Genetic & Pediatric Glomerular Disease

The contract between this chapter and the reader.

1. 1. Explain how inherited mutations cause glomerular disease.
2. 2. Recognise when to suspect a genetic cause.
3. 3. Recognise Alport syndrome and thin basement membrane disease.
4. 4. Recognise the genetic podocytopathies and congenital nephrotic syndrome.
5. 5. Recognise genetic complement-mediated disease.
6. 6. Diagnose with genetic testing and biopsy.
7. 7. Treat genetic disease supportively and avoid futile immunosuppression.
8. 8. Apply the pediatric lens to glomerular disease.
9. 9. Counsel, screen the family, and plan transplantation.

A sixty-second reading. Each bullet stands alone.

• Inherited mutations in glomerular barrier or complement genes cause glomerular disease.
• The logic is gene to protein to a structural or functional defect to disease.
• Genetic disease is often steroid-resistant and does not respond to immunosuppression.
• A genetic cause is suspected with early onset, a family history, steroid resistance, or syndromic features.
• Alport syndrome is a type IV collagen disease causing hematuria, progressive CKD, and hearing and eye abnormalities.
• Thin basement membrane disease is a milder collagen IV disorder causing usually benign isolated hematuria.
• The genetic podocytopathies (nephrin, podocin) cause steroid-resistant nephrotic syndrome and congenital nephrotic syndrome.
• Atypical HUS and C3 glomerulopathy can arise from complement gene variants.
• Genetic testing is increasingly first-line when a genetic cause is suspected.
• Genetic disease is treated supportively, avoiding futile immunosuppression.
• Many genetic diseases do not recur after transplantation, with good outcomes.
• Genetic diagnosis enables counseling, family screening, and transplant planning.
• In children, genetic causes are more likely and a pediatric lens is applied.

The medical core. An expert should agree genetic and pediatric glomerular disease is fully covered here.

Why it matters at the bedside

Some glomerular disease is written in the genes, and recognising it changes everything you do. A steroid-resistant nephrotic child, a young adult with haematuria and a deaf relative, a congenital nephrotic infant — these are not failures of immunosuppression but signals to stop reaching for it, test the genes, and switch to supportive care, counselling, and family screening. The genetic diagnosis is a fork in the road.

The unifying concept: gene to defect to disease

• The organising logic is simple: an inherited mutation in a gene encoding part of the glomerular filtration barrier — the podocyte slit diaphragm, the type IV collagen of the basement membrane — or a complement protein produces a structural or functional defect, and that defect is the disease. Because the defect is built in, genetic disease is typically steroid-resistant and does not respond to immunosuppression — the single most important practical consequence.

When to suspect a genetic cause

• Genetic disease announces itself through a recognisable set of clues: early onset (congenital or infantile), a family history of kidney disease, steroid resistance, syndromic features (such as hearing or eye involvement), and consanguinity. Any of these should prompt a genetic question — because the answer changes whether immunosuppression is even attempted and opens the door to counselling and screening.

Alport syndrome and thin basement membrane disease

• Alport syndrome is the type IV collagen disease: mutations in COL4A3/4/5 produce a defective basement membrane, causing haematuria, progressive chronic kidney disease, and — characteristically — sensorineural hearing loss and ocular abnormalities. It is most often X-linked (COL4A5). On electron microscopy the GBM shows early thinning then thickening and splitting (the ‘basket-weave’). At the milder end of the same collagen IV spectrum is thin basement membrane disease (often heterozygous COL4A3/4) — isolated, usually benign haematuria.

The genetic podocytopathies and congenital nephrotic syndrome

• Mutations in the genes of the slit diaphragm — nephrin (NPHS1), podocin (NPHS2), and many others — produce the genetic podocytopathies: steroid-resistant nephrotic syndrome and hereditary FSGS (the FSGS chapter). The most severe present as congenital nephrotic syndrome in the first months of life (NPHS1, the Finnish type). These are the diseases in which immunosuppression is futile, and recognising their genetic basis prevents needless, harmful treatment.

Genetic complement-mediated disease

• Genetics also drives the complement diseases met earlier: atypical HUS (the thrombotic microangiopathy chapter) and C3 glomerulopathy (the complement-driven nephritides chapter) can both arise from complement gene variants causing alternative-pathway dysregulation. Here the genetic insight points toward complement-directed treatment and informs transplant planning, since these can recur.

Diagnosis: genetic testing and biopsy

• Diagnosis pairs genetics with histology. Genetic testing — increasingly gene panels, often first-line when a genetic cause is suspected — identifies the mutation; biopsy (electron microscopy especially) shows the structural lesion (the Alport GBM, podocyte foot-process effacement). A careful family history and pedigree complete the picture and identify relatives to screen.

Treating genetic disease

• Treatment turns on one principle: treat supportively and avoid immunosuppression. The supportive backbone — RAAS blockade above all (the supportive-therapy chapter) — slows progression in Alport and the genetic podocytopathies; immunosuppression is futile and harmful in genetic disease and should be withheld once the diagnosis is made. Extrarenal features (hearing, eyes in Alport) are managed, and complement disease is treated with complement-directed therapy.

The pediatric lens

• Children warrant a distinct lens. A child with nephrotic syndrome is presumed to have minimal change and treated empirically with steroids (the minimal change chapter); steroid resistance then triggers genetic testing, because genetic FSGS is more likely than in adults. Other diseases are also age-skewed — IgA vasculitis and post-infectious GN are commoner in children. Growth, development, and the transition to adult care round out the pediatric perspective.

Counseling, screening, and transplantation

• A genetic diagnosis carries obligations and opportunities beyond the index patient. It enables genetic counselling (inheritance, prognosis, family planning) and family screening to identify affected or at-risk relatives. For transplantation, the news is largely good: many genetic diseases — Alport, most genetic FSGS — do not recur in the graft, giving good outcomes; but related living donors must be screened, since they may be affected or carriers.

The principle

• The chapter resolves to one pathway: suspect a genetic cause (early onset, family history, steroid resistance, syndromic features) → test the genes (and biopsy) → if genetic, treat supportively rather than with immunosuppression, manage extrarenal features, counsel, screen the family, and plan transplantation. The genetic diagnosis does not just label the disease — it redirects the whole management.

Five fully-built tables.

Table A — The unifying concept

Table B — The major genetic glomerular diseases

Table C — When to suspect and how to diagnose

Table D — Treatment principles

Table E — Transplant and counseling

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — The collagen defect

A type IV collagen mutation → a defective basement membrane → Alport syndrome (haematuria, progressive CKD, hearing/eye disease) → ACTION: treat supportively (RAAS) and manage the extrarenal features.

Chain 2 — The slit-diaphragm defect

A slit-diaphragm gene mutation (nephrin/podocin) → an intrinsically defective podocyte barrier → steroid-resistant or congenital nephrotic syndrome → ACTION: treat supportively, not with immunosuppression.

Chain 3 — The complement variant

A complement gene variant → alternative-pathway dysregulation → atypical HUS or C3 glomerulopathy → ACTION: complement-directed treatment and transplant planning.

Chain 4 — The futile drug

The defect is genetic, not immune → immunosuppression cannot correct it → it is futile and harmful → ACTION: avoid immunosuppression once the genetic diagnosis is made.

Chain 5 — The graft that holds

Many genetic diseases lack a circulating factor → they do not recur in a transplant → good graft outcomes → ACTION: plan transplantation, screening related donors and counselling the family.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Five cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Patient Decisions

Outcomes as natural frequencies. Figures are representative; the direction of effect is given where precise numbers are uncertain.

Apply & Test

Copy-paste chart notes that map to the real decisions in this chapter.

Template 1 — Genetic / pediatric assessment note

• Genetic clues: age of onset; family history; steroid resistance; syndromic features; consanguinity ___.
• Extrarenal: hearing, eyes (Alport) ___.
• Genetic testing (panel) sent: ___.
• Biopsy (EM): Alport GBM / podocyte effacement ___.
• Provisional diagnosis: Alport / thin GBM / genetic podocytopathy / complement ___.

Template 2 — Treatment / counseling / transplant note

• Supportive: RAAS blockade; immunosuppression avoided (genetic) ___.
• Extrarenal features managed (hearing/eyes): ___.
• Complement disease: complement-directed (if applicable) ___.
• Transplant: recurrence risk (low for most genetic); related donor screened ___.
• Counseling and family screening: ___.

Pre-rounds compression. Rules only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Nine items, each anchored in this chapter. At least one per objective.