Chronic Renal Failure

2021
George van der Watt
Chemical Pathologist
Red Cross Childrens’ Hospital
University of Cape Town and NHLS
Reminder – the main functions of the kidneys

1.Maintenance of ECF volume homeostasis

(Renin/A2/Aldo, ADH, BNP)
2.Maintenance of ECF pH homeostasis - metabolic
compensation for acid/base derangements
3.Excretion of waste – urea(NH3), creatinine, K,
Phos, and buffered acid
4.Endocrine – Vitamin D and EPO
Introduction – CRF
1. Chronic Renal Failure (CRF)

 Permanent loss of nephrons. Remaining

nephrons are intact and retain function,
establishing a new ‘steady-state’.
 Blood urea and creatinine are high but
unchanging unless disease progresses.

Most Common Causes

 Glomerulonephritis
 Diabetic Nephropathy
 Hypertensive renal disease

All have the net effect of progressive loss in the

number of functioning nephrons as a result –
patients often have small sclerotic kidneys
Major Biochemical Consequences of CRF
 Total loss of nephrons means that as with ARF – patients with CRF produce “poor quality
urine” – ie urine begins to resemble plasma because not enough tubular function exists to
maintain ECF homeostasis.

Urine contains things it should not

 Too much sodium and water – low osmolality, polyuria (nocturia), patients can dehydrate
and fluid intake must be carefully adjusted to match losses as patients are unable to deal as
effectively with fluid restriction or overload (as renal function deteriorates the opposite can
happen and patients cannot secrete a water or salt load – overhydration/hypernatraemia)

 Hyperglycaemia very easily leads to dehydration as the renal threshold for glucose drops –
osmotic diuresis, uraemia can also contribute as an osmotic diuretic.

Urine contains too little of the things it should contain

 Loss of compensatory mechanisms to deal with acid load ( production of ammonia and
regeneration of HCO3) – chronic anion gap metabolic acidosis
 Loss of regulation of distal tubular regulation of acid and potassium excretion –
hyperkalaemia and acidosis
 Loss of proximal tubular phosphate excretory function – hyperphosphataemia

Loss of renal endocrine functions

 Erythropoetin – anaemia
 Vitamin D activation (alpha 1 hydroxylase) – hypocalcaemia and renal osteodystrophy
Measuring Renal Function in CRF – the GFR
The glomerular filtration rate (GFR) is considered to be the most accurate measure of
renal functional capacity and reliably reflects the number of functional nephrons.

As a physiological measurement it has high sensitivity and specificity for changes in renal
function and by convention is expressed in ml/min/1.73m2.

GFR is a dynamic measurement and is defined as the volume of plasma that can be
cleared of an ideal substance per unit of time corrected to body surface area.

Clearance of an ideal substance is therefore considered to be equal to the GFR where:

Clearance = [U] / [P] × V

[U] is the urine concentration of the substance

[P] the plasma concentration and
V the urine flow rate in ml/min.

Body surface area is usually calculated according to the Haycock formula and is used to
standardize creat clearance for different size people so we can use the same reference range for
everyone

BSA (m2) = 0.024265 x weight (kg)05378 x height (cm)0.3964

Estimating GFR with Creatinine Clearance
For a clearance measurement to be equal to the GFR, the substance to be
measured should fulfil so-called “ideal criteria, namely:

1. be present at a stable plasma concentration and stays in the ECF

compartment
2. be freely filterable through the glomerulus
3. not be reabsorbed or secreted by the tubules

Thus, the substance is neither added to urine nor removed from urine during its path
through the glomerulus and tubules – everything that is filtered ends up in the urine

 Creatinine is the nitrogen containing cyclic anhydride of phospho-creatine, an intracellular

component of skeletal muscle involved in the temporary storage and transfer of high energy
phosphate moieties required for muscle contraction ( think of creat phos as a spare battery
pack for quick bursts of muscle contraction).
 Creatine is synthesized in the liver, pancreas and kidneys prior to transport to muscle
tissue where it is phosphorylated and utilized in a cyclical manner.
 Approximately 1 – 2% per day of total muscle creatine spontaneously converts to creatinine,
giving rise to a stable production rate.

 The stable plasma concentration of creatinine is therefore a function of

muscle mass relative to the body surface area and the GFR.
Measuring GFR with Creatinine Clearance - CrCl
Normal range: To calculate CrCl
 75 – 115 ml/min/ in females, you must have an
 85 – 125 ml/min in males accurately collected
 much lower in children, reaches adult values by 2 years timed urine sample

Creatinine clearance = [urine creatinine]

----------------------- X Urine volume per minute (= 24 hour
volume/1440) [plasma creatinine]
(1440 = no of minutes in 24 hrs)

Creatinine is not the best ideal substance to use because at high concentrations
It gets secreted by renal tubules and the GIT but we use it because its readily and
Easily available
Recommended Equations for estimating GFR (mL/min/1.73 m2) based on plasma
creatinine values and demographic characteristics. We use these equations because
collecting a 24 hour urine specimen is onerous and prone to mistakes (under/over-
collection) and really not suitable for outpatients

Age Recommended SI Units – Creat in µmol/L, height in cm

Equations

<18 yrs Bedside IDMS-traceable GFR = (36.20 x Height) / S Creat

Schwartz eGFR
Adult IDMS-traceable MDRD
Study Equation eGFR
Adult IDMS-traceable CKD-EPI
Equatation eGFR

CKD-EPI is preferred by Kidney Disease Improving Global

Outcomes (KDIGO)

• Provides a better estimation of GFR between 60 and

120 mL/min/1.73 m2 .
• Performs as accurately as MDRD for patients with
eGFR less than 60 mL/min/1.73 m2 .
• Is better at detecting mild renal impairment.
 Estimating GFR equations (eGFR) - limitations
It is very important to understand the limitations of using eGFR formulae – eGFR can be misleading in the
following

• People with unstable renal fx or s-creat (AKI/ARF/IV fluids) – these are mostly hospitalised
ptnts
• People with extremes of muscle mass (body builders, amputees, paraplegics, muscle
wasting)
• People with extremes of creatinine or creatine intake ( vegans, high protein diet, creat
supplements)
Reference ranges are derived from 95 th centiles of a“normal” population
S- creat is a classical example of the limitations of reference ranges if not interpreted
in a clinical context – reference ranges Are NOT cast in stone

S- creat of this guy is above ref range S- creat of this guy is below ref range
eGFR could predict renal failure eGFR can be normal despite
despite Normal renal Fx The fact that renal failure is present

An eGFR equation is not going to work very well

In both these guys despite the fact that they both
Have the same number of nephrons
so if in doubt, rather do a Formal creat clearance
By collecting a 24 hour urine sample
 Estimating GFR with Serum Cystatin C

 Cystatin C is a non-glycosylated low molecular weight protein of 13.3 kd produced in all

cells.
 Plasma levels are less significantly influenced by age, gender and muscle mass
compared to creatinine
 Renal handling of cystatin C is by complete filtration with near total reabsorption and
catabolism in the proximal tubule and little or no urinary excretion .
 Little or no cystatin C therefore appears in the urine
 Plasma Cystatin C based eGFR equations do not more accurately predict GFR
than the creatinine based equations but equations derived from both analytes
(eGFR-creat-cys) such as the CKD-EPI creatinine-cystatin C 2012 are more
precise with less bias at the critical threshold of 60ml/min/m2

The problem with cystantin C is that its expensive to measure, creatinine

is cheap
Measuring GFR with Exogenous Tracers
CLEARANCE of TRACERS: is the most accurate way of measuring GFR but it
is expensive, takes time and is usually only used to accurately measure GFR
before and after kidney transplant

 Exogenous tracers fulfil the ideal requirements – they remain exclusively in the ECF and are
only cleared by glomerular filtration and not secreted or reabsorbed in the tubules
 These investigations require the injection of a tracer substance with collection of serial blood
samples to measure their levels in plasma, and calculation of their rate of clearance.

 Cr-51 EDTA: (radioactive tracer) works very well but is radioactive. It is however easy to
measure
 Iohexol - Radiocontrast agent – used more commonly now as people move away from
using radioactive substances. More expensive to measure – HPLC Mass spectrometry

The stable rate of elimination in the elimination

EDTA Phase is entirely via glomerular filtration – the steeper the slope iohexol
The better the GFR
Risk assessment needs to be done periodically in patients at risk of CKD such
As Diabetics and patients with hypertension
 Management of Complications of CKD

Kidney Failure – GFR < 15ml/min/1.73 m2 = renal replacement therapy (dialysis)

Renal osteodystrophy (= bone disease secondary to chronic renal failure)
Pathogenesis

● Renal failure → Pi retention → ↑FGF-23 → ↓ Vitamin D activation

→ ↓Ca →  PTH → bone resorption
● Chronic acidosis also directly favours bone demineralization

Biochemical features:
● High serum Pi
● slightly reduced serum Ca (PTH keeps osteoclasts resorbing bone to
maintain s-Ca levels
● high PTH (secondary hyperparathyroidism) – may even remain high after renal transplant (=
3o hyperparathyroidism)

Treatment:

• Phosphate binders by mouth to ↓ GIT Pi absorption (eg CaCO3)

• Calcimimetics (cinacalcet) – bind the Calcium Sensing Receptors (CASR) in parathyroid
to reduce PTH levels
• Renal Replacement Therapy - Dialysis, renal transplant
• Active vitamin D (1,25 OH D3) and Calcium supplementation (note: danger of metastatic
tissue calcification if Ca X Pi > 4.5
• Parathyroidectomy may be necessary (esp once 3o hyperparathyroidism develops) –
tertiary hyperparathyroidism develops after long term stimulation of Chief cells (PTH) results
in hyperplasia and autonomous PTH production.