G-067 Therapy With Targeted-Release Budesonide and Iptacopan in Rapidly Progressive IgA Nephropathy: A Case Report

Vascular risk factors in first degree relatives of patients with insulin dependent diabetes mellitus are known to increase the risk of that patient developing diabetic nephropathy. We explored the influence of vascular risk factors in first degree relatives on patients with stable (serum creatinine < 150 mumol/l for > 5 years) and progressive (serum creatinine > 200 mumol/l, and > 150% serum creatinine at presentation, after minimum follow-up at 2 years) IgA nephropathy (IgAN). We compared sodium-lithium countertransport activity (SLC Vmax), plasma lipoprotein(a) and von Willebrand factor (vWf) concentrations, incidence of vascular disease, and incidence of hypertension in 37 first degree relatives of 23 patients with stable IgAN and 33 first degree relatives of 17 patients with progressive IgAN. The two groups of relatives were comparable with respect to other risk factors: age, smoking, blood pressure, and plasma glucose, creatinine, cholesterol and triglyceride concentrations. SLC Vmax was higher in relatives of stable patients (mean 0.37 mmol/h/l RBC [S.D. 0.18] vs 0.30 [S.D. 0.09]; P = 0.034 two-sample t-test). There was no difference between the relatives of stable and progressive patients in plasma lipoprotein(a) concentration (median 11.5 mg/l vs 13.0: P = 0.45; 95% C.I. -12 to 3; Mann-Whitney test), plasma vWf concentration (149.4 IU/dl [S.D. 55.6] vs. 163.2 IU/dl [S.D. 57.3]; P = 0.31 two-sample t-test), or incidence of hypertension (13/37 [35.1%] vs 10/33 [30.3%]; chi 2 = 0.185; P = 0.667). Relatives of patients with progressive IgAN had a slightly higher incidence of vascular disease (10/33 [30.3%] vs 8/37 [21.6%]; chi 2 = 0.688; P = 0.407). Familial vascular risk may increase the likelihood of progressive renal failure in patients with IgAN but the influence is likely to be small and unrelated to the factors we measured. SLC Vmax was significantly higher in relatives of patients with stable disease which contrasts with data from other studies and is unexplained.

IgA nephropathy (IgAN) is the most common glomerulonephritis in the Western world. Generally, the diagnosis of IgAN is based on clinical history, laboratory data, and histopathological reports. The rapidly progressing and crescentic subtype is quite uncommon. The clinical picture and spectrum of severity upon presentation varies between individual cases. In this case report, we present a previously healthy 20-year-old Latin American male with anti-neutrophil cytoplasmic antibodies seropositive rapidly progressing IgAN leading to severe acute renal impairment, uremic pericarditis, and uremic encephalopathy. Prognostic markers and histopathological types of injury have been proposed as tools to assess severity of disease and in guiding therapeutic options. This case report highlights histopathological, serological, and clinical characteristics of severe IgAN. J Med Cases. 2016;7(6):230-233 doi: http://dx.doi.org/10.14740/jmc2498w

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a leading cause of end-stage renal disease globally. Although mesangial IgA deposition defines its pathology, this alone does not predict disease progression. Current biomarkers lack specificity for forecasting outcomes or guiding early intervention. Recent advances have highlighted the potential of exosome-derived tRNA-derived small RNAs (tsRNAs) as novel diagnostic tools and mediators of disease processes, but their role in IgAN remains insufficiently explored. In this study, serum exosomes were isolated from patients with progressive or non-progressive IgAN and healthy controls. tsRNA expression profiles were obtained using small RNA sequencing and validated by qRT-PCR. Bioinformatic analyses were conducted to identify target pathways. Functional effects of candidate tsRNAs were evaluated using luciferase reporter assays, tsRNA mimic/antago transfections, and co-culture of B cell-derived exosomes with collecting duct epithelial cells (CDECs). Among 566 identified exosomal tsRNAs, tRNA-Pro-TGG was significantly upregulated in patients with progressive IgAN. It was enriched in B lymphocytes and correlated with serum soluble TNFR1 levels. Functional assays revealed that exosomal tRNA-Pro-TGG suppressed MAPK translation and activated proinflammatory responses in CDECs, including increased secretion of TNF-α, IL-6, and CCL2. ROC analysis demonstrated its robust diagnostic power for distinguishing progressive from non-progressive disease (AUC = 0.9618). This study identifies exosomal tRNA-Pro-TGG as a novel, non-invasive biomarker for IgAN progression and implicates it as a mediator of immune-driven renal inflammation. These findings offer valuable insights into IgAN pathogenesis and support the potential clinical utility of tsRNA-based diagnostics in nephrology.

Although diffuse crescentic formation in immunoglobulin A (IgA) nephropathy, histologically characterized by extensive extracapillary proliferation, is assumed to have a poor prognosis, there has still been no established treatment because of the low prevalence of the condition, especially in pediatric patients. This paper reports on a 5-year-old boy with rapidly progressive IgA nephropathy requiring dialysis for 1 month. He had been treated with plasma exchange (PE) combined with immunosuppressive treatment, including steroids and mizoribine, because renal function deteriorated rapidly despite initial treatment with intravenous methylprednisolone pulse. The histological findings at that time revealed IgA nephropathy, with large circumferential cellular crescent formation in approximately 80% of the glomeruli. Three weeks after PE initiation, serum levels of creatinine and IgA-containing immune complexes returned to normal, and urinary protein excretion gradually decreased. The second renal biopsy taken 7 months later demonstrated mild IgA nephropathy with small fibrocellular crescents. This case report indicates that PE combined with immunosuppressive treatment may benefit children with rapidly progressive IgA nephropathy, even when extensive crescent formations are present.

Delayed-release (DR) budesonide received expedited approval from the US Food and Drug Administration (FDA) as a treatment for reducing proteinuria in individuals with primary IgA nephropathy (IgAN) who are at significant risk of disease progression. The approval was based on clinical trials primarily involving patients with an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2. However, the efficacy of DR budesonide in reducing kidney function decline, especially in patients with an eGFR less than 30 mL/min/1.73 m2 and proteinuria less than 1 g/d, remains unclear. We report the case of a 43-year-old man with a long-term history of hypertension and biopsy-proven IgAN who experienced a progressive increase in proteinuria and serum creatinine, along with a decline in eGFR to 28 mL/min/1.73 m2 despite maximal supportive management. Following therapy with DR budesonide, a decreasing trend in proteinuria and a stabilization of eGFR were observed in the recent measurements. While initial data suggested the effectiveness of DR budesonide primarily in patients with an eGFR over 30 mL/min/1.73 m2, our case demonstrates the potential of DR budesonide for use in scenarios beyond its currently approved indications. This underscores the need for additional research on patients with advanced stages of chronic kidney disease.

Antineutrophil cytoplasmic autoantibody (ANCA) positive immunoglobulin A (IgA) nephropathy: Case reports and review of literature

A rapidly progressive and crescentic IgA nephropathy (IgAN) is uncommon, but it has a high risk of progression to end-stage renal disease and variable response to immunosuppression. The importance of a positive anti-neutrophil cytoplasmic antibody (ANCA) serology in this group of patients is not fully understood but may have prognostic significance. On the other hand, there is growing evidence of the role of complement in the pathogenesis of IgAN, especially in cases of crescentic IgAN. Therapies directed against the complement system are a potential and rational therapeutic approach. In this issue, two clinical studies of crescentic IgAN are presented. The first work, is a retrospective case–control study describing clinical presentation, histological findings and response to treatment of crescentic IgAN/positive ANCA patients, comparing them with IgAN/negative ANCA patients and ANCA vasculitis patients. The second is a case report showing the effect of eculizumab, a humanized monoclonal antibody that is a terminal cascade complement inhibitor, as salvage therapy for crescentic IgAN resistant to conventional immunosuppression. Both studies broaden our approach to patients with aggressive forms of IgAN.

Introduction: The best treatment of IgA nephropathy (IgAN) is currently not well defined. The Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP IgAN) trial aims to answer if, in IgAN patients, an immunosuppressive treatment is more effective than a supportive treatment. Methods: In a randomized prospective multicenter study (www.clinicaltrials.gov, NCT00554502), we will treat 148 patients at risk for progressive IgA nephropathy following a 6-month run-in phase, in 2 groups: (group a) supportive treatment: patients with a persistent proteinuria &amp;gt;0.75 g/day will receive a maximized therapy to reduce blood pressure and urinary protein loss using angiotensin- converting enzyme inhibitors and AT1 blockers, statins, dietary counseling for a low-sodium and low-protein diet and education/intervention programs to stop smoking. (group b) immunosuppressive treatment: in addition to the identical treatment of group a, patients will receive treatment with steroids (glomerular filtration rate [GFR] ≥60 ml/min) or steroids plus cyclophosphamide/ azathioprine (GFR &amp;lt;60 ml/min). Study end points are the complete remission of the disease and the individual degree of renal functional loss. If the immunosuppressive therapy shows a superior efficacy with respect to prevention of renal failure, the potentially higher therapy cost and risk might be justified. Finally, our trial can serve as a model for various other types of glomerulonephritis, for which such trials are very difficult to perform, given their infrequency.

Therapeutic Plasma Exchange: Core Curriculum 2008

Infiltration of the kidney by αβ and γδ T cells: Effect on progression in IgA nephropathy

Abstract: Background: In progressive IgA nephropathy (IgAN), cyclophosphamide or steroids have been used to reduce the loss of renal function, but disease progression may occur after the end of treatment. The value of mycophenolic acid (MPA) maintenance therapy following initial immunosuppression in progressive IgAN is largely unknown. Methods: In a prospective single-center trial, 20 patients with advanced IgAN (median glomerular filtration rate [GFR], 22 ml/min) and disease progression after cyclophosphamide pulse (CyP; n=18) or steroid pulse therapy (n=2) were treated with MPA for a median of 27 months. MPA dosages (initially mycophenolate mofetil 500 mg twice daily) were adjusted according to predose plasma concentrations (target concentrations 1.5 to 4 μg/mL). The course of renal function was assessed by linear regression of glomerular filtration rates. Results: Median loss of renal function per month was significantly reduced from -0.8 ml/min to -0.03 ml/min per month after 6 months, to -0.05 ml/min per month after 12 months, and to -0.12 ml/min per month at the end of the study after median 27 months (p&amp;lt;0.05). An improved or stable GFR was observed in 16 of 20 patients during the first 12 months, and sustained in 10 patients during 24 months of follow-up. Proteinuria decreased significantly from 1.1 g/L to 0.4 g/L during MPA treatment (p=0.018). Conclusion: Our results indicate that MPA may be beneficial to slow down the loss of renal function in patients with progressive IgAN after previous immunosuppressive treatment.

Currently, approved disease-specific therapies for patients with immunoglobulin (Ig) A nephropathy in Switzerland are scarce. According to the 2024 KDIGO guidelines, current treatments focus on reducing proteinuria and nephron loss using nephroprotective regimens consisting of renin-angiotensin system blockade, the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and the dual endothelin angiotensin receptor antagonist sparsentan. Systemic glucocorticoids and a targeted-release formulation of budesonide are other therapeutic options to reduce IgA nephropathy-specific drivers of nephron loss. However, their use has been associated with adverse effects, even with targeted-release budesonide, and the benefit of these therapies remains to be weighed against the risk of treatment-emergent toxicity. This highlights the ongoing need to identify more effective and safer therapies for the treatment of IgA nephropathy. In the last few years, increasing understanding of the pathogenetic role of alternative complement pathway dysregulation in the onset and progression of IgA nephropathy has led to the development of new complement-targeting therapies. Iptacopan is an oral inhibitor of complement factor B that effectively blocks the alternative complement pathway. We report the successful treatment of a 40-year-old female patient suffering from IgA nephropathy with iptacopan. In this patient, despite maximum tolerated renin-angiotensin system blockade and fully dosed SGLT-2 inhibitor administration, we failed to achieve the desired reduction in proteinuria to <0.5 g/day. Proteinuria persisted at a level of >1 g/day despite the goal of blood pressure ≤120/70 mm Hg being achieved. Impressively, within just two months after the initiation of iptacopan, we noted a reduction in proteinuria to 0.5 g/day, and after nearly six months, we reached our goal, with proteinuria at <0.3 g/day, a value continuing to the present day. Further, the medication was well-tolerated. To the best of our knowledge, our case report is the first in Switzerland to show that selective inhibition of the alternative complement pathway in IgA nephropathy results in significant and ongoing reduction of proteinuria after six months of therapy, supporting the innovative concept of targeting the alternative complement pathway with iptacopan to treat IgA nephropathy.

Objective To investigate the factors affecting the efficacy of leflunomide combined with medium/low dose corticosteroids in the treatment of progressive IgA nephropathy (IgAN). Methods Clinical and pathological parameters were collected retrospectively in patients of primary IgAN with proteinuria>1.0 g/24 h and chronic kidney disease (CKD) stage 1-3 treated with leflunomide combined with medium/low dose corticosteroids in Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University from Jan 2005 to Dec 2010. According to the treatment effects, patients were divided into complete remission group and non-complete remission group. The biochemical and pathological indexes of the two groups were compared. Results A total of 42 patients were included. The remission rates at 3, 6, 9 and 12 months were 62%, 64%, 67% and 74%, respectively. Seventeen (40.5%) and fourteen (33.3%) patients achieved complete and partial remission after one-year treatment, and the remission rate remained stable within one year after withdrawal of drugs. The 24-hour proteinuria was 1.50 (0.67, 2.66) g, which was significantly reduced compared with the baseline 2.44 (1.36, 3.74) g (P<0.01). The decrease rate was 31.3%. There was a slight decrease in proteinuria within one year after withdrawal of drugs. Estimated glomerular filtration rate (eGFR) remained stable during the treatment and a year of follow-up. No serious adverse event was observed during the follow-up period. Among 31 responder patients, 6(19.4%) patients relapsed. Logistic multivariate regression analysis suggested that the degree of renal interstitial inflammatory infiltration was an independent predictor of complete remission with one-year treatment of leflunomide combined with medium/low dose corticosteroids (HR=0.067, 95% CI 0.008-0.535, P=0.011). Conclusions IgAN treated with leflunomide and medium/low dose corticosteroids can achieve remission in early stage, and the remission rate remains stable after withdrawal of drugs. It is a safe option for the treatment of IgAN. Renal interstitial inflammatory infiltration is an independent predictor of complete remission. Key words: Glomerulonephritis, IGA; Immunosuppressive agents; Glucocorticoids; Relapse; Leflunomide

Renal function and blood pressure are tightly linked. Physiologically, the kidneys provide a key mechanism of chronic blood pressure control via their infinite gain mechanism [1], whereas elevated blood pressure affects renal function via the pressure natriuresis mechanism [2,3]. Pathophysiologically, long-standing hypertension attenuates pressure natriuresis [4] and can cause, or at least contribute to, renal damage [5], whereas an impaired renal function can lead to, or at least aggravate, arterial hypertension [6]. Hypertension is a well-established risk factor for myocardial infarction, other cardiovascular events and premature death. Recent studies indicate that, independent of the presence of hypertension, even a mild impairment of renal function (i.e. a reduction of glomerular filtration rate by 10 ml/min) is a significant risk factor for myocardial infarction [7], cardiovascular events in general, hospitalization and death from any cause [8]. These complex relationships make it important to better understand the pathogenesis of impaired renal function in hypertensive patients. The renin-angiotensin-aldosterone system (RAAS) is a key regulator of both blood pressure and renal function, and may play an important role in their interaction. Thus, the RAAS at least partly mediates pressure natriuresis [2] and also contributes to blood pressure elevations associated with impaired renal function [9]. Hence, RAAS inhibitors [i.e. both angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers] lower blood pressure and can attenuate or even prevent renal damage [9]. However, major inter-individual treatment responses to RAAS inhibition have been noted [10], and it remains difficult to predict responders based on known pathophysiological characteristics [11]. Genetic variability in the genes encoding for one or more components of the RAAS is likely to contribute to the heterogeneous treatment responses to RAAS inhibition. Polymorphisms have been described in the genes encoding several important components of the RAAS, including angiotensinogen [12], ACE [13], angiotensin type 1 (AT1) receptors [14] and aldosterone synthase (also known as CYP11B2) [15]. Most of these studies have focused on the insertion/deletion (I/D) polymorphism in the ACE gene, where the D allele is associated with a dose-dependent increase in plasma ACE activity [13]. Despite numerous studies investigating a possible association between any of these gene polymorphisms on the one hand and the presence of hypertension on the other hand, such relationships have remained elusive [13]. Similarly, a smaller number of studies investigating the relationship between such polymorphisms and blood pressure responses to drugs acting on the RAAS have also yielded inconclusive results [16]. In 1994, associations between diabetic nephropathy and genotype at the locus of the ACE gene were described for the first time [17,18]. Interestingly, one study looked at polymorphisms in the ACE gene using restriction length polymorphisms [18], whereas the other, similar to most later studies in the field, used the I/D polymorphism of the ACE gene [17]. Both studies reported an association of genotype at the ACE locus with progression of diabetic patients to nephropathy, with the D allele of the I/D polymorphism conferring a greater risk. An association of the D allele with the risk of developing diabetic nephropathy was also confirmed in studies of both type 1 [19] and type 2 diabetes [20]. Studies in both type 1 and type 2 diabetes patients also demonstrated an association of this allele with a fast progression of diabetic nephropathy [21,22]. Two studies demonstrated that the D allele was associated with a poorer response to nephroprotective treatment, particularly ACE inhibition, in such patients [23,24]. Studies on graft function in kidney transplant patients also support the view that the D allele of the ACE gene may adversely affect renal function [25-28]. Although the above studies have been very encouraging with regard to a role of ACE gene polymorphisms in the pathophysiology and treatment of diabetic nephropathy and/or renal allograft dysfunction, similar studies in other types of nephropathy have yielded inconsistent results. For example, studies in autosomal dominant polycystic kidney disease have reported adverse effects of the D allele of the ACE gene in some cases [29-32], whereas a greater number of studies did not confirm such associations [33-39]. Similarly, an adverse effect of the D allele of the ACE gene was found in some studies in immunoglobulin (Ig)A nephropathy [40-44] or end-stage renal failure in general [45-48], whereas other studies in IgA nephropathy [49-53] or end-stage renal failure [54-56] did not confirm this. One study in hypertensive nephropathy reported that carriers of the D allele of the ACE gene are at greater risk for developing nephropathy [57]. In the absence of studies demonstrating a beneficial effect of the D allele of the ACE gene with regard to renal function, the cumulative evidence suggests that this allele, which is associated with increased ACE activity [13], conveys a greater susceptibility to develop or progress in nephropathy. However, the large number of studies failing to detect such associations indicates that the relationship may not be that simple. Three main factors are most likely to explain the inconsistencies in the above studies. First, an altered RAAS activity is likely not to be the only factor controlling the development or progression of nephropathy. Second, given the likely involvement of additional factors, many of the above studies may have been underpowered to detect the contribution of the RAAS. Unfortunately, power calculations are largely absent in most reported studies. Third, ACE is not the only player in the RAAS. Therefore, it is possible that polymorphisms other than that in the ACE gene also contribute to the development of renal failure. These include polymorphisms in angiotensinogen, the AT1 angiotensin receptor gene and the aldosterone synthase gene. However, studies investigating a possible role of polymorphisms of the angiotensinogen gene [27-29,32,35,38,43,44,46,47,49,55,58], the AT1 receptor gene [27-29,32,44,55] and the aldosterone synthase gene [47,55] have also yielded inconsistent results. In the present issue of the journal, Fabris et al. [59] report on the impact of such polymorphisms on hypertension-associated renal insufficiency. Their study is based upon a comparison between 86 hypertensive subjects with renal insufficiency and 172 hypertensive patients without renal damage who were matched for age and duration of hypertension. In these groups, they assessed the presence of the M235T polymorphism of the angiotensinogen gene, the I/D polymorphism of the ACE gene, the A1166C polymorphism of the AT1 receptor gene and the -344C/T polymorphism of aldosterone synthase. They report that patients with nephropathy are significantly more likely to carry the D allele of the ACE gene, which is in agreement with a previous report in hypertensive nephropathy [57]. The T allele of the angiotensinogen gene and the C allele of the AT1 receptor gene were found more frequently in subjects with nephropathy, but this barely missed statistical significance with the given sample size (P = 0.054 and 0.065, respectively), and the genotype at the aldosterone synthase gene was not in Hardy-Weinberg equilibrium in the control group. Given that the data on each of these polymorphisms for several nephropathy forms have remained somewhat inconclusive, these data in their own right are interesting but cannot yet be taken as definitive evidence. However, it should be considered that these genes act in concert to elicit angiotensin II and aldosterone-mediated responses in the organism. Therefore, it is possible that specific combinations of polymorphisms in multiple genes encoding for components of the RAAS are a better predictor for the development of renal failure than either of them alone, particularly if any given polymorphism alone has only a moderate effect. Indeed, a study in IgA nephropathy patients detected a significant adverse effect of the D allele of the ACE gene only in a subgroup of subjects who were homozygous for the M allele of the angiotensinogen gene [49]. Fabris et al. [59] now report for the first time on combinations of up to four loci as possible predictors of nephropathy. Although the individual polymorphisms had only a minor effect on the overall risk of developing renal insufficiency, some of their combinations were associated with an odds ratio in excess of 4. These adverse genotype combinations mostly included the D allele of the ACE gene, the T allele of the angiotensinogen gene, the A allele of the AT1 receptor gene and the C allele of the aldosterone synthase gene. Another recent study in the journal has reported an association of polymorphism of the angiotensinogen, AT1 receptor and aldosterone synthase (but not ACE) genes with hypertension, where the A allele of the AT1 receptor and the T allele of aldosterone synthase are associated with risk; the three variants together appeared to have an additive effect in this regard [60]. A further recent study used a similar approach with regard to hypertension and proximal tubular sodium handling in the kidney [61]. The authors report that carriers of the D allele of the ACE gene in combination with homozygosity for the M allele of the angiotensinogen gene, the A allele of the AT1 receptor gene and the C allele of the aldosterone synthase gene, had an odds ratio of 3.4 for being hypertensive, which was associated with significant alterations of proximal tubular sodium handling [61]. Interestingly, the three studies disagree with regard to which alleles of the various genes convey adverse effects. This highlights an important problem in such studies. By definition, specific allelic combinations occur much more rarely than each allele alone. For example, in the study by Fabris et al. [59], most combinations associated with marked odds ratio increases for renal insufficiency were found in less than 10 patients. This results in major reductions of statistical power to reliably detect existing associations between genotype and phenotype. Therefore, the present data should not be over-interpreted as proving a hypothesis, but rather as exploratory. Nevertheless, they illustrate a promising approach for a better understanding of the genetic risk factors for complex diseases. Future investigators in this interesting field would be well advised to strive for large multinational collaborations to enable collection of sample sizes that are sufficient to analyse multiple gene loci.

BackgroundThere is currently a lack of noninvasive biomarkers that effectively predict the progression of IgA nephropathy. We investigated the value of urinary IL-18 in predicting the progression of IgA nephropathy and whether its combination with clinical variables improved risk prediction.MethodsA total of 136 patients with IgA nephropathy were followed up for a median of 36 months in four academic medical centers. The levels of three biomarkers, urinary IL-18, urinary KIM-1 and urinary NGAL, were measured via ELISA in patients with 136 IgA nephropathy. The progression of IgA nephropathy was defined as a > 50% decrease in the eGFR or end-stage kidney disease. Multivariate Cox regression analyses of urine biomarkers for predicting the progression of IgA nephropathy were performed, and the AUCs of the clinical prediction models were calculated.ResultsKaplan–Meier analysis revealed that high levels (> 28.1 pg/mg of creatinine) of urinary IL-18 were associated with a significantly poor renal outcome (P < 0.01), and Cox analysis further confirmed this result. High levels of urinary IL-18 were associated with a 4.7-fold greater risk for IgA nephropathy progression in adjusted analyses. For predicting IgA nephropathy progression, urinary IL-18 yielded a C-statistic of 0.77 (95% CI, 0.67–0.86), renal injury molecule 1 yielded 0.75 (95% CI, 0.65–0.86), and uNGAL yielded 0.70 (95% CI, 0.59–0.80). Urinary IL-18 levels significantly improved the C statistic from 0.77 to 0.89, outperforming the clinical and MEST-C scores.ConclusionUrinary IL-18 is a significant predictor of poor renal outcomes and improves the risk prediction of IgA nephropathy.