Pathological staging
According to the scheme of FSGS pathological staging issued in 2004, it is currently classified into the following five types
1.Non-specific FSGS (not otherwise specified FSGS)
Formerly known as classic or common type. It is characterized by segmental solid glomerular capillary collaterals with increased stroma and occlusion of the capillary lumen. The site of sclerosis may be located at the vascular pole, but it may also be seen in the periphery or at other sites, and it is easy to see spherical sclerosis, balloon adhesions and vitreous changes.
The clinical indicators associated with the prognosis of non-specific FSGS are the degree of creatinine and proteinuria, and the prognostic pathological changes are the degree of interstitial fibrosis. The proliferation of thylakoid cells and stroma in pediatric FSGS and the short interval between onset and renal biopsy suggest that thylakoid lesions may be an early pathological change in the development of FSGS, independent of prognosis, and therefore the new subtyping does not include thylakoid lesions as a separate type. Among 212 cases in our department, 86 cases of non-specific FSGS accounted for 40.6%.
2. portal FSGS (FSGS perihilar variant)
It refers to glassy changes in the vascular pole of at least one glomerulus, with or without sclerotic lesions. In segmental sclerosis, more than 50% of the segmental sclerotic lesions are located at the glomerular hilar or vascular pole. The diagnosis of this type requires exclusion of the presence of cytosolic, apical and collapsed FSGS. It may be associated with glomerular hypertrophy, adhesions, and other areas of vitreous lesions. Vitreous lesions in the walls of the small arteries are also common, and sometimes vitreous lesions in the small arteries entering the glomerulus are seen in continuity with the portal sclerotic lesions. Foam cells in the lumen of capillaries may be seen, but hyperplastic hypertrophy of pedunculated cells is rarely seen. Hyperfiltration secondary to FSGS often presents as a hilar lesion and should be differentiated.
The relationship between the site of segmental sclerosis within the glomerulus and the prognosis remains controversial; Ito H et al. observed 27 cases of FSGS in children, of which 11 cases of circumferential FSGS showed normal renal function after 6 years, whereas only 6 of 16 cases of hilar FSGS showed normal renal function, but it has also been reported that only a few cases showed purely circumferential lesions, and most cases often showed circumferential However, it has also been reported that only a few cases showed purely circumferential lesions, and most cases often showed circumferential type superimposed on hilar segmental sclerosis with no difference in proteinuria and prognosis; therefore, it is difficult to judge the prognosis based solely on the site of segmental sclerosis. Among the 212 cases in our department, 25 cases of portal FSGS accounted for 11.5%.
3.Cellular variant of FSGS (FSGS cellular variant)
It means that at least 25% of the capillary collaterals of one glomerulus exhibit proliferation of intracapillary cells (including endothelial cells, foam cells and infiltrating leukocytes) with lumen occlusion, and swelling, hyperplasia and vacuolar degeneration of pedunculated cells can be seen, which can form a cap-like group of cells or “cellular cap”. The involvement of glomerular capillary collaterals can be anywhere (hilar, peripheral), and the cells in the capillaries often show nuclear shrinkage, nuclear fragmentation, and other regulatory phenomena. The diagnosis of this type requires exclusion of apical and collapsed FSGS. Fibrin is seen in the lumen of the capillaries of the involved segments, but there is no fracture of the basement membrane, which should be distinguished from segmental fibrinoid necrotic lesions. Balloon adhesions and vitreous changes are not seen frequently.
4. FSGS tip variant
It is a segmental lesion of at least one glomerulus occurring at the ureteral pole including the proximal tubule from the beginning of the glomerulus, manifested by adhesions of capillary collaterals to the wall of the capsule at the opening of the tubule, or fusion of the pedicle with the mural epithelium or tubular epithelium at the ureteral pole. The affected capillary collaterals may be accompanied by intracapillary cell hyperplasia or sclerotic lesions, some of which may extend and herniate into the tubular lumen. Hyperplasia and hypertrophy of pedunculated cells are common around the lesioned segments, and foam cells are common at the sclerotic sites, sometimes with glassy changes.
5.Collapsing FSGS (FSGS collapsing variant)
It refers to segmental or bulbous field occlusion of capillary collaterals in at least one glomerulus, GBM crinkling and collapse, accompanied by hypertrophy and hyperplasia of podocytes, and HIV-associated nephropathy should be excluded for the diagnosis of this type. The pathologic changes of this type are characterized by acute injury, with capillary lumen occlusion due to GBM crinkling, but without intracapillary cell proliferation and proliferation of the thylakoid matrix, and increased podocyte size with vacuolated nuclei and sometimes binucleated cells, with cytoplasm filled with protein uptake droplets. Cellular proliferation nuclei may form pseudocrescent. In addition to the common tubular atrophy, interstitial fibrosis and inflammatory cell infiltration, the tubular manifestations are more severe than the glomeruli. It shows severe epithelial cell degeneration, disintegration and regeneration, and the tubules are cystically dilated and contain a lightly stained protein tubular pattern. This type needs to be differentiated from cytotic FSGS, which has significant intracapillary cell proliferation,.
Collapsed FSGS is clinically characterized by severe nephrotic syndrome and high creatinine levels that do not respond to hormonal therapy and progresses rapidly to renal failure, and is known as “malignant FSGS”. The formation of collapsed FSGS has been reported to be related to the mechanism of viral infection. The diagnosis of this type should exclude those with secondary HIV infection. Among the 212 cases in our department, 12 cases of collapsed FSGS accounted for 5.7%.
Etiology and pathogenesis
The classification is based on the main lesion characteristics, and it is not clear whether the significance of the classification is related to the etiology, but it is certain that the more obvious the mixed type is, the more likely it is to be secondary to FSGS. The more advanced the disease is, the more obvious the mixed type is.
The portal type FSGS is mainly due to the rich blood flow in the vascular pole, slight diffuse injury in the glomerulus, altered hemodynamics, or the first pathological changes in the pathophysiological state of the glomerulus, which is also the result of the adaptive response.
Apical FSGS has been suggested that the primary pathogenesis may be first involved in the tubular interstitium, including interstitial edema, infiltration and fibrosis, tubular compression or/and abnormalities of antigens, blood circulation metabolic substances, altering the permeability of the tubular and capillary walls, and activating abnormal active proliferation of podocytes under abnormal plasma components stinging fluid forming early periurethral FSGS changes, and later with non-specific type essentially the same.
Cellular FSGS is currently considered to be the underlying cause of FSGS, and cellular FSGS may be an early manifestation of primary FSGS, with hyperplasia and hypertrophy of injured podocytes accompanied by degeneration and cell death within the collaterals, which may develop into non-specific FSGS or collapsed FSGS.
In collapsed FSGS, the disorder of phenotypic regulation of podocytes is related to the pathogenesis of the disease. Mature glomerular podocytes rely on high expression of the cyclin kinase inhibitor P27Kipl and usually do not undergo podocyte proliferation; in collapsed glomerulopathy, the expression of P27Kipl is lost at the collapsed site, and podocytes are prompted to proliferate and dedifferentiate. Evidence suggests that parvovirus infeltion is more common in this type of GBM collapse, suggesting an association between the two. HIV infection, pamidronate therapy, nephrotoxicity of cyclophilin A, and reinfection after autologous transplantation are all associated with the formation of collapsed FSGS.
Differential diagnosis
1. Minimal change disease (MCD): Since the clinical manifestations of FSGS and MCD are similar, and the pathological patterns of non-sclerotic glomeruli are similar, the two are easily confused, so the kidney biopsy specimens should contain sufficient number of glomeruli and consecutive sections, preferably including the corticomedullary junction, in order not to miss the diagnosis. Statistically, the rate of missing FSGS is 35% for specimens with 10 glomeruli, while the rate drops to 12% for specimens with 20 glomeruli. are superimposed. The clinical presentation of pediatric nephrotic syndrome changes from hormone sensitive to hormone insensitive, indicating that they may have superimposed or transformed pathological types during the process of lesion development with repeated infections and other acquired environmental factors, and it is difficult to distinguish FSGS from MCD in the early stage, therefore, the possibility of FSGS should be considered even if segmental sclerotic glomeruli are not found. The following indicators are available.
(1) Glomerular hypertrophy is seen. If the glomerular area of early FSGS exceeds 50% of the glomerular area of normal children of the same age, it is an enlarged glomerulus, and more than 50% of the glomeruli of the kidney biopsy tissue can be diagnosed as glomerular enlargement, and enlargement of the renal capsule only is a pathological phenomenon secondary to interstitial changes in the renal tubules. Enlargement of the glomerulus is a sensitive high-risk indication for progression to FSGS.
(ii) Extensive peduncle fusion is a common feature of MCD and FSGS, but the extensiveness of peduncle fusion in FSGS is non-complete and small segments of normal peduncles can be seen, which is related to the extent and degree of the lesion.
(iii) On electron microscopic examination, there is severe vacuolar degeneration of epithelial cell proliferation.
④The finding of spherical sclerosis should be highly alert to FSGS. The pathogenesis of glomerulonephritis from mild to sclerosis is inherent in the development of the disease, with abnormal glomerular adaptive changes and growth factors involved in the development of primary FSGS. If glomerulosclerosis is found, one should also be on high alert and continue to look for glomerular, tubular or interstitial changes with segmental sclerotic lesions.
⑤ Differentiation from IgMN: The significance of light microscopy showing IgMN is difficult to evaluate, and most believe that IgMN is a transitional type of MCD transforming FSGS. Repeat renal puncture can see the pathological type transformation in the same case, but it cannot explain IgMN in those with a good prognosis, so as a diagnosis of the disease, the established conditions should be present: immunofluorescence examination with IgMN predominantly deposited in the thylakoid zone particles rather than focal mass deposition, electron microscopic deposition consistent with the form of IF deposition, and light microscopy consistent with thylakoid proliferative glomerulonephritis without segmental sclerosis, then should be independently diagnosed as thylakoid immune complex glomerulonephritis IgM nephropathy.
(6) Clinical belonging to true hormone resistant nephrotic syndrome: even if the renal biopsy does not reveal segmental sclerotic glomeruli, the diagnosis of FSGS should be highly, FSGS existing outside the sample should be suspected, too few or less than 25 glomeruli on renal puncture, excessive glomerular volume, focal presence of tubular atrophy and interstitial fibrillation, not parallel to the severity of glomerular changes, no immune complexes present, etc The diagnosis of FSGS should be excluded and the renal biopsy should be repeated when necessary.
2, secondary FSGS due to glomerular disease: from microscopic lesions or other pathological types of disease, the gradual progression process can also develop into the stage of focal segmental sclerosis, is secondary FSGS, although all can appear FSGS histological lesions, but various glomerular diseases have their own clear clinical features, immunopathological and ultrastructural features, such as focal hyperplastic sclerosing lgA nephropathy, the Alport syndrome, etc. Non-lgA mild tegumentary proliferative glomerulonephritis is easily confused with MCD in the absence of sclerotic lesions and is difficult to differentiate from FSGS with tegumentary proliferation if segmental glomerulosclerotic lesions are present. Electron microscopic examination revealed non-extensive pedunculated fusion and clear electron dense material deposition, supporting the diagnosis of thylakoid proliferative glomerulonephritis.
3. Secondary FSGS caused by glomerular hyperperfusion or high pressure: Compensatory responses in renal structure and function due to reduced functional renal units or hemodynamic hyperload often result in lesions of FSGS. Glomerular hypertrophy is the prominent feature, and segmental sclerosis is most often seen in the glomerular hilum, which needs to be differentiated from hilar FSGS. The pathology is characterized by lighter pedunculated fusion of peduncle cells, which may be accompanied by hyperplastic sclerosis of the thylakoid matrix, and the renal tubular interstitium is generally without obvious pathological changes. clinical manifestations are mostly moderate amount of proteinuria, and even if proteinuria of nephrotic syndrome range occurs, typical nephrotic syndrome is rarely seen, and it is not difficult to diagnose secondary FSGS according to its clinical features. treatment is based on improving hemodynamics, and the prognosis is better.
4, HIV-related collapsed glomerulopathy: its pathological histological features are similar to collapsed FSGS, with differences at the ultrastructural level. endothelial cells of glomerular capillary collaterals and vascular endothelial cells of the renal interstitium in HIV patients can be observed as tubular reticular inclusion bodies, nucleosomes and granular fiber-like structure formation can be seen in the nuclei of renal tubular epithelial cells, and variant structures of rough endoplasmic reticulum can be seen in the cytoplasm. clinically detected markers of HIV infection as secondary FSGS.
Treatment
The main objectives are: symptomatic reduction of proteinuria, delaying the progression of renal impairment, timely improvement of pathophysiological status, and timely prevention and treatment of comorbidities. Primary FSGS manifesting as nephrotic syndrome should be treated actively regardless of the pathological type. At present, the main treatment guideline is the Chinese pediatric nephrotic syndrome treatment guideline (please see the original article), combined with my own treatment experience, I try to explain the application of classical treatment of pediatric FSGS and experience exchange: 1.
1.Application of glucocorticoids: The initial treatment is the same as the primary simple and microscopic nephrotic syndrome, with a remission rate of 20-30% in 4-8 weeks of initial treatment with sufficient hormones, and relapse and retreatment can turn into drug resistance or partial drug resistance.
2.CTX shock: It is generally believed that hormone with CTX shock therapy can make some hormone resistant cases remit. It can make frequent relapses turn into infrequent relapses. For hormone resistant and partially resistant cases, renal biopsy should be done. The remission is complete in 70% of cases in 18-42 months. In recent years, the combination of double impact therapy is mostly applied.
3, Methylprednisolone (MP) shock, ①1-2 weeks weekly shock MP 3 times, can be flushed daily and then every other day ②3-10 weeks every 2 weeks shock ③ after that 1 time per month for 8 months ④ then every other month for 6 months. If there is no improvement of urine protein after the second week of diagnosis and CsA is added orally, or if there is repeated and still proteinuria/urine creatinine ≥2 in the 10th week, Airova 0.25-0.5mg/kg.d can be added to maintain treatment for more than 3-6 months to 1 year, and the dosage can be gradually reduced (half dosage every 3 months).
4., cyclocytomycin A (CsA): often the second-line drugs for pediatric FSGS, Liberman et al. reported CsA 5-6mg//kg.d 12 cases, control observation on proteinuria effective (12 cases 100%, control group 2/12 cases), Cattran et al, CSA 3.5mg/kg.d combined with prednisone 1.5mg/kg.d treatment 26 cases, partial The Waldo regimen gave alternate day MP shocks for 2 weeks, once a week for 6 weeks, and from week 3 + oral prednisone 2mg/kg.qod and CsA 5-6mg/kg.d for 10 cases, with 8 cases in complete remission and 1 case in partial remission, and only 1 case entering ESRD.
5, mycophenolate lipid: (MMF): Choi et al. reported that 0.5-1.0g Bid treated 18 cases, 44% complete remission and partial remission, the side effects are not serious.
6, FK506 that tacrolimas (FK506), Looffler et al. gave a dose of 0.2mg/kg.d 13/16 cases of complete remission.
7, ACEI and ARB preparations: used for hormone resistant nephrotic syndrome, for: ① hormone ineffective when there are obvious side effects should be discontinued hormone or trailing therapy, add this and spleen and kidney tonic drugs. ②It is used to reduce proteinuria, improve the state of three high, ③Anti-proliferative and anti-fibrotic effect, antioxidant stress state to protect renal function and delay the progress of renal function damage. ④ Combined with blood activation and blood stasis medicine Yi kidney granules to improve the hypercoagulable state is better than Pansentin.
ACEI and ARB preparations side effects A) mildly elevated creatinine and urea nitrogen: with mild renal insufficiency should be cautious, available ARB class Cr>250umol/L is generally not used B) affect the concentration dilution function of the renal tubules, attention should be paid to the monitoring of hyperkalemia, C) attention to hypotension D) attention to allergic reactions, angioneurotic edema and blood leukopenia, etc.
8, other treatment: elevated blood pressure with loxodil, etc., elevated blood lipids with statins, etc. If the above treatment is ineffective or ACEI and ARB cannot be applied, plasma replacement and renal transplantation can be considered if necessary.
9.Primary FSGS is a group of hormone-resistant nephrotic syndrome with clinical and pathological polymorphic changes associated with genetic factors. Environmental factors are also very important in the development of the disease, and it is not easy to distinguish from secondary FSGS, it is very important to prevent and avoid secondary factors and their comorbidities. If an immunosuppressive drug has no effect for 3 years, stop using this drug. Excessive application of immunosuppressive drugs is the cost of life in exchange for temporary reduction of urine protein, but creatinine rises, renal tissue intrinsic cells and abnormal proliferation of infiltrated inflammatory cells and fibroblasts together with apoptosis, glomerular sclerosis continues, the final outcome will be drug accelerated renal failure and uremic syndrome.
Prognosis
The prognosis of this disease is poor, it is generally believed that 70% of cases enter ESRD in 10-15 years, and 70% of pediatric ESRD have FSGS as the primary cause. early diagnosis by renal biopsy, early formal treatment can improve the prognosis, the prognosis is good for those with predominantly negative perennial proteinuria, and poor for those with long-term massive proteinuria or/and hypertension, the prognosis is better for those with early hormone sensitive/microscopic lesions or from IgMN with slow progression. The prognosis is better for those with early onset of disease and <3 years of age who have already entered the reversible phase of renal insufficiency, and poor for those with living kidney transplantation as a relative donor. Those with primary FSGS with significant tethered hyperplasia are prone to recurrence after transplantation.