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Pathogenesis of focal segmental glomerulo sclerosis

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"focal segmental glomerulosclerosis" AND pathogenesis

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Pathogenesis of Focal Segmental Glomerulosclerosis (FSGS)

FSGS is not a single disease but a clinical-pathologic syndrome with multiple causes and pathogenic mechanisms. The unifying pathologic lesion is focal (affecting only a portion of glomeruli) and segmental (involving only a segment of the affected glomerulus) sclerosis, but the underlying mechanisms differ substantially by subtype.

The Central Event: Podocyte Injury and Loss

FSGS is fundamentally a podocytopathy. It can be considered on the same spectrum as minimal change disease (MCD), but with a key distinction: in FSGS, podocyte injury and loss exceeds the capacity of surviving podocytes to compensate. Podocytes are terminally differentiated cells with minimal capacity for regeneration. Once areas of the glomerular tuft are denuded of covering podocytes, the exposed GBM becomes adhesive to Bowman's capsule, high-molecular-weight plasma proteins are entrapped in hyperpermeable foci, capillaries collapse, and extracellular matrix is deposited - resulting in the segmental sclerosis that defines this lesion. With progressive podocyte loss, more glomeruli become involved, eventually leading to global glomerulosclerosis, tubular atrophy, and interstitial fibrosis. - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 847

Classification and Pathogenic Mechanisms

1. Primary (Idiopathic) FSGS - Circulating Permeability Factor

Primary FSGS is characterized by a diffuse podocytopathy driven by one or more unidentified circulating factors that target podocytes. The strongest evidence for this comes from transplantation studies: massive proteinuria can recur within 24 hours of kidney transplantation, and the lesion of FSGS subsequently develops de novo in the donor kidney - behavior that is only explicable by a persistent systemic factor. Plasma exchange and immunoadsorption can induce remission, consistent with removal of this factor. - Comprehensive Clinical Nephrology 7th Ed., p. 1473
Several candidate circulating factors have been proposed:
  • Soluble urokinase-type plasminogen activator receptor (suPAR): Proposed to contribute to FSGS pathogenesis by activating podocyte integrin αvβ3, interfering with podocyte migration. However, subsequent studies have not consistently validated suPAR as the primary mediator. - Brenner & Rector's The Kidney
  • Cardiotrophin-like cytokine 1 (CLC-1): A more recently proposed candidate circulating factor.
  • CD80 (B7-1): The costimulatory molecule expressed on podocytes has been proposed to mediate recurrence, but anecdotal reports and subsequent studies have failed to prove its consistent role. - Comprehensive Clinical Nephrology, p. 1473
The precise circulating factor(s) in primary FSGS remain unknown as of current evidence.

2. Genetic FSGS - Slit Diaphragm and Cytoskeletal Mutations

Inherited forms of FSGS result from mutations in genes encoding podocyte structural proteins. What these proteins have in common is their localization to the slit diaphragm and adjacent cytoskeletal structures. Key mutations include:
GeneProteinInheritanceNotes
NPHS1NephrinARCongenital nephrotic syndrome (Finnish type); MCD-like phenotype with massive foot process effacement
NPHS2PodocinARSteroid-resistant nephrotic syndrome of childhood; some variants show incomplete penetrance and may increase susceptibility to acquired FSGS
ACTN4α-Actinin-4ADInsidious onset; high rate of progression to renal insufficiency
INF2Inverted Formin-2ADActin cytoskeleton regulation
TRPC6TRPC6 channelADAdult onset; pathogenic mutations increase calcium flux in podocytes
PLCE1Phospholipase Cε1ARAssociated with diffuse mesangial sclerosis and FSGS
These mutations account for less than 30% of hereditary cases and only ~20% of sporadic FSGS cases - monogenic inheritance explains only a fraction of cases. - Brenner & Rector's The Kidney (citing Brenner)

3. FSGS Associated with High-Risk APOL1 Alleles

In 2010, two sequence variants (the G1 and G2 risk alleles) in the apolipoprotein L1 (APOL1) gene were discovered to be strongly associated with chronic kidney disease and FSGS, particularly in individuals of African descent. These alleles are remarkably common in West African populations because they confer resistance to trypanosome infection (Trypanosoma brucei rhodesiense), explaining their high prevalence via evolutionary selection pressure.
The mechanism whereby APOL1 risk variants cause FSGS is not yet completely understood, but:
  • Experimental expression of APOL1 risk alleles in a podocyte-specific manner produces foot process effacement, proteinuria, and glomerulosclerosis
  • One line of evidence suggests increased APOL1 expression leads to podocyte cell death
  • APOL1 risk alleles are particularly associated with the collapsing variant of FSGS and HIV-associated nephropathy (HIVAN)
  • Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 848

4. Secondary FSGS - Adaptive Hyperfiltration Injury

Adaptive FSGS develops as a complication of conditions that cause a structural or functional reduction in renal tissue, leading to compensatory glomerular hypertrophy and hyperfiltration in remaining nephrons. This increased glomerular capillary pressure and flow damages podocytes over time.
Causes include:
  • Reduced nephron mass: Unilateral renal agenesis, partial nephrectomy, reflux nephropathy
  • Obesity-related glomerulopathy: Glomerular enlargement with perihilar sclerosis; BMI-related hyperfiltration
  • Sickle cell disease: Medullary ischemia with hyperfiltration
  • Low birth weight / premature birth: Reduced nephron endowment
  • Advanced stages of any glomerular disease with significant nephron loss (vascular disease, diabetic nephropathy)
This form often shows a perihilar pattern of sclerosis with glomerulomegaly and hyalinosis, reflecting the hemodynamic mechanism. - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 848

5. Viral and Toxic Podocyte Injury

Direct viral infection or toxic insult can cause podocyte loss leading to FSGS:
  • HIV-associated nephropathy (HIVAN): The collapsing variant of FSGS. HIV directly infects podocytes and tubular cells; APOL1 risk alleles amplify susceptibility. Characterized by tubuloreticular inclusions in endothelial cells (from high type-I interferon levels), tubular microcysts, and interstitial inflammation.
  • COVID-19-associated nephropathy (COVAN): Similar collapsing glomerulopathy mediated via APOL1 risk alleles and direct podocyte injury; shares morphologic features with HIVAN.
  • Drugs: Pamidronate, heroin, interferon (α, β, γ), sirolimus, calcineurin inhibitors, anabolic steroids, and direct-acting antivirals (ledipasvir/sofosbuvir) can all cause toxic podocyte injury.
  • Parvovirus B19, CMV: Less common viral causes.
  • NKF Primer on Kidney Diseases 8e, p. 190

Morphologic Consequences of Podocyte Loss

Once podocytes are lost from a segment of the glomerular tuft, the following sequence occurs:
  1. GBM denudation - exposed basement membrane becomes adhesive
  2. Hyalinosis - entrapment of plasma proteins (IgM, C3) in hyperpermeable foci; lipid droplets and foam cells appear
  3. Capillary collapse and increased ECM deposition = segmental sclerosis
  4. Synechia formation - adhesion of the denuded segment to Bowman's capsule
  5. Progression - with further podocyte loss, global sclerosis, tubular atrophy, interstitial fibrosis
By electron microscopy, foot process effacement is seen in both sclerotic and non-sclerotic glomeruli, though it is more diffuse in primary FSGS than in secondary forms. Focal detachment and denudation of the GBM may also be visible.
Focal segmental glomerulosclerosis - PAS stain showing segmental sclerosis (A) and hyaline insudation with lipid vacuoles (B)
Fig. FSGS - PAS stain. (A) Segmental sclerosis involving the upper half of both glomeruli. (B) High-power view showing hyaline insudation (arrow) and lipid (vacuoles) in sclerotic area. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Columbia Classification - Morphologic Variants and Their Pathogenic Correlates

VariantMorphologyPathogenic Association
CollapsingCollapse of capillary loops; hypertrophy/hyperplasia of podocytes; prominent protein resorption dropletsAPOL1 high-risk alleles, HIVAN, COVAN, pamidronate; most aggressive clinical course
Tip lesionSclerosis at the segment adjacent to the proximal tubule originOften primary FSGS; typically presents with marked nephrosis but better prognosis
CellularNumerous cells (foam cells, endocapillary hypercellularity) in consolidated segmentsBroadly distributed tuft lesions; variant of primary FSGS
PerihilarSclerosis + hyalinosis at the hilumAdaptive/secondary FSGS (obesity, reduced nephron mass); associated with glomerulomegaly
NOS (not otherwise specified)Non-specific; doesn't fit other categoriesHeterogeneous

Summary: Unifying Pathogenic Model

Primary FSGS:     Circulating factor(s) → Podocyte injury → Foot process effacement
                                                           ↓
Genetic FSGS:     Slit diaphragm/cytoskeletal mutations → Podocyte dysfunction
                                                           ↓
APOL1-related:    G1/G2 risk alleles + second hit        → Podocyte cell death
                                                           ↓
Adaptive FSGS:    Hyperfiltration / hemodynamic stress   → Podocyte detachment
                                                           ↓
Viral/Toxic:      Direct podocyte infection/injury        → Podocyte loss
                                                           ↓
                                          GBM denudation → Hyalinosis → Segmental Sclerosis
                                                                             ↓
                                          Progressive nephron loss → Global sclerosis → ESKD
Key teaching points:
  • The podocyte is the central target in all forms of FSGS
  • Primary FSGS is driven by an unidentified circulating permeability factor - recurrence post-transplant within 24 hours is the strongest evidence
  • APOL1 G1/G2 alleles explain the high prevalence of FSGS (especially collapsing type) in individuals of African descent
  • Genetic mutations in nephrin (NPHS1), podocin (NPHS2), α-actinin-4 (ACTN4), INF2, TRPC6 all disrupt the slit diaphragm-cytoskeletal complex
  • Adaptive FSGS reflects hemodynamic injury (hyperfiltration) in the setting of reduced nephron mass, and shows a characteristic perihilar pattern
  • Collapsing glomerulopathy (HIVAN, COVAN) reflects accelerated podocyte loss with parietal epithelial cell activation
Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease (p. 847-848); Brenner and Rector's The Kidney, 2-Volume Set (p. 1347); National Kidney Foundation Primer on Kidney Diseases, 8e (p. 190); Comprehensive Clinical Nephrology, 7th Edition (p. 1045, 1473)

Give flow chart of it

Generating Image

A detailed medical flowchart showing the pathogenesis of Focal Segmental Glomerulosclerosis (FSGS). The flowchart should have a clean white background with professional medical illustration style. At the top, show 5 parallel entry boxes (causes/triggers): 1. "Primary FSGS - Circulating Permeability Factor (unknown)" 2. "Genetic FSGS - Mutations: NPHS1(nephrin), NPHS2(podocin), ACTN4, INF2, TRPC6" 3. "APOL1 High-Risk Alleles (G1/G2) - African descent" 4. "Adaptive/Secondary FSGS - Hyperfiltration, obesity, reduced nephron mass" 5. "Viral/Toxic Injury - HIV, SARS-CoV-2, pamidronate, heroin" All 5 boxes have arrows pointing down to a central box: "PODOCYTE INJURY & LOSS" (highlighted in red/orange) From "PODOCYTE INJURY & LOSS" arrow points down to: "Foot Process Effacement + GBM Denudation" Then arrow to: "Loss of Glomerular Filtration Barrier Integrity" Then splits into two parallel paths: Left: "Massive Proteinuria (Nephrotic Syndrome)" Right: "GBM Adhesion to Bowman's Capsule (Synechia)" Both arrows converge down to: "Hyalinosis - Plasma protein entrapment (IgM, C3), Lipid droplets, Foam cells" Arrow down to: "SEGMENTAL SCLEROSIS (focal, affecting subset of glomeruli)" - highlighted in blue Arrow down to: "Progressive Podocyte Loss from More Glomeruli" Arrow down to: "Global Glomerulosclerosis + Tubular Atrophy + Interstitial Fibrosis" Arrow down to final box: "END-STAGE KIDNEY DISEASE (ESKD)" - highlighted in dark red On the right side, a separate column showing Columbia Classification variants: - Collapsing (APOL1, HIV, COVID) - Tip Lesion (Primary, good prognosis) - Cellular (Primary) - Perihilar (Adaptive/Secondary) - NOS Use color coding: red for podocyte injury, blue for morphologic changes, orange for clinical consequences, green for the variant classification box. Use bold arrows between boxes. Clean, professional medical education style.

Running Command

mkdir -p /tmp/workspace/fsgs && cat > /tmp/workspace/fsgs/flowchart.html << 'HTMLEOF' <!DOCTYPE html> <html> <head> <meta charset="UTF-8"> <style> * { box-sizing: border-box; margin: 0; padding: 0; } body { background: #fff; font-family: 'Segoe UI', Arial, sans-serif; padding: 30px; } h1 { text-align: center; font-size: 20px; font-weight: bold; color: #1a1a2e; margin-bottom: 24px; letter-spacing: 1px; border-bottom: 3px solid #c0392b; padding-bottom: 10px; } .flow { display: flex; flex-direction: column; align-items: center; width: 100%; } /* CAUSES ROW */ .causes-row { display: flex; gap: 10px; justify-content: center; width: 100%; margin-bottom: 0; } .cause-box { border-radius: 8px; padding: 10px 12px; font-size: 11px; font-weight: 600; text-align: center; width: 168px; color: #fff; line-height: 1.4; } .c1 { background: #6c3483; } .c2 { background: #1a5276; } .c3 { background: #117a65; } .c4 { background: #b7770d; } .c5 { background: #922b21; } .cause-label { font-size: 9px; font-weight: 400; margin-top: 4px; opacity: 0.9; } /* ARROWS */ .arrow-down { text-align: center; font-size: 22px; color: #555; line-height: 1; margin: 4px 0; } .arrow-merge { width: 100%; text-align: center; margin: 0; } /* MAIN BOXES */ .box { border-radius: 10px; padding: 12px 20px; font-size: 12.5px; font-weight: 700; text-align: center; margin: 2px 0; color: #fff; min-width: 420px; max-width: 680px; line-height: 1.5; } .box-sub { font-size: 10.5px; font-weight: 400; margin-top: 3px; } .pod { background: #c0392b; } .filt { background: #922b21; } .prot { background: #8e44ad; width: 280px; min-width: unset; } .syn { background: #1f618d; width: 280px; min-width: unset; } .hyal { background: #b7770d; } .seg { background: #1a5276; } .prog { background: #117a65; } .eskd { background: #1a1a2e; font-size: 14px; letter-spacing: 1px; } /* SPLIT ROW */ .split-row { display: flex; gap: 20px; justify-content: center; align-items: flex-start; margin: 0; } .split-arrows { display: flex; gap: 20px; justify-content: center; } /* VARIANT BOX */ .variants-section { margin-top: 20px; border: 2px solid #117a65; border-radius: 10px; padding: 14px 18px; max-width: 680px; width: 100%; } .variants-title { font-size: 12px; font-weight: 700; color: #117a65; text-align: center; margin-bottom: 10px; letter-spacing: 0.5px; } .variants-row { display: flex; gap: 8px; justify-content: center; flex-wrap: wrap; } .var-box { border-radius: 6px; padding: 7px 10px; font-size: 10px; font-weight: 600; color: #fff; text-align: center; min-width: 110px; } .v1 { background: #922b21; } .v2 { background: #1f618d; } .v3 { background: #7d6608; } .v4 { background: #117a65; } .v5 { background: #6c3483; } .var-sub { font-size: 9px; font-weight: 400; margin-top: 2px; } .merge-line { width: 100%; display: flex; justify-content: center; align-items: center; margin: 2px 0; } .merge-line svg { width: 360px; height: 30px; } /* Arrow connector between cause boxes and central box */ .multi-arrow { display: flex; flex-direction: column; align-items: center; } .big-arrow-container { display: flex; justify-content: center; width: 100%; margin: 2px 0; } .big-arrow-container svg { width: 920px; height: 50px; } </style> </head> <body> <h1>PATHOGENESIS OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)</h1> <div class="flow"> <!-- CAUSES ROW --> <div class="causes-row"> <div class="cause-box c1">Primary FSGS<div class="cause-label">Circulating permeability factor(s) (unknown) — suPAR, CLC-1 proposed</div></div> <div class="cause-box c2">Genetic FSGS<div class="cause-label">NPHS1 (nephrin), NPHS2 (podocin), ACTN4, INF2, TRPC6 mutations</div></div> <div class="cause-box c3">APOL1 Risk Alleles<div class="cause-label">G1/G2 alleles — African descent; resistance to trypanosomes</div></div> <div class="cause-box c4">Adaptive / Secondary<div class="cause-label">Hyperfiltration, obesity, reduced nephron mass, reflux nephropathy</div></div> <div class="cause-box c5">Viral / Toxic Injury<div class="cause-label">HIV, SARS-CoV-2, pamidronate, heroin, interferons</div></div> </div> <!-- CONVERGING ARROWS SVG --> <div class="big-arrow-container"> <svg viewBox="0 0 920 50" xmlns="http://www.w3.org/2000/svg"> <!-- Lines from each cause box center to center --> <line x1="84" y1="2" x2="460" y2="48" stroke="#888" stroke-width="2"/> <line x1="252" y1="2" x2="460" y2="48" stroke="#888" stroke-width="2"/> <line x1="460" y1="2" x2="460" y2="48" stroke="#888" stroke-width="2"/> <line x1="668" y1="2" x2="460" y2="48" stroke="#888" stroke-width="2"/> <line x1="836" y1="2" x2="460" y2="48" stroke="#888" stroke-width="2"/> <polygon points="455,44 465,44 460,50" fill="#888"/> </svg> </div> <!-- CENTRAL PODOCYTE BOX --> <div class="box pod"> ⚠ PODOCYTE INJURY &amp; LOSS <div class="box-sub">Terminally differentiated cells with minimal regenerative capacity</div> </div> <div class="arrow-down">↓</div> <div class="box filt"> Foot Process Effacement + GBM Denudation <div class="box-sub">Diffuse in primary FSGS; focal in secondary forms | Slit diaphragm disruption</div> </div> <div class="arrow-down">↓</div> <div class="box pod" style="background:#7d3c98;"> Loss of Glomerular Filtration Barrier Integrity <div class="box-sub">Increased permeability to plasma proteins</div> </div> <!-- SPLIT: Proteinuria + Synechia --> <div class="split-arrows"> <svg width="360" height="32" viewBox="0 0 360 32" xmlns="http://www.w3.org/2000/svg"> <line x1="180" y1="0" x2="80" y2="30" stroke="#888" stroke-width="2"/> <line x1="180" y1="0" x2="280" y2="30" stroke="#888" stroke-width="2"/> <polygon points="75,26 85,26 80,32" fill="#888"/> <polygon points="275,26 285,26 280,32" fill="#888"/> </svg> </div> <div class="split-row"> <div class="box prot"> Massive Proteinuria <div class="box-sub">Nephrotic syndrome: oedema, hypoalbuminaemia, hyperlipidaemia</div> </div> <div class="box syn"> GBM Adhesion to Bowman's Capsule <div class="box-sub">Synechia formation at denuded segment</div> </div> </div> <!-- MERGE BACK --> <div class="merge-line"> <svg viewBox="0 0 360 32" xmlns="http://www.w3.org/2000/svg"> <line x1="90" y1="0" x2="180" y2="30" stroke="#888" stroke-width="2"/> <line x1="270" y1="0" x2="180" y2="30" stroke="#888" stroke-width="2"/> <polygon points="175,26 185,26 180,32" fill="#888"/> </svg> </div> <div class="box hyal"> Hyalinosis <div class="box-sub">Entrapment of plasma proteins (IgM, C3) in hyperpermeable foci | Lipid droplets + foam cells | ECM deposition ↑</div> </div> <div class="arrow-down">↓</div> <div class="box seg"> SEGMENTAL SCLEROSIS <div class="box-sub">Focal (subset of glomeruli) | Segmental (part of capillary tuft) | Capillary collapse + matrix expansion</div> </div> <div class="arrow-down">↓</div> <div class="box prog"> Progressive Podocyte Loss — More Glomeruli Recruited <div class="box-sub">Sclerosis spreads within and across glomeruli | Tubular atrophy | Interstitial fibrosis</div> </div> <div class="arrow-down">↓</div> <div class="box eskd"> END-STAGE KIDNEY DISEASE (ESKD) </div> <!-- COLUMBIA CLASSIFICATION --> <div class="variants-section"> <div class="variants-title">Columbia Classification — Morphologic Variants &amp; Pathogenic Correlates</div> <div class="variants-row"> <div class="var-box v1">Collapsing<div class="var-sub">APOL1, HIV (HIVAN), COVID (COVAN), pamidronate — worst prognosis</div></div> <div class="var-box v2">Tip Lesion<div class="var-sub">Adj. to proximal tubule origin — primary FSGS, better prognosis</div></div> <div class="var-box v3">Cellular<div class="var-sub">Foam cells + endocapillary hypercellularity — primary FSGS</div></div> <div class="var-box v4">Perihilar<div class="var-sub">Hilar sclerosis + hyalinosis — adaptive/secondary FSGS, glomerulomegaly</div></div> <div class="var-box v5">NOS<div class="var-sub">Non-specific; does not fit other categories</div></div> </div> </div> </div> </body> </html> HTMLEOF echo "HTML written"

Running Command

cd /tmp/workspace/fsgs && python3 - << 'PYEOF' from PIL import Image, ImageDraw, ImageFont import textwrap W, H = 1200, 1700 img = Image.new("RGB", (W, H), "#ffffff") d = ImageDraw.Draw(img) def try_font(size, bold=False): try: return ImageFont.truetype("/usr/share/fonts/truetype/dejavu/DejaVuSans-Bold.ttf" if bold else "/usr/share/fonts/truetype/dejavu/DejaVuSans.ttf", size) except: return ImageFont.load_default() fT = try_font(22, bold=True) fH = try_font(16, bold=True) fN = try_font(13) fNB = try_font(13, bold=True) fS = try_font(11) def box(x, y, w, h, fill, text, sub=None, text_font=None, sub_font=None, radius=10, text_color="#ffffff"): tf = text_font or fNB sf = sub_font or fS # rounded rect d.rounded_rectangle([x, y, x+w, y+h], radius=radius, fill=fill, outline="#cccccc", width=1) # main text — wrap wrapped = textwrap.wrap(text, width=max(10, w//9)) ty = y + (h//2) - (len(wrapped)*16)//2 - (5 if sub else 0) for line in wrapped: lw = d.textlength(line, font=tf) d.text((x + w//2 - lw//2, ty), line, font=tf, fill=text_color) ty += 18 if sub: wrapped_s = textwrap.wrap(sub, width=max(10, w//7)) for line in wrapped_s: lw = d.textlength(line, font=sf) d.text((x + w//2 - lw//2, ty+2), line, font=sf, fill=text_color) ty += 14 def arrow(x1, y1, x2, y2, color="#555555"): d.line([(x1,y1),(x2,y2)], fill=color, width=3) # arrowhead import math angle = math.atan2(y2-y1, x2-x1) size = 10 for da in [0.4, -0.4]: ax = x2 - size*math.cos(angle-da) ay = y2 - size*math.sin(angle-da) d.line([(x2,y2),(int(ax),int(ay))], fill=color, width=3) # ---- TITLE ---- title = "PATHOGENESIS OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)" tw = d.textlength(title, font=fT) d.text(((W-tw)//2, 18), title, font=fT, fill="#1a1a2e") d.line([(60,50),(W-60,50)], fill="#c0392b", width=3) # ---- CAUSE BOXES (row 1) ---- causes = [ ("#6c3483", "Primary FSGS", "Circulating factor(s)\n(suPAR, CLC-1 proposed)"), ("#1a5276", "Genetic FSGS", "NPHS1, NPHS2, ACTN4\nINF2, TRPC6 mutations"), ("#117a65", "APOL1 G1/G2", "African descent\nTrypanosome resistance"), ("#b7770d", "Adaptive", "Hyperfiltration\nobesity, reduced nephrons"), ("#922b21", "Viral/Toxic", "HIV, COVID-19\npamidronate, heroin"), ] bw, bh = 186, 76 gap = 12 total_w = len(causes)*bw + (len(causes)-1)*gap start_x = (W - total_w)//2 cy1 = 65 centers = [] for i,(col,title_c,sub_c) in enumerate(causes): bx = start_x + i*(bw+gap) box(bx, cy1, bw, bh, col, title_c, sub_c.replace("\n"," ")) centers.append((bx + bw//2, cy1 + bh)) # Converging arrows -> central pod box pod_box_y = 220 pod_cx = W//2 for cx, cy_bottom in centers: arrow(cx, cy_bottom, pod_cx, pod_box_y, "#888888") # ---- MAIN BOXES ---- mb_w = 700 mb_x = (W - mb_w)//2 def main_box(y, h, fill, text, sub=None): box(mb_x, y, mb_w, h, fill, text, sub) return y + h def down_arrow(y): arrow(W//2, y, W//2, y+28, "#555") return y + 30 y = pod_box_y y = main_box(y, 58, "#c0392b", "PODOCYTE INJURY & LOSS", "Terminally differentiated cells — minimal regenerative capacity") y = down_arrow(y) y = main_box(y, 55, "#922b21", "Foot Process Effacement + GBM Denudation", "Diffuse in primary FSGS; focal in secondary forms | Slit diaphragm disruption") y = down_arrow(y) y = main_box(y, 48, "#7d3c98", "Loss of Glomerular Filtration Barrier Integrity", "Increased permeability to plasma proteins") y_after_filt = y # SPLIT split_y = y + 30 lx = W//2 - 20 rx = W//2 + 20 arrow(W//2, y, lx, split_y, "#888") arrow(W//2, y, rx, split_y, "#888") # LEFT BOX lb_w = 290 lb_x = W//2 - lb_w - 30 lb_y = split_y box(lb_x, lb_y, lb_w, 68, "#8e44ad", "Massive Proteinuria", "Nephrotic syndrome: oedema, hypoalbuminaemia, hyperlipidaemia") arrow(W//2 - 175, y, lb_x + lb_w//2, lb_y, "#888") # RIGHT BOX rb_x = W//2 + 30 rb_y = split_y box(rb_x, rb_y, lb_w, 68, "#1f618d", "GBM Adhesion to Bowman's Capsule", "Synechia formation at denuded segment") arrow(W//2 + 175, y, rb_x + lb_w//2, lb_y, "#888") merge_y = lb_y + 68 + 5 # Merge arrows arrow(lb_x + lb_w//2, merge_y, W//2, merge_y+30, "#888") arrow(rb_x + lb_w//2, merge_y, W//2, merge_y+30, "#888") y = merge_y + 30 y = main_box(y, 60, "#b7770d", "Hyalinosis", "Plasma protein entrapment (IgM, C3) | Lipid droplets + foam cells | ECM deposition increased") y = down_arrow(y) y = main_box(y, 58, "#1a5276", "SEGMENTAL SCLEROSIS", "Focal (subset of glomeruli) | Segmental (part of capillary tuft) | Capillary collapse + matrix expansion") y = down_arrow(y) y = main_box(y, 58, "#117a65", "Progressive Podocyte Loss - More Glomeruli Recruited", "Sclerosis spreads | Tubular atrophy | Interstitial fibrosis") y = down_arrow(y) y = main_box(y, 52, "#1a1a2e", "END-STAGE KIDNEY DISEASE (ESKD)", None) # ---- COLUMBIA CLASSIFICATION ---- y += 22 d.rounded_rectangle([mb_x, y, mb_x+mb_w, y+135], radius=10, outline="#117a65", width=2, fill="#f0faf7") title_col = "Columbia Classification — Morphologic Variants" tw2 = d.textlength(title_col, font=fNB) d.text(((W - tw2)//2, y+10), title_col, font=fNB, fill="#117a65") variants = [ ("#922b21","Collapsing","APOL1/HIV/COVID\nWorst prognosis"), ("#1f618d","Tip Lesion","Primary FSGS\nBetter prognosis"), ("#7d6608","Cellular","Foam cells\nPrimary FSGS"), ("#117a65","Perihilar","Adaptive/Secondary\nGlomerulomegaly"), ("#6c3483","NOS","Non-specific\nResidual category"), ] vbw, vbh = 116, 62 vgap = 10 vtotal = len(variants)*vbw + (len(variants)-1)*vgap vx0 = (W - vtotal)//2 for i,(col,vt,vs) in enumerate(variants): vbx = vx0 + i*(vbw+vgap) box(vbx, y+32, vbw, vbh, col, vt, vs.replace("\n"," ")) img.save("/tmp/workspace/fsgs/fsgs_pathogenesis_flowchart.png", dpi=(150,150)) print("Saved!") PYEOF

Reading File
Here is the flowchart of FSGS pathogenesis:
FSGS Pathogenesis Flowchart
You can also download it here:

fsgs pathogenesis flowchart

Image · PNG

Reading the flowchart top to bottom:
  1. 5 causes (top row) - Primary (circulating factor), Genetic (NPHS1/NPHS2/ACTN4/INF2/TRPC6), APOL1 G1/G2 alleles, Adaptive (hyperfiltration), and Viral/Toxic - all converge on a single central event
  2. Podocyte Injury & Loss - the universal pivot point; all mechanisms ultimately target the podocyte
  3. Foot process effacement + GBM denudation - structurally disrupts the slit diaphragm
  4. Filtration barrier failure - splits into two parallel consequences: massive proteinuria (nephrotic syndrome) and synechia formation (GBM adhesion to Bowman's capsule)
  5. Hyalinosis - protein entrapment, lipid accumulation, ECM expansion
  6. Segmental Sclerosis - the defining morphologic lesion
  7. Progressive glomerular loss - tubular atrophy + interstitial fibrosis
  8. ESKD - end point
  9. Columbia Classification (bottom) - the 5 morphologic variants with their pathogenic correlates color-coded.
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