The kidney – an organ of critical importance in physiology

This edition of The Journal of Physiology adds to the series of special editions that have been published in the last few years, this time with a focus on renal physiology. The physiology and pathophysiology of the kidney have been the topic of many articles published by the journal over the years. Indeed, a search of the archive shows that the very first paper on renal physiology was published in The Journal in 1900 (Thompson, 1900). This paper described the impact of injection of sodium chloride solutions on renal output and blood pressure in dogs, showing that such an injection leads to a marked diuresis, in keeping with Bowman's (of Bowman's capsule fame) theory of urinary secretion. Reflecting the relatively low level of knowledge and understanding of the time and the lack of experimental approaches, this article is very descriptive in nature. In contrast, research into renal physiology in modern times is very mechanistic, with novel and groundbreaking approaches used to help us get to grips not only with what the kidney does, but more importantly, how the kidney plays such a critical role in whole-body physiology. What is clear from such studies is that the kidney is a complex organ that impacts widely on many physiological processes and systems.

In the review by Ivy & Bailey (2014), the role that the kidney plays in the long-term regulation of blood pressure is discussed. Such regulation is multifaceted, involving a complex interplay between the kidney, cardiovascular and autonomic nervous systems. Although controversial, for many years the kidney has been thought to be the main player in the long-term control of blood pressure, and this review presents the evidence for and against this role of the kidney in preventing hypertension. It is clear that mutations in proteins that impact on sodium handling by the kidney, for example in Liddle's syndrome and apparent mineralocorticoid excess, lead to hypertension. In addition, transplantation of a normal kidney into animal models of hypertension reduces blood pressure, indicating that the kidney plays a dominant role in determining blood pressure. However, more recent work challenges this model, showing that there are changes in the immune system in hypertensive animals. Given the worldwide estimates of the occurrence of hypertension (over one billion individuals), a thorough understanding of the mechanisms controlling blood pressure regulation are essential if we are to win the fight against this silent killer.

Another example of the kidney having a wide impact is in cardiorenal syndrome (Lekawanvijit & Krum, 2014). In this syndrome, there is cross-linking between the systems, such that failure in one organ leads to failure in the other. Interestingly, a decrease in renal function following the development of cardiovascular disease is a strong predictor of mortality in patients, while cardiovascular disease is the main factor in the death of many dialysis patients. In this review, the authors have examined the current state of play in terms of renal biomarkers to identify cardiorenal syndrome and the role of uraemic toxins in disease progression. A number of markers are discussed, such as creatinine, cystatin C, neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, but all have issues meaning that they are not as effective as they need to be for use in the clinic, highlighting that more work is needed in this area. The review also identifies uraemic toxins as possible players in the development of cardiorenal syndrome, discussing the impact of these toxins on the fibrosis, inflammation and endothelial dysfunction that is typically observed. Interestingly, this review raises the possibility that uraemic toxins impact on the levels of serum fibroblast growth factor 23 and klotho, factors that are known to regulate Ca²⁺ and phosphate handling by the kidney.

This links with our third review, which focuses on the regulation of serum phosphate by parathyroid hormone, vitamin D and fibroblast growth factor 23 (and the cofactor klotho; Lederer, 2014). Abnormal serum phosphate levels are a known risk factor in both renal and cardiovascular diseases. The regulation of phosphate handling by the kidney, intestine and bone is therefore critical for normal physiology. What is clear from the work presented is that all three of these systems work in an integrated manner and are important for normal phosphate homeostasis. Changes in the levels of any one of these hormones, for example due to inherited disorders such as familial humoral calcinosis or as a consequence of autoimmune disease, have a significant impact on the physiology of the individual. Of interest, there are also changes in the levels of these hormones in chronic renal disease, leading to changes in serum phosphate levels that contribute to vascular calcification. Once again, this highlights the close links that exist between the renal and cardiovascular systems.

In the fourth review, Mora-Fernández et al. (2014) focus on the impact of diabetes mellitus (one of the most common chronic diseases) on renal physiology. Many patients with this disease have significant renal dysfunction (diabetic kidney disease, DKD) and often develop end-stage renal disease. Diabetes is, in fact, the most common cause of end-stage renal disease, and given the worldwide rise in individuals diagnosed with this disease (366 million in 2011) it is critical that we have an in-depth understanding of the reasons underlying DKD. In their review, Mora-Fernández et al. (2014) consider the role of genetic factors (not everyone with diabetes will develop DKD), metabolic processes (exactly how is glucose handled by cells in patients?), haemodynamic changes (here again is a strong link between the renal and cardiovascular systems), inflammatory mediators (changes in signalling molecules have been observed) and novel, emerging factors. The multitude of factors presented shows the complexity of the progression of DKD.

The final review (Savige, 2014) also considers chronic renal failure, this time in the context of the inherited disease, Alport syndrome. As with DKD, patients show progressive loss of renal function, with proteinuria and a fall in glomerular filtration. Patients also have hearing loss and ocular defects, indicating an impact across more than one organ system. The mutations carried by these patients impact on collagen IV, which is a key component of the basement membranes in the glomerulus, cochlea and retina. The mutations lead to changes in the composition of the basement membrane, meaning that membranes are more prone to damage due to mechanical stresses. In patients, the kidney demonstrates intraglomerular hypertension, and this increased pressure contributes even further to the fall in glomerular function over time. To link back to the recurring theme in these topical reviews (the kidney and the cardiovascular system), one treatment that slows progression of the renal symptoms in Alport syndrome is block of the renin–angiotensin system. This reduces the hypertension observed in patients, reducing the damage to the glomerular basement membrane and therefore slowing (although not stopping) the progression of renal failure.

These five reviews, which highlight examples where defects in renal function impact widely, underscore the critical role of the kidney in whole-body function. These impacts include altered renal sodium handling and the development of hypertension, the increased risk of cardiovascular disease when renal function is compromised and vice versa, changes in bone and the development of ectopic calcifications in response to alterations in renal phosphate handling, the renal impact of diabetes mellitus, and the impact that apparent small changes in basement membrane structure can have in Alport syndrome. The interorgan connections made by the kidney highlight for me one of the key features of physiology, that it is an integrated science. In this molecular age, it is all too easy to end up focusing not simply on one organ, but on one protein, in one cell type in an organ. The reviews presented in this special edition remind us that as physiologists we must consider the whole picture and not forget the importance of looking more globally across the organ systems.

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Competing interests

None declared.