Management Of IgA Nephropathy Research Articles

180 Navigating Uncharted Waters: Management of IgA Nephropathy with combined Budesonide and Sparsentan

180 Navigating Uncharted Waters: Management of IgA Nephropathy with combined Budesonide and Sparsentan

Non-immunosuppressive treatment for IgA nephropathy.

Non-immunosuppressive treatment for IgA nephropathy.

Emerging perspectives in the management of IgA nephropathy: a comprehensive review.

IgA nephropathy (IgAN) is the most prevalent form of primary glomerulonephritis worldwide and a leading cause of chronic kidney disease and renal failure. This disorder is characterized by the deposition of immune complexes containing galactose-deficient forms of IgA and complement C3 in the glomeruli. Until now, disease management relied mainly on optimized supportive care. Systemic corticosteroid therapy is proposed for patients at high risk of disease progression, but the effectiveness and safety of this approach are under debate. A significant proportion of patients do not respond to current therapies and require kidney replacement therapy at a young age, with substantial costs and impact on quality of life. Recently, there have been multiple joint efforts to improve the understanding of IgAN pathophysiology. International collaborations resulted in multiple ongoing clinical trials that are providing new insights toward innovative therapeutic options such as SGLT2 inhibitors, dual endothelin and angiotensin receptor blockers, targeted-release budesonide, B-cell proliferation and differentiation inhibitors, and complement system blockers. Based on this new evidence, revision of the guidelines to manage IgAN is expected to occur in the near future. In addition to the novelty in therapeutic agents, there is also a growing interest in new noninvasive biomarkers for IgAN screening, risk stratification to monitor the course of the disease, and the response to treatment. In this review, we discuss current knowledge on the pathophysiology of IgAN, disease management, and emerging advances in clinical translation of IgAN research.

Treatment of IgA Nephropathy: A Rapidly Evolving Field.

The pivotal event in the pathophysiology of IgA nephropathy is the binding of circulating IgA-containing immune complexes to mesangial cells, with secondary glomerular and tubulointerstitial inflammation and fibrosis. The paramount difficulty in the management of IgA nephropathy is the heterogeneity in its clinical presentation and prognosis, requiring an individualized treatment approach. Goal-directed supportive care remains the bedrock of therapy for all patients, regardless of risk of progression. Sodium-glucose transporter 2 inhibitors and sparsentan should be integral to contemporary supportive care, particularly in patients with chronic kidney damage. Pending the development of reliable biomarkers, it remains a challenge to identify patients prone to progression due to active disease and most likely to derive a net benefit from immunosuppression. The use of clinical parameters, including the degree of proteinuria, the presence of persistent microscopic hematuria, and the rate of eGFR loss, combined with the mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents score, is currently the best approach. Systemic glucocorticoids are indicated in high-risk patients, but the beneficial effects wane after withdrawal and come at the price of substantial treatment-associated toxicity. Therapies with direct effect on disease pathogenesis are increasingly becoming available. While targeted-release budesonide has garnered the most attention, anti-B-cell strategies and selective complement inhibition will most likely prove their added value. We propose a comprehensive approach that tackles the different targets in the pathophysiology of IgA nephropathy according to their relevance in the individual patient.

IgA nephropathy in adults with epidermolysis bullosa.

Epidermolysis bullosa (EB) is a devastating genetic condition caused by mutations in genes that give rise to aberrant proteins. There are 16 different such proteins implicated in EB that are important in maintaining the integrity of the dermoepidermal junction. It is classified into four major subtypes: (i) EB simplex; (ii) junctional EB (JEB); (iii) dystrophic EB (DEB); and (iv) Kindler EB. Renal disease is a recognized complication of EB and the aetiology is complex. We describe our experience of managing five patients with EB and IgA nephropathy. We recommend that patients with recessive DEB and JEB routinely have the following monitored: renal function, urinary albumin/creatinine ratio, urine analysis, serum albumin levels and immunoglobulins; specifically serum IgA. Management of IgA nephropathy in the context of EB should be tailored to the individual and be carried out within a specialist multidisciplinary team. Our case series provides important insights into the treatment of IgA nephropathy in patients with EB and will help inform treatment in this rare genetic disease. Case series and reports like ours are key in gaining real-life data to quantify the actual risk of morbidity and mortality from each of the treatment modalities discussed.

Blind Spot in the Radar of MEST-C Score: Type and Severity of Tubulointerstitial Nephritis in IgA Nephropathy.

The updated version of predictive classification for immunoglobulin A nephropathy (IgAN) prognosis "The Oxford Classification" identifies five histopathological features including mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C), the MEST-C. However, few studies suggest that tubulointerstitial inflammation, which is not included in the MEST-C, is also linked to disease progression and is, consequently, a neglected determinant of prognosis among others. Therefore, there is a need to evaluate this histopathological parameter in patients with IgA nephropathy. This cross-sectional descriptive study was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan. Data of histopathological and immunofluorescence proven renal biopsies (300) of IgA nephropathy patients from January 2016 through May 2022 were extracted using a convenient sampling technique. Biopsies were histologically reviewed for type and severity of tubulointerstitial inflammation, in addition to the MEST-C score. Renal biopsies of patients who had a history of transplant, autolyzed tissue, no glomeruli on histological examination, and/or a tubular atrophy/interstitial fibrosis score of 2 (T2) in MEST-C scoring were excluded. Data were analyzed using SPSS 20. An association between the variables was analyzed using the chi-square and Fischer exact tests. A p value less than 0.05 was considered statistically significant. A total of 247/300 biopsies were eligible for inclusion. The mean age at the time of biopsy was 31.90 ± 12.48 with 63.6% in the age group between 21 and 40 years, and 69.6% were male. Tubulointerstitial inflammation was observed in 90.2% cases with 49.4% showing moderate while 4.5% showing severe degree of inflammation. A strong association of both the type and severity of tubulointerstitial inflammation was found with M, E, T, and C scores (p value < 0.05). The high-frequency and strong statistical association of tubulointerstitial inflammation with the M, E, T, and C scores in our study elucidate its prognostic role in the progression and management of IgA nephropathy.

Management of IgA Nephropathy in Pediatric Patients

The onset of IgA nephritis in childhood and adolescence often develops into chronic glomerulonephritis with declining renal function. Although these long-term consequences are known, there is still a lack of evidence-based treatment recommendations in this age group. We report data from 22 pediatric patients who were biopsied to confirm the diagnosis of IgAN at our clinical center. 14 of them were treated with corticosteroids according to the recommendations for IgA nephritis vasculitis of the German Society of Pediatric Nephrology (GPN). Improvement was achieved in the majority of all cases, with a significant reduction in proteinuria five months after initiation of therapy. Our data suggest that treatment regimens for acute IgA nephritis and IgA vasculitis nephritis may be unified and are discussed in the context of current studies.

Drug Therapies for Patients with IgA Nephropathy: A Network Meta-analysis of Randomized Clinical Trials.

Several drugs are used for treating IgA nephropathy (IgAN). We carried out a network meta-analysis evaluating these drugs. Electronic databases were searched for appropriate randomized clinical trials carried out in patients with IgAN. The primary outcome was proteinuria remission rates and there were several other secondary outcome measures. The risk of bias was assessed. Mixed treatment comparison estimates were modelled from direct and indirect comparison estimates. Grading of the evidence for key comparisons was carried out. Fifty-seven clinical trials were included in the systematic review and 51 in the metaanalysis. Polyunsaturated fatty acids, corticosteroids/angiotensin receptor blockers (ARB), ARB, angiotensin converting enzyme inhibitors (ACEI), ARB/ACEI, corticosteroids/ACEI and hypolipidemics/ ARB were observed with significantly higher rates of proteinuria remission than the standard of care. Several benefits were observed with other drugs on the secondary outcome measures. A very low grade was observed for the interventions. We observed a few interventions to perform better in the management of IgAN. The results of this study will aid in further evaluation of such drugs that may assist in saving the resources and time. However, the readers should interpret the findings with great caution as the results might change with the advent of future head-to-head clinical trials.

37-Year-Old Woman With Bilateral Lower Extremity Edema, Proteinuria, and Microscopic Hematuria

37-Year-Old Woman With Bilateral Lower Extremity Edema, Proteinuria, and Microscopic Hematuria

New strategies and perspectives on managing IgA nephropathy

IgA nephropathy is an inflammatory renal disease characterised by the deposition of IgA in the glomerular mesangium and is the most commonly reported primary glomerulonephritis worldwide. Thirty to forty percent of patients with the disease develop progressive renal function decline, requiring renal replacement therapy within two decades of diagnosis. Despite this, accurate individual risk stratification at diagnosis and predicting treatment response remains a challenge. Furthermore, there are currently no disease specific treatments currently licensed to treat the condition due to long standing challenges in the nature and prevalence of the disease. Despite this, there have been exciting recent advances in the field that may represent paradigm shifts in the way IgA nephropathy is managed in the near future. In this review, we explore the evidence base informing current approaches to management and explore new strategies and future directions in the diagnosis and management of IgA nephropathy.

Candidate Urine Peptide Biomarkers for IgA Nephropathy: Where Are We Now?

Early detection, prognosis, and management of IgA nephropathy (IgAN) remain a challenge. Histological examination of renal tissue still comprises the only way to confirm an IgAN diagnosis. It is of great importance to establish noninvasive diagnostic, prognostic, and predictive biomarkers that would improve the clinical care and outcome of patients suffering from IgAN. This review summarises the findings from previous mass spectrometry- (MS-) based studies dedicated to the discovery of urinary peptide profiles specific to IgAN. There is a substantial number of urinary peptides that have been discovered to date, which show promise as biomarkers of IgAN; however, all of them require further, rigorous validation in well-planned studies, involving a large number of subjects who represent diverse and numerous populations.

Recent advances in the understanding and management of IgA nephropathy.

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.

Optimal proteinuria target for renoprotection in patients with IgA nephropathy.

BackgroundProteinuria is a target for renoprotection in kidney diseases. However, optimal level of proteinuria reduction in IgA nephropathy (IgAN) is unknown.MethodsWe conducted a retrospective observational study in 500 patients with biopsy-proven IgAN. Time-averaged proteinuria (TA-P) was calculated as the mean of every 6 month period of measurements of spot urine protein-to-creatinine ratio. The study endpoints were a 50% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease (ESRD), and slope of eGFR.ResultsDuring a median follow-up duration of 65 (12–154) months, a 50% decline in eGFR occurred in 1 (0.8%) patient with TA-P of <0.3 g/g compared to 6 (2.7%) patients with TA-P of 0.3–0.99 g/g (hazard ratio, 2.82; P = 0.35). Risk of reaching a 50% decline in eGFR markedly increased in patients with TA-P of 1.0–2.99 g/g (P = 0.002) and those with TA-P≥3.0 g/g (P<0.001). ESRD did not occur in patients with TA-P<1.0 g/g compared to 26 (20.0%) and 8 (57.1%) patients with TA-P of 1.0–2.99 and ≥3.0 g/g, respectively. Kidney function of these two groups deteriorated faster than those with TA-P<1.0 g/g (P<0.001). However, patients with TA-P of 0.3–0.99 g/g had a greater decline of eGFR than patients with TA-P<0.3 g/g (−0.41±1.68 vs. −0.73±2.82 ml/min/1.73 m2/year, P = 0.03).ConclusionIn this study, patients with TA-P<1.0 g/g show favorable outcomes. However, given the faster eGFR decline in patients with TA-P of 0.3–0.99 g/g than in patients with TA-P<0.3 g/g, the ultimate optimal goal of proteinuria reduction can be lowered in the management of IgAN.

Update on the management of IgA nephropathy

Abstract IgA nephropathy is the commonest primary glomerular disease worldwide. A high prevalence has been noted in Asia including India. The clinical course has a wide spectrum of presentation varies from isolated microscopic hematuria to crescentic glomerulonephritis. The approach of the treatment has to be decided as per the clinical and histopathological manifestation of the disease. Risk assessment is important to determine management and also to balance between the risks of therapy by the selection of patients. Clinical features appear to be the stronger prognostic indicators however certain renal histopathological findings have been associated with an increased risk of progressive disease. There is no definitive therapeutic approach despite of better understanding of pathogenic mechanism of the disease. The expected outcome of therapy is slowing the deterioration in kidney function as well as a reduction in proteinuria and control of blood pressure by suppression of angiotensin II with ACE inhibitors or angiotensin II-receptor blockers (ARBs). The indications for the use of corticosteroid alone or in combination with other immunosuppressive agents e.g. Azathioprine or cyclophosphamide are not well defined. Different regimens have been used, consisting of corticosteroids alone or in combination with other immunosuppressive agents. Despite retrospective studies in IgA nephropathy supporting the use of immunosuppressive therapy other than corticosteroid, few randomized control trials have demonstrated a benefit. Corticosteroid combined with cyclophosphamide or azathioprine can be considered in patients with rapidly progressive disease with crescentic IgA nephropathy. Fish oil can be used in the treatment of IgA nephropathy with proteinuria above 1 g/day despite 3–6 months of optimized therapy with ACE inhibitors or ARBs and blood pressure control.

Changes in Nephritogenic Serum Galactose-Deficient IgA1 in IgA Nephropathy following Tonsillectomy and Steroid Therapy

BackgroundRecent studies have shown that galactose-deficient IgA1 (GdIgA1) has an important role in the pathogenesis of IgA nephropathy (IgAN). Although emerging data suggest that serum GdIgA1 can be a useful non-invasive IgAN biomarker, the localization of nephritogenic GdIgA1-producing B cells remains unclear. Recent clinical and experimental studies indicate that immune activation tonsillar toll-like receptor (TLR) 9 may be involved in the pathogenesis of IgAN. Here we assessed the possibility of GdIgA1 production in the palatine tonsils in IgAN patients.MethodsWe assessed changes in serum GdIgA1 levels in IgAN patients with clinical remission of hematuria and proteinuria following combined tonsillectomy and steroid pulse therapy. Further, the association between clinical outcome and tonsillar TLR9 expression was evaluated.ResultsPatients (n = 37) were divided into two groups according to therapy response. In one group, serum GdIgA1 levels decreased after tonsillectomy (59%) alone, whereas in the other group most levels only decreased after the addition of steroid pulse therapy to tonsillectomy (41%). The former group showed significantly higher tonsillar TLR9 expression and better improvement in hematuria immediately after tonsillectomy than the latter group.ConclusionsThe present study indicates that the palatine tonsils are probably a major sites of GdIgA1-producing cells. However, in some patients these cells may propagate to other lymphoid organs, which may partially explain the different responses observed to tonsillectomy alone. These findings help to clarify some of the clinical observations in the management of IgAN, and may highlight future directions for research.

Self-assessment questions: Evaluation and management of IgA nephropathy

1. Regarding clinical presentation in IgA nephropathy (IgAN): 1. Recurrent episodes of macroscopic haematuria classically occur 1–2 weeks following an upper respiratory tract infection 2. Development of IgAN is related to high levels of circulating levels of IgA 3.

Role of tonsillectomy in the management of IgA nephropathy

Background :The tonsils represent a site of local immunity where immunoglobulin-bearing cells are capable of producing IgA. The tonsils have been considered the foci of abnormal IgA production in IgAN, thus, a relationship is suggested between the tonsillar immune response and the pathogenesis of IgAN. IgAN, then, is considered a tonsillar focal infection. Patients and methods :This study was done on 15 patients their ages ranged between 15 and 35 (10 males and 5 females). All patients were already diagnosed by renal biopsy-proven IgA nephropathy by the nephrologists and under medical treatment by conventional steroid. The diagnosis of IgA nephropathy was based on histologic assessment of percutaneous renal biopsy tissue. The main problem in all patients is that development of gross haematoria, deterioration of urinary findings and deterioration of the general condition of the patient after any acute attack of upper respiratory tract infection especially acute tonsillitis. Tonsillectomy was done after one month from controlling the acute infection. Postoperative follow up for all patients was done at 1st, 3rd, 6th, 12th month by clinical examination and laboratory investigations Results :The gross haematoria was completely stopped in all patients after tonsillectomy except two patients one of them was complicated by hypertension and the other one was complicated by nephritic syndrome. Also there was marked reduction in proteinuria, microscopic haematoria, marked reduction in the serum IgA concentration, urinary abnormalities disappeared and also improvement of renal function for the patients with serum creatinin less than 2mg/dl while in the two patients with serum creatinin more than 2mg/dL there was no much improvement after tonsillectomy with more deterioration of renal function of both patients with the development of chronic renal failure in the patient with nephritic syndrome 9 month postoperative Conclusion :Tonsillectomy is effective in improving renal function ,urinary symptoms, gross haematoria and decreasing the level of IgA in patients with IgAN if it is done in mild to moderate cases with serum creatinin less than 2mg/dL while has no much efficacy on moderate to severe cases with serum creatinin more than 2mg/dL or complicated cases.

Role of tonsillectomy in the management of IgA nephropathy

Background :The tonsils represent a site of local immunity where immunoglobulin-bearing cells are capable of producing IgA. The tonsils have been considered the foci of abnormal IgA production in IgAN, thus, a relationship is suggested between the tonsillar immune response and the pathogenesis of IgAN. IgAN, then, is considered a tonsillar focal infection. Patients and methods :This study was done on 15 patients their ages ranged between 15 and 35 (10 males and 5 females). All patients were already diagnosed by renal biopsy-proven IgA nephropathy by the nephrologists and under medical treatment by conventional steroid. The diagnosis of IgA nephropathy was based on histologic assessment of percutaneous renal biopsy tissue. The main problem in all patients is that development of gross haematoria, deterioration of urinary findings and deterioration of the general condition of the patient after any acute attack of upper respiratory tract infection especially acute tonsillitis. Tonsillectomy was done after one month from controlling the acute infection. Postoperative follow up for all patients was done at 1st, 3rd, 6th, 12th month by clinical examination and laboratory investigations Results :The gross haematoria was completely stopped in all patients after tonsillectomy except two patients one of them was complicated by hypertension and the other one was complicated by nephritic syndrome. Also there was marked reduction in proteinuria, microscopic haematoria, marked reduction in the serum IgA concentration, urinary abnormalities disappeared and also improvement of renal function for the patients with serum creatinin less than 2mg/dl while in the two patients with serum creatinin more than 2mg/dL there was no much improvement after tonsillectomy with more deterioration of renal function of both patients with the development of chronic renal failure in the patient with nephritic syndrome 9 month postoperative Conclusion :Tonsillectomy is effective in improving renal function ,urinary symptoms, gross haematoria and decreasing the level of IgA in patients with IgAN if it is done in mild to moderate cases with serum creatinin less than 2mg/dL while has no much efficacy on moderate to severe cases with serum creatinin more than 2mg/dL or complicated cases.

Management of IgA nephropathy: Evidence-based recommendations

The condition known as IgA nephropathy was first identified when Berger observed mesangial staining for IgA in healthy patients with isolated hematuria. These patients often presented with recurrent synpharyngitic hematuria or less frequently with asymptomatic microscopic hematuria and proteinuria. Although initially considered benign, we now recognize it as a common cause of end-stage renal failure. The overall prognosis may be better than suggested in the literature, as patients with mild asymptomatic hematuria are often not biopsied and, therefore, frequently are not included in published articles. We reviewed prospective and retrospective adult studies published after 1976 and analyzed them to produce evidence-based recommendations. Patients with proteinuria over 3 g/day, mild glomerular changes only, and preserved renal function (creatinine clearance over 70 ml/min) should be treated with prednisone. Steroids reduce proteinuria (grade B recommendation) and stabilize kidney function (grade C). The combination of cyclophosphamide, dipyridamole and warfarin should not be used (grade A), nor should cyclosporine A (grade B). In patients with progressive disease (creatinine clearance of less than 70 ml/min), fish oil should be given (grade B). A tonsillectomy could reduce proteinuria and hematuria in those patients with recurrent tonsillitis (grade D). Those with hypertension should be treated promptly with an angiotensin-converting enzyme inhibitor (grade B).

Strategies for the management of IgA Nephropathy

Strategies for the management of IgA Nephropathy