FOUR VICIOUS CIRCLES ACCELERATE THE DESTRUCTION OF THE KIDNEYS
The progression of chronic kidney disease (CKD) is influenced by various mechanisms, all of which lead to further nephron loss. This loss of nephronsNephrone sind die Filtereinheiten der Nieren...., in turn, causes a reduction in renal function, further exacerbating renal insufficiency. The progression of the disease is driven by such self-reinforcing mechanisms (vicious circles):
Compensation and overexertion, uraemic toxinsToxic, nitrogen-containing urinary substances responsible for uraemia and kidney damage...., hyperphosphataemiaIncreased phosphate in the blood., hypertensionHigh blood pressure..
The compensation and overburden vicious circle
Cat’s kidneys contain about 200,000 nephrons. Not all nephrons are utilised simultaneously. The kidney has a reserve of nephrons, which is depleted throughout life when nephrons are lost, as naturally occurs from time to time. The lost filtration units are replaced by reserve nephrons – until these run out. When this occurs, the remaining nephrons compensate for the lost filtration units.
The kidneys have an enormous capacity for compensation; existing nephrons can take over the tasks of degenerating nephrons until they themselves are overburdened. Continuous overburdening of the nephrons causes them to die off. Thus, further nephrons are lost and the number of surviving nephrons is continually reduced. This is why clinical symptoms appear very late, when 2/3 to 3/4 of the nephrons have already been irretrievably destroyed.
The high capacity of the kidney to compensate is down to its ability to increase filtration through nephrons. It does this by raising blood pressure, forcing not only more substances but also different substances from the blood that would otherwise have remained there, such as proteins. Increased blood pressure can therefore also lead to increased protein in the urine, known as proteinuriaIncreased protein in urine, leading to loss of protein. Normally, only a very small amount of protein is excreted in the urine. In chronic kidney disease, the amount lost may increase. High blood pressure damages blood vessels in the nephrons making them more permeable and..., and therefore loss of protein.
The uraemic toxin vicious circle
The decline in the performance of the kidneys initiates another vicious circle. As nephrons are progressively lost and renal insufficiency worsens, ever fewer urinary substances such as creatinineCreatinine is a breakdown product of muscle metabolism. Its blood level is dependent, among many factors, on age, weight, nutritional status and muscle mass. Hence, creatinine levels in the blood vary from individual to individual. Creatinine is continuously excreted in the urine. Increased blood creatinine... and ureaUrea is the nitrogen-containing breakdown product of protein metabolism. The nitrogen from the proteins is converted to ammonia in the liver, which is combined with carbon dioxide to form urea. This is continuously excreted via the kidneys but also via sweat. Urea is one of... are filtered out and excreted. Neither of these are uraemic toxins, but their levels are measured to diagnose progression of the disease (→ see Diagnostics and Stages). Renal insufficiency leads to an accumulation of nitrogen-containing urinary substances in the blood (azotaemiaIncreased levels of nitrogen-containing breakdown products of protein metabolism in the blood....).
Elevated blood levels of such urinary substances indicate an azotaemia. Creatinine and urea serve as indicators of kidney performance and are tested in the blood. Chronic kidney disease (CKD) is diagnosed and classified into four stages on the basis of the plasma levels of these substances.
Uraemic toxins need to be excreted in the urine. They are toxic substances from the natural processes of protein metabolism and are usually excreted via the kidneys. If their level rises in the blood due to reduced kidney filtration capacity, they can accumulate in the blood and directly damage the kidneys. Uraemic toxins include indoxyl sulfate and para-cresyl sulfate. These are very harmful to the kidneys. Extensive studies in humans and rats have shown that indoxyl sulfate is directly linked to mortality in chronic kidney disease. Indoxyl sulfate causes destruction of cells, leading to inflammation. The result is a destruction of nephrons and their replacement by scar tissue, continuing the cycle of reduced renal performance and further nephron destruction. In addition, uraemic toxins can have an adverse effect on bone metabolism.
Ongoing accumulation of uraemic substances in the blood, also known as uraemiaA raised level in the blood of urea and other urinary substances, which in chronic kidney disease can no longer be adequately excreted due to impaired renal function (glomerular filtration rate). This leads to renal damage due to uraemic toxins, toxic urinary substances The symptoms..., is toxic for the body. This is associated with clinical symptoms, such as vomiting, nausea, lethargy, diarrhoea, weakness, bad breath, shaggy coat – and even comatose states. Being able to control urinary substances and especially uraemic toxins is very important, as it is not feasible to provide the equipment for dialysis (blood cleansing) of cats.
This vicious circle can be influenced, as the level of uraemic toxins is directly related to the amount of protein in the diet and protein digestion in the gut. In human medicine, patients can be treated with an approach that prevents uraemic toxin precursors from being taken up into the body from the intestine. This can reduce the burden on the kidneys, since fewer uraemic toxins are produced.
The hyperphosphataemia vicious circle
As shown in the adjacent figure, damage to the kidneys compromises their ability to filter out sufficient phosphates, which accumulate in the blood (hyperphosphataemia). At the same time, kidney damage also adversely affects calcitriolCalcitriol is the active form of vitamin D3. It is synthesised in the kidney from vitamin D. It is independently activated by three factors: increased parathyroid hormone levels, reduced calcium levels or indirectly via reduced phosphate levels. Calcitriol acts on four organs: 1) Bones: It... production. Both lead to reduced calcium in the blood (hypocalcaemia). Physiologically, a balance exists between calcium and phosphate. Reduced calcium levels lead to the release of parathyroid hormoneParathyroid hormone (PTH) is a hormone secreted by the parathyroid glands, which regulates calcium levels in the blood. PTH is secreted in response to low blood calcium levels (hypocalcaemia). An increase in calcium concentration above the normal value inhibits PTH production (negative feedback). PTH stimulates... (PTH) via activation of the parathyroid gland, which in turn leads to resorptionThe re-uptake of substances from tissues, in particular bone, into the blood. It should not be confused with absorption, the initial uptake of substances into the body, for instance from food in the intestines, through the lungs and via the skin. Reabsorption, in contrast, occurs... of bone and release of calcium and, with it, phosphate. PTH also enhances the absorption of calcium in the intestine and decreases loss of calcium in the kidneys.
The main effect of PTH is to increase calcium in the blood. It does this chiefly, however, by lowering phosphate, as, in healthy kidneys, the phosphate from bone breakdown is lost in the urine and reduced blood phosphate promotes further bone resorption and calcium release. In the early stages of CKD, the kidneys are still capable of excreting the liberated phosphate, so normal phosphate levels do not indicate that the disease is not present. The calcium-phosphate balance and blood levels are controlled by both parathyroid hormone and calcitriol. PTH stimulates the production of calcitriol, which, in contrast, inhibits PTH release. In chronic kidney disease (CKD), the kidneys are unable to produce sufficient amounts of calcitriol, so that PTH can no longer stimulate the calcitriol production. In turn, calcitriol can no longer inhibit PTH release. In addition, levels of phosphate in the blood are significantly elevated (hyperphosphataemia), indirectly lowering calcitriol production. As a result, more PTH is released from the parathyroid glands, which react less and less to calcium as a stop signal (down-regulation). The consequence is renal (secondary) hyperparathyroidism, causing increased release of PTH. This leads to increased bone resorption – and even bone softening (osteodystrophy). The calcium released from the bones can seriously affect the health of kidneys, blood vessels, skin and heart and, together with the phosphate that is also released, further fuels the vicious circle.
The hypertension vicious circle
The kidneys can autoregulate (regulate their own) blood pressure and perfusion. They rely on a variety of mechanisms to help them do so. Nephrons rely on blood pressure for filtration. If blood pressure rises, filtration rate increases. However, persistent high blood pressure can also lead to kidney damage. It results in overburdening and hardening of the blood vessels (sclerosisThe hardening of an organ or tissue caused by a replacement of normal tissue with connective tissue. Sclerotic tissues and organs are less elastic....), due to the lack of protective substances. This leads to progressive damage of the vascular system of the nephrons and finally to their destruction.
High blood pressure occurs in about 20% of CKD cats. However, there are indications that this figure is actually much higher.
An elevated blood pressure can be the cause of a variety of clinical symptoms. It can lead to central nervous disorders such as seizures, cramps, lethargy, as well as stroke, difficulty in walking and visual disturbances – and even blindness due to retinal detachment.
In addition, high blood pressure leads to more protein passing from the blood during filtration. This cannot be reabsorbed, so the urine contains more protein (proteinuria).