determination of additional independent predictors for CKD is clinically necessary. At present, there is evidence associating non-alcoholic fatty liver disease (NAFLD) with CKD, thereby suggesting that NAFLD patients may require intensive surveillance to reduce their risk of CKD. In 2008, genome-wide association studies documented an association between the variant rs738409 (C > G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene (mainly implicated in the lipid regulation) and the entire spectrum of NAFLD (i.e., liver steatosis, non-alcoholic steatohepatitis, fibrosis, and hepatocellular carcinoma). In the last years, accumulating epidemiological evidence suggests the existence of a relationship between PNPLA3 rs738409 and risk of CKD, indicating that rs738409 may also contribute to the kidney injury. This is of particular scientific interest, as such association may explain, at least in part, the epidemiological association between liver and kidney disease. In this narrative review, we will discuss the accumulating evidence regarding the association between PNPLA3 rs738409 and risk of CKD, the putative biological mechanisms underpinning such relationship, and the possible future perspective.

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Recent advances in the understanding and management of IgA nephropathy

F1000Research ◽

10.12688/f1000research.7352.1 ◽

2016 ◽

Vol 5 ◽

pp. 161 ◽

Cited By ~ 2

Author(s):

Kar Neng Lai ◽

Joseph C.K. Leung ◽

Sydney C.W. Tang

Keyword(s):

Iga Nephropathy ◽

Specific Treatment ◽

Developed Countries ◽

Current Data ◽

Therapeutic Approaches ◽

Clinical Progression ◽

Primary Glomerulonephritis ◽

New Therapeutic Approaches ◽

Stage Renal Disease ◽

End Stage

Since its first description in 1968, IgA nephropathy has remained the most common form of primary glomerulonephritis leading to chronic kidney disease in developed countries. The clinical progression varies, and consequent end-stage renal disease occurs in 30% to 40% of patients 20 to 30 years after the first clinical presentation. Current data implicate overproduction of aberrantly glycosylated IgA1 as being pivotal in the induction of renal injury. Effective and specific treatment is still lacking, and new therapeutic approaches will be developed after better understanding the disease pathogenesis.

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Polymorphism in the GATM Locus Associated with Dialysis-Independent Chronic Kidney Disease but Not Dialysis-Dependent Kidney Failure

Genes ◽

10.3390/genes12060834 ◽

2021 ◽

Vol 12 (6) ◽

pp. 834

Author(s):

Špela Šalamon ◽

Sebastjan Bevc ◽

Robert Ekart ◽

Radovan Hojs ◽

Uroš Potočnik

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Failure ◽

Association Studies ◽

Genetic Difference ◽

Genome Wide Association Studies ◽

Healthy Controls ◽

Genome Wide ◽

Stage Renal Disease ◽

End Stage

The ten most statistically significant estimated glomerular filtration rate (eGFRcrea)-associated loci from genome-wide association studies (GWAs) are tested for associations with chronic kidney disease (CKD) in 208 patients, including dialysis-independent CKD and dialysis-dependent end-stage renal disease (kidney failure). The allele A of intergenic SNP rs2453533 (near GATM) is more frequent in dialysis-independent CKD patients (n = 135, adjusted p = 0.020) but not dialysis-dependent kidney failure patients (n = 73) compared to healthy controls (n = 309). The allele C of intronic SNP rs4293393 (UMOD) is more frequent in healthy controls (adjusted p = 0.042) than in CKD patients. The Allele T of intronic SNP rs9895661 (BCAS3) is associated with decreased eGFRcys (adjusted p = 0.001) and eGFRcrea (adjusted p = 0.017). Our results provide further evidence of a genetic difference between dialysis-dialysis-independent CKD and dialysis-dependent kidney failure, and add the GATM gene locus to the list of loci associated only with dialysis-independent CKD. GATM risk allele carriers in the dialysis-independent group may have a genetic susceptibility to higher creatinine production rather than increased serum creatinine due to kidney malfunction, and therefore, do not progress to dialysis-dependent kidney failure. When using eGFRcrea for CKD diagnosis, physicians might benefit from information about creatinine-increasing loci.

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Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Journal of Clinical Medicine ◽

10.3390/jcm10194501 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4501

Author(s):

Barbora Knoppova ◽

Colin Reily ◽

R. Glenn King ◽

Bruce A. Julian ◽

Jan Novak ◽

...

Keyword(s):

Iga Nephropathy ◽

Immune Complexes ◽

Mesangial Cells ◽

Specific Treatment ◽

Kidney Injury ◽

Pathogenic Potential ◽

Clinical Observations ◽

Circulating Levels ◽

Disease Specific

IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.

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In Acute IgA Nephropathy, Proteinuria and Creatinine Are in the Spot, but Podocyturia Operates in Silence: Any Place for Amiloride?

Case Reports in Nephrology ◽

10.1155/2017/1292531 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4

Author(s):

H. Trimarchi ◽

M. Paulero ◽

R. Canzonieri ◽

A. Schiel ◽

A. Iotti ◽

...

Keyword(s):

Iga Nephropathy ◽

Specific Treatment ◽

Young Male ◽

Normal Subjects ◽

Response To Therapy ◽

Long Term Prognosis ◽

One Year ◽

Stage Renal Disease ◽

End Stage

IgA nephropathy is the most frequent cause of primary glomerulonephritis, portends erratic patterns of clinical presentation, and lacks specific treatment. In general, it slowly progresses to end-stage renal disease. The clinical course and the response to therapy are usually assessed with proteinuria and serum creatinine. Validated biomarkers have not been identified yet. In this report, we present a case of acute renal injury with proteinuria and microscopic hematuria in a young male. A kidney biopsy disclosed IgA nephropathy. Podocyturia was significantly elevated compared to normal subjects. Proteinuria, renal function, and podocyturia improved promptly after steroids and these variables remained normal after one year of follow-up, when steroids had already been discontinued and patient continued on valsartan and amiloride. Our report demonstrates that podocyturia is critically elevated during an acute episode of IgA nephropathy, and its occurrence may explain the grim long-term prognosis of this entity. Whether podocyturia could be employed in IgA nephropathy as a trustable biomarker for treatment assessment or even for early diagnosis of IgA nephropathy relapses should be further investigated.

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Faculty Opinions recommendation of Low Birth Weight and Risk of Progression to End Stage Renal Disease in IgA Nephropathy--A Retrospective Registry-Based Cohort Study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726295475.793520368 ◽

2016 ◽

Author(s):

Luis Ruilope ◽

Enrique Morales

Keyword(s):

Cohort Study ◽

Birth Weight ◽

Low Birth Weight ◽

Renal Disease ◽

Iga Nephropathy ◽

End Stage Renal Disease ◽

Risk Of Progression ◽

Stage Renal Disease ◽

End Stage

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Characteristics of patients with coexisting DNAJB9-associated fibrillary glomerulonephritis and IgA nephropathy

Clinical Kidney Journal ◽

10.1093/ckj/sfaa205 ◽

2020 ◽

Author(s):

Samar M Said ◽

Alejandro Best Rocha ◽

Anthony M Valeri ◽

Mohamad Sandid ◽

Anhisekh Sinha Ray ◽

...

Keyword(s):

Iga Nephropathy ◽

Immunoglobulin A ◽

Renal Survival ◽

Hepatitis C Infection ◽

Clinicopathologic Characteristics ◽

Fibrillary Glomerulonephritis ◽

Kaplan Meier ◽

Dense Deposits ◽

End Stage

Abstract Background Coexistence of fibrillary glomerulonephritis (FGN) and immunoglobulin A (IgA) nephropathy (IgAN) in the same kidney biopsy (FGN–IgAN) is rare, and the clinicopathologic characteristics and outcome of this dual glomerulopathy are unknown. Methods In this study, 20 patients with FGN–IgAN were studied and their characteristics were compared with 40 FGN and 40 IgAN control patients. Results Concurrent IgAN was present in 1.8% of 847 consecutive FGN cases and was the second most common concurrent glomerulopathy after diabetic nephropathy. FGN–IgAN patients were overwhelmingly White (94%) and contrary to FGN patients were predominantly (60%) males. Compared with IgAN patients, FGN–IgAN patients were older, had higher proteinuria, a higher incidence of renal insufficiency, and a lower incidence of microhematuria and gross hematuria at diagnosis. Six (30%) patients had malignancy, autoimmune disease or hepatitis C infection, but none had a secondary cause of IgAN or clinical features of Henoch–Schonlein purpura. Histologically, all cases exhibited smudgy glomerular staining for immunoglobulin G and DnaJ homolog subfamily B member 9 (DNAJB9) with corresponding fibrillary deposits and granular mesangial staining for IgA with corresponding mesangial granular electron-dense deposits. On follow-up (median 27 months), 10 of 18 (56%) FGN–IgAN patients progressed to end-stage kidney disease (ESKD), including 5 who subsequently died. Serum creatinine at diagnosis was a poor predictor of renal survival. The proportion of patients reaching ESKD or died was higher in FGN–IgAN than in IgAN. The median Kaplan–Meier ESKD-free survival time was 44 months for FGN–IgAN, which was shorter than IgAN (unable to compute, P = 0.013) and FGN (107 months, P = 0.048). Conclusions FGN–IgAN is very rare, with clinical presentation and demographics closer to FGN than IgAN. Prognosis is guarded with a median renal survival of 3.6 years. The diagnosis of this dual glomerulopathy requires careful evaluation of immunofluorescence findings, and electron microscopy or DNAJB9 immunohistochemistry.

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