| | |  | | NEWSLETTER ::: NO. 14 ::: JUNE 2017 | | SIDE EFFECTS OF CHRONIC KIDNEY DISEASE | | Renal diseases can accelerate the progress of cardiovascular diseases, significantly reducing life expectancy and leading to increasing medical costs. It is therefore important to further explore the reciprocal effect of chronic-kidney and cardiovascular diseases. | | SIDE EFFECTS OF CHRONIC KIDNEY DISEASE | Globally, an increasing number of people are suffering from chronic kidney disease (CKD), causing personal suffering and leading to rising costs for the healthcare system. The effects of renal disease are particularly serious, because they are closely related to cardiovascular disease. Current research shows that CKD plays an important role in the development of cardiovascular disease, which in turn further aggravates or accelerates the progression of kidney disease. This reciprocal effect is particularly noticeable in industrialised countries due to their higher life expectancy levels. However, despite evidence not only that cardiovascular mortality in CKD patients greatly exceeds levels in the general population but also that the majority of CKD patients die due to cardiovascular disease before they even reach end-stage renal disease, the medical community continues to underestimate the impact of CKD on cardiovascular disease.
Up to 13 per cent of people suffer from CKD
CKD is defined as kidney damage or decreased kidney function (i.e. a decrease in the glomerular filtration rate (GFR)), which lasts more than three months. Kidney damage is generally diagnosed by imaging or the presence of albuminuria, commonly expressed as the urinary albumin to urinary creatinine ratio (ACR). For a decrease in GFR, a cut-off value of less than 60 ml/min is now widely accepted. Using this cut-off, about 11 to 13 per cent of the world’s population have chronic kidney disease, with the majority of patients having GFRs between 30 and 59 ml/min (CKD stage 3). In people over 70, the chronic renal disease figure rises to 35 per cent.
Traditionally, it was assumed that CKD would inevitably progress. This progression is caused by intrarenal mechanisms (for example more rapid ‘aging’ of surviving nephrons and higher physical stress in the glomeruli due to the increase in filtration per surviving nephron) as well as systemic mechanisms such as hypertension and metabolic diseases like diabetes, obesity, phosphate toxicity and acidosis. However, better and earlier treatment of underlying diseases like diabetes and polycystic kidney disease as well as improved medical care with regard to hypertension and probably acidosis fortunately seem to stop the progression (these patients are labelled ‘non-progressors’) or even to improve kidney function—at least in well cared for CKD cohort populations. In cohorts of progressive CKD, the decline in GFR has recently been reduced to a little over 1 ml/min per year.
Consequences of the late stages of CKD
According to current research, the severity of CKD is closely related to a decrease in GFR. In severe impairment with GFR around or below 15 ml/min, increases in blood pressure are present and decreased renal erythropoietin (a growth factor for the production of red blood cells in the bone marrow) production will lead to anaemia, which will require treatment with recombinant hormone. In addition, the inability of the kidneys to eliminate acids leads to acid overload with increased respiratory work and decreases in bone and muscle masses, while the impairment of the elimination of potassium can lead to life-threatening cardiac arrhythmias. The metabolic intoxication caused by the accumulation of endogenous toxins that would normally be eliminated by the kidneys (among others ammonium and urea) is called uraemia. It causes nausea and vomiting and is characterised by various neuromuscular and central nervous system disorders.
Effects on the cardiovascular systems of CKD patients are associated both with arterial disease and left ventricular hypertrophy (LVH)—a thickening of the muscle layers of the left heart chamber, which develops in up to 95 per cent CKD patients. LVH leads to a peculiar type of heart failure (stiff heart chambers), rhythm disturbances and sudden death.
In contrast to cholesterol-induced arterial disease, which affects the inner layers of the arteriae (‘intima’), the changes in CKD primarily concern the muscle layer (‘media’), which leads to wall stiffening and calcification. Uptake of phosphate via a phosphate-transport protein in vascular and cardiac smooth muscle cells is pivotal in initiating this life-threatening process. If phosphate overload is diagnosed by relying on the detection of an increased plasma phosphate concentration, arteriopathy and LVH are likely to be quite far advanced. The problem is that two phosphate eliminating hormones (osteocytic fibroblast growth factor 23 (FGF-23) and parathyroidal hormone (PTH)) increase long before the rise in plasma phosphate (see Figure) and are in fact homeostatic as they both stimulate the renal elimination of phosphate. Currently, some researchers are pursuing the possibility that LVH and arteriopathy are caused by this phosphate homeostatic response, notably the rise in FGF-23.
However, an alternative hypothesis defines CKD primarily as a Klotho-deficiency state. Healthy kidneys are the major source of Klotho, a protein that has important anti-ageing effect by inhibiting the ageing of the heart and the blood vessels. Novel scientific findings suggest that the cardiac and arterial diseases of CKD patients can be managed by using recombinant Klotho or a monoclonal antibody or small molecule inhibitors of the FGF-23 receptor. Clinical studies testing these hypotheses are underway.
Metabolic bone disease associated with CKD
It is not only cardiovascular diseases that are often CKD-induced, a certain metabolic bone disease (MBD) is also associated with CKD. Patients with MBD still exhibit only moderate decreases in renal function (GFR of 30‒59 ml/min; i.e. CKD stage 3) and the bone disease is often only detected at a rather late stage. Nephrologists now consider this a disease in its own right (so-called CKD-MBD). MBD is a complex bone disease characterised by poor bone mineralisation, hyper-resorption of bone dictated by increased PTH, and low bone volume leading to fractures and bone pain. This metabolic bone disease is triggered because failing kidneys produce less bioactive vitamin D (1,25(OH)2D) and will gradually eliminate phosphate less and less efficiently. As a result, FGF-23 and PTH increase, which is also a consequence of Klotho deficiency (FGF-23, see Figure). Klotho is a co-receptor for FGF-23 and its absence results in renal resistance to FGF-23, explaining—at least in part—high FGF-23 levels. To treat CKD-MBD, dietary changes are strongly recommended, including lower phosphate intake, a replacement of vitamin D with vitamin D analogues and the oral administration of drugs that bind dietary phosphate, thereby reducing its intestinal absorption.
In summary, it is important to detect and treat cardiovascular and metabolic bone diseases already in the early stages of CKD. Otherwise they put patients at an increased risk of additional morbidity and even premature death and will also increase the economic burden caused by CKD.
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| | | | Kidney - Control of Homeostasis | | is a Swiss research initiative, headquartered at University of Zurich, which brings together leading specialists in experimental and clinical nephrology and physiology from the universities of Bern, Fribourg, Geneva, Lausanne, and Zurich, and corresponding university hospitals. |
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