Focal segmental glomerulosclerosis, referred to as FSGS, is a relatively common group of primary glomerular diseases. It is defined as a sclerotic disease involving part of the glomerulus and part of the capillary collaterals of the glomerulus. What are the advances in the evaluation and treatment of refractory focal segmental glomerulosclerosis in humans?
I. Remission and prognosis of FSGS
The clinical manifestations of FSGS are mostly seen in nephrotic syndrome, which accounts for about 55% of the cases, and is a refractory glomerular disease. Most of them are hormone-resistant and therefore have poor healing. Serum creatinine doubles within four years in 50% of hormone-insensitive patients. However, if clinical symptoms can be relieved after hormone therapy, less than 15% of patients develop end-stage renal failure after five years, and conversely, half of patients develop end-stage renal failure after six years, which shows that the healing of FSGS is closely related to the efficacy of hormones.
After hormone therapy, the rate of people whose clinical symptoms are relieved finally develop renal failure is much lower than those whose clinical symptoms are not relieved, so what is the reason for this phenomenon?
II. Mechanism of glucocorticoid action in renal disease
The appearance of this phenomenon is related to the mechanism of action of glucocorticoids in renal disease. The mechanism of action of hormones includes suppression of immunity and inflammation and blockage of antibody production, clearance and closure of antibodies already produced, blocking the action of inflammatory mediators and inhibition of aldosterone and antidiuretic hormone.
Detailed links of action include direct genomic and indirect genomic actions. The direct genomic effect is the binding of the hormone to the corresponding receptor on the cell membrane, forming the hormone receptor complex GCR, which is transferred to the nucleus and binds to the glucocorticoid response element GRE, a specific high-affinity DNA sequence, and the resulting conjugate can affect gene transcription and RNA protein translation processes in the nucleus. Direct genomic effects result in a dose-dependent clinical effect, meaning that low-dose responses are slow to take effect, often over several hours and days.
Indirect genomic effects are the basis for high-dose shock therapy. The so-called high dose is often greater than 200 mg of total prednisone, and the clinical effect is rapid, with an onset of action in seconds to minutes.
Whether it is direct genomic effect or indirect genomic effect, the effect of hormone is a cell membrane-mediated biochemical effect, which means that hormone binds to the corresponding cell membrane receptors and initiates a series of intracellular effects related to gene regulation through the second messenger mainly calcium ion, IP3, cAMP and PKC signaling pathways.
III. Therapeutic principles of hormones
According to the mechanism of hormone action, the clinical principles of hormone administration are 16 words: starting adequate dose, slow dose reduction, long-term maintenance, and joint anti-exemption. The initial adequate dose is the dosage of prednisone 1 mg?d-1?kg-1, and the duration is 8-12 weeks. Slow dose reduction is the reduction of 10% of the original treatment dosage every two weeks after the full dosage. Long-term maintenance is a reduction to 20 mg per day for 2-4 weeks until the minimum effective dose of 10 mg per day, which is 6-12 months. When refractory kidneys such as FSGS exhibit hormone dependence or resistance, these patients should be advocated for combined anti-exemption.
The clinical response of patients receiving hormone therapy is variable. They can be divided into three types, first hormone sensitivity, second hormone dependence, and third hormone resistance. Hormone sensitivity refers to the remission of clinical symptoms within 8 weeks of medication; hormone dependence refers to the relapse of hormone reduction to a certain degree; the latest concept of hormone resistance is the ineffective application of hormone in sufficient amount for 6 months and still, it is called hormone resistance. The different responsiveness to hormone therapy is related to the molecular basis of the disease, clinical factors and the type of pathology.
After understanding the mechanism of action of glucocorticoids in kidney disease and the principles of hormone therapy, what is the pathogenesis of glucocorticoid resistance?
IV. Pathogenesis of glucocorticoid resistance
The pathogenesis of glucocorticoid resistance is discussed in three aspects: molecular mechanism, clinical and pathological types. Firstly, the molecular mechanism mainly occurs at the hormone receptor, including the pre-receptor level, the receptor level and the interaction between the hormone receptor and other proteins.
(i) Molecular mechanisms of hormone resistance
Pre-receptor level, referring to the intervening effects of inflammatory factors and abnormal hormone metabolism. Clinical studies have confirmed that interleukin-2 and interleukin-4 can induce hormone resistance in T cells, and interleukin-13 can reduce the binding capacity of hormone receptors in monocytes. cd28 can counteract the inhibition of c-fos expression in CD4+ cells by hormones. Therefore, if these cytokines are over-expressed, they will affect the binding capacity of hormone receptors and decrease them, which will eventually lead to the clinical manifestation of hormone resistance.
Also in terms of abnormal hormone metabolism, MDR-1 is a diverse drug resistance gene, which is the gene encoding P-glycoprotein. Also called ATP-dependent drug efflux pump, its main role is to transport lipophilic drugs outside the cell, so if MDR-1 expression is too high, there will be intracellular drug concentration lower than the therapeutic concentration, resulting in a decrease in the amount of intracellular hormones and a decrease in hormone effects. Cyclosporine, on the other hand, can inhibit the expression of P-glycoprotein and, therefore, can be used in the treatment of hormone-resistant renal syndrome.
The glucocorticoid receptor gene is named NR3C1 receptor. NR3C1 can produce four isoforms by shearing, and the main physiological effects are hormone receptor α and hormone receptor β. Hormone receptor α can bind to hormone and then nuclear translocation binds the gene to exert hormonal effects. Hormone receptor beta, however, can inhibit the activity of endogenous hormone receptor alpha. It does not bind hormones and does not activate gene translocation of hormone effectors. If a genetic variant occurs at the receptor level, the clinical manifestation is an increase in blood cortisol concentration but a clinical absence of Cushing’s syndrome. The disease is called primary glucocorticoid resistance syndrome.
In vitro experiments have shown that the combination of interleukins 2, 4 and 8 and tumor necrosis factor alpha with hormones induces the formation of hormone receptor β. Some of the hormone receptor β is hormone-independent and binds to glucocorticoid reflective elements. Another part of the formed hormone receptor β binds to the glucocorticoid reflecting element as a heterodimer with hormone receptor α, thus inhibiting the activity of hormone receptor α. This theory is also supported by clinical studies. In 15 patients in each of the hormone-sensitive, resistant and relapsed groups, the expression of hormone receptor α and receptor β in renal tissue was examined, and it was seen that the expression of α receptor was lower in both the hormone-resistant and relapsed groups than in the hormone-sensitive group, while the expression of β receptor was higher in both groups, and there was a statistical difference.
The third aspect of the molecular mechanism of hormone resistance is the interaction between the receptors of hormones and other proteins. Cytokines are able to induce activation and transitional expression of the transfer factor AP-1, then AP-1 interacts with hormone receptors and affects the binding of hormone receptors to hormone reflective elements, and also STATS has a similar action with hormone receptors. Thus, it also interferes with the interaction of hormone receptors with glucocorticoid response elements. Therefore, the current indicators of patients with hormone resistance that can be predicted at the molecular level are, serum interleukin-1β, tumor necrosis factor alpha, and increased serum concentrations of these indicators the patient is likely to be of the hormone resistant type. In addition, the fragmentation of IgG secretion can also respond to the patient’s response to hormone therapy and the remission of the disease.
(ii) Clinical factors of hormone resistance
The second aspect of hormone resistance is due to clinical factors.
(1) Irregular hormone therapy, insufficient dose, or too rapid reduction of dose, or poor compliance from the patient’s side and irregular dosing.
(2) Inappropriate use of hormones, such as oral application of glucocorticoids in patients with severe edema or prednisone in patients with hepatic impairment. Another thing that is very easy to ignore is the interaction between drugs.
(3) Some comorbidities of the nephrotic syndrome also affect the efficacy of hormones, the most common being infection. Secondly, because the nephrotic syndrome is in a hypercoagulable state, it is prone to embolism of blood clots, which also affects the efficacy of hormones.
(4) Hypoproteinemia and malnutrition.
(5) Renal failure. Clinically, a relatively rare primary glucocorticoid resistance syndrome can also be manifested, and about 30 cases have been reported so far.
V. Pathological type and prognosis
The type of pathology is the most critical factor affecting the healing of FSGS. According to the distribution characteristics of foot cell injury and segmental sclerosis, FSGS can be divided into the following five subtypes, non-specific type, portal type, cellular tip type and collapsed type.
(1) Non-specific type: It is characterized by hyperplasia of thylakoid cells and thylakoid stroma; balloon adhesions and glassy lesions are more common; podocytes can have hypertrophy and this type is more common. It is consistent with the general clinicopathological features of FSGS, but it may also be the result of the development of the other four types, and this type has a poorer healing.
(2) Apical type: This type is characterized by lesions mainly in the urinary pole, foot cell hyperplasia with large (please check PPT), common foam cells, and spherical sclerosis may occur. This pathological type is the best healing type of FSGS, with better efficacy of hormonal therapy and slower development.
(3) Portal type: Its pathology is characterized by sclerotic capillary collaterals mainly distributed near the glomerular pole, often accompanied by glass-like lesions, glomerular hypertrophy, and foot cell hyperplasia is uncommon. This type of pathology also has a poor healing process. It should be noted that this type needs to be differentiated from secondary FSGS and hypertensive nephropathy.
(4) Cellular type: The pathology is characterized by cellular hyperplasia, including focal hyperplasia of thylakoid cells, endothelial cells and podocytes. In particular, the hyperplasia of podocytes is hypertrophic, the vacuolar deformation is very obvious, and pseudocrescent can be formed, and any part of the glomerulus can be involved. The progression of the histological type of lesion is very fast, and glomerular adhesions and sclerosis can gradually appear.
(5) Collapsed type: Its pathology is characterized by collapse of capillary collaterals and hyperplasia of pedunculated cells. The main difference between it and the cellular type is the lack of proliferation of endothelial cells and thylakoid cells, and balloon adhesions and vitelliform changes are uncommon. This pathological type progresses rapidly and may gradually develop balloon adhesions and spherical sclerosis.
The main indicators of poor prognosis in pathology are the proportion of spherical sclerosis, the degree of podocyte hyperplasia and the proportion of interstitial fibrosis in the kidney, so the prognostic relationship according to the pathological type is smoothly arranged from mild to severe as apical, hilar, nonspecific, cytosolic and collapsed type. The apical type responds relatively well to hormone therapy and heals better. The cellular and collapsed types progress quickly and have the worst healing with heavy clinical manifestations. The hilar and non-specific types are in between.
After having an understanding of the pathological types and prognosis of focal segmental glomerulosclerosis, how to treat FSGS?
VI. Treatment of FSGS
The most common clinical manifestation of FSGS is nephrotic syndrome, so the preferred therapeutic drug is glucocorticoid. The now accepted principle of glucocorticoid application is that one must receive prednisone therapy 0.5-2 mg?d-1?kg-1 for a duration of 6 months. If the clinical dosage is greater than 60 mg per day, a change to 0.5 mg?d-1?kg-1 for 3 months is recommended after 3 months of administration. However, it must be noted that the total glucocorticoid therapy should be of a long duration, not less than 6 months. Second, FSGS is mostly hormone-dependent or hormone-resistant, so other immunosuppressive agents need to be combined. Cyclosporine is recognized to be effective in lowering proteinuria, and the recommended daily dosage is 5-6 mg/kg. However, the characteristic of cyclosporine is that relapse often occurs after dose reduction, especially after discontinuation of the drug in 75% of patients, and long-term low-dose maintenance is required. Other possible applications are cyclophosphamide, azathioprine and benzodiazepine. In addition, for renal transplant patients, plasma replacement or protein adsorption can be indicated for FSGS relapse. It is currently believed that ACEI and AIIR can reduce proteinuria and delay the progression of renal failure, so they can also be used in the treatment of FSGS. These views are based on a large amount of clinical evidence-based medicine, which are described below.
The first is the long course regimen, prednisone 0.5-2 mg?d-1?kg-1, with a complete remission rate of less than 30% if the course is less than 2 months, and more than 30% if the course is more than 5 months.
If hormone-resistant FSGS is present, a combination of cytotoxic agents after intravenous methylprednisolone is recommended, and the combination can result in a remission rate of 60%. The combination of cytotoxic agents includes CTX, which can be applied orally or intravenously. The recommended dose is 2 mg?d?kg-1 orally, with better intravenous efficacy. 0.6-1 g once a month is recommended. 0.1-0.2 mg?d-1?kg-1 of nitrogen mustard phenylbutyrate can also be used, but these cytotoxic drugs must be used in conjunction with hormones.
CTX is a frequent combination drug in hormone-resistant patients with FSGS. A clinical study showed that in 54 hormone-dependent or hormone-resistant patients, the complete remission rate was 20.4% and partial remission reached 14.8% in seven years of hormone application alone. If combined with CTX, the complete remission rate reached 26.7% and partial remission rate reached 20%. Not only does the combination of CTX increase the remission rate, but more importantly, after seven years of follow-up, 1/4 of the patients on hormone alone progressed to end-stage renal failure, whereas only 10% of the patients on cyclophosphamide combination progressed to end-stage renal failure.
Cyclosporine is also a more effective treatment for FSGS. The total course of treatment should be greater than one year, with an initial dose of 3-5 mg?d-1?kg-1, which can be reduced to 3.5 mg?d-1?kg-1 after six months. Most of them are effective within one month and have a rapid onset of action, but there are many relapses after dose reduction, so it is recommended that the course of treatment can be extended in the absence of contraindications. Up to 2 to 3 years.
In another five-year follow-up study, 51 patients with FSGS renal syndrome were treated with prednisone alone or in combination with azathioprine or cyclosporine 3 mg?d-1?kg-1 in 25 of them. 26 control subjects were not treated with immunosuppressive drugs. The results of the study showed that the remission rate was significantly higher in the group treated with immunosuppression than in the group not receiving immunosuppression. It was 75% and 0.7%, respectively, which was statistically significant. Secondly, it was the remission rate of hormone application alone was 62.5%, while the remission rate in combination with azathioprine was 80% and in combination with cyclosporine was 85.7%, therefore, the combination of hormone and cyclosporine or azathioprine is more recommended for the treatment of FSGS nephrotic syndrome.
Another clinical study of 49 hormone-resistant patients with cyclosporine showed that in the prednisone and placebo application group, 4% remission was achieved after four years, while the cyclosporine combination achieved a 70% remission rate, with 60% partial and 9% complete remission. More importantly, the effect on renal function combined with cyclosporine resulted in a decrease in renal function by half in one quarter of patients, compared to only half of patients on hormones alone.
MMF is a second-line drug for FSGS combination, the initial recommended dosage is 1 to 2 g/d. The drug is well tolerated and less toxic, so MMF can be considered when side effects occur with other immunosuppressive agents or cannot be applied. uncontrolled studies suggest that MMF can reduce proteinuria, but the complete remission rate is low and there is a lack of long-term evaluation of therapeutic efficacy.
Duncan reported that patients who were not responding to cyclosporine could achieve remission with FK506 and that renal function could be improved. Whether FK506 is more effective than cyclosporine has not been studied in controlled randomized studies and the sample size is small, so it is only used as third-line therapy.
Combinations of multiple immunosuppressive agents have been proposed in evidence-based medicine for the treatment of FSGS. a clinical study showed 15 hormone-resistant patients and cyclosporine resistant FSGS nephrotic syndrome. The dosing regimen was cyclosporine ineffective, followed by the addition of MMF, which was tapered after every 4 months, during which time intravenous CTX was given once a month, and if there was still no remission, CTX could be combined again three times with intravenous shock therapy with methylprednisolone, and then switched to oral application of hormones.
ACEI and ARB have been recognized to slow the progression of renal function, so they are now also used in refractory primary FSGS. the general recommendation is that they can be used in the absence of contraindications. Once hormone resistance is present, ACEI or ARB can be added along with immunosuppressive agents to help reduce proteinuria and protect renal function.
LDL isolation therapy is a new treatment option recently proposed. LDL is one of the important independent risk factors for FSGS progression. muso reported 10 hormone-resistant cases, and LDL isolation therapy was instituted in 7 cases over 9 weeks, resulting in reduced proteinuria and improved remission rate. Yokoyama et al. reported another 6 LDL isolation treatments resulting in improvement in both clinical symptoms and histology. However, it must be noted that LDL isolation therapy may achieve faster and better remission when combined with hormonal immunosuppressive therapy.
In a recent report of 36 hospitals in Japan that treated patients with refractory FSGS renal syndrome at five-year follow-up, 29 cases achieved 62% remission with LDL isolation at two years of follow-up and 15 cases achieved 87% remission at five years of follow-up, suggesting that the rapid decline in blood LDL with early isolation therapy is a favorable factor for long-term treatment efficacy.
Plasma exchange and immunosorbency are also therapeutic tools for primary FSGS and refractory FSGS. However, fewer cases have been reported, and in recent years for the treatment of nephrotic syndrome with refractory idiopathic FSGS in combination with hormonal immunosuppressive agents, it can achieve a remission rate of 50%. However, it is difficult to make a definitive determination of its efficacy because its humoral factors are not yet clear.
Other treatments include dietary control, blood pressure stabilization and lipid lowering. Chinese herbal medicine is also a good approach, and the treatment of comorbidities such as infections and edema should not be neglected. A better approach, in addition to not neglecting to treat some comorbidities such as infections, edema, etc.
The article describes the mechanism of action of glucocorticoids in renal disease and the principles of hormone therapy, the pathogenesis of glucocorticoid resistance, the pathological types and the prognosis. In conclusion, FSGS is a common pathological type of refractory nephrotic syndrome, and its incidence has increased significantly in the last 20 years, and its refractoriness is related to multiple factors. It is now advocated that prolonged courses and combination of drugs can improve the clinical remission rate.