Complement and renal TMA

Alright, this is totally complicated. What is the best way to approach this?

Slowly. And my way of understanding it.

Ok, let’s start with what TMA actually is: thrombosis in capillaries and arterioles, due to an endothelial injury.

Clinical features?

  1. Thrombocytopenia
  2. MAHA
  3. Organ injury

Simply put, TMA can be subcategorised MANY different ways.

They include HUS, TTP,disseminated intravascular coagulation, scleroderma renal crisis, malignant hypertension, antiphospholipid antibody syndrome, and drug toxicities, e.g. calcineurin inhibitor toxicity

For the purpose of this entry, I will focus on HUS (typical and atypical), TTP, aHUS and just very quickly, because it is renal – TMA in transplant rejection.

Haemolytic Uraemic Syndrome

The syndrome of:

  • MAHA (shearing of RBC through platelet micro thrombi)
    • Tests: Coombs (will be negative), haemolytic screen, blood film, LDH
  • Thrombocytopenia
  • AKI (normally hypertensive)

Causes:

Typical/Secondary:

  • Infection
    • Shiga toxin-producting E. Coli (STEC)/verotoxin 0157
    • Shigella
    • Strep Pneumonia
    • HIV
  • Drugs
  • Preganancy
  • Other autoimmune conditions

Other organs affected:

  • Central nervous system – Manifestations of central nervous system (CNS) involvement include seizures, coma, stroke, hemiparesis, and cortical blindness.In addition, severe hypertension may result in CNS symptoms and require emergent therapy to decrease blood pressure. The presence of severe hypertension and the response to antihypertensive therapy differentiates CNS involvement due to elevated blood pressure.
  • Gastrointestinal tract – Any area from the esophagus to the perianal area can be involved. The more serious manifestations include severe hemorrhagic colitis (which may be misdiagnosed as ulcerative colitis), bowel necrosis and perforation, rectal prolapse, peritonitis, and intussusception. Transmural necrosis of the colon may lead to subsequent colonic stricture.
  • Cardiac dysfunction – Cardiac dysfunction can be due to cardiac ischemia detected by elevated levels of troponin and fluid overload.
  • Pancreas – During the acute phase, up to 10 percent of patients develop glucose intolerance. Transient diabetes mellitus may occur, and rarely permanent diabetes mellitus, which may develop years later.
  • Liver – Hepatomegaly and/or increased serum transaminases are frequent findings.
  • Hematology – In addition to anemia and thrombocytopenia, leukocytosis is common in diarrhea-induced HUS; the prognosis is worse with increased white blood cell counts

 

Thrombotic Thrombocytopenic Purpura

Slide1

  • Severe AKI is unusual in TTP
  • Hereditary TTP (also called Upshaw–Schulman syndrome) is caused by homozygous or compound heterozygous ADAMTS13 mutations.
  • Acquired TTP is an autoimmune disorder caused by autoantibody inhibition of ADAMTS13 activity
    • ADAMTS13 is a von Willebrand Factor cleaving protease
    • Inhibition leads to large multimers of vWF, increasing risk of platelet thrombi leading to damage to endothelium
    • This leads to TMA and organ failureADAMTS13

 

  • In a nutshell, if you suspect TTP, TREAT! but send ADAMTS13 assay. If it is negative, it generally rules out TTP.

 

TMA in Transplant Rejection

  • Antibody mediated rejection
  • C4d + : Acute humoral rejection(AHR); C4d – : Acute cellular rejection (ACR)
  • Risk of graft loss is greater in AHRSlide2
    The Ab-Ag complex in AHR activates C1 which starts the pathway. C4d is a by product of this

 

Renal histology findings:

  • thrombosis of vessels
  • fibrinoid necrosis of arterioles
  • oedematous expansion of arteries – double contouring

Treatment

  1. Plasma exchange
  2. Eculizumab, an a monoclonal antibody to C5 that blocks the terminal complement cascade
  3. Renal +/- hepatic transplant
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Anti GBM Disease

Goodpasture’s Syndrome in old terms.

Again, one of these very renal specific diseases that can likewise cause pulmonary haemorrhage in 40-60% of cases.

Sometimes, it is easier to understand the mechanism of the disease in the first instance.

So, for whatever reason : idiopathic; a chest infection that causes damage to the pulmonary lining – hence revealing an epitope that triggers the Ab to be formed; damage to the GBM with urinary tract obstruction or lithotripsy; genetic susceptibility : HLA-DR15 (confirmed in Chinese and Japanese population0 and DR4 appear to be at increased risk, while those with DR1 and DR7 are at lesser risk – sucks to be me; causes anti GBM Ab (typically IgG 1 or 3 but can also be IgA or IgM) to be made which targets type 4 collagen. If you really want to know – the NC1 domain of the alpha 3 chain -stop being a nerd. Well, they bind most strongly to alpha-3(IV) NC, but the majority also recognized alpha-5(IV) and, to a lesser extent, alpha-4(IV).

So these tiny bastards are floating around your body looking for any basement membrane to bind to and damage it – namely the GBM in your kidneys or alveolar basement membranes in your lungs. BUT!!  Patients without alveolar haemorrhage were found to also carry similar autoAb against alpha-3(IV) NC hence some sort of increase in alveolar permeability is required for access to the alveolar basement membrane. Patients with pulmonary haemorrhage were found to have some underlying lung damage – smoking, cocaine inhalation, infections, hydrocarbon exposure —- time to pack them ciggies away and  kick the coke habit.

So a patient pitches up – they can become completely anuric and alarm bells should start to ring..

Urine dip can show proteinuria (but not in the nephrotic range) and microscopy show dysmorphic red cells, white cells, red and granular casts.

Chest XRays can show pulmonary haemorrhage and a raised KCO due to increase diffusion across the alveoli because of bleeding.

You panic, stuff in a catheter,  get an urgent US to ensure they haven’t completely thrombosesd off their vasculature, take some bloods and send them off for an acute nephritic screen. And the results come back showing raised anti GBM titres but also a positive ANCA. Up to 1/3 of patient with anti GBM have a positive ANCA- mostly MPO-ANCA and blood tests of a batch of military men (they keep their blood many years in advance, why?!) who went on to develop anti GBM disease later showed that they had low levels of ANCA in the past. Mechanism moi? Not sure.

A kidney biopsy is done (of course, ain’t nephrologists for nothing) and light microscopy normally shows a crescentic GN and immunofluorescence – the pathognomonic features of linear IgG deposition along the glomerular capillaries or the distal tubules,

How to treat?

Principle 1 is to get rid of the circulating antibodies. The most efficient way is via plasmapheresis. Quick to do, stick a line in and start.

Principle 2 is to immune suppress. Steroids at 1mg/kg and taper when remission is induced or cyclophosphamide at 2mg/kg and consider azathioprine in the longer term. Of course, our good friend rituximab has also shown to be anecdotally useful.

As a general finding, those with < 30% crescents and a plasma creatinine below 265 micromol/L did well, while those with severe crescentic involvement and a plasma creatinine 354 micromol/L did poorly.

KDIGO guidelines recommend that treatment should be initiated in all patients with

  • pulmonary haemorrhage independent of kidney involvement
  • anti GBM GN at presentation UNLESS they are dialysis dependant or have 100% crescents on biopsy and do not have pulmonary haemorrhage
  • no maintenance IS for anti GBM GN
  • to consider transplantation after anti GBM Ab remain undetectable for 6 months

The predictors of kidney survival in anti-GBM GN are

  • SCr at presentation
  • the need for dialysis at presentation, and the
  • percentage of glomerular crescents

Like all autoimmune diseases, this is a shitty one to have as it is aggressive, treatment options aren’t great and although most patients spontaneously go into remission in 12 months, it can reoccur and once ESRF sets it, very few patients come of dialysis.

 

IgG4-related disease

Right. I admit, I’ve never heard of this disease until this year. That is 2016.

Is it rare? Yes it is.

Do you need to know about it? Probably not.

Yet, there it is in all literature.

What is it?

It is a immune-mediated condition comprised of a collection of disorders that share particular pathologic, serologic, and clinical features.

There. See? It all makes sense now.

They all mostly share features including:

  • a tumour-like swelling of involved organs
  • a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cell
  • a variable degree of fibrosis that has a characteristic “storiform” pattern

What do they get? A whole range of disorders, but mainly:

  1. Type 1 (IgG4-related) autoimmune pancreatitis (AIP)
  2. Sclerosing cholangitis
  3. Aortitis/periaortitis
  4. Sialedinitis- Mikulicz’s disease and sclerosing sialadenitis (Küttner’s tumor)
  5. Retroperitoneal fibrosis – involve the infrarenal aorta and iliac arteries. Chronic inflammation and fibrotic change can involve ureters -> obstructive uropathy
  6. Renal involvement in 1/3
  7. Reidel’s thyroiditis / fibrous variant of Hashimoto’s thyroiditis
  8. Lung & pleural disease – visceral/parietal thickening can occur, tissues have lymphoplasmacytic infiltrates enriched in IgG4+ plasma cells. Obliterative arteritis is common
  9. Orbital pseudotumor or proptosis

Renal Involvement

The most common finding is tubulo-interstitial nephritis. Histology shows lymphoplasmacytic rich infiltrate in the renal interstitium and fibrosis. Immunohistochemistry shows IgG4+ plasma cells.

Patients have profound hypocomplementaemia – but IgG4 binds poorly to complement. Is IgG1 or 3 responsible activating this?

A small group has IgG4-related membranous nephropathy and occurrence together with TIN is possible.

Treatment

The evidence is overall poor, but:

  1. steroids can induce remission in 4 weeks
  2. Next line: Rituximab – off lable
  3. If RTX not available – Azathioprine or MMF  -but no trials

 

Kidney Biopsies

Linear IgG deposition, occurs in:

  • Anti GBM disease (crescents, very strong staining)
  • Diabetes (no crescents, diabetic glomerosclerosis, IgG is non selectively absorbed into the highly permeable capillary wall, there is deposition of albumin & other plasma proteins)
  • Fibrillary GN (IgG absorbed into the fibrils)