Disorders of the Basement Membrane

General Points

  • GBM disorder primarily associated with collagen IV
  • The collagen IV family is composed of 6 chains (α1 – α6)
  • Glomerular and tubular basement membrane, lung, cochlea, eye and testis are α3.α4.α5 (IV) collagen (more resistant to proteases)
  • Skin, smooth muscle, esophagus and Bowman capsules are α5.α5.α6 (IV) collagen

Anti-GBM disease

  • When haemoptysis is present, it is called Goodpasture’s syndrome
  • Pathology
    • The provoking epitope is the quartenary structure of the α3 NC1 domain of collagen IV
    • Epitopes are normally sequestered but can be exposed by smoking, infection, oxidants or solvents
    • Biopsy shows focal or segmental necorsis which combines with with capillary destruction by cellular proliferation leads to crescent formation
    • Concomitant interstitial nephritis and tubular atrophy
  • Epidemiology
    • Goodpastures has two peaks – males in their 20s and females in their 60s
    • Haemoptysis largely associated with smokers
  • Diagnosis
    • Biopsy – staining for IgG (or rarely, IgA) anti-α3 NC1 confirms diagnosis ( anti-α1 NC1 seen in paraneoplastic syndromes, tests that use whole GBM as target will confuse the two)
    • 10-15% will have ANCA against MPO
  • Prognostication
    • Worse out come if >50% crescents, creatinine >5mg/dL, oliguria, acute dialysis
  • Treatment
    • Plasmapheresis
    • Pred + cyclophosphamide
    • Transplant is possible but at risk for disease recurrence

Alport’s Syndrome

  • Presentation
    • Triad of renal involvement, sensorineural deafness and eye abdnormalities
    • May rarely present with retardation or leiomyomatosis
    • Renal
      • Haematuria
      • Thinning and splitting of GBM
      • Mild proteinuria late in the course
      • Progressive glomerulosclerosis
    • Eye
      • Lenticonus of anterior lens capsule
      • Dot and fleck retinopathy
  • Genetics
    • 85% X-linked α5 mutations
      • Female carriers have variable penetrance dependent on type of mutation, mosaicism and X inactivation
    • 15% autosomal recessive disease of α3 or α4
    • Rarely some have autosomal-dominant or dominant-negatie mutations in α3 or α4
  • Diagnosis may be supported in skin biopsy (since skin has α5) or renal biopsy
  • Treatment
    • ACE-I
    • Control of systemic hypertension
    • Renal allograft (develop AB against non-native epitopes but overt anti-GBM disease is uncommon)

Thin Basement Membrane Disease / Benign Familial Haematuria

  • Persistent haematuria NOT associated with proteinuria, hypertension, renal impairment or systemic symptoms
  • Usually presents in childhood
  • Genetic disorder of type IV collagen
  • GBM shows diffuse thining but is otherwise normal
  • Usually benign with a good prognosis

Nail-Patella Syndrome

  • Presentation
    • Iliac horns on pelvis
    • Dysplasia of the dorsal limbs (nail, patella, elbow)
    • Variable
      • Neurosensory hearing loss
      • Glaucoma
      • Haematuria / heavy proteinuria / FSGS
  • Autosomal dominant – deficits in LMX1B which regulates α3 and α4 chains of collagen IV, interstitial type III collagen, podocin and CD2AP which contribute to the porous membranes connecting podocytes
  • Renal transpant for end-stage disease

Inherited Renal Disorders II

Nephronophthisis

  • Pathology
    • 11 distinc genetic mutaitons
    • Defective nephrocystins and inversin localise to primary cilium and basal body of renal epithelial cells
  • Presentation
    • Specific presentation dependent on specific mutation
    • Classified into infantile, juvenile and adolescent forms based on onset
    • Bland urinary sediment
    • Juvenile
      • Shrunken kidneys with tubular atrophy, diffuse fibrosis, thickened basement membranes and microscopic medullary cysts
      • Symptoms appear after age 1
      • Impaired concentrating ability > salt wasting
        • Polyuria
        • Polydipsia
        • Hypovolemia
        • Acidosis
      • Growth retardation due to renal disease
      • 15% have extrarenal manifestations (e.g. retinitis pigmentos, amaurosis, oculomotor apraxia, cerebellar ataia, polydactyly, mental retardation, hepatic fibrosis, situs inversus and VSD)
    • Infantile
      • Kidneys large with similar histopathology to juvenile form
      • Occurs by age 3
  • Diagnosis
    • Imaging based on a suggestive family history
  • Treatment
    • Salt and volume replacement
    • Bicarb or citrate for acidosis
    • Transplanted kidneys remain disease free

Medullary Cystic Kidney Disease

  • Pathology
    • Autosomal dominant with two loci
      • MCKD1 – Chromosome 1q21
      • MCKD2 –  UMOD (encodes Tamm-Horsfall protein)
  • Presentation
    • Typical declares in young adults
    • Bland urinary sediment
    • Atrophic kidneys
    • Diffuse interstitial fibrosis
    • Medullary cysts
    • Salt wasting
    • Polyuria
    • MCKD2 has further extrarenal features of severe hyperuriciemia leading to gout
  • Diagnosis
    • Genetic analysis
  • Treatment
    • Supportive
    • Allopurinol if hyperuricaemic
    • Disease does not recur in transplants

Medullary Sponge Kidney

  • Pathology
    • Unknown aetiology
    • Ectasia of papillary collecting ducts of the kidneys
    • Urinary stasis, hypocitraturia, incomplete distal RTA > calcium calculi
  • Presentation
    • Asymptomatic in majority of cases
    • Haematuria
    • Nephrolithiasis
    • Recurrent UTI
    • Association with Caroli’s disease (hepatic duct ectasia)
  • Diagnosis
    • USS
      • Hyperdense papillae + small stones
    • IV urography
      • Paintbrush collecting ducts
  • Treatment
    • Usually benign course requiring no treatment
    • High fluid intake > reduced risk of nephrolithiasis
    • Patients with hypocitraturia + incomplete dRTA: potassium citrate

 

 Tuberous Sclerosis

  • Pathology
    • Autosomal dominant disorder of TSC1 (hamartin) or TSC2 (tuberin)
    • Hamartin + tuberin = complex that regulates cell growth through mTOR
    • Mutations provoke cellular proliferation in kidney, skin, CNS  and heart
  • Renal presentation
    • Occurs in 80% of patients
    • 3 forms
      • Angiomyolipoma
        • Bilateral, multiple and asymptomatic unless haemorrhage occurs
      • Cysts
        • Usually asymptomatic
        • Only evident on imaging in early aduthood
        • Rarely, cysts may be large and mimic ADPKD
      • Renal cell carcinoma
  • Management
    • Screen at initial diagnosis with USS or CT
    • Regular surveillance thereafter

Von Hippel-Lindau Disease

  • Pathology
    • Mutation in one allele of the VHL tumor supressor
    • Abnormal angiogenesis > tumours across different tissue types
  • Presentation
    • Retinal angioma
    • CNS haemangioblastoma
    • Pheochromocytoma
    • Kidney adenoma
    • Multicentre clear cell cysts
    • Haemangiomas
  • Renal presentation
    • 75% patients have renal involvement of which half develop clear cell carcinomas in renal cysts
    • 70% of patients who survive to age 60 develop renal cell carcinoma
  • Management
    • Yearly surveillance
    • Tumor <3cm can be monitored; >3cm = partial nephrectomy

Inherited Renal DIsorders I – The Polycystic Kidney Diseases

Autosomal Dominant Polycystic Kidney Disease

Aetiology

  • Mutations in PKD-1 or PKD-2 gene
  • Transmembrane proteins present in all parts of the nephron
  • Disruption of normal gene function > epithelial dedifferentiation / unregulated growth/apoptosis / altered cell polarity / extracellular matrix disruption / unregulated fluid secretion / abnormal growth factor secretion
  • Vasopressin > increased cAMP > cell proliferation + fluid secretion > cyst formation

Renal Presentation

  • Marked heterogeneity in phenotype
  • Frequently asymptomatic
  • Mass effects
    • Early satiety
    • Abdominal discomfort
    • Progressive renal failure
  • Altered RAA system activation
    • Hypertension
  • Impaired concentrating ability
    • Polyuria
    • Nocturia
  • Cyst rupture / haemorrhage
    • Acute flank pain
    • Acute abdomen
    • Hemorrhage
  • Nephrolithiasis in 20%
  • Infected cyst
    • Flank pain, fever chills
    • Negative urine cultures (cysts do not communicate)

Extrarenal Presentation

  • 3X risk of ruptured intracranial aneurysm
  • Aortic root and annulus dilatation
  • 25% have valvular disease – usually MVP or AR
  • 85% have hepatic cysts
  • Colonic diverticulae
  • Hernias

Diagnosis

  • Age 15-39 : 3 or more cysts on USS
  • Age 40-59: 2 or more cysts
  • Age 60+: 4 or more cysts
  • Genetic analysis for equivocal cases

Treatment

  • No current evidence to prevent progression of renal failure
  •  Hypertension
    • Aim 130/80 with ACE-I / ARB
  • Infected cysts
    • Cotrimoxazole / quinolones (good cyst penetration)
  • Pain
    • Drainage
    • Sclerotherapy with EtOH

 

Autosomal Recessive Polycystic Kidney Disease

Aetiology

  • Defect in PKHD1 on chromosome 6p21
  • Codes for fibrocystin / polyductin in the cortical and medullary collecting ducts, thick ascending limb of the LoH, biliary and pancreatic ductal epithelial
  • Multiple possible mutations
  • Two mutations = death shortly after birth

Clinical features

  • Primarily disease of newborns
  • 50% die of pulmonary hypoplasia (intrauterine kidney disease > oligohydramnios)
  • Of the 50% who survive, 20% will die by age 10 and 1/3 will have ESRD
  • Enlarged kidneys, impaired concentrating ability, hypertension

Diagnosis

  • Large echogenic kidneys on USS visible by 24/40
  • Cysts tend to appear after birth
  • Parental cysts differentiate ARPKD from ADPKD

Treatment

  • General supportive

 

Renal Tubular Acidosis

Companion Review of Renal Physiology Notes to be added soon. A bit lacking in detail, apologies, but I felt that massive revision of renal pumps would be needed before going further. Will update later.

Type I Renal Tubular Acidosis / Classic Distal RTA

  • Review of physiology
    • The DCT and CT together reclaim about 15% of filtered HCO3
    • In the cortical collecting tubule (CCT)
      • Urinary acidificaiton is indirectly coupled to Na+ transport and is influenced by the pd across membranes
      • Active Na+ reabsorption = active H+ secretion
      • Aldosterone increases the pd = H+ secretion
    • In the medullary collecting tubule (MCT)
      • Acidification not related to Na+ transport
      • Acidification occurs against an electrical gradient as an active process
    • Hydrogen ion secretion is mediated by 2 proton pumps in the intercalated cells
      • H+ATPase – regulated by aldosterone
      • H+,K+ ATPase –  responds to serum K+ level
  • Pathophysiology
    • Inability to adequately acidify urine due to decreased proton secretion in the distal nephron
    • 3 main mechanisms
      • Inability of proton pump to work against a high proton gradient
      • Back diffusion of pumped protons
      • Inadequate numbers of proton pumps due to tubular damage
    • Calcium is released from bone to buffer acid = hypercalciuria
    • Enhanced proximal citrate absorption = hypocitraturia
  • Causes
    • Genetic
    • Autoimmune (SS, SLE< thyroiditis)
    • Diseases associated with nephrocalcinosis
    • Intoxication (Amphotericin B, toluene)
    • Obstruction
  • Labs
    • Urine pH > 5.5 despite plasma HCO3 < 15mmol/l
    • NH4Cl acid loading test if HCO3 > 15mmol/l – load drops plasma bicarbonate but urine pH > 5.5
    • Renal Na+ wasting > hypovolemia > increased K+ urinary loss
    • Therefore, hyperchloraemic acidosis with alkaline urine
  • Presentation
    • Renal stones from hypercalciuria
    • Sx of hypokalemia
    • Marble-brain disease with dRTA
      • Mutation in carbonic anhydrase II
      • Osteopetrosis, short stature, and mental retardation
  • Treatment
    • Lifelong replacement of 1–3 mmol/kg bicarbonate

 

Type II Renal Tubular Acidosis / Proximal RTA

  • Pathophysiology
    • Impaired HCO3 reabsorption in the PCT
    • Two main variants
      • Isolated HCO3 wasting
      • Generalised proximal tubule dysfunction ( part of Fanconi syndrome)
    • Typically waste HCO3 until the serum level drops under 17mmol/l at which HCO3 becomes maximally reabsorbed
  • Causes
    • Autoimmune
    • Drug induced
    • Infiltratitive or other tubulopathies
    • Inherited diseases with tubular accumulation of toxic metabolites
      • Wilson’s
      • Cystinosis
      • Tyrosinemia
      • Galatosemia
      • Glycogen storage disease type I
      • Lowe’s
  • Labs
    • Fractional excretion of HCO3 > 15% when plasma HCO3 is at least 20 mmol/l
  • Treatment
    • Alkali treatment
      • When serum HCO3 is raised above the 17mmol/l threshold, wasting occurs which leads to hypokalemia s K+ is secreted down an electrical gradient
      • Therefore, 5-15mmol/kg daily of HCO3 + K+ supplementation

Type III Renal Tubal Acidosis

  • Historical term, now subtype of Type I where there is proximal HCO3 leak + distal loss of acidification

Type IV Renal Tubular Acidosis

  • Pathophysiology
    • The CCT actively reabsorbs Na+
      • Accompanied by passive Cl- reabsorbtion and K+ secretion
      • The negative intraluminal electric gradient geenrated by taking out Na+ is replaced helps active H+ secretion
    • Aldosterone stimulates both Na+ reabsorption and the H+ ATPase
    • If both pumps are affected hyperkalemic hyperchloremic metabolic acidosis will ensue
  • Causes
    • Aldosterone disorders
    • Voltage-dependent distal RTA
      • Urinary tract obstruction
      • Amiloride and lithium
  • Labs
    • Hyperkalemia (unlike the other RTAs)
    • Hyperchloraemia (like all the other RTAs)

 

Glomerular Disease 3 – Nephrotic Syndrome

Classic presentation

  • Heavy proteinuria
  • Minimal haematuria
  • Hypoalbuminemia
  • Hypercholestermia
  • Oedema
  • Hypertension

Minimal Change Disease

  • Numbers
    • 80% of childhood disease
    • 10% adult disease
  • Causes
    • Primary renal (main cause)
    • Hodgkin’s
    • Allergies
    • NSAID (typical an interstitial nephritis picture)
  • Pathology
    • No obvious light microscopy lesion
    • Small mesangial IgM / no deposits on immunofluorescence
    • Effacement of foot processes + slit membrane weakening on electron microscopy
  • Pathophysiology
    • Unclear
    • Possibly alteration of podocyte integraty by circulating cytokine
  • Clinical presentation
    • Abrupt nephrotic syndrome
    • Acellular urine
    • Proteinuria around 10g/day
      • In children, primarily albumin and less high MW proteins; selective proteinuria
    • Atopy / allergic symptoms in 1/3
    • Acute renal failure most commonly due to intrarenal oedema (responsive to diuresis and IV albumin)
  • Treatment
    • Steroids
      • Steroid resistance in adults = 4 months
      • 95% children have complete remission after 8/52
        • Prior to universal treatment of children with steroids, 30% would spontaneously resolve
      • 85% adults have complete remission after 24/52
      • Steroid resistance may be due to developing FSGS
    • Cyclophosphamide, clorambucil, mycophenolate, cyclosporin usually reserved for relapses

Focal Segmental Glomerulosclerosis

  • Numbers
    • 33% of adult cases
  • Causes
    • Primary
    • Viral
    • Hypertensive nephropathy
    • Opiods
    • Lymphoma
    • Sickle cell disease
    • Familial pdoctyopathies
    • Many, many other things
  • Pathology
    • Most prominent at corticomedullary junction
    • As the name suggests, there is focal and segmental scarring
    • Divided into 5 types
      • FSGS not otherwise specified
      • Perihilar FSGS
      • Cellular FSGS
      • Tip FSGS
      • Collapsing forms of FSGS
  • Presentation
    • Classic nephortic syndrome symptoms
  • Management
    • Primary FSGS
      • RAA-I
      • Steroids
      • Cyclosporin (but often relapse once off)
      • 35% of allografts relapse of which 50% loose the graft
    • Secondary
      • Underlying cause
      • No role for immunosupression

Membranous Glomerulonephritis

  • Numbers
    • 30% of adult disease
    • M:F 2:1
    • Rare in childhood, most common cause of nephrotic syndrome in the elderly
    • 30% associated with malignancy, infection or rheumatological disease
  • Pathology
    • Light: Uniform thickening of basement membrane along peripheral capillary loops
    • IHC: Diffuse granular deposits IgG and C3
    • EM: Subepithelial deposits
    • Subendothelial deposits / tubuloreticular inclusions = membranous lupus nephritis
  • Pathophysiology
    • In-situ immune complex formation
    • Putative antigens = neutral endopeptidase, hepatitis antigens B/C, H. pylori, tumor antigens, etc.
  • Presentation
    • 80% present with nephrotic syndrome
    • Microscopic haematuria in 50%
    • Highest rate of thromboses among the nephortic syndromes
  • Course
    • 1/3 will spontaneously remit late int he disease course
    • 1/3 have relapsing disease but maintain normal renal function
    • 1/3 progress to ESRD
  • Treatment
    • Steroids + and cyclophosphamide, chlorambucil, mycophenolate mofetil, or cyclosporine
    • Rituximab may be of benefit in refractory cases
    • Consider therapeutic anticoagulation

Diabetic Nephropathy

  • Covered elsewhere

Glomerular Deposition Diseases

  • Light chain deposition disease
    • Light chains either cause cast nephropathy which causes an acute interstitial nephitis or the nephrotic picture of LCD
    • Kappa light chains which do not form amyloid fibrils
    • Aggregation and deposition along glomerular capillary and mesangium, tubular BM and Bowman’s capsule
    • Detect with anti-light chain IHC / as granular deposits on EM
    • Treat underlying disease
  • Renal amyloidosis
    • See notes on amyloidosis
  • Fibrillary-immunotactoid glomerulopathy
    • Rare
    • Glomerular accumulation of nonbranching randomly arranged fibrils
    • Congo Red stains negative
    • Associations with CLL / B cell lymphoma

Fabry’s Disease

  • X-linked defeciency of lysosomal α-galactosidase A activity
  • Classic presentation of acroparesthesias, angiokeratoma, and hypohidrosis in childhood
  • Adult presentation of renal disease, cardiomyopathy and CVA
  • Covered elsewhere

 

 

 

 

 

Glomerular Disease 2 – The Acute Nephritic Syndromes

Slightly more detail than expected

Common Nephritic Presentation

  • Hypertension
  • Haematuria
  • RBC casts
  • Pyuria
  • Mild to moderate proteinuria

Poststreptococcal Glomerulonephritis

  • Pathology
    • Streptococcal antigens > immune complexes > deposition disease + activation complement leading to cell-mediated injury
  • Presentation
    • Antecedent disease of skin and throat infections with M strains of streptococci  (2-6/52 after skin infection; 1-3/52 after pharyngitis)
    • Classic nephritic syndrome
    • Systemic symptoms of
      • Hadache
      • Malaise
      • Anorexia
      • Flank pain
  • Labs
    • ASO titres (30%)
    • Anti-DNAse (70%)
    • Antihyaluronidase (40%)
    • Complement
      • CH50 low in 90% during first week of symptoms
      • Decreased C3, normal C4
    • Immunological panel
      • RF (35%)
      • Anti-MPO ANCA (10%)
  • Biopsy
    • Mesangial / endothelial hypercellularity
    • PMNL glomerular infiltrate
    • Subendothelial deposits of IgG, IgM, C3, C4, and C5-9
    • Subepithelial deposits
  • Treatment
    • Supportive
    • No role for immunosuppresive therapy

Subacute Bacterial Endocarditis

  • Develops over 10-14 days
  • Therefore unusual as treatment usually started before it can develop
  • Pathogenesis
    • Renal deposition of immune complexes
    • Activation of complement
  • Clinical picture
    • Haematuria, pyuria, mild proteinuria
    • PRGN
  • Labs
    • FBC: normocytic anaemia
    • Low complement
    • High RF titre
    • Type III cryoglobulins
    • Circulating immune complexes
  • Treatment
    • Eradication of infection

Lupus

  • Pathogenesis
    • Immune complex deposition > complement activation >  damage
    • Glomerular binding of nuclear antigens > in-situ deposition disease > damage
    • APL antibodies > thrombotic microangiopathy
  • Labs
    • Anti ds-DNA
    • Low complement
    • Biopsy
  • Pathological classification on biopsy
    • Class I – normal
    • Class II – mesangial immune complexes with mesangial proliferation
    • Class III – focal lesions with proliferation of scarring
    • Class IV – global, diffuse proliferative lesions
    • Class V – subepithelial immune deposits in a membranous pattern
  • Treatment
    • Class dependent
    • I and II – no tx
    • III – V
      • Induction with high dose steroids or cyclophosphamide
      • Maintenance with lower-dose steroids or mycophenate mofetil
      • Consideration of anticoagulation (class IV, V at risk of renal vein thrombosis + also possibility of APL)

IgA Nephropathy

  • Pathogenesis
    • Mesangial IgA compelx deposition + mesangial hypercellularity
    • IgM, IgG, C3 or IG light chains may also be deposited
  • Pathology
    • Light microscopy – DPGN, segmental sclerosis, segmental necrosis with cellular crescent formation
  • Presentations
    • Recurrent episodes of macroscopic haematuria +/- proteinuria following URTI
    • Persistent microscopic haematuria
    • Generally benign
  • Treatment
    • ACEI
    • Questionable benefit: tonsillectomy, steroids, fish oil
    • RPGN: steroids, cytotoxics, plasmapheresis

Small Vessel Vasculitis

  • The following vasculitis may cause a pauci-immiune glomerulonephritis
    • Wegener’s
    • Microscopic polyangiitis
    • Churg-Strauss
  • Pathogenesis
    • ANCA
      • Anti-proteinase 3
      • Anti-myloperoxidase
    • Unclear role of anti-Lamp-2
    • T cells produce ANCA > activate leukocytes + monocytes > endothelial damage > more leukocytes
  • Treatment
    • Induction: plasmapheresis +/- cyclophosphamide + methylpred
    • Maintenance: cyclophosphamide / azathioprine

Membranoproliferative Glomerulonephritis / Mesangiocapillary GN / Lobar GN

  • Pathology
    • Thickening of the GBM + mesangioproliferative changes
    • Divided into types
      • I
        • persistent hepatitis C, autoimmune disease or neoplasm
        • deposition or in-situ formed immune complexes
        • mesangial proliferation + lobular segmentation
        • mesangial interposition between BM and endothelium –  tram tracking
      • II
        • idiopathic, complement factor H deficiency, C3 nephritic factor, partial lipodystrophy
        • Dense depositis
        • Lobular glomerular tuft
        • nephirtic factors (autoantibodies that stabilise C3 convertase)
      • III
        • idiopathic, complement receptor deficiency
        • proliferation and mesangial interposition less common
        • nephirtic factors (autoantibodies that stabilise C3 convertase)
  • Presentation
    • Classic nephritic syndrome or RPGN
  • Tx
    • Steroids in primary disease, underlying cause in secondary disease
    • Known to recur in allografts

Mesangioproliferative Glomerulonephritis

  • Triad of
    • Mesangial expansion + hypercullarity
    • THin capillary walls
    • Mesangial immune deposits
  • Causes
    • IgA nephropathy
    • P. falciparum
    • Resolving postinfectious GN
    • Lupus Class II
    • Primary (idiopathic)
  • Pathology
    • IgM, C1q, C3 deposits
  • Treatment
    • RAA ihibitors, steroids
    • No clear consensus