From The Laboratory To The Clinic, The Pathological Mechanism Of IgAN Ushered in A Breakthrough

Immunoglobulin A nephropathy (IgAN) is a common primary glomerular disease. Although the most accepted pathological mechanism is currently the multiple-hit theory or the 4-hit theory, there are some clinical phenomena that cannot be explained, such as abnormal activation of complement, possible combined autoinflammatory diseases, and genetic factors. influence, etc. In addition, there are currently few drugs for the treatment of IgAN, which may be related to the fact that we do not fully understand the pathological mechanism of the occurrence and development of IgAN.

Click on Cistanche for kidney disease

From April 13 to 16, 2024, the 2024 World Congress on Nephrology (WCN) opened in Argentina, the country farthest from our country. At this conference, a total of more than 1,000 abstracts were exhibited, of which 5 This abstract clarifies new progress in the pathological mechanisms of the occurrence and development of IgAN. Among these 5 abstracts, 4 are clinical cases or clinical studies, and 1 is an animal/laboratory model study. They revealed that some biomarkers and kidney biopsy conditions may be related to the occurrence and development of IgAN, and also proposed some new therapeutic targets.

Important information

① Case reports suggest that there may be a causal relationship between IgAN, renal cortical necrosis, and systemic autoinflammatory disease (SAID).

② The presence of podocyte pathology/injury in IgAN patients is related to the severity of the disease.

③ Moderate to severe renal arteriosclerosis and circulating GDF-15 levels may affect the cardiorenal prognosis of IgAN patients.

④ JAK/STAT signaling is activated in IgAN patients and is a potential therapeutic target for IgAN.

⑤ T cell infiltration may be the key mechanism for IgA deposition in the kidney.

Case Report: Coincidence or Causation, IgAN and SAID1

Case Background: Systemic autoinflammatory disease (SAID) is a genetic disease characterized by multiple diseases throughout the body, but renal involvement is rarely reported.

Case report: The patient, male, 38 years old, had fever once a month for 3 to 7 days, accompanied by fatigue, maculopapular rash, aphthous ulcer/stomatitis, cervical lymphadenopathy, splenomegaly, episodic diarrhea, and abdominal pain. , joint pain. In 2011, he went to the hospital because of gross hematuria accompanied by a small amount of proteinuria during fever. On biochemical analysis, serum creatinine was 0.6 mg/dl, hemoglobin++ was present in the urine, and urine protein/creatinine ratio (UPCR) was 0.5 g/g. The IgA level was 397 mg/dl (normal reference value <350). Renal biopsy (RBx) showed IgAN without inflammatory activity and no histological chronicity, so a low-sodium diet and ramipril treatment were given. As systemic symptoms persisted, the patient was treated with prednisone, azathioprine, and tocilizumab. During the follow-up period, the patient developed persistent hematuria, 3 times of RBx monitoring confirmed IgAN, and the level of chronic inflammation increased significantly. During this period, methylprednisolone (MP), cyclophosphamide, rituximab, and mycophenolate mofetil were given. In 2018, he started taking canakinumab 150 mg once a month, and his systemic symptoms completely disappeared.

In 2022, the patient was admitted to the hospital due to a paravertebral muscle abscess. Stage III acute kidney injury (AKI) requiring brief renal replacement therapy occurred concurrently, but without sepsis or hypotension. Immunological, serological, and prothrombotic features were normal. Phase III abdominal CT showed bilateral diffuse renal cortical hypoperfusion (Figure 1-A). We performed a fifth RBx, which showed infarct with ischemic necrosis and interstitial hemorrhage, IgA-GN with fibrocytic crescents, with fibrosis, and moderate chronic interstitial inflammation. MP treatment was given again, and the patient's renal function began to recover.

In 2023, a genetic study identified two genetic variants (p.Val377IIe and p.Pro11Leu) associated with mevalonate kinase deficiency (MKD). Due to the recurrence of systemic symptoms, he was restarted on canakinumab with good clinical response. The patient is currently asymptomatic, with a creatinine of 1.46 mg/dl and persistent microscopic hematuria and proteinuria of approximately 1 g/d.

Case Discussion and Summary: In this patient, two diseases converged, namely recurrent infections and inflammatory episodes leading to quantitative increases and qualitative defects in IgA (which may explain the pathogenic relationship between MDR and IgAN), and marked histological damage Progression (non-response to different immunosuppressive regimens).

On the other hand, SAID patients are prone to thrombotic events. The Schwartzman phenomenon may play a role in the development of renal cortical necrosis (RCN) in the context of ongoing inflammation and infection. In MKD, there have been no reports of glomerular involvement in canakinumab-treated RCN. The described pathogenic mechanisms allow us to hypothesize that MKD is a secondary etiology in the development of renal manifestations.

Cytopathy correlates with disease severity2

Research background: Since 2017, people have begun to study the clinical value of podocyte damage in IgAN. The occurrence of podocyte hypertrophy and tip lesions is a sign of podocyte damage. It has been observed that these histological manifestations tend to have a better renal prognosis with immunosuppressive therapy, but patients who do not receive immunosuppression have a poorer prognosis. There are no cohorts evaluating the clinical course of these lesions in Latin America.

Research Methods: Case and Control Study

Research results: A total of 37 IgAN patients were included with an average follow-up of (41±32) months. Among them, 27% showed podocyte lesions (IgAN-p) and 72.9% showed IgAN without histological manifestations of podocyte lesions (IgAN-np). ). Clinically, proteinuria in IgAN-P patients was higher than that in the IgAN-np group, specifically 3.9±3.0g/g vs 1.6±1.5g/g, with no statistical significance (p=0.54). The renal function of the IgAN-p group was slightly lower, with an average eGFR of 65.9±45ml/min/1.73㎡ vs 80.2±36.4 ml/min/1.73㎡ (p=0.23). The IgAN-p group had more granular cast nephropathy. (92% vs 80% p=0.02), indicating that it may be accompanied by acute tubular injury. Histologically, 80% of IgAN-p patients show podocyte hypertrophy and 2% show tip-type focal segmental glomerulosclerosis (FSGS). MST-C score results did not differ between the two groups, except that mesangial hyperplasia occurred in 96.3% of patients with podocytosis compared with 70% of patients without podocytosis (p=0.02). The prognosis based on the international SCORE score was not statistically significant between groups (p=0.59). Patients with podocytosis tended to receive immunosuppressive therapy before biopsy (50% vs 37%, p=0.01), and once histological diagnosis was obtained, the decision to continue immunosuppression was more common among patients with podocytosis agent (90% vs 63%, 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 terms of ESKD, a 40% decrease in eGFR, and the need for renal replacement therapy.

Study conclusion: In previous reports, 16% of IgAN patients had podocyte hypertrophy and tip lesions. In this study, this phenomenon was more common (27%). Compared with IgAN-np patients, we observed that IgAN-p patients had more proteinuria and poorer renal function, thus requiring a higher frequency of immunosuppressive treatment, but affecting renal outcomes similar to those of patients without podocytosis. same. Results were similar to those observed in previous cohorts.

Moderate-to-severe renal arteriosclerosis and circulating GDF-15 levels may affect cardiorenal prognosis in patients with IgAN3

Research background: The cardiovascular risk of IgAN patients has gradually received attention. The KDIGO guidelines clearly emphasize the importance of assessing cardiovascular risk and implementing appropriate interventions when necessary in the management of patients with IgAN. This study aimed to explore the risk factors affecting cardiorenal prognosis in patients with IgAN.

Research design: This study was a retrospective study. A total of 353 IgAN patients who were regularly followed up for at least 1 year in Beijing Anzhen Hospital were selected. According to whether the cardiorenal composite endpoint event occurred, the patients were divided into group A (n=85, yes) and group B (n=268, no). The clinicopathological characteristics of the two groups of patients were compared and analyzed. Single-factor and multi-factor Cox models were used to analyze the risk factors affecting cardiac and renal prognosis in patients with IgAN. The serum GDF-15 levels of IgAN patients were also detected.

Research 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), 24h urinary 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), presence of intracapillary proliferation (E1) (HR=1.697; 95% CI, 1.079~2.669; P=0.022), tubular atrophy/interstitium 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) are the most important factors affecting the heart disease of IgAN. independent risk factor for renal prognosis. In IgAN patients with moderate to severe intrarenal arteriosclerosis, 24h 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) are independent risk factors affecting the cardiorenal prognosis of IgAN patients. 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 cardio-renal composite outcome was significantly higher than that in the group with benign cardio-renal composite outcome [1591.69 (1001.65~2546.36) pg/ml vs 775.85 (546.82~1310.29) pg/ml, P<0.001].

Study conclusion: IgAN patients have a higher incidence of cardiovascular disease. In addition to traditional risk factors related to IgAN such as hypertension, initial proteinuria, eGFR, E1 and T2 lesions, moderate to severe intrarenal arteriosclerosis also affects the cardiorenal prognosis of IgAN patients. Among IgAN patients with moderate to severe intrarenal arteriosclerosis, Oxford-E lesions are an independent risk factor affecting the cardiorenal prognosis of IgAN patients. This study suggests that damage to endothelial cells may be a potential link between heart and kidney disease. Circulating GDF-15 levels may be related to the cardiorenal prognosis of IgAN.

JAK/STAT signaling pathway, a potential therapeutic target for IgAN4

Research background: The Janus kinase (JAK)-signal transducer 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 immunity. System adjustment. Research in recent years has explored the role of abnormal activation of receptor tyrosine kinases in the pathogenesis of IgAN.

Study design: This was a retrospective analysis that included the clinical data of 63 IgAN patients diagnosed from January 2002 to December 2016. Clinical and laboratory data were collected at baseline and at the end of follow-up. Kidney tissue sections were stained with antibodies specific for JAK-STAT pathway components. The marginal tissues of another 6 cases of renal tumors were used as controls.

Study results: The study population was followed for an average of 102 months. More than half of the patients achieved remission, and 31.1% achieved the primary outcome, defined as end-stage renal disease (ESRD) or doubling of baseline creatinine. JAK3 is mainly expressed in renal tubules and glomeruli. Compared with controls, IgAN patients had enhanced JAK3 staining.

Research summary: The JAK/STAT signaling pathway is activated in IgAN patients and may be a therapeutic target for IgAN.

There is a large amount of CD4+ T cell infiltration in the kidneys of IgAN mice5

Research background: Current pathological models do not fully elucidate why IgA antibodies (Abs) are selectively deposited in the glomerular mesangial area. Recently, an animal model found that IgA autoantibodies against the mesangial antigen βIIspectrin may be related to the above mechanism. We also found that a large number of IgA+ plasmablasts (PBs) accumulated in the kidneys of spontaneous IgAN model mice (gddY) mice, and the IgA autoantibodies produced by these PBs bound to βII-membrane contractile proteins and mesangial cell surfaces. sequenced the variable regions of the IgA heavy and light chains of IgA+ PBs isolated from gddY mouse kidneys and found that most of them contained a large number of somatic mutations, suggesting that they are generated through germinal centers in a T-cell-dependent manner. . However, the detailed mechanisms of IgA autoantibody production, such as which types of T cells are responsible for inducing autoantibodies, are not yet clear. In this study, we analyzed infiltrating CD4+ T cells in the kidneys of gddY mice.

Research design: This study uses spontaneous IgAN model mice as the research subjects. All gddY mice showed proteinuria and glomerular IgA deposition at 8 weeks of age and then developed obvious renal failure, with pathology similar to human IgAN. Leukocytes were isolated from the kidneys of 8-week-old gddY or BALB/c mice, stimulated with monensin, ionolysin, and phorbol ester (PMA), stained for CD4 on the surface, and IFN-γ and IL-17 intracellularly. Or FoxP3. Flow cytometry analysis. Samples were analyzed using FACS Canto II (BD Biosciences).

Research results: We found that compared with BALB/c mice, gddY mice had a large accumulation of CD4+ T cells in the kidneys. Compared with BALB/c, Th1 (CD4+ IFN-γ+), Th17 (CD4+ IL-17+), regulatory T (Treg, CD4+ Foxp3+) and follicular helper T (Tfh, CD4+ CXCR5+ PD-1+) cells increased significantly. 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.

Research conclusion: We found that there are a large number of CD4+ T cells, including Th1, Th17, Treg, and Tfh, in the kidneys of gddY mice, while Th2 cells did not accumulate. At present, the direct connection between these infiltrating CD4+ T cells and the production of IgA-type autoantibodies is unclear. We will continue to elucidate the role of these cells in inducing IgA autoantibodies in IgAN. After its role is clarified, it may be one of the potential therapeutic targets for IgAN.

How Does Cistanche Treat Kidney Disease?

Cistanche is a traditional Chinese herbal medicine used for centuries to treat various health conditions, including kidney disease. It is derived from the dried stems of Cistanche deserticola, a plant native to the deserts of China and Mongolia. The main active components of cistanche are phenylethanoid glycosides, echinacoside, and acteoside, which have been found to have beneficial effects on kidney health.

Kidney disease, also known as renal disease, refers to a condition in which the kidneys are not functioning properly. This can result in a buildup of waste products and toxins in the body, leading to various symptoms and complications. Cistanche may help treat kidney disease ase through several mechanisms.

Firstly, cistanche has been found to have diuretic properties, meaning it can increase urine production and help eliminate waste products from the body. This can help relieve the burden on the kidneys and prevent the buildup of toxins. By promoting diuresis, cistanche may also help Reduce high blood pressure, a common complication of kidney disease.

Moreover, cistanche has been shown to have antioxidant effects. Oxidative stress, caused by an imbalance between the production of free radicals and the body's antioxidant defenses, plays a key role in the progression of kidney disease. ies help neutralize free radicals and reduce Oxidative stress, thereby protecting the kidneys from damage. The phenylethanoid glycosides found in cistanche have been particularly effective in scavenging free radicals and inhibiting lipid peroxidation.

Additionally, cistanche has been found to have anti-inflammatory effects. Inflammation is another key factor in the development and progression of kidney disease. Cistanche's anti-inflammatory properties help reduce the production of pro-inflammatory cytokines and inhibit the activation of inflammation mandatory pathways, thus alleviating inflammation in the kidneys.

Furthermore, cistanche has been shown to have immunomodulatory effects. In kidney disease, the immune system can be dysregulated, leading to excessive inflammation and tissue damage. Cistanche helps regulate the immune response by modulating the production and activity of immune cells, such as T cells and macrophages. This immune regulation helps reduce inflammation and prevent further damage to the kidneys.

Moreover, cistanche has been found to improve renal function by promoting the regeneration of renal tubes with cells. Renal tubular epithelial cells play a crucial role in the filtration and reabsorption of waste products and electrolytes. In kidney disease, these cells can be damaged, leading to damaged renal function. Cistanche's ability to promote the regeneration of these cells helps restore proper renal function and improve overall kidney health.

In addition to these direct effects on the kidneys, cistanche has been found to have beneficial effects on other organs and systems in the body. This holistic approach to health is particularly important in kidney disease, as the condition often affects multiple organs and systems. che has been shown to have protective effects on the liver, heart, and blood vessels, which are commonly affected by kidney disease. By promoting the health of these organs, cistanche helps improve overall kidney function and prevent further complications.

In conclusion, cistanche is a traditional Chinese herbal medicine used for centuries to treat kidney disease. Its active components have diuretic, antioxidant, anti-inflammatory, immunomodulatory, and regenerative effects, which help improve renal function and protect the kidneys from further damage. , cistanche has beneficial effects on other organs and systems, making it a holistic approach to treating kidney disease.