Oh stones.

So exciting!!! And how very, very boring.

Let’s get it over and done with.

Epidemiology, commonest stone to least common:

Calcium oxalate + phosphate combined
Calcium oxalate
Calcium phosphate
Uric Acid

Calcium Oxalate (envelope shape)
– precipitates in alkaline urine

ca oxalate

The triad that causes it to form:

  • Hypercalciuria
    • Primary hyperPTH
    • Familial
    • High dietary salt – in the PT, salt loading reduces reabsorption of both calcium and sodium —-> high calcium loss in urine
    • (high protein load)
    • immobilisation
  • Hyperoxaluria
    • High dietary oxalate – rhubarb, tea, Vit C
    • Severe calcium restriction (need calcium to chelate oxalate in the gut)
    • Enteric hyperoxaluria
    • Primary hyperoxalosis
  • HyPOcitraturia
    • High dietary protein
      • hypocitraturia and acidic urine favours calcium oxalate stone
  • Hyperoxalosis
  • Others
    • Deficiency in intestinal flora –> oxalobacter fomigenes
    • Ethylene glycol

Hence to combat calcium oxalate stones:


  1. Hypercalciuria : Limit sodium intake
  2. Hyperoxaluria : Limit oxalate rich foods / calcium as binder
  3. Hypocitraturia : Limit protein intake, increase vege/fruit

Recurrent stones:

1, Hypercalciuria: : Thiazides —-> blocks NCC in DT, but also actives calcium channel, increasing calcium reabsorption from urine

2. Hypocitraturia : K citrate to alkalanise urine

3. NB Can have hyperuricosuria (with normal uCa) : allopurinol

Struvite (Coffin shape crystals)
– precipitates in alkaline urine


History of UTIs
– urease producing bacteria like proteus /Klebsiella
Urea + water ——urease—–> ammonia + co2
Ammonia causes an alkaline urine ——> precipitates Mg/urea/phosphate

Diagnosis: Staghorn calculi

Treatment :

  • Treat UTI and prophylaxis’
  • Surgical management


Calcium Phosphate
– precipitated in alkaline urine


  • T1 RTA/ dRTA (hypokalaemic hyperchloraemic metabolic acidosis)
  • Primary hyperPTH


  • K citrate


Uric Acid
– precipitates in acidic urine
– lucent on XR – cannot see


  • Acidic Urine
    • High protein intake
    • Chronic diarrhoea
    • Ileostomy
    • Obesity
  • Hyperuricosuria
    • Hyperuricaemia
      • Myoproliferative disease
      • Tumour lysis
      • Gout
    • Single gene defects
    • Drugs : e.g. losartan


  • 1st line : Alkalinise the urine : K citrate to raise urine pH to stop stone precipitation
  • 2nd line : Add in allopurinol as adjunct if K citrate not helpful


Cystine (Hexagonal crystals)
– precipitates in acidic urine

cystine stones

  • Defect in dibasic amino acid transport in renal tubules
    • Cystine
    • Orthinine
    • Lysine
    • Arginine
      • Lysine & Arginine are very soluble –> do not precipitate as stones

Type 1:

  • AR (ie often no FHx)
  • SCL3A1 mutation -> rBAT

Type 2

  • AD(?) (parents usually have high urinary cystine but no stones)
  • SCL7A9 mutation -> b0,+AT


  • Childhood or young adults
  • Mildly opaque stones
  • Can cause staghorns
  • Renal failure uncommon
  • Hexagonal cystine crystals in fresh sample pathognomonic
  • Stone analysis diagnostic if available


  • Cyanide-nitroprusside screening test
  • 24 hour urinary cystine excretion


  • Fluid intake (often 4L needed!)
  • Low salt dieet
  • Moderate dietary protein
  • Alkalinisation (aim >7)
  • Thiol drugs eg tiopronin or D-penicillamine or captopril or Vit C


APRT Deficiency

  • Deficiency of adenine phosphoribosyltransferase
  • 2,8-dihydroxyadeninuria
    • Nephrolithiasis
    • Tubulointerstitial nephritis and CKD
  • Autosomal recessive (AR)
  • Young age, red-brown smear in nappy
  • Radiolucent calculi
  • Stone analysis diagnostic
  • Maltese cross appearance of crystals on polarised microscopy
  • APRT enzyme activity in RBCs
  • Genetic testing helpful
  • Treatment = allopurinol or febuxostat





Membranous GN

How does it happen?

Build up of immune complexes along the GBM –> lost of podocyte foot processes –> thickening of the GBM –> sclerosis & hyalinisation of glomeruli

membranous-immunecomplex.pngImage from UNC Kidney Centre


What is seen on light microscopy?

Thickening of the GBM with little or no cellular proliferation or infiltration. As the disease progresses – chronic sclerosing glomerular and tubulointerstitial changes develop.


Image from

Long arrows show thickened GBM compared to short arrows showing tubular wall. *=mesangial expansion


Silver stain


Image from

Arrow showing ‘spikes’ along the GBM, which are new basement membrane growing in between the sup epithelial deposits.



IF ?

Diffuse granular pattern of IgG or C3 staining along the GBM.


Image from 

Diffuse granular IgG along the capillary walls


Subepithelial electron dense deposits on the outer aspect of the GBM, effacement of the foot processes of the overlying podocyte, and expansion of the GBM by deposition of new extracellular matrix between the deposits – known as ‘spikes’.

Primary/Idiopathic Membranous

  • electron dense deposits are exclusively sub epithelial and intramembranous.
  • tubular basement membrane staining is rare
  • IgG deposits are mostly IgG4
  • Staining for PLA2R and C1q
  • Staining for IgG1 and IgG3 and leukocyte invasion of the glom tuft is more in keeping with secondary MN


Causes of MN

  1. Specific targets
    1. Transmembrane receptor expressed in podocytes
      • Phospholipase A2 Receptor Ab – PLA2R Ab
      • Thrombospondin type-1 domain containing 7A (THSD7A)
    2. Peptides expressed by podocytes
      • neutral endopeptidase (from mom to child)
    3. Abs directed against other antigens
      • IgG4 against PLA2R etc
  2. Genetics
    1. PLA2R on chromosome 2q24
    2. HLA-DQA1 on chromosome 6p21
  3. SLE
    1. Stains for IgA,M and C1q with sub endothelial and sub epithelial deposits and tubuloreticular structures in the glomerular endothelial cells
  4. Drugs
    1. Penicillamine
    2. Gold
    3. Anti TNF agents
    4. NSAIDS
  5. Infections
    1. Hepatitis B with hypocomplementanaemia
    2. Hep C but less so
    3. Syphillis
  6. Malignancy
    • mostly solid tumours – prostate/lung/GI tract
    • less commonly haematological malignancy – CLL
      • deposition of tumor antigens in the glomeruli promotes antibody deposition and complement activation, leading to epithelial cell and GBM injury, and consequent proteinuria
      • in situ binding of antibodies to podocyte antigens – THSD7A & PLA2R
  7. IgG4 disease


and lastly MN can also be seen in conjunction with:

  1. Diabetes
  2. Crescentic GN – ANCA/GBM
  3. FSGS
  4. IgA
  5. Lupus


Tests to be carried out if kidney biopsy shows MN

  1. PLA2R Ab tires
  2. Complement (should be normal in just MN, but affected in SLE/Hepatitis)
  3. ANCA/dsDNA
  4. Malignancy screen


ACEi/ARB first

IS only if nephrotic AND AT LEAST ONE OF:

  1. UPCR > 400 + 50% over baseline value that has not improved since starting ACEi/ARBs AFTER 6 months
  2. Life threatening complications with nephrotic sydrome
  3. Creat increase >30% in 6-12 months AND GFR remains 25-30 with changes not explained by superimposed complications

1st line: Treat with Ponticelli regimen :

  • 6 months
  • alternative oral/IV steroids and oral CYC (preferred) or chlorambucil
  • After 6 months, manage conservatively for another 6 months
  • Can use continuous daily oral CYC/chlorambucil

2nd line (if 1st line contra indicated or resistant):

  • CNI  – CyA /Fk
    • For at least 6 months
    • IF fail : STOP CNI
    • IF remission : decrease CNI every 4-8 weeks to 50% of starting dose and continue for 1 year

– use initial therapy that worked to achieve remission
– Ponticelli can only be repeated ONCE. Do not use more than once in children


Drugs Used in Renal Transplantation

I use these drugs rather a lot. In fact, all the time. This would be a good time to revise their actual indications and what they are; I mean it will be embarrassing if someone asks what EXACTLY do they do and I cannot answer… so, without much further ado:


Induction Therapy

Basiliximab (Simulect) : IL2 receptor antagonist. Interleukin 2 (IL2) is a cytokine signallfing molecule for T cells proliferation. IL-2 is activated via calcineurin-mediated pathways of transcription, translation and section of IL-2 by activated T cells, dendritic cells and B cells. IL-2 then binds to IL-2 receptor expressing cells further activating proliferation of CD4+ and CD8+ cells, NK cells and macrophages. It also produces regulatory T cells in the thymus – has roles in both tolerance and immunity.

Alemtuzumab (Campath) : humanized anti CD52 panlymphocytic (B and T cells) monoclonal antibody. CD52 is a protein present on mature lymphocytes (not in the stem cells) and Campath binds to these lymphocytes and it is removed by our immune system

ATG; rabbit antithymocyte globulin : Polyclonal antibody against a wide variety of T-cell surface antigens including the MHC (major histocompatibility complex) antigens.

Rituximab : anti CD 20 antibody. Anti CD20 is expressed on the surface of all B cells in the early pre-B cells to later in differentiation but not present in terminally differentiated plasma cells. Function of CD20 is not fully known, but it allows activation of the B cell by maintaining intracellular calcium concentrations. RTX sticks to CD20 forming a cap drawing NK cells to kill it.

Maintainence Therapy

Calcineurin Inhibitors : Cyclosporin (CyA) & Tacrolimus (FK52) : selectively inhibit calcineurin thus prevents transcription of IL-2 and other cytokines in T lymphocytes

Cyclosporin : binds to cyclophillins; Tacrolimus : binds to FK-binding protein; both part of the family of cytoplasmic proteins present in most cells. When bound (CyA-Cyclophillins , FK52-FK) these drug-receptor complex binds and selectively inhibits calcineurin, a calcium/calmodulin-dependant phosphatase thus preventing transcription of IL2, IL3, IL4, TNF, granulocyte-macrophage colony-stimulating factor, and interferon-gamm :  ultimately preventing the formation of T cells

Problems with CNIs:

System Target Mechanism of Action Side Effects
Renal Vasoconstriction of afferent & efferent arterioles Endothelial cell impairment

Reduced production of vasodilators (PG & NO)

Enhanced release of vasoconstrictors (thromboxane & endothelin)

Increased sympathetic tone

Reduced renal blood flow (RBF)

Reduced GFR

Renal vasoconstriction and sodium retention

Stimulation of the Na-Cl cotransporter


– calcium channel blockers are considered drug of choice to Rx HTN e.g. diltiazem; also reduces acute vasoconstriction (in the short term)

Inhibition of Na-K-ATPase in the cortical collecting duct Hyperkalaemia


Damage to tubules and reduced RBF Decreased uric acid secretion Hyperuriecaemia


Reduced Mg reabsorption HypoMg
Phosphate wasting Hypophosphatemia
Impaired acid secretion

Decreased aldo activitu

Metabolic acidosis (type 4 RTA)
Injury to the vascular endothelial cells HUS


Obliterative arteriolopathy (suggesting primary endothelial damage), ischemic collapse or scarring of the glomeruli, vacuolization of the tubules, global and focal segmental glomerulosclerosis, and focal areas of tubular atrophy and interstitial fibrosis (producing a picture of “striped” fibrosis) Chromic CIN toxicity
Liver Substrate for cytochrome P450 3A4/5 & CYP3A4/5 Drugs such as ketoconazole, diltiazem increases CNI concentratioins
Neuro Tremor


Marrow oedema seen on MRI CNI-pain syndrome. Symmentrical bone pain of lower extremeties. Helped by Ca channel blocker


Reversible toxicity to islet cells May directly affect transcriptional regulation of insulin expression &

severe swelling and vacuolization of islet cells

Cosmetic – only with CyA Gums Gingival hyperplasia
Hair Hirsustism



Mycophenolate mofetil (MMF) : Reversibly inhibits inosine monophosphate , the enzyme that controls the rate of synthesis of guanine monophosphate in de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes.

Azathioprine : A prodrug that gets broken down to 6 mercaptopurine (6 MP) by reductive cleavage of the thioester and mediated by glutathione and other enzymes.6MP is metabolised to natural purines, collectively we shall call them 6 thioguanine nucleotides (6 TGN) which:

  1. blocks purine synthesis ie blocking DNA synthesis, particularly in B and T cells
  2. incorporated into RNA, compromising functionality
  3. causes activation of T cell apoptosis
  4. blocks CD28 stimulation; required for T cell activation
  5. aza-mech-action


Sirolimus/Rapamycin : inhibits the mammalian/mechanistic targetof rapamycin (mTOR); a serine/threonine specific protein kinase. mTOR regulates cellular metabolism, growth and proliferation through signalling via 2 protein complexes mTORC1 and mTORC2. Sirolimus enters the cytoplasm -> binds to FK binding protein -> inhibits IL2 mediated signal transduction -> cell cycle arrest G1-S phase. Blocks the cytokines -> unable to activate B and T cells to proliferate (in contrast, CNIs inhibit the production of cytokines).

Finally, the picture below illustrates where these drugs all work and for ease sake:


and just because the above doesn’t cater to all my needs and understanding, here is another coloured picture that shows oust IL-2 receptor is also known as CD 25, CD52 is also found on the surface of T cells and ATG affects loads of other CD receptors on the T cell.



Cryoglubulins & The Kidney

In short – CG

CGs are immunoglobulins and complement components that precipitate upon refrigeration of plasma.

Brouet’s Classification of CG



Everyone in general has a low level of CG; this reflects ongoing background clearance of endogenous immune complexes with RF activity. Abnormally raised levels of  CG would mean:

  1. Chronic immune stimulation or lymphoproliferative disease leading to higher concentrations of mono, oligo or polyclonal CGs.
  2. Immune complex formation between the CGs and their target antigens
  3. Insufficient or defective clearing of CGs

Mixed CGs

  • Deposition of Ab-Ag complexes in capillaries and small arterioles along the vessel wall with cryoproteins within the vessel lumen
  • Skin biopsy shows a leukocytoclastic vasculitis
  • C4 is normally low (but not always) reflecting complement consumption via the classical pathway of the complement cascade

CGs and the Kidney

  • >80% show MPGN with thickening of the GBM and cellular proliferation and +++macrophages
  • Light microscopy : capillary microthrombi
  • Immunofluoroscence : Diffuse IgM deposition in the capillary loops
  • EM : Subendothelial deposits in the mesangium with characteristics ‘finger print’ appearance. CGs are too big to pass through the GBM hence uncommon to appear in the sub epithelial space
  • Presentation can be:
    • Haematuria +/- renal insufficiency
    • Nephrotic syndrome
    • Acute nephritis
    • AKI



Source : The Lancet, 2012



Focal segmental glomerulosclerosis – a histologic lesion which is due to injury to visceral epithelial cell or podocyte which is attached to the GBM via foot processes. Can also involve injury to parietal epithelial cells.

How is FSGS formed in the kidney?

  1. Podocyte injury


2. Sclerosis



  1. Insidious onset of nephrotic syndrome
  2. Microscopic haematuria with varying ranges of proteinuria
  3. Hypertension
  4. Renal insufficiency

Primary/Idiopathic FSGS

  • most often presents with nephrotic syndrome
    • Causes postulated:
      • High level of suPAR (soluble urokinase plasminogen activating receptor)
        • induces FSGS in mice
      • Expression of microRNA in podocytes leading to down regulation of Wilms Tumour protein (important for a variety of genes involved in podocyte function) may be an intracellular mechanism responsible
        • found in glomeruli of patients with acquired (non genetic) FSGS

Secondary FSGS

  • normally non-nephrotic range proteinuria with some CKD
  • result from scarring due to a previous injury
    • Focal proliferative GN, e.g. active IgA, lupus nephritis, vasculitis
    • Hereditary nephritis, e.g. Alport’s
    • Membranous
    • TMA
  • refers to FSGS due to adaptive response/compensation to hyper filtration or glomerular hypertrophy
    • Disorders with reduced renal mass and/or renal vasodilation, e.g. unilateral renal agenesis, CAN
    • Renal vasodilatation e.g. in diabetes, sickle cell anaemia, Type 1 glycogen storage disorders, familial autonomic insufficiency
    • Intraglomerular hypertrophy/hyperfiltration e.g. due to severe pre eclampsia, anabolic steroid use, interferon use and obesity
    • Prior nephron loss e.g. reflux nephropathy
    • Ischaemia e.g. in benign hypertensive nephrosclerosis
  • Infections/Virus Associated
    • HIV (HIVAN)
    • Parvovirus B19
  • Toxins/drugs
    • CyA, pamidronate/alendronate, heroin, interferon-a, Lithium
  • Genetic abnormalities/Familial
    • Autosomal dominant with variable penetrance.
    • Normally steroid resistant
    •  NPHS1 – nephrin (can be tested), NPHS2 – podocin (can be tested), alpha-actinin-4, the TRPC6 ion channel, CD2AP
    • 2ndy FSGS familial forms copy
    • Microsoft Word - cqn_61_Figures
      Parts of the podocyte where genetics can cause podocytopathy
  • renal atherothromboembolic disease
  • Malignancy
    • Lymphoma

Differentiation between primary and secondary FSGS

  • Primary normally presents with acute or subacute onset of nephrotic syndrome; secondary will have non nephrotic range proteinuria, presenting with increasing proteinuria and rising Cr over a period of time
  • Histologically, primary FSGS has diffuse foot process fusion; in secondary FSGS, this tends to be focal and limited to the sclerotic areas
  • Treatment wise, 50-60% of primary FSGS respond to steroids while aim of treating secondary FSGS is to reduce intraglomerular pressure, i.e. with the use of ACEi.

Diff FSGS copy

And as if that isn’t enough, someone decided that FSGS can also be subdivided to their histologic variants.


  • fsgs_4-types

Collapsing variant associated with

  • Parvovirus
  • APOL1 gene
  • Bisphosphonate therapy

APOL1 – Apolipoprotein L1 gene

  • An important gene to talk about.
  • Polymorphism in the region of MYH9 on chromosome 22
  • Common in African Americans vs European (60% vs 4%)
  • Increase risk of FSGS and HIVAN
  • Defense against a subspecies of Trypanosomes, conferring an advantage against the sleeping sickness


KDIGO Definition of FSGS in Adults

Classification Definition
Complete remission <0.3g/d proteinuria

Normal Cr

Albumin >35

Partial remission 0.3-3.5g/d

Cr change <25% OR


Decrease > 50% Cr and change in Cr <25%

Relapse >3.5g/d after complete remission
Frequent relapse Not defined
Steroid dependent 2 relapses during therapy OR

within 2 weeks of completing steroid therapy

Steroid resistant Persistence of proteinuria despite pred 1mg/kg/d or 2mg/kg/d alt day for >4months

Initial treatment

Only FSGS with nephrotic syndrome – steroids/IS therapy

1st line therapy : Steroids to be given at 1mg/kg/d (max 80mg) or 2mg/kg/d alt days (max 120mg)

Treatment continuation for steroids

  • Min 4 weeks to max 16 weeks, as tolerated
    • Until remission has been achieved or 16 weeks, whichever is earlier
  • Tapered over 6 months when remission achieved
  • If steroids CI e.g. diabetes/osteoporosis/psychiatric condition
    • 1st line therapy : CNIs


  • 1st line : oral cyclophosphamide 2-2.5mg/kg/d for 8 weeks
  • 2nd line: relapse despite cyclo/wish to protect fertiliity : CNI; Fk 0.05-0.1mg/kg/d or CyA 3-5mg/kg/d in divided doses
  • 3rd line : if not tolerant of steroids/cyclo/CNIs : MMF 500-1g BD for 1-2 years

Steroid resistant FSGS

  • CyA 3-5mg/kg/d in divided doses for 4-6 months
    • if partial/complete remission, continue with slow taper for at least 12 months
  • If CyA NOT tolerated
    • MMF and high dose dexamethasone

Complement Pathways

And then there were 3.

3 pathways to rule them all – destroying microbes, clearance of cellular debris/apoptotic cells and promote inflammation.

The classical, lectin and alternative pathways.

Each pathway is activated by a different mechanism. The major goal of all three cascades is the deposition of large quantities of C3b on a target (opsonization), which marks it for elimination. Engagement of each pathway also leads to the release of proinflammatory anaphylatoxins (C3a and C5a) and assembly of the membrane attack complex (MAC).


But I mean, let’s face it. What we really want to know is how to interpret the tests and what they mean right?

So let’s make it simple.

Classical pathway is represented by C4 levels.
Alternative pathway is represented by C3 levels


Low C3/C4 or Low C3 only can represent – both pathways activated:

  1. Antiphospholipid syndrome
  2. Mixed cryoglobulinemia
  3. Sjögren’s syndrome
  4. MPGN
  5. Any causes of circulating immune complexes – IE, hepatitis, mononucleosis, shunt nephritis

Low C4 but normal C3

  1. Hereditary angioedema
  2. Acquired C1 inhibitor deficiency
  3. Genetic partial deficiency of C4

But sometimes SLE too as C3 is 6x higher in concentration than C4 and while it falls, the level might still remain in the ‘normal limit’ whereas C4 levels will have dropped below the lab limit.

Things to note : The complement system is designed to work onthe biological membrane. In diseases like angioedema, C3 convertase works poorly in the plasma (fluid) phase, hence C3 levels appear normal (but they are also consumed) as they are not broken down whereas C4 levels are low.

But in syndromes involving excessive soluble immune complexes, such as mixed cryoglobulinemia, SLE, and MPGN can also lead to ‘normal’ C3 but low C4. Hence, screen for all the above if complement is low!

Alternative pathway activation is indicated by low levels of factor B, low C3 with normal C4 and is a pathway that is constantly working at a low level behind the scenes (like how your heart beats all the time!)


Now, sometimes I feel certain things are easier to be explained using layman terms. Too much medical jargon makes one’s head go round and round.

Especially explaining things that are just LETTERS. I mean H, I, B … they are just that. Alphabets.

So I’m going to say there are accelerators and brakes in the alternative pathway system.

Complement Factor H (CFH), Factor I (CFI) and Membrane cofactor protein (MCP) are all BRAKES.

Complement Factor B (CFB) and D (CFD) are ACCELERATORS.

So something comes along and activates our dear old alternative pathway. C3 generates C3b which binds indiscriminately to pathogens and host cells. On a foreign surface, such as a bacterium, C3b binds CFB, which is then cleaved by Factor D to form the C3 convertase C3bBb. This amplifies the C3 convertase loop leading to formation of the MAC that kills of the bacteria.

Now if this continues to go into overdrive (i.e. the accelerators are being stepped on all the time) pretty soon we will be attacking all cell surfaces which leads to all sorts of problems. Our brakes CFH, CFI and MCP are there to police this. Competition between CFH (which is the main player) binding to C3b limits the binding of CFB instead hence reducing C3 convertases and reducing MAC formation.

Got it?

In summary (but not exclusively)

 Disease C3 (Alternative, spont hydrolysis, pathogens, damaged cells) C4 (Classical, Ag-Ab complex)
SLE ↓↓
MCGN type 1 ↓ or → ↓↓
Cryo ↓ or → ↓↓
Hereditary angiooedema ↓↓
C3GN ↓ or →
Infection eg SBE ↓ or →
Severe sepsis ↓ or →
Hepatic failure


Membranoproliferative glomerulonephritis, i.e. mesangiocapillary glomerulonephritis.

What a bloody mouthful.

Again, one of the GNs that just sound difficult in medical school and needs some thinking into it. The problem is that the definitions and classifications have been changed multiple times throughout the years and what I learned 10 years ago is probably not relevant anymore now.

Anyhow, I digress.

Firstly – MPGN has characteristic changes on LIGHT MICROSCOPY.

  • Immune complex/complement factors deposit onto the GBM, leading to thickening of the GBM. This then leads to inter positioning of the mesangium & endothelial cells  with the GBM leading to laying down of new GBM; hence double contouring of the glomerular capillary walls.
  •  This also leads to mesangial hypercellularity and endocapillary proliferation, causing a lobular appearance of the glomerular tuft.

Electron microscopy (EM) in immunoglobulin-positive MPGN typically demonstrates subendothelial and mesangial deposits. EM does not differentiate immune complex or complement mediated MPGN.

MPGN can be classified into 2 separate entities:

Immune complex mediated – c3 and Ig staining along capillary wall in a granular pattern vs linear pattern in anti GBM  :


i)chronic infections (HCV : shows granular deposition of IgM, C3, and both kappa and lambda light chains +/- IgG; HBV, TB, coxiella, brucella, nocardia) or carrier state (mycoplasma, Neisseria, strep) -> this causes chronic low grade Ab production.

ii)Monoclonal gammopathies like MGUS (deposition of monotypic kappa or lambda light chains but not both), and less likely, myeloma, Non Hodgkin’s lymphoma and CLL.

iii) Autoimmune diseases :  typically characterized by the “full house” pattern of immunoglobulin deposition, including IgG, IgM, IgA, C1q, C3, and kappa and lambda light chains. Most common is SLE, followed by Sjogren’s and then RA

Recurrence of MPGN with monoclonal IgG deposits has been described in transplanted kidneys (idiopathic immune complex mediated MPGN)

Complement mediated – dysregulation and persistent activation of the alternative complement pathway. Immunoflorescence demonstrates bright c3 staining (No Ig in the mesangium and capillary walls). Complement can be low or not, especially in the chronic phase of DDD and C3GN


Dense Deposit Disease – activation of the alternative complement pathway (negative staining for C1q and C4 which is the classical complement pathway)

EM shows characteristic sausage-shaped, wavy, densely osmophilic deposits along the glomerular basement membranes (GBM) and mesangium.

Aetiology is likely due to an absence of a constitutive inhibitor of the alternative complement pathway (factor H) or the presence of a circulating autoantibody (C3 nephritic factor; CNefs) that binds to and prevents inactivation of the alternative pathway C3 convertase (80% have elevated levels).

External manifestations:

  • drusen in Bruch’s membrane of the retina (like macular deposits in age related macular degeneration, however, drusen in DDD occurs at a much younger age).
  • Acquired partial lipodystrophy characterized by loss of subcutaneous fat in the upper half of the body

DDD is also occasionally diagnosed in older adults, some of whom have been found to have an underlying monoclonal gammopathy

Age of onset 5-15 years
ESRF in 50% by 10 years

C3 glomerulonephritis

C3GN has also been reported in association with monoclonal gammopathies and anti-factor H activity, as well as with inherited disease due to mutations in the CFHR5 gene (CFHR5 nephropathy) and a mutation producing a CFHR1-CFHR3 hybrid gene.

Similar appearances in light microscopy and immunoflorescence BUT EM demonstrates deposits that are similar to those seen with immune complex-mediated MPGN but does not show the typical sausage-shaped intramembranous and mesangial deposits observed in DDD

CFHR5 nephropathy – a familial form of C3GN, in cypriot families  due to a mutation in the gene for complement factor H-related protein 5. Autosomal dominant with 90% penetrance. Can reoccur in transplanted kidney.
IgA like phenotype, Greek Cypriot patient can present with haematuria after a LRTI

What if one gets sub epithelial deposits and sub endothelial deposits too ? If they are both complement + and Ig + , post infections GN is what is happening. What if its complement + but Ig – ? It could be resolving post infections GN, OR undiagnosed C3GN – check their complement pathway!!

And finally, MPGN features but negative for complement or immunoglobulins?

  • TMA : TTP, HUS, drug induced
  • Antiphospholipid Ab Syndrome
  • Nephropathy associated with bone marrow transplantation
  • Chronic renal allograft nephropathy
  • Radiation nephritis
  • Malignant hypertension


Treatment, according to KDIGO

Treat if:

  1. Nephrotic syndrome AND
  2. progressive decline in GFR AND OR
  3. Crescents

With immunosuppression, COMBINED

ie steroids + MMF or CYC

Therapy < 6 months