How to treat lupus renal microvascular disease?

*It is only for medical professionals to read and reference.
On May 20-22, 2021, the 25th academic conference of the Rheumatology Society of the Chinese Medical Association was held in Shenzhen.
This conference was full of big names and bright spots.

Professor Minghui Zhao from Peking University First Hospital gave a wonderful introduction on "Lupus Nephritis: Thrombotic Microangiopathy" at the conference.
The editor compiled the wonderful views of Professor Minghui Zhao.

1LN is an important cause of death in SLE patients.
Systemic lupus erythematosus (SLE) is the most common systemic autoimmune disease in my country.
The kidney is the most commonly involved organ in SLE.
40% to 60% of SLE patients have it at the beginning of the disease.
LN.

LN is mainly caused by kidney damage caused by circulating or in situ immune complex deposition.
A small part of SLE damages the kidney through non-immune complex pathways (such as lupus interstitial nephritis) or renal vascular disease.

The 10-year renal survival rate of LN in my country is 81%~98%, which is one of the common causes of end-stage renal disease (ESRD) and an important cause of death in SLE patients.

2SLE combined with TMA concept Thrombotic microangiopathy (TMA) is a rare, high fatality rate, and multiple systems of microangiopathy.

TMA is a pathological diagnosis with complex etiology and diverse names, including clinically well-known thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and so on.

TMA can be divided into heredity and acquired.
Heredity is caused by some genetic defects.
According to different defective genes, it can be divided into 4 types: ①Von Willebrand factor cleavage protease (ADAMTSl3) gene defects; ② Complement factor H (CFH), complement factor I (CFI), complement factor B (CFB) gene mutations; ③ TMA caused by metabolic-related gene defects; ④ Coagulation-related genes, such as plasminogen and thrombomodulin gene mutations And so on, can lead to the occurrence of hereditary TMA. There are 5 types of acquired: ① TMA caused by reduced ADAMTS13 activity may be related to anti-ADAMTS13 antibody; ② TMA caused by anti-complement related antibodies (anti-factor H antibody); ③ TMA caused by Shiga toxin, which is common in children TMA (called HUS in the past); ④ Drug toxicity leads to TMA (such as vascular endothelial factor inhibitor); ⑤ TMA related to drug immune response.

Kidney damage in SLE can be directly caused by thrombotic microangiopathies, called lupus thrombotic microangiopathies (lupus TMA).

The vast majority of lupus TMA coexists with immune complex LN (such as type IV and type IV+V LN), and a small number of SLE kidney biopsies can only show renal TMA without immune complex LN.

The mechanism of 3SLE combined with TMA is not clear about the mechanism of SLE combined with TMA, but more and more TMA related studies have found that the formation of anti-ADAMTS13 antibody and the decrease of anti-ADAMTS13 activity lead to the formation of von Willebrand factor (vWF) aggregates , And then combine with platelets, causing platelet reduction, leading to the occurrence of TMA.

The pathogenesis of SLE combined with TMA is also related to the production of anti-ADAMTS13 antibody and the decrease of ADAMTS13 activity.

At the same time, antibody-mediated activation of the complement pathway is also involved, including the decrease in the activity of factor H and factor I, and the activation of the complement system, thereby forming a membrane attack complex, leading to the occurrence of TMA.

In addition, CD4 and CD25 regulatory T cells play an important role in immune tolerance.
The decrease in the number of regulatory T cells in patients with SLE and TMA is related to the occurrence of TMA, and small-scale clinical trials believe that CD4, CD25+ regulatory T cells Cells are related to the severity of the disease.

4 Pathological manifestations of SLE combined with TMA.
The pathological type of LN recommends the 2003 International Society of Nephrology/Renal Pathology (ISN/RPS) classification criteria.
In 2018, the RPS working group reviewed the pathological types of LN and NIH renal tissue activity (AI) and chronicity.
The index (CI) scoring standard proposes revision opinions, suggesting the addition of two special pathological types of lupus podocyte disease and lupus TMA.

Lupus TMA can involve renal interstitial arterioles (arterioles, interlobular arteries) and glomeruli.

Acute lesions of vascular TMA manifested as renal interstitial arteriole endothelial cell proliferation, intimal mucoid edema, thrombosis, lumen stenosis or atresia, and vascular wall necrosis.
Immunofluorescence showed no immune deposits on the vascular wall.

Glomerular TMA showed vascular loop endothelial cell proliferation and swelling, microthrombosis, broken red blood cells were seen in the loop; electron microscopy showed that the endothelium was loose and widened, and amorphous material was seen in the endothelium, and there was no electronic compact under the endothelium.

In the chronic phase of TMA, intimal fibrous hyperplasia of interstitial arterioles, "onion skin" changes in endothelium, stenosis or atresia of lumen; glomerulus or segmental sclerosis, capillary loop basement membrane thickening, It is a "dual track" sign.

When the glomerular TMA and LN coexist, it is easy to miss the diagnosis, which requires light microscopy combined with electron microscopy to identify them.

5SLE combined with TMA diagnosis TMA is a group of syndromes, currently there is no high specific diagnostic criteria.
Therefore, the diagnosis of SLE combined with TMA requires comprehensive judgment by clinical manifestations and objective examination indicators.

Thrombotic microangiopathic hemolytic anemia and thrombocytopenia that cannot be explained by other reasons in SLE patients are the two main criteria, accompanied by fever, nervous system involvement, kidney involvement, and reduced ADAMTSl3 activity.
One of the secondary criteria, and needs to be excluded Other causes of thrombocytopenia, such as autoimmune hemolytic anemia, diffuse intravascular hemolysis, tumors, eclampsia, drug poisoning, stem cell transplantation, and malignant hypertension.

Among them, ADAMTSl3 activity is significantly reduced (<5%-10%) and H factor detection can support diagnosis and help determine the cause of the disease.
However, because of the long inspection cycle, it is not possible to rely on and wait for the result of ADAMTSl3 activity to initiate the treatment plan.

In addition, renal pathological biopsy can also confirm the presence of kidney TMA, but it is necessary to determine whether the kidney biopsy can be tolerated according to the actual state of the patient.

Therefore, for SLE combined with TMA, it is necessary to comprehensively judge the patient's clinical manifestations and various laboratory indicators, and initiate treatment as soon as possible.

6 Lupus TMA treatment For patients with lupus TMA, if renal function is progressively decreased or severe renal insufficiency requires renal replacement therapy, in addition to traditional high-dose MP intravenous shock and immunosuppressive therapy, plasma exchange (PE) or double plasma exchange should be combined (DFPP) treatment.

Those with positive serum APL or with APS should use anticoagulants and hydroxychloroquine (HCQ).

The treatment of lupus TMA lacks clinical research evidence, and guidelines issued by different international organizations have different recommendations.

The KDIGO guidelines recommend PE for SLE-related TTP, the American College of Rheumatology (ACR) recommends PE for lupus TMA, and the European Union Against Rheumatism (EULAR)/ERA-EDTA guidelines emphasize anticoagulation, immunosuppression and HCQ.

Figure: 2020 KDIGO LN and thrombotic microangiopathy (TMA) diagnosis and treatment Figure 7 The prognosis of SLE combined with TMA is poor! The overall mortality rate of SLE combined with TMA is very high.
The main cause of death is single or multiple organ dysfunction caused by SLE combined with TMA.
The most important cause of other deaths is infection, especially lung infection.

TMA is a serious and rare complication of lupus.
The condition is severe and the prognosis is poor.
Currently, there is no clear diagnostic standard.
It can only be comprehensively judged by typical clinical manifestations and laboratory tests.

As research progresses, more and more monitoring methods and treatments have improved the prognosis.

However, more clinical studies are still needed in the future to gradually improve the sensitivity and specificity of diagnosis, and to discover more treatment avenues.

Reference materials: [1]Guidelines for the diagnosis and treatment of lupus nephritis in China[J].
Chinese Medical Journal,2019(44):3441-3455.
[2]Diagnosis, treatment and prognosis of systemic lupus erythematosus with thrombotic microangiopathy[J].
Chinese Journal of Rheumatology, 2018,22(9):642-645.
[3]Improving Global Outcomes(KDIGO)Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation.
Transplantation.
2020 Apr;104(4): 708-714.