Chronic kidney disease

Chronic kidney disease (CKD) is defined either as kidney damage, evident from abnormalities in blood or urine tests or imaging studies, or as abnormally low GFR for over three months. ∼10% of the world’s population has CKD. CKD can be classified into 5 stages based on GFR, with stage 1 representing the mildest form with normal or increased GFR (≥90 mL/min/1.73m2), and with stage 5 representing kidney failure, with GFR < 15 mL/min/1.73m2 or requiring dialysis. The end stage renal disease (ESRD) requires dialysis or transplantation. GFR is calculated from a validated equation including creatinine concentration in the blood serum, age, gender, race, and body size. However, serum creatinine concentration does not increase before about half of nephrons are nonfunctional.

CKD can be caused by numerous primary diseases; individuals with metabolic syndrome are at increased risk, and diabetic nephropathy is a very common cause of end-stage renal disease (Whaley-Connell & Sowers, 2017). In the early stage of metabolic syndrome it is common that GFR is increased; oxidative stress and hyperinsulinemia increase VEGF, which stimulates angiogenesis. Insulin may also cause renal vasodilation (Zhang & Lerman, 2017).

Pathobiology of CKD includes processes such as inflammation, hypoxia and apoptosis. Renal hypoxia accelerates CKD progression, and CKD worsens hypoxia (Hirakawa et al., 2017). ROS-induced damage has an important role in diabetic nephropathy. Renal blood volume is reduced markedly in murine models (Ehling et al., 2016). Despite, or possibly because of, strongly reduced mGFR and sodium re-absorption, cortical and medullary oxygenation is normal in CKD patients, measured as deoxyhemoglobin concentration (Khatir et al., 2015); most MR studies however have shown reduced oxygenation in subjects with CKD or diabetes (Liu et al., 2017). Myofibroblasts and extracellular matrix proteins accumulate in the glomeruli and tubulointerstitium, leading to tubular atrophy and atubular glomeruli, progressive fibrosis and scarring.

Reflux nephropathy (RN) is a major cause of ESRD in children and young adults. Vesicoureteric reflux (VUR) is common in children with urinary tract infection. Apoptotic cells are found in collecting ducts, and inflammatory cells infiltrate the tubulointerstitial tissue in RN, leading to fibrosis and atrophy (Rolle et al., 2002).

Chronic kidney disease - mineral and bone disorder (CKD-MBD) is a systemic complication associated with CKD. It includes abnormalities of calcium, phosphate, PTH, or vitamin D metabolism, vascular or other soft-tissue calcification, and abnormalities in bone turnover and mineralization. It is diagnosed by bone biopsy, but biopsies could be replaced with [18F]fluoride PET (Messa et al., 1993; Frost et al., 2013; Aaltonen et al., 2018). In a rat model of CKD, fluorescent microsphere measurement has shown increased blood flow in bone cortex and reduced blood flow in bone marrow (Aref et al., 2018).

Renal fibrosis

Renal fibrosis is a pathologic hallmark of CKD, and it is associated with loss (rarefaction) of glomerular and peritubular capillaries. Peritubular microvasculature is maintained by angiogenic factors, including VEGF-A (Dimke et al., 2015), but in CKD and renal fibrosis these factors are downregulated (Bábí&ccaron;ková et al., 2017). This leads to progressive decrease in blood volume (Ehling et al., 2016). Irregular capillary shapes and increased vascular permeability are observed in animal models of renal fibrosis (Bábí&ccaron;ková et al., 2017). Peritubular capillary rarefaction may also lead to increase in renal EPO production (Dimke et al., 2015). Renal nerve activity may be one of the initiating steps in fibrosis, because renal denervation or blocking of renal norepinephrine- and α2-receptors has almost fully prevented development of fibrosis in animal models (Boor & Papasotiriou, 2015).

Fibrosis in kidneys does not include marked proliferation of fat cells. Metabolic syndrome and obesity increases perirenal and perivascular adipose tissue, and renal intracellular adiposity in animal models and in obese human subjects, although the amount of lipids in kidney cells still is low, maximally in the range of few percentages (Sijens et al., 2010; Li et al., 2011; Zhang et al., 2013; Hammer et al., 2013). Lipid droplets are predominantly seen in tubular cells, and to a lesser extent in glomeruli (Bobulescu et al., 2014). Obesity and visceral adiposity, via angiotensin II and aldosterone, contribute to endothelial cell dysfunction, vascular smooth muscle cell proliferation and stiffness, extracellular matrix expansion, and tubulointerstitial fibrosis (Whaley-Connell & Sowers, 2017).

MR- and ultrasound-based methods are being developed for imaging fibrosis in kidney (Morrell et al., 2017; Correas et al., 2017; Caroli et al., 2018).

Age

Generally, cortical volume decreases and medullary volume increases with age (Wang et al., 2014). The loss of functioning nephrons is seen as decreasing GFR, but the drop in GFR is smaller than in nephron number, because of the remaining nephrons undergo hypertrophy (Schmitt & Melk, 2017).

As the regenerative potential is decreased, proportion of sclerotic glomeruli increases with ageing, with primarily vascular origin for the lesions (Glassock & Rule, 2012; Schmitt & Melk, 2017). The sclerosis of juxtamedullary glomeruli leads to formation of direct connections between afferent and efferent arterioles. Tubular atrophy and interstitial fibrosis also increases with ageing (Glassock & Rule, 2012). Elderly population is however very heterogeneous: some have very modest reduction in GFR, and the highest decrease in GFR is observed in subjects with hypertension or congestive heart failure.

Acute kidney injury

Acute kidney injury (AKI) can occur as a result of renal ischemia, followed by reperfusion damage, and subsequent cell death. Severe sepsis and septic shock often lead to AKI via changes in glomerular and periglomerular micro-vasculature (Calzavacca et al., 2014; Kumar & Molitoris, 2015). Major surgery can cause AKI; incidence of AKI is ∼15-30% in cardiac surgeries and over 50% after liver transplantation. Obstruction to urinary flow causes dilatation of the calices, pelvis, or ureters, possibly leading to AKI and obstructive nephropathy; SNMMI and EANM have published a guideline for diuretic renal scintigraphy in case of suspected upper urinary tract obstruction. Some patients recover fully from AKI, but cumulative episodes of AKI can lead to CKD, and CKD is a risk factor for AKI (Chevalier, 2016). Ischemia-reperfusion damage leads to shedding of the endothelial glycocalyx. Peritubular capillaries are among the first structures to be damaged, but tubular epithelial cells can also be repaired (Kumar, 2018). Detachment of pericytes from endothelial cells may be a key event leading to loss of peritubular capillaries (rarefaction). Tubular injury impairs reabsorption of sodium and water, and to limit urinary loss of water and sodium, GFR is reduced. Since proximal tubules are largely dependent on β-oxidation; of fatty acids in their ATP production, ischemia not only reduces ATP production but also leads to accumulation of fatty acids in the cytoplasm. Tubular cells respond to ischemia by increasing the levels of glycolytic enzymes.

Oxygen extraction is increased during septic shock, but still remains at ∼10% (Larsson et al., 2018). During AKI, oxygen extraction can be markedly increased, to ∼16-17% (Redfors et al., 2011 and 2011; Bragadottir et al., 2012). Mannitol and levosimendan can be used to increase renal blood flow and GFR, but it does not affect renal oxygen extraction (Bragadottir et al., 2012 and 2013). Dopamine infusion increases renal blood flow and reduces oxygen extraction (Redfors et al., 2010). Renal sodium reabsorption can be reduced with furosemide, leading to lower oxygen consumption and extraction (Ricksten et al., 2013).

The decrease in blood flow is most prominent in the outer medulla. Increased microvascular permeability leads to interstitial oedema, tubular obstruction, and vascular congestion, also through trapping red blood cells (Sutton, 2009). Many contrast media lead to in vivo aggregation and trapping of red blood cells and reduction of oxygen tension (Liss et al., 1996 and 1998).

P2 purinoceptors affect tubular function and renal perfusion, and have a role in development of fibrosis (Menzies et al., 2017). Activation of endothelial S1P 1 receptors may decrease ischemia-induced AKI (Bartels et al., 2014). Inhibition of sodium and glucose transport reduces the demand for oxygen in the medulla, and may decrease tubular damage (Fattah & Vallon, 2018).

Haematocrit and EPO

Kidneys function as oxygen and haematocrit sensor. Peritubular fibroblasts of the renal cortex produce erythropoietin (EPO) in response to hypoxia; EPO stimulates the production of red blood cells in the bone marrow. Kidneys produce most of the EPO in the body, and EPO production is decreased in CKD and ESRD, leading to anaemia and hypoxia. Normally, the tips of the juxtamedullary region of the cortical labyrinth are the place where the oxygen balance is most sensitive to changes in haematocrit, and where the EPO is produced. Anaemia causes the partial pressure of oxygen to drop in more superficial regions of the renal cortex, leading to EPO production in increasingly larger volumes of the cortex (Dunn et al., 2007).

Renal transplantation

The indication for kidney transplantation is end-stage renal disease, although CKD patients may undergo transplantation already before requiring dialysis if suitable transplant is available. Both kidney and pancreas can be transplanted simultaneously to patients whose renal failure is caused by type 1 diabetes. The existing kidneys are not removed, but the new kidney is placed lower in the pelvis, and connected to the iliac artery and vein. Renal arteries, veins, and ureter are from the donor. Immunosuppressants are needed to reduce the rejection, and periodical ultrasonography is required to assess the changes that may reveal transplant rejection. Renal needle-biopsy, renal scintigraphy, or MRI are needed to confirm post-transplant renal dysfunction if possible problems are found in the ultrasound imaging (Benjamens et al., 2018).

CXCR4 imaging has shown promise in detecting infection in the renal allografts (Derlin et al., 2017).


See also:



References:

Alpern RJ, Caplan MJ, Moe OW (eds.): Seldin and Giebisch’s The Kidney - Physiology and Pathophysiology, 5th ed., Academic Press, 2013, ISBN: 978-0-12-381462-3.

Ashley C, Morlidge C (eds.): Introduction to Renal Therapeutics. Pharmaceutical Press, 2008, ISBN: 978-0-85369-688-9.

Fogo AB, Cohen AH, Jennette JC, Bruijn JA, Colvin RB: Fundamentals of Renal Pathology. Springer, 2006.

Fogo AB, Kashgarian M: Diagnostic Atlas of Renal Pathology, 3rd ed., Elsevier, 2017. ISBN: 978-0-323-39053-8.

Grabner A, Kentrup D, Schnöckel U, Gabriëls G, Schröter R, Pavenstädt H, Schober O, Schlatter E, Schäfers M, Reuter S. Non-invasive imaging of acute allograft rejection after rat renal transplantation using 18F-FDG PET. J Vis Exp. 2013; 74:e4240. doi: 10.3791/4240.

Guerci P, Ergin B, Ince C. The macro- and microcirculation of the kidney. Best Pract Res Clin Anaesthesiol. 2017; 31(3): 315-329. doi: 10.1016/j.bpa.2017.10.002.

Krishnan N, Perazella MA. The role of PET scanning in the evaluation of patients with kidney disease. Adv Chronic Kidney Dis. 2017; 24(3): 154-161. doi: 10.1053/j.ackd.2017.01.002.

Koeppen BM, Stanton BA: Renal Physiology, 5th ed., Elsevier, 2013, ISBN: 978-0-323-08691-2.

Koivuviita N: Vascular function in chronic kidney disease and in renovascular disease. Thesis, 2011, ISBN 978-951-29-4590-0.

Schnellmann RG. Toxic responses of the kidney. In: Klaassen CD (ed.): Casarett and Doull’s Toxicology: The Basic Science of Poisons, 8th ed., McGraw-Hill Medical, 2013, ISBN: 978-0-07-176922-8, pp. 665-690.

Singh P, Ricksten S-E, Bragadottir G, Redfors B, Nordquist L. Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. Clin Exp Pharmacol Physiol. 2013; 40(2): 138-147. doi: 10.1111/1440-1681.12036.

Skorecki K, Chertow GM, Marsden PA, Taal MW, Yu ASL, Wasser WG. Brenner & Rector’s The Kidney. 10th ed. Elsevier, 2016. ISBN: 978-1-4557-4836-5.

Verma SK, Molitoris BA. Renal endothelial injury and microvascular dysfunction in acute kidney injury. Semin Nephrol. 2015; 35(1): 96-107. 10.1016/j.semnephrol.2015.01.010.

Waikar SS, Murray PT, Singh AK (eds.): Core Concepts in Acute Kidney Injury. Springer, 2018. doi: 10.1007/978-1-4939-8628-6.



Tags: , ,


Created at: 2017-02-23
Updated at: 2018-11-04
Written by: Vesa Oikonen