69. Chronic renal failure. Causes, characteristics and progression

This condition was previously called chronic renal failure, but it’s nowadays called chronic kidney disease (CKD), as the definition no longer only includes those with “failing” kidneys. Chronic kidney disease is defined as any kidney abnormality which lasts for more than 3 months. This abnormality can be any of the following:

Abnormal GFR (high or low)
Abnormal albuminuria
Abnormal urine analysis
Abnormal electrolyte balance
Abnormal histology
Kidney abnormality on imaging
Previous kidney transplant

This topic will focus on those cases where the GFR is decreased.

Chronic kidney disease is a progressive disorder. There’s a gradual, unstoppable and progressive loss of nephrons. The loss is irreversible and can’t be cured, however the progression can be slowed or almost stopped.

The reason that CKD is progressive is because, as soon as a significant number of nephrons are lost will the remaining nephrons also take damage, for reasons we will se below. Therefore, CKD can occur due to any kidney condition where the number of functioning nephrons is reduced, and as soon as enough nephrons have been lost, the ball is already rolling and the loss of further nephrons is inevitable.

It can be caused by primary damage to the kidney (in 20% of cases) or due to secondary damage to the kidney due to some other disease (80% of cases). The most common causes worldwide are hypertension and diabetes mellitus.

Etiology

Primary renal damage:

Chronic glomerulonephritis
Interstitial nephritis
Pyelonephritis
Polycystic kidney
Drug side effects

Secondary renal damage due to diseases like:

Diabetes mellitus (30% of all cases)
Hypertension (20% of all cases)
Autoimmune diseases (especially SLE)
Heart failure
Cirrhosis
Gout
Hypercalcaemia

Pathophysiology

Four mechanisms or principles are important in understanding this progressive loss of kidney function:

The intact nephron principle states that a nephron functions only when all parts of it are morphologically intact. So a nephron does not work if some tubular function or some glomerular function is lost. However, that doesn’t necessarily mean that the function of all morphologically intact nephrons is normal.
Hyperfiltration is the principle where, in cases where the number of functioning nephrons decreases, will the remaining intact nephrons increase their filtration to compensate (SNGFR increases). This allows continued normal clearance of the plasma. This increased SNGFR isn’t good for the nephrons in the long-term as they’ll sustain damage for it. However the increased SNGFR is necessary to excrete enough urea and creatinine so that they don’t build up in the plasma.
The magnification phenomenon has already been discussed, and is basically the same as tubular adaptation. It states that when the number of functional nephrons decreases will the remaining nephrons increase their salt excretion so that the total salt excretion of the kidney is approximately normal, despite the lower number of functioning nephrons.
The retention of certain substances cause damaging secondary changes. Recall from topic 64 that when total GFR is decreased can’t the tubules do anything to get rid of urea and creatinine in the blood, because there’s no tubular adaptation. This causes accumulation of uraemic toxins, which damage other stuff.

Clinical features

The biggest problem with CKD is that it’s mostly asymptomatic. In patients who don’t have symptoms of the cause of the CKD, the kidney may progressively worsen until they barely function before it is diagnosed. In the latest stages, symptoms of fluid overload and uraemia develop.

In the later stages, the kidney loses it’s ability to regulate the salt and fluid balance of the body. At this point, the kidney can not get rid of excess fluid or salt, if the person drinks more or eats more salt, instead causing hypervolaemia with peripheral or even pulmonary oedema.

Stages of chronic kidney disease

Chronic kidney disease has five stages based on the GFR:

Stage	Functioning nephron amount (out of normal 2 million total for both kidneys)	GFR (in mL/min)	Pathophysiological kidney changes
G1	> 50%	> 90	Nothing yet
G2	50 – 25%	60 – 89	Azotaemia. SNGFR is so high that hyposthenuria occurs.
G3a	30 – 20%	45 – 59	Hyposthenuria is now so severe that the kidneys can’t adapt properly to water or salt excess.
G3b	30 – 20%	30 – 44	Hyposthenuria is now so severe that the kidneys can’t adapt properly to water or salt excess.
G4	20 – 5%	15 – 29	Oliguria occurs. Hyposthenuria is even more severe.
G5	< 5%	< 15	Worse oliguria/anuria. Asthenuria.

We usually call stage G4 and G5 “chronic kidney failure”, while stage G5 is referred to as end-stage kidney disease (ESKD) or end-stage renal failure (ESRF).

Factors that promote the progression of chronic kidney disease

Certain factors increase the rate of progression of chronic kidney disease (CKD):

Overactivation of the RAAS, due to a variety of factors, contribute to the progression.

Systemic hypertension, especially if the mean arterial pressure exceeds the range of autoregulation for the RBF (above 160 mmHg). This increases the GFR, which progressively damage the glomeruli.

Intraglomerular coagulation for any reason progresses CKD. Endothelial damage and hypercoagulable states must therefore be prevented.

Metastatic calcification of the kidney may occur due to the high PTH levels often seen in CKD, although this is very rare.

Hyperlipidaemia, especially LDL, can bind to GAGs in the basement membrane and decrease the negative charge, which increases the permeability of the glomerulus which further damages it.

High dietary protein intake in the context of kidney disease does three things:

Increases the protein filtration. As more protein is filtered will more protein be reabsorbed in the proximal tubule. When protein reabsorption is increased will sodium reabsorption also be increased. When less sodium reaches the macula densa will tubero-glomerular feedback (TGF) cause increase filtration
Increases the intraglomerular pressure due to (presumably?) binding water, which causes the volume of blood that enters the glomeruli to be increased. This enhances coagulation.
Increases inflammation, because increased protein filtration activates mesangial cells which produce pro-inflammatory cytokines.
Enhances fibrosis. Inflammation of the glomeruli enhances parenchymal fibrosis

Things we can do to slow down the progression of CRF

These things mostly work by inhibiting the processes outlined above:

Controlling blood pressure. 130/80 mmHg should be the maximum.
Low protein diet
Reduction of hyperlipidaemia, by changes diet and use of statins (HMG-CoA reductase inhibitors)
Glycaemic control to reduce endothelial injury. HbA1c should be below 8%
Smoking cessation
Give RAAS-inhibitors (like ACE inhibitors, ARBs)

In addition, salt and fluid intake must be restricted to prevent hypervolaemia.

Chronic renal failure’s effect on non-excretory renal functions

When nephrons stop functioning and die the kidney as a whole will be affected. Renal parenchyme will be lost, where most of the non-excretory functions lie.

Hypertension

Renoparenchymal hypertension occurs due to deficiency of the renal depressor system and in the late stages will there also be increased blood volume due to increased sodium retention. This further progresses the renal damage (see above) and also progresses other diseases, like left ventricular failure, ischaemic heart disease and atherosclerosis, which may have been important in causing the CRF in the first place.

Anaemia

Anaemia occurs due to multiple mechanisms. Iron and protein deficiency, lack of EPO production and uraemic toxicity of the bone marrow are important.

Bone deformities

Bone deformities occur. The increased phosphate and PTH causes calcium to mobilize from the bones, however the kidney loses calcium faster than it can be reabsorbed from the bones, so serum calcium is low anyway. The vitamin D-producing ability of the kidney is also deficient.