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For medical professionals only
JASN Case Challenge!
The immune system can cause kidney damage
through countless processes.
Indirect and direct mechanisms can lead to acute kidney injury (AKI), the development of chronic kidney disease, and even kidney failure
.
Immunosuppressants can be used clinically to attenuate these immune processes
.
Recently, JASN published a literature summarizing the precautions of commonly used immunosuppressants and sorting out 3 classic cases for everyone to learn and discuss
.
Cyclophosphamide
Cyclophosphamide is a predominantly used immunosuppressant in glomerular diseases and is an inactive prodrug
.
Cyclophosphamide has demonstrated therapeutic efficacy in minimal lesions, membranous nephropathy, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), anti-GBM disease, and lupus nephritis.
However, cyclophosphamide also has adverse reactions that cannot be ignored, such as bone marrow suppression, infection, bladder injury, malignant tumors, infertility, etc
.
Diagnosis and treatment
.
Patients have decreased renal function, serum creatinine level (Scr) of 2.
0 mg/dL, urinalysis shows protein 2+, protein-to-creatinine ratio of 2.
1 g/mg, and red blood cells (RBCs) of 25 cells/HP
.
In addition, the patient had an antinuclear antibody (ANA) titer of 1:320 and a positive double-stranded DNA antibody (anti-dsDNA) test
.
Renal biopsy shows grade IV lupus nephritis with crescents
.
She began receiving the National Institutes of Health (NIH) cyclophosphamide regimen
.
One month later, before receiving the next cyclophosphamide treatment, the patient's white blood cell (WBC) count dropped from 8400/μL to 4500/μL
.
Question 1: What is the next step in cyclophosphamide administration?
A.
Continue according to the NIH protocol with the cyclophosphamide dose unchanged;
B.
Use of granulocyte colony-stimulating factor (G-CSF);
C.
Half of the planned dose of cyclophosphamide given;
D.
Switch to mycophenolate mofetil (MMF).
Preparing measures to deal with adverse reactions in advance is a key part of clinical treatment, so the answer to one is coming out (the best answer to question 1 is C).
Toxicity mitigation measures:
.
Myelosuppression: half dose (reduced by one-third or less in dialysis patients) if WBC count < 5000/microliter or age > 65 years or eGFR < 40 mL/min/1.
73m2
。 If the WBC count < 3000/microliter, the drug
is discontinued.
Bacterial and viral infections: appropriate dose adjustment, simultaneous infection prevention and vaccination
.
Gonadal toxicity: cryopreserved eggs or sperm
should be considered.
antimetabolite
The 2 main antimetabolites used in kidney disease are mycophenolate mofetil (MMF) and azathioprine
.
MMF
.
The efficacy
of MMF in induction and maintenance therapy of lupus nephritis has been demonstrated.
In addition, it has been used to induce remission of refractory nephrotic syndrome in minimal change nephropathy and FSGS, as well as C3 glomerulopathy; However, efficacy remains to be confirmed
in randomized controlled trials.
A complete blood count is recommended 1-2 weeks after the start of MMF, with monitoring
every 6-8 weeks.
Azathioprine
Azathioprine is an analogue of 6-mercaptopurine, and a dose reduction is usually recommended in the case of oliguuria / acute tubular injury
.
Xanthine oxidase inhibitors (allopurinol and febuxostat) should be avoided during azathioprine use, as 6-mercaptopurine carries the risk of accumulation by slowing elimination, leading to severe toxicity
.
Calcineurin inhibitors
The development of traditional calcineurin inhibitors (CNIs) – tacrolimus and cyclosporine (both from fungi) – has provided tremendous benefits
not only in the field of transplantation but also in glomerular disease.
It is mainly used in
minimal lesions, membranous nephropathy and FSGS.
Both CNIs are metabolized by the CYP3A system and excreted via the biliary pathway (liver dysfunction prolongs the half-life of both drugs).
Monitoring tacrolimus immediate-release agents and cyclosporine
with 12-hour troughs is recommended.
Dose changes for both CNIs are usually reflected within 2-3 days
.
For tacrolimus, the dose of 0.
5 to 1.
0 mg per dose should be adjusted according to the trough concentration; cyclosporine varies from 25 to 50 mg
.
Complement inhibitors
Question 2
A 45-year-old man with a history of type 2 diabetes was admitted to hospital
with nausea and vomiting.
He has AKI with an Scr of 4.
5 mg/dL
.
In addition, he has anemia (hemoglobin 6 g/L) and thrombocytopenia (platelet count 90× 103/ml), and the peripheral blood smear shows schistocytes
.
Renal biopsy shows thrombotic microangiopathy, and eculizumab is
planned.
A) trimethoprim/sulfamethoxazole B) angiotensin-converting enzyme (ACE) inhibitor
C) amoxicillin
D) hydroxyurea
The role of the complement system in kidney disease is increasingly recognized, so multiple therapies
targeting various pathways are being developed.
Ideally, patients should receive vaccines against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b, as well as prophylactic antibiotic coverage
against Neisseria meningitidis before starting treatment.
Therefore, the best answer to question 2 is C
.
Corticosteroids
The two most commonly used steroid preparations in kidney disease include oral prednisone and intravenous methylprednisolone
.
Corticosteroids are used in induction and maintenance regimens
of crescent/rapidly progressive forms of minimal lesions, FSGS, AAV, anti-GBM disease, lupus nephritis, C3 glomerulopathy, and IgA nephropathy.
Adverse effects of corticosteroids are related to the dose and duration of treatment and are multisystem in nature, such as metabolic and endocrine, infectious, musculoskeletal effects, gastrointestinal, psychiatric, and ocular (cataract) abnormalities
Rituximab
Rituximab is a classic anti-CD20 therapy
.
Rituximab has an elimination half-life of 3 weeks (may vary depending on the disease) and persists in circulation for 3-6 months
.
Rituximab has been approved for the treatment of AAV for the treatment of membranous nephropathy, minimal lesions, lupus nephritis, and cryoglobulinemia
.
The following are the adverse reactions associated with rituximab: 1.
Infusion reactions:
usually encountered during the first infusion, rarely during administration
.
It can be relieved
by pretreatment with acetaminophen, antihistamines, and steroids.
2.
Delayed neutropenia: defined as absolute neutrophil count < 1.
0×109/L, more than 1 month after the last rituximab infusion and spontaneous recovery, when other causes are excluded
.
It is reported that it appears 38-175 days after the end of treatment and lasts 5-77 days
.
Immunomodulatory drugs
Intravenous immunoglobulin (IVIG) is used not only to prevent infection and alloimmunity, but also for immune regulation
.
The elimination half-life of IVIG is 14-24 days; High metabolic states lead to a shortened
half-life.
Adverse effects of IVIG are classified as immediate (infusion reactions, arrhythmias and hypotension, skin diseases, transfusion-related lung injury) and delayed (neurologic disorders, thrombotic manifestations, AKI, IVIG-related hemolysis).
Immunosuppression in special populations
Question 3
.
She is receiving tacrolimus, MMF, and low-dose corticosteroids as part of
her rejection prevention medication.
The SCR was 1.
2 mg/dL and the urine albumin-to-creatinine ratio was within the normal range
.
Question 3: Which of the following is most correct at this point?
A.
Pregnancy is absolutely contraindicated, as the risk to the mother is considered high
.
B.
The drug will remain unchanged
during pregnancy.
C.
MMF should be discontinued and replaced
with azathioprine prior to conception.
D.
Tacrolimus increases the risk of gestational diabetes mellitus and should be discontinued
.
E.
Renal biopsy is required prior to conception to exclude chronic renal transplant rejection
.
An analysis by the UK Pregnancy Registry showed that pregnancy was not associated with
decreased renal function in kidney transplant recipients with a pre-pregnancy Scr < 150 μmol/L.
There is no such recommendation for autoimmune kidney disease, but it should be directed at the disease quiescent phase or minimal disease activity in the months prior to conception
.
Cyclophosphamide is absolutely contraindicated in the first trimester of pregnancy, as its use in humans is associated with
severe embryonic disease.
MMF and MPA are teratogenic in animal models, and there is growing evidence to support their teratogenicity
in humans.
Patients who wish to become pregnant should discontinue MMF
at least 6 weeks before conception.
Women planning pregnancy are advised to switch from MMF to azathioprine as early as possible
.
The best answer to question 3 is (C).
summary
In the treatment of immune-mediated kidney disease, appropriate use of immunosuppressants is important
.
Drug selection, initiation time, intensity and duration of treatment are essential for maintaining organ function and life, and are also important
for mitigating treatment-related adverse effects.
The main challenges are to discern when to start immunosuppressive therapy, to identify patients who should not be initiated, and the most appropriate time
to stop immunosuppressive therapy.
Where to see more rheumatology clinical knowledge? Come to the "Doctor's Station" and take a look 👇 at the references:
[1] Sam Kant.
Principles of Immunosuppression in the
Management of Kidney Disease: Core
Curriculum 2022,Am J Kidney Dis.
80(3):393-405
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