FSGS is a histological lesion, rather than particular disease subset, that’s commonly seen underlying NS in adults & children.
Focal segmental glomerulosclerosis (FSGS)
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| Glomerulonephritis-FSGS |
FSGS is a histological lesion, rather than particular disease subset, that’s commonly seen underlying NS in adults & children. FSGS is characterizing by sclerosis in parts (segmental) involving at least one glomerulus (focal) in renal biopsy samples, if examined by LM, IF, or EM. Lesions of FSGS can be categorized as:
1) Primary (FSGS1),
2) Secondary (FSGS2), &
3) Genetic forms.
FSGS1 Ptns, injury to glomerular visceral epithelial cells (podocytes) observed likely owing to a circulating permeability factor (s) or, its reality has not yet been recognized. Glomerulosclerosis (GSc) of FSGS2 usually results from an adaptive response to glomerular hypertrophy & hyperfiltration or other factors (e.g., involved glomerular basement membrane (GBM)) or due to direct toxic damage to podocytes. However, in substantial (>50 %) percent of ptns with clinical & histopathological criteria suggesting FSGS2, particular aetiology, however, cannot be recognized in clinical work-up. Many of these ptns have undiagnosed genetic types of FSGS, and genetic analysis including next-generations sequencing, should be applied.
PATHOGENESIS OF SECONDARY FSGS (FSGS2):
FSGS2 usually developed as an adaptive response to:
1) [Glomerular hypertrophy + hyperfiltration],
2) Glomerular alterations (e.g., involving GBM), or
3) Direct toxic injury to the podocyte (e.g., drugs, virus).
It is crucial, to DD FSGS2 from FSGS1 as ttt of FSGS2 is usually conservative directed to low-protein/low-salt diet & BP control via RAAS inhibition with No added steroids or im/m. therapy. Proteinuria in FSGS2, like FSGS1, reflects podocyte injury, but the mechanism differs. The visceral epithelial cell cannot replicate. With hypertrophic response to the current nephron loss or direct epithelial damage, it is suggested that this inability to replicate >> diminished podocyte density + GBM focal denudation. So, the barrier of filtration is currently lost in these locations. The rise in fluxing of small solutes & water via these locations carries albumin along via solvent dragging.
Glomerular cell proliferation + macrophage infiltration + the progressively accumulated extracellular elements >> sclerotic lesion. Cytokines, e.g., TGF-B, may be partially responsible for accumulated matrix. TGF- B can facilitate podocyte injury by altering transcriptional process allowing expressed cytosolic cathepsin L. The latter in podocytes may cleave the GTPase dynamin, synaptopodin, & CD2-related protein (CD2AP), leading to ultrastructural alterations in podocytes observed in FSGS. Almost >50 % of ptns with FSGS2 have no definite diagnosis with clear aetiology for their disease. These cases seldom responding to steroids with low frequency of recurrence after KTx. Slowly progressed to ESKD is commonly seen, although the rate of progression may be declined by robust control of BP & limiting proteinuria. Many of cases may exhibit undiagnosed genetic types of FSGS, and genetic studies including next-generation sequencing, should be proceeded. Identifying a genetic cause is important since it would avoid exposing ptns to SE of prolonged im/m.
Adaption to hyperfiltration: that refers to an adaptive and abnormal rise in single-nephron GFR that triggers GFR higher than expected from the limited number of glomeruli. It includes disorders with either nephron loss and/or intraglomerular HT + initially normal quantity of nephrons.
Reduced renal mass: FSGS induced via adaptive response to nephron loss seen with many varieties of CKD, including non-glomerular lesions e.g., reflux nephropathy & ischemic HT with nephrosclerosis. It can also be observed with markedly reduced renal mass (e.g., congenital absence or surgical removal). Compensatory intra-glomerular HT & hypertrophy in the other glomeruli >> rising nephron filtration rate to maintain GFR. By time, "HT" injury associating intraglomerular HT >> FSGS with drop in GFR. The beneficial effect of ACEi is provided via decline in glomerular capillary pressure. Risk of FSGS2 development after nephron loss is dose-related, with clinical data suggest loss of > 50 % of nephrons is currently required. However, long-term kidney outcome is generally excellent after losing one kidney (50 % nephron loss). There was no evidence that Nc >> increased prevalence of renal impairment or HT, but there was a small % rise in proteinuria + systolic BP. Moreover, long-term renal survival is generally excellent in kidney donation for KTx. Despite losing 50 % of renal mass >> minor, long-term risks, unilateral kidney agenesis >> higher incidence of FSGS2.
Low birth weight + premature birth: reduced renal mass > evolution of FSGS.
Reflux nephropathy: > HT + CKD + FSGS2-induced mild/moderate proteinuria
Severe obesity: FSGS2 has been reported with massive/extreme) obesity. The term ORG "Obesity-related glomerulopathy" refers to obesity-related FSGS. However, some obese ptns with moderate/heavy proteinuria show little or no GS with NO epithelial damage or foot process effacement on biopsy finding; but there’s clear mesangial expansion & enlarged glomerular capillary loop (GM). These findings suggest: obesity alone cannot be responsible to induce FSGS, more triggering factors may be warranted. Biopsy findings suggesting ORG include fewer glomeruli with FSGS, perihilar variant, GM, with <50 % foot process effacement via EM. Morbid obesity in human show marked rise in GFR. After losing weight in obese ptns by e.g., 32 % decline in BMI, mean GFR fell from 145 to 110 mL/min that supports role of intraglomerular HT in evolution of proteinuria & sclerotic lesions in obesity related FSGS. Lowered adipose-related hormone, adiponectin, have been related to proteinuria in obese ptns and may have a role in GS development. Some morbid obesity ptns have subclinical disease defined as sclerotic lesions in a few glomeruli in ptns with little or mild proteinuria + normal GFR. Both weight loss & ACEi agents can dramatically decrease protein excretion (up to 80-85 %) in ptns with obesity induced FSGS.
Others: Segmental areas of GS can be induced by intraglomerular HT seen in ptns with initially normal renal mass, e.g.:
1) Sickle cell anemia.
2) Dc Np (Diabetic nephropathy)
3) Familial dysautonomia
4) Congenital cyanotic heart dis.
5) Deficient Glucose-6-PO4 (glycogen storage dis. I, von Gierke)
Drugs & toxins: agents implicated in FSGS may include:
[1] Heroin abuse > FSGS, including ptns who’re HIV -ve. In addition to FSGS, secondary amyloidosis (chronic suppurative SC infection), MN (HBV), & MPGN due to HC can be also observed. Heroin-related FSGS has a black race predilection. Slowly progressed RF. Pathogenesis of heroin nephropathy (HNp) still uncertain. A heroin adulterant-induced glomerular epithelial injury has been proposed. It’s observed that HNp has greatly disappeared in large cities with the street heroin has greatly purified. 💀👽💀
[2] Interferon: IFN-a has been accused for both FSGS & minimal change disease.
[3] Bisphosphonates: pamidronate >> collapsing variant of FSGS in particular.
[4] Anabolic steroids: FSGS & proteinuria were associated with the long-term use of anabolic steroids. Altered hemodynamics + direct nephrotoxicity of anabolic steroids.
Other drugs: they include:
1) Lithium.
2) CNI (in KTx recipients).
3) Anthracyclines (e.g., doxorubicin).
4) Sirolimus (especially with high plasma levels)
Viruses: Viral infection, particularly HIV that can cause > collapsing variant of FSGS. Moreover, it has been observed with parvovirus B19, CMV, Epstein-Barr virus & HCV.
wish all the success Dr / Fedaey
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