Endocrine functions of the kidney

This chapter seems relevant to the aims of Section H1(iv) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "outline the endocrine functions of the kidney". Question 4 from the first paper of 2017 was the only time this has ever appeared in the CICM First Part Exam, and the syllabus entry waves the term "outline" at the reader as a signal to treat this subject only very superficially. Erythropoietin renin and calcitriol were the only hormones the examiners seemed interested in, and specifically "the area where the hormone is produced or modified; stimuli for release; factors which inhibit release; and the subsequent actions / effect" were viewed as essential elements. 

In summary:

Acharya & Olivero (2018) is a free article that covers this territory with enough detail to pass CICM questions, and should be viewed as a solid alternative to reading unreliable non-peer-reviewed online weblogs for exam preparation. Another good option is this 1994 article by the Hendersons. 

Hormones which are secreted by the kidney

Erythropoietin

• Source: fibroblasts in the renal cortex are apparently the origin of this hormone. This is not normal behavioir for fibroblasts (otherwise all of them would be doing this) and these are not normal fibroblasts (Souma et al, 2015, decided that they were different enough to call them renal erythropoietin-producing cells, or REPs).
• Stimuli for release: Mainly hypoxia seem to stimulate EPO release, and mainly by modifying the oxygen tension in the renal parenchyma. When Pagel et al (1990) perfused some disembodied kidneys with an oxygen-rich solution, the kidneys had no desire to secrete EPO even though there were no red cells in the solution. When they dropped the PO₂ to 20 mmHg, a fierce increase in EPO secretion was observed, and it did not subside even when the perfusate was reddened up to a haematocrit of 40%. In summary, hypoxia is the main simulus. According to an insanely detailed article by Jelkmann et al (2011), angiotensin-II also plays a role, which is probably how normoxic people recover red cell counts after haemorrhage. 
• Factors which inhibit release are mainly inflammatory cytokines. Enough red cells for you, the immune system says; you've got more important things to do, like fighting off this swarm of staphylococci. Jelkmann et al (1994) established that it was mainly TNF-α, IL-1, IL-6 and interferon-γ. Together with multiple other factors, this contributes to the anaemia of chronic disease.
• Effects of erythropoietin release are mainly seen in the bone marrow, where it prevents the apoptotic death of red cell precursors by binding to the erythropoietin receptors. The result is an increase in the rate of red cell production and maturation.

Renin

• Source are storage vesicles of the juxtaglomerular cells in the renal cortex. These are also the cells that synthesise this stuff. 
• Stimuli for release are systemic hypotension, hyponatremia, sympathetic stimulation and (if it somehow happens in isolation) renal hypoperfusion. 
• Factors which inhibit release are mainly counterregulatory effects of angiotensin II, normalised blood flow to juxtaglomerular cells and the increase in ANP or endothelin (which increase the  circulating volume and the blood pressure, respectively).
• Effect is the activation of the renin-angiotensin-aldosterone system. Renin is the rate-limiting step in the pathway of RAAS activation, which leads to increased sodium and water retention. The details are expanded upon in the chapter on the humoral regulation of blood pressure and flow. 

Thrombopoietin

• Source  is usually the liver, but kidneys do contribute some of this hormone, which usually stimulates the production of platelets. But not so much that end stage renal failure has any impact on thrombopoiesis (Stockelberg et al, 1999). The cells of the proximal convoluted tubule seem to be the origin.
• Stimuli for release are basically limited to thrombocytopenia, though apparently various proinflammatory cytokines can also stimulate its release 
• Factors which inhibit release  are mainly thrombopoietin levels (a negative feedback loop) and platelet numbers
• Effect is to stimulate megakaryocytes, promoting their maturation and therefore platelet production.

Urodilatin, a natriuretic peptide

• Source is the cells of the distal and connecting tubule, and this substance is secreted into the lumen (Forssmann et al, 2001).
• Stimuli for release are unclear; logically increased distal tubular sodium delivery should be one such stimulus.
• Factors which inhibit release are equally unclear
• Effect is on the cortical collecting duct, decreasing the reabsorption of sodium and water by several mechanisms. This appears to be a paracrine signalling mechanism, where the upstream cells of the tubule send messages to downstream cells. The second messenger seems to be cGMP.

Hormones which are modified by the kidney

Calcitriol (activated Vitamin D)

• Site of conversion is the proximal tubule. The original source is actually the skin, where 7-dehydrocholesterol is converted into the inactive prohormone form of Vitamin D (D₃), which is then hydroxylated in the liver into 25(OH)D₃. This, in turn, is what the kidney converts into 1-alpha,25(OH)₂D₃, more conveniently named "calcitriol", which is the active form. The whole process is explained in much more detail by Norman (2008).
• Stimuli for conversion are low serum calcium level, parathyroid hormone (which is stimulated by a low serum calcium level), and low Vitamin D levels.
• Factors which inhibit conversion are 1-alpha,25(OH)₂D₃ itself (a negative feedback loop), low PTH and hypercalcemia.
• Effect  is the increased absorption of calcium in the gut, increased liberation of calcium from bone (by increased osteoclast activity) and the increased reabsorption of calcium in the distal convoluted tubule.

Hormones which are metabolised or cleared by the kidney

Insulin

• Insulin is filtered freely in the glomerulus, and then undergoes proximal tubular  reabsorption, where it is degraded in endosomes. In fact its clearance rate (200ml/min) is higher than the glomerular filtration rate (120ml/min), which means that some additional peritubular uptake of insulin must take place (Rabkin et al, 1972).  
• This is in fact the main physiological mechanism of insulin clearance. The decreased degradation of insulin in patients with renal failure is thought to increase their risk of hypoglycaemia with erratic dose changes, particularly when using long-acting forms.

Gastrin

• Gastrin is the hormone which increases the secretion of stomach acid, of which about 30% is metabolised by the kidney (Davidson et al, 1973). It is not clear where precisely, only that the dominant site is somewhere in the cortex.
• Chronic renal failure patients are known to be at a higher risk of gastric ulceration, and gastrin levels are markedly increased in this population, but Taylor et al (1980) did not think that a decreased renal clearance contributed signfiicantly to this phenomenon, because it's apparently the wrong gastrin that is renally metabolised.

Other hormones

• According to Davidson et al (1973, the kidneys are also involved in the clearance of
  • Vasopressin
  • Oxytocin
  • PTH
  • growth hormone
  • luteinising hormone
  • TSH