KDIGO Guidelines For Glomerular Diseases

Glomerular diseases are a group of diseases involving the glomerulus of both kidneys and their etiology, pathogenesis, pathological changes, clinical manifestations, course of disease, and prognosis is different. In 2021, KDIGO released the first guidelines on glomerular diseases, involving 12 glomerular diseases. However, almost two years have passed since the guideline was issued, and many new developments have been made in the study of glomerular diseases, but these advances have not been included in the guideline.

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In June 2023, experts commented and recommended each glomerular disease involved in the KDIGO guidelines by evaluating existing evidence and combining clinical practice, and adding some new content. These latest research results and expert consensus can help doctors make more accurate diagnoses and treatment decisions, and at the same time provide better medical services for patients.

a membranous nephropathy

The recommendations for membranous nephropathy (MN) in the 2021 KDIGO guidelines for glomerular diseases are derived from the 2012 guidelines for MN. The importance of anti-phospholipase A2 receptor (PLA2R) antibodies for the diagnosis of MN and the therapeutic role of recently updated B cell depletion therapies in MN are highlighted. This chapter is divided into diagnosis, risk prediction, treatment, and special cases of MN.

1 diagnosis

① KDIGO guidelines suggest that for patients with nephrotic syndrome who are positive for anti-PLA2R antibodies, renal biopsy is not required to confirm the diagnosis of MN.

Pro tip: This is a surprising stance. Although anti-PLA2R antibody testing has an important place in the diagnosis of MN and its availability is increasing, renal biopsy remains the gold standard for MN diagnosis. This is because the anti-PLA2R antibody can only accurately diagnose primary MN, but cannot identify secondary MN and whether there are other pathological injuries in the kidney. Renal biopsy can not only identify secondary MN but also identify specific pathological conditions in the kidneys of MN patients, such as chronic interstitial fibrosis and tubular atrophy. Renal biopsy should be considered for patients who received MN treatment due to positive anti-PLA2R antibody, but the disease course/condition did not improve as expected.

In general, experts recommend that for patients with positive anti-PLA2R antibodies, MN treatment should be started immediately, and renal biopsy should be performed if there is no response or poor response to treatment.

② KDIGO guidelines suggest that MN patients should be evaluated for intrarenal/extrarenal symptoms regardless of whether the patient is positive for anti-PLA2R or THSD7A.

Expert Tip: This opinion is very pertinent. Other diseases or infections occasionally lead to anti-PLA2R or THSD7A positivity, while these diseases may lead to MN, i.e. secondary MN. In clinical practice, doctors should pay attention to whether patients develop infection because the treatment regimen of MN includes immunosuppression, and once immunosuppressive treatment is received, the infection will be exacerbated.

2 Risk prediction

The KDIGO guidelines suggest that in MN patients, biomarkers and clinical indicators should be used to assess the risk of renal failure.

Expert tips: The existing methods are insufficient for the risk prediction of MN, and cannot fully predict the course and prognosis of patients. Recent studies have found that the cornerstone of risk prediction in MN patients is still proteinuria and estimated glomerular filtration rate (eGFR), but the anti-PLA2R antibody titer test can replace traditional renal biopsy results, that is, to avoid repeated renal biopsy. Several other studies have found that antibody levels (immune remission) precede (≥6 months) decline in proteinuria levels. However, there are large individual differences in the peak value of anti-PLA2R antibodies in different patients, so there is no corresponding standard. However, risk prediction can be made by the change in the titer of the anti-PLA2R antibody. Patients with elevated antibody levels had a higher risk of long-term disease progression than those with reduced antibody levels.

Overall, for clinicians, anti-PLA2R antibody levels should be included in the risk prediction of MN and together with other traditional risk factors such as eGFR, urinary albumin excretion rate, and serum albumin level, predict disease progression in MN patients risk. It is worth noting that the focus of anti-PLA2R antibody level monitoring should be the trend (increase/decrease), rather than the establishment of a threshold (such as 50RU/ml).

3 treatments

① KDIGO guidelines recommend that MN patients with at least one risk factor for disease progression should receive rituximab/cyclophosphamide and alternate glucocorticoid therapy for 6 months; or receive calcineurin inhibitor ( CNI) treatment for a period of ≥6 months, the choice of treatment depends on the risk assessment value.

Expert Note: Current evidence suggests that immunosuppressive therapy should be administered to achieve immune and clinical remission. However, when to start the above treatment, and which drug to choose remain difficult. Alkylating agents combined with glucocorticoids are very effective and the only therapy proven to preserve renal function in long-term follow-up. Other anti-CD20 drugs such as rituximab can also effectively relieve immune and clinical indicators, but they also have a higher risk of adverse events, which limits their use by the population. CNI can reduce proteinuria, but its effect on immune relief is poor. After stopping the drug, the proteinuria level and anti-PLA2R antibody titer can rebound.

② KDIGO guidelines suggest that for MN patients with normal eGFR and no nephrotic syndrome, immunosuppressive therapy is not required unless there is a risk factor for disease progression or serious complications, such as acute kidney injury (AKI), infection, Thromboembolism.

Pro tip: This is a somewhat subjective recommendation. As mentioned above, deciding whether a patient receives immunotherapy should not pass a single time point, but should observe changes in anti-PLA2R antibody titers. For some patients with anti-PLA2R antibody titer > 50 RU/ml, if the titer continues to decline, immunosuppressive therapy may not be accepted.

③ KDIGO guidelines suggest that longitudinal monitoring of anti-PLA2R antibody levels 6 months after the start of treatment may help assess the treatment response of MN patients and can be used to guide treatment adjustments.

EXPERT TIP: This is one of the most important updates in MN treatment, as changes in anti-pla2r antibody levels precede changes in clinical parameters and help to adjust treatment for patients.

4 special circumstances

Experts agree with the recommendations on MN recurrence in the KDIGO guidelines, but for refractory MN, it is suggested that the goals of treatment should include changes in eGFR, proteinuria levels, serum anti-podocyte antibodies, and anti-PLA2R antibodies. If the above indicators do not change or If the disease worsens, the existing treatment plan should be reconsidered. If the patient has no previous antibody indicators, but his kidney disease has not improved or worsened, it can be considered as a refractory MN. At this time, immunosuppressants can be used as a second-line alternative treatment. However, in some cases, even in patients with stable eGFR, alkylating agents can be used as a second-line treatment option.

In terms of kidney transplantation, there are currently no best recommendations regarding the timing of kidney transplantation. Kidney transplant recipients with higher antibody levels, however, had a higher risk of MN recurrence compared with those with lower antibody levels. If the antibody level of the patient tends to increase, the risk of MN recurrence may further increase. In general, there are large individual differences in the risk of MN recurrence in kidney transplant recipients.

KDIGO guidelines recommend that patients with MN and nephrotic syndrome should receive prophylactic anticoagulant therapy to prevent venous thrombotic events (VTE).

Expert tip: MN patients have a higher risk of VTE than other nephrotic syndrome patients, especially when serum albumin <2.9g/dL. Therefore, physicians should pay attention to serum albumin in MN patients. In addition, despite the increasing use of direct oral anticoagulants, they have not been clinically tested in the prophylaxis of nephrotic syndrome-associated VTE, and available data suggest that they should not be used. Finally, the recommended doses of anticoagulants are those used to treat VTE.

2. Nephrotic syndrome in children

Recommendations for nephrotic syndrome in children can be divided into diagnosis and treatment.

1 diagnosis

The KDIGO guidelines suggest that the diagnosis of nephrotic syndrome in children should be consistent with relevant clinical manifestations, such as albumin <3.0g/dL.

Expert tip: According to the 2012 KDIGO guidelines, maintenance nephrotic syndrome is defined as albumin ≤ 2.5g/dL. However, there is no relevant evidence in recent years to suggest that this definition should be changed. Therefore, this definition is still controversial. Currently, it is unclear what renal pathology is in children with nephrotic-level proteinuria and lower levels of albuminemia (2.6 to 2.8 g/dL), or whether they will respond to treatment.

2 treatments

① KDIGO guidelines recommend that children with kidney disease receive glucocorticoids for 8 weeks (daily for the first 4 weeks; one day for the next 4 weeks) or 12 weeks (daily for the first 6 weeks; one day for the next 6 weeks) treat.

Expert Tip: Glucocorticoid treatment for 8 weeks or 12 weeks is related to the individual status of the child. In children who enter remission rapidly (≤7 days) or who are at higher risk of developing glucocorticoid complications such as obesity, diabetes, or psychiatric disorders, 8 weeks of treatment is associated with fewer side effects than 12 weeks of treatment and Little effect on long-term disease course.

② KDIGO guideline recommendation: For children who are taking glucocorticoids every other day, with frequent relapses or steroid-dependent nephrotic syndrome, it is recommended to give 0.5 mg/kg glucocorticoids daily for 5-7 days during upper respiratory tract infection or other infections. to reduce the risk of recurrence.

Expert tip: Recent evidence suggests that corticosteroids should not be used during upper respiratory infections. The traditional concept is that giving children glucocorticoids during upper respiratory tract infection can effectively reduce the risk of renal disease recurrence. However, in 2022, a large, well-documented controlled clinical study, the PREDENOS 2 study, will show that glucocorticoid therapy during upper respiratory tract infection does not reduce the risk of renal disease recurrence in children.

③ KDIGO guideline recommendation: Klonopin or tacrolimus is recommended as the initial second-line treatment for children with steroid-resistant nephrotic syndrome.

Expert Tip: I basically agree with the above suggestions, but for institutions that have the ability to perform genetic testing, genetic testing should be performed on children before medication. It is reported that 11% to 30% of children with steroid-resistant nephrotic syndrome have a single gene variation. For these children, immunosuppressants have little effect on them but can increase the risk of adverse events.

How does Cistanche treat kidney disease? 

Cistanche is a traditional Chinese herbal medicine that has been 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. Cistan may help treat kidney disease 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. Cistanche's antioxidant properties 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 inflammatory pathways, thus alleviating inflammation in the kidneys.

Furthermore, cistanche has been shown to have immunomodulatory effects. In kidney disease, 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 tub epith 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 impaired 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. Cistanche has been shown to have protective effects on the liver, heart, and blood vessels, which are commonly affected in 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 that has been 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. Moreover, cistanche has beneficial effects on other organs and systems, making it a holistic approach to treating kidney disease.

References:

1. Beck LH Jr, Ayoub I, Caster D, et al. KDOQI US Commentary on the 2021 KDIGO Clinical Practice Guideline for the Management of Glomerular Diseases. Am J Kidney Dis. 2023 Jun 9:S0272-6386(23)00591-7.