Immunoglobulin A nephropathy (IgAN) is a common primary glomerular disorder. Although the most accepted pathological mechanism conjecture is the multiple blow theory or the quadruple hit theory (4-hit), there are some clinical phenomena that cannot be explained, such as abnormal activation of complement, possible concomitant autoinflammatory diseases, and the influence of genetic factors. In addition, there are fewer drugs for the treatment of IgAN, which may be related to the fact that we do not fully grasp the pathological mechanism of the occurrence and development of IgAN.
On April 13~16, 2024, the 2024 World Congress of Nephrology (WCN) opened in Argentina, the farthest country from the mainland, and more than 1,000 abstracts were exhibited at this conference, of which 5 abstracts clarified the new progress in the pathological mechanism of the occurrence and development of IgAN. Of these 5 abstracts, 4 were clinical cases or clinical studies, and 1 was an animal/laboratory model study. They revealed that some biomarkers and kidney biopsies may be related to the occurrence and development of IgAN, and also proposed some new therapeutic targets.
Key Messages:
(1) Case reports suggest that there may be a causal relationship between IgAN, renal cortical necrosis, and systemic autoinflammatory diseases (SAIDs).
(2) The presence or absence of podocytic lesions/injuries in IgAN patients is related to disease severity. (3) Moderate-severe renal arteriosclerosis and circulating GDF-15 levels may affect the cardiorenal prognosis of patients with IgAN. (4) JAK/STAT signaling is activated in IgAN patients and is a potential therapeutic target for IgAN. (5) T cell infiltration may be a key mechanism of IgA deposition in the kidney.
Case report: Coincidence or causation, IgAN versus SAID1
Background: Systemic autoinflammatory disease (SAID) is an inherited disease characterized by a variety of systemic diseases, but renal involvement has rarely been reported.
Case report: The patient, a 38-year-old male, had fever once a month for 3~7 days, accompanied by fatigue, maculopapular rash, aphthous ulcer/stomatitis, cervical lymphadenopathy, splenomegaly, episodic diarrhea, abdominal pain, and arthralgia. In 2011, he presented to the hospital with gross hematuria with a small amount of proteinuria during fever. In biochemical analysis, serum creatinine was 0.6 mg/dl, hemoglobin ++ was present in the urine, and the urine protein/creatinine ratio (UPCR) was 0.5 g/g. The IgA level is 397 mg/dl (normal reference value < 350). Renal biopsy (RBx) showed IgAN, no inflammatory activity, no histologic chronicity, and was therefore treated with a low-sodium diet and ramipril. Due to persistent systemic symptoms, patients were treated with prednisone, azathioprine, and tocilizumab. During follow-up, the patient developed persistent hematuria, confirmed IgAN with 3 RBx surveillances, and a significant increase in chronic inflammation. During this period, methylprednisolone (MP), cyclophosphamide, rituximab, and mycophenolate mofetil were given. In 2018, canakimab 150 mg 1 time a month was started, and the systemic symptoms completely disappeared.
In 2022, the patient was admitted to the hospital with a paravertebral muscle abscess. Acute kidney injury (AKI) stage III requiring transient renal replacement therapy occurs at the same time, but there is no sepsis or hypotension. Immunological, serological, and prethrombotic features are normal. Phase III abdominal CT showed bilateral diffuse renal cortical hypoperfusion (Fig. 1-A). We performed a fifth RBx, which showed infarction with avascular necrosis and interstitial hemorrhage, IgA-GN with fibroblastic crescents with fibrosis and moderate chronic interstitial inflammation (Figure 1-B-F). MP treatment was given again, and the patient's kidney function began to recover.
Fig.1 Imaging and renal biopsy results
In 2023, a genetic study identified two genetic variants associated with mevalonate kinase deficiency (MKD) (p.Val377IIe and p.Pro11Leu). Due to the recurrence of systemic symptoms, he restarted canakinumab with a good clinical response. Currently, the patient is asymptomatic with a creatinine of 1.46 mg/dl and persistent microscopic hematuria and proteinuria of about 1 g/day.
Case discussion and summary: In this patient, two diseases converged, i.e., recurrent infections and episodes of inflammation leading to increased quantity and quality defects in IgA (which may explain the pathogenic relationship between MDR and IgAN), and significant progression of histological damage (failure to respond to different immunosuppressive regimens).
On the other hand, patients with SAID are prone to thrombotic events. Schwartzman's phenomenon may play a role in the development of renal cortical necrosis (RCN) against the background of persistent inflammation and infection. In MKD, there have been no reports of canakinumab-treated RCN with glomerular involvement. The described pathogenic mechanism allows us to hypothesize that MKD is an auxiliary etiology for the occurrence and development of renal manifestations.
Podocytic lesions correlate with disease severity2
Background: Since 2017, people have begun to study the clinical value of podocyte injury in IgAN, and the appearance of podocyte hypertrophy and tip lesions are hallmarks of podocyte injury. These histologic findings have been observed to favor immunosuppressive therapy, resulting in a better renal prognosis, but worse outcomes in patients who are not immunosuppressed. In Latin America, there were no cohorts to assess the clinical course of these lesions.
Methods: Case-based and controlled studies
Results: A total of 37 patients with IgAN were included with an average follow-up of (41±32) months, of which 27% showed podocytopathy (IgAN-p) and 72.9% showed histological manifestations of IgAN-podocytopathy (IgAN-np). Clinically, proteinuria in IgAN-P patients was higher than that in IgAN-np group, specifically 3.9±3.0 g/g vs 1.6±1.5 g/g, which was not statistically significant (p=0.54). Renal function was slightly lower in the IgAN-p group, with a mean eGFR of 65.9±45 mL/min/1.73㎡ vs 80.2±36.4 mL/min/1.73㎡ (p=0.23), and there were more granular casts in the IgAN-p group (92% vs 80% p=0.02), indicating that acute tubular injury may be present. Histologically, 80% of patients with IgAN-p present with podocyte hypertrophy and 2% present with tip-type focal segmental glomerulosclerosis (FSGS). The results of MST-C scores did not differ between the two groups, except that the incidence of mesangial hyperplasia in patients with podocytopathy was 96.3% compared to 70% in patients with podocytopathy, (p=0.02). The prognosis based on the international SCORE score was not statistically significant between groups (p=0.59). Patients with podocytosis preferred immunosuppressive therapy prior to biopsy (50 versus 37 percent, p=0.01), and once histologic diagnosis is available, the decision to continue immunosuppressive therapy is more common in patients with podocytosis (90 versus 63 percent, p=0.11). Finally, long-term results showed no difference in the need for renal replacement therapy. There was no difference between the two groups in ESKD, a 40% decrease in eGFR, and the need for renal replacement therapy.
Conclusions: In previous reports, 16% of patients with IgAN had podocyte hypertrophy and tip lesions. In this study, this phenomenon was more common (27%). We observed that patients with IgAN-p had more proteinuria and poorer renal function, requiring a higher frequency of immunosuppressive therapy compared to patients with IgAN-np, but affected the same renal outcomes as patients without podocytic disease. The results were similar to those observed in the previous cohort.
Moderate-severe renal arteriosclerosis and circulating GDF-15 levels may affect the cardiorenal prognosis of patients with IgAN3
Background: Cardiovascular risk in patients with IgAN is gradually gaining attention. The KDIGO guidelines clearly emphasize the importance of assessing cardiovascular risk in the management of patients with IgAN and implementing appropriate interventions if necessary. The purpose of this study was to investigate the risk factors affecting the cardiorenal prognosis of patients with IgAN.
Study design: This study is a retrospective study. A total of 353 patients with IgAN who were regularly followed up for at least one year in Beijing Anzhen Hospital were enrolled. According to the occurrence of cardiorenal composite endpoint events, they were divided into group A (n=85, yes) and group B (n=268, none). The clinicopathological features of the two groups were compared and analyzed. Univariate and multivariate Cox models were used to analyze the risk factors affecting the prognosis of heart and kidney in patients with IgAN. At the same time, the serum GDF-15 level of IgAN patients was measured.
Results: 14.7% (52/353) of IgAN patients had cardiovascular disease at the time of renal biopsy. 55.8% (197/353) of the patients had hypertension. Prognostic analysis showed that hypertension (HR = 1.810; 95% CI, 1.073 ~ 3.053; P=0.026), 24-hour urine protein quantification (24hUTP) (HR = 1.081; 95% CI, 1.006 ~ 1.162; P=0.033), eGFR (HR=0.980; 95% CI, 0.973 ~ 0.987; P). <0.001), intracapillary proliferation (E1) (HR=1.697; 95% CI, 1.079~2.669; P=0.022), tubular atrophy/interstitial fibrosis (T2) (HR=3.757; 95% CI, 1.959~7.203; P<0.001) and moderate to severe intrarenal arteriosclerosis (HR=3.320; 95% CI, 1.289~8.548; P=0.013) were independent risk factors for cardiovascular and renal prognosis of IgAN. In patients with IgAN with moderate to severe intrarenal arteriosclerosis, 24-hour urine protein quantification (24hUTP) (HR=1.131; 95% CI, 1.014 ~ 1.261; P=0.028), eGFR (HR=0.982; 95% CI, 0.971 ~ 0.993; P=0.001) and E1 (HR=2.583; 95% CI, 1.379 ~ 4.841; P=0.003) were independent risk factors for cardiorenal prognosis in patients with IgAN. Serum GDF-15 levels were positively correlated with 24hUTP (r=0.405, P<0.001) and negatively correlated with eGFR (r= -0.606, P<0.001). The serum GDF-15 level in the group with poor cardiorenal composite outcome was significantly higher than that in the benign cardiorenal composite outcome group [1591.69 (1001.65~2546.36) pg/ml vs 775.85 (546.82~1310.29) pg/ml, P<0.001].
Conclusions: The incidence of cardiovascular disease in patients with IgAN is high. In addition to traditional risk factors associated with IgAN, such as hypertension, initial proteinuria, eGFR, E1 and T2 lesions, moderate to severe intrarenal arteriosclerosis also affects the cardiorenal prognosis of patients with IgAN. In patients with IgAN with moderate to severe intrarenal arteriosclerosis, Oxford-E lesions are an independent risk factor for cardiorenal prognosis in patients with IgAN. This study suggests that damage to endothelial cells may be a potential link between heart and kidney disease. Circulating GDF-15 levels may be associated with the cardiorenal prognosis of IgAN.
JAK/STAT信号通路,IgAN的潜在治疗靶点4
Background: The Janus kinase (JAK)-signal transduction and activator of transcription (STAT) pathway is an intracellular signal transduction pathway that is widely expressed and involved in a variety of biological processes, including cell proliferation, differentiation, apoptosis, and regulation of the immune system. Recent studies have explored the role of aberrant activation of receptor tyrosine kinases in the pathogenesis of IgAN.
Study design: This is a retrospective analysis of clinical data from 63 patients with IgAN diagnosed between January 2002 and December 2016. Clinical and laboratory data were collected at baseline and at the end of follow-up. Kidney tissue sections were stained with JAK-STAT pathway component-specific antibodies. In addition, 6 cases of renal tumor marginal tissues were used as controls.
Results: The mean follow-up of the study population was 102 months. More than half of patients achieved remission, and 31.1% of patients achieved primary outcomes, defined as end-stage renal disease (ESRD) or doubling of baseline creatinine. JAK3 is mainly expressed in the renal tubules and glomeruli. JAK3 staining was enhanced in patients with IgAN compared to the control group (Figure 2).
Fig.2 JAK3 staining results
Study summary: The JAK/STAT signaling pathway is activated in IgAN patients and may be a therapeutic target for IgAN.
There is a large infiltration of CD4+ T cells in the kidneys of IgAN mice5
Background: Current pathological models do not fully elucidate why IgA antibodies (Abs) are selectively deposited in the mesangial region of the glomeruli. Recently, an animal model found that IgA-type autoantibodies against mesangial antigen βIIspectrin may be involved in this mechanism. We also found that a large number of IgA+ plasmablasts (PBs) were clustered in the kidneys of spontaneous IgAN model mice (gddY) mice, and that these PBs produced IgA autoantibodies bound to β ii-membrane contractile protein and mesangial cell surface. The variable regions of the IgA heavy and light chains of IgA+ PBs isolated from the kidneys of gddY mice were sequenced and found that most of them contained a large number of somatic mutations, suggesting that they were generated in a t-cell-dependent manner by germinal centers. However, the detailed mechanisms by which IgA autoantibodies are produced, such as which types of T cells are responsible for inducing autoantibodies, are not well understood. In this study, we analyzed infiltrated CD4+ T cells in the kidneys of gddY mice.
Study design: In this study, spontaneous IgAN model mice were used as the research objects. At 8 weeks of age, gddY mice showed proteinuria and glomerular IgA deposition, followed by obvious renal failure, and the pathology was similar to that of human IgAN. Leukocytes were isolated from the kidneys of 8-week-old gddY or BALB/c mice, stimulated with monensin, ionolysin, and phorbolate (PMA), stained with CD4 surface, and stained intracellularly with IFN-γ, IL-17, or FoxP3. Flow cytometry analysis. Samples were analyzed using FACS Canto II (BD Biosciences).
Results: We found that gddY mice had a large number of CD4+ T cell aggregation in their kidneys compared to BALB/c mice. Th1 (CD4+ IFN-γ+), Th17 (CD4+ IL-17+), regulatory T (Treg, CD4+ Foxp3+) and follicular helper T (Tfh, CD4+ CXCR5+ PD-1+) cells were significantly increased in the kidneys of gddY mice compared with BALB/c. On the other hand, there was no significant difference in the number of Th2 (CD4+ IL-4+) cells in the kidneys of gddY and BALB/c mice.
Conclusions: We found that there were a large number of CD4+ T cells, including Th1, Th17, Treg, and Tfh, in the kidneys of gddY mice, while there was no aggregation of Th2 cells. Currently, the direct link between these infiltrating CD4+ T cells and the production of IgA-type autoantibodies is unknown. We will continue to elucidate the role of these cells in inducing IgA autoantibodies in IgAN. Once the effect is confirmed, it may be one of the potential therapeutic targets of IgAN.
Bibliography:
1. Pehuén Fernández, et al. WCN24-788. WCN24 abstracts.
2. BELENGALLEGOS VAZQUEZ,et al. WCN24-2478. WCN24 abstracts.
3. Hong Cheng, et al. WCN24-2269. WCN24 abstracts.
4. Mateus Luvizotto, et al. WCN24-186. WCN24 abstracts.
5. Hiroyuki Iwasaki, et al. WCN24-1104. WCN24 abstracts.
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