Anaemia in CKD


A quick update in interpreting blood tests


In CKD stages 1,2 and 3a, anaemia is not solely due to EPO loss

Why do they become anaemic

HD patients have normal EPO levels but need higher levels to maintain Hb, hence they are commonly anaemic.

EPO replacement

  • When to start?   Hb< 10, symptomatic. Aim for Hb 10-12
  • Why is there a poor response?



  • Adverse effects of high levels of EPO
  1. Hypertension (Increased RAS activation)
  2. Vascular remodeling (Angiogenesis, VSMC proliferation)
  3. Proliferative retinopathy
  4. Tumour genesis
  5. Thrombosis (Platelet activation)
  • TREAT study – EPO doubled stroke risk, VTE risk, increased in arterial thromboembolic events , increase in cancer related deaths


Iron replacement

  • When to start?  Ferritin < 100, hypochromic red cells >6%, TSAT < 20%
  • Give IV iron. Why?
    • Poor absorption in dialysis patients
    • State of inflammation up regulates hepcidin levels –> iron trapping within macrophages and liver cells and decreased gut iron absorption
    • GI adverse effects
  • Adverse effects? Unknown. Await PIVOTAL trial (in the UK)
  • So far, iron appears to be safe in increasing Hb in patients with no side effects seen


The Future?

Hypoxia Inducible Factor (HIF) stabilisers

  • Mimicking high altitude
  • HIF is activated under hypoxic situations
  • HIF stabilisers inhibit the enzyme that breaks down HIF
  • Increases patients EPO level
  • Undergoing trials

Now for some guidelines for exam purposes:


KDIGO 2012 RA 2017 K-DOQI 2006
%HRC >6%
CHr <29 pg
TSAT <30% <20% <20%
Ferritin <500 (if TSAT <30%)

Avoid if >500

<200 (HD)

<100 (CKD/PD)

Review if >500

Avoid allowing levels >800

<200 (HD)

<100 (CKD / PD)

Aim 200-500

Do not start ESA if ferritin <100

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)



  • 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


  • 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.

2ndy causes TMA copy

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


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

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 population and DR4 appear to be at increased risk, while those with DR1 and DR7 are at lesser risk; 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.

Peripheral eosiniphilia in 33-48%

Positive ANA in 30%

Raised IgE 

Low Complements


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

Anatomy of the Bowman’s Capsule

Kidney bx cartoon copy

EP : epithelial membrane
LRE : Lamina rara externa
LD : Lamina densa
LRI : Lamina rara interna
EN : Endothelial membrane

The Glomerular Basement Membrane

Layer Location Composition Function
lamina rara externa adjacent to podocyte processes heparan sulfate blocks by charge
lamina densa dark central zone type 4 collagen and laminin blocks by size (Molecular Weight > 5800kDa)
lamina rara interna adjacent to endothelial cells heparan sulfate blocks by charge

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)
  • Light chain disease
  • Alport’s after transplantation

Nodular mesangium:

  • Light chains
  • Amyloid
  • Diabetes
  • Chronic MPGN
  • Organised glomerular deposits disease
    • fibrillary GN
    • immunotactoid GN
    • fibronectin GN
    • collagen III GN
  • Idiopathic
    • Smoking
    • HTN
  • Chronic hypoxic/ischaemic conditions
    • Takayasu’s , RAS
    • cyanotic congenital heart disease
    • CF

Granular IgG deposition:

  • membranous
  • MPGN
  • PIGN

Mesangial Proliferation Differential Diagnosis:

DD mesangial prolif copy


Presence of tubuloreticular inclusion bodies:

  • lupus nephritis
  • Alfa interferon therapy
  • HIV(AN)
  • Viral infections

Full house Ig staining:

  • Lupus
  • SBE / shunt nephritis
  • PIGN (Rare)

Kidney bx of SLE copy


Anti Ro/SSA Ab : Associated with SLE/PBC

Anti La/SSB Ab : Sjogrens

Anti – RNP Ab : MCTD/SLE. More prominent in Raynaud’s with mild renal involvment

Anti Scl-70 Ab : Systemic sclerosis

Anti Sm Ab : SLE. Assoc with increased severity and activity of renal disease. Can be induced by EBV by molecular mimicry.

Anti Mi-2 : 25% of dermatomyositis

Anti Jo-1 : Polymyositis (+/- dermatomyositis)


MM copy

Appearances of monoclonal immunoglobulin deposition disease

monoclonal deposition copy