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. Insufficient renal function causes metabolic disturbances in all organs. CKD is associated with up to 30 times higher morbidity and mortality from cardiovascular causes than general population. Common cause of death in patients with ESRD is sudden cardiac death, attributable to ventricular arrhythmias.
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; tubular reabsorption of glucose and Na+ via SGLT1 and SGLT2 is increased as well, leading to increased demand for oxygen. 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 and predicts CKD progression, and CKD worsens hypoxia (Hirakawa et al., 2017; Pruijm et al., 2018; Sugiyama et al., 2018). ROS-induced damage has an important role in diabetic nephropathy. Mitochondrial dysfunction is implicated in renal damage. Protection of cardiolipin in mitochondria using elamipretide prevent renal injury in experimental metabolic syndrome (Eirin et al., 2017). 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 deoxyhaemoglobin 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).
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 (Bábíčková 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 (Bábíčková 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; Ferguson et al., 2018). 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).
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.
Progression of CKD is associated with increased activity of sympathetic nervous system and increased blood pressure (Converse et al., 1992; Grassi et al., 2011; Sata et al., 2018). Afferent renal nerve activity from the kidneys mediates the increase in systemic sympathetic nerve activity. In end-state renal disease persistent hypertension is common and often resistant to treatment (Agarwal, 2003; Agarwal et al., 2014), even after kidney transplantation (Lakkis & Weir, 2014).
Cardiac dysfunction leads to decreased blood flow to organs because of reduced cardiac output. Renal dysfunction is a common co-morbidity in heart failure patients. Perfusion in renal cortex is reduced, except in heart disease patients without previous or current oedema (Kilcoyne et al., 1973).
Juárez-Orozco et al (2015) tried to study the effect of cardiac dysfunction on renal perfusion in a rat model using [13N]NH4+. Coronary arterial ligation was used to induce myocardial infarction. Only a 17% reduction of RBF was seen, as compared to sham-operated rat. RBF reduction tended to be greater in cortex than in the medulla.
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. Possible kidney toxicity is a major issue in drug development (Radi, 2019). Near-drowning in seawater causes AKI with reduced oxygen delivery and increased oxygen consumption (Heyman et al., 2019). 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. Obstruction of urine flow can happen already in the tubules, caused for example by fibrosis, kidney stones, or drugs that are insoluble in urine (“crystal nephropathy”). Extensive tissue injury may cause myoglobinuria or haemoglobinuria, blocking tubules. Autoimmune processes can cause deposition of immune complexes in the glomeruli (Ostermann & Liu, 2017).
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 and tubular epithelial cells because of disrupted integrin-ECM interplay. 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. Physiological TIGAR activation under low ischemic burden protects proximal tubular cells, but inhibition of TIGAR protects cells from severe ischemia-reperfusion injury (Kim et al., 2015).
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 (Bayati et al., 1990; Hellberg et al., 1991; Sutton, 2009). Contrast media used in CT angiography and MRI may cause nephropathy. That may include aggregation and trapping of red blood cells and reduction of oxygen tension (Liss et al., 1996 and 1998). In a pig model of AKI, induced ischemia led to decrease of renal perfusion, measured with [13N]NH4+ PET, and perfusion was later returned to normal (Killion et al., 1993). In mice, antibody-induced nephritis caused marked changes in the level and kinetics of [18F]FDG SUV (Hao et al., 2013).
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).
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).
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).
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. Only one kidney is transplanted. In a pig study, one of the kidneys was removed, and renal perfusion increased until it was ∼2 times higher than normal (Killion et al., 1993).
Sympathetic over-activity is frequently observed following renal transplantation. Hypertension contributes to graft failure and cardiovascular morbidity (Weir et al., 2015; Schneider et al., 2015). This caused by increased sympathetic afferent activity from the patient’s own preserved non-functional kidneys, in the absence of efferent feedback to the renal transplant. Blood pressure is normalized after bilateral nephrectomy (Sata et al., 2018). Renal sympathetic denervation (RSDN) in renal transplant recipients reduces blood pressure more than medical treatment alone (Schneider et al., 2015). Regeneration of efferent, but not afferent, nerves in kidney transplant arteries has been demonstrated few months after kidney transplantation, developing in association with hypertension and renal arterial damage (Mauriello et al., 2017).
Ischemic damage, leading to acute tubular necrosis, is present in many cadaveric kidneys, but it will resolve by itself. Chronic rejection leads to progressive arterial narrowing, reduced graft perfusion, and interstitial fibrosis (Dubovsky & Russell, 1989). 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). Possible approaches for PET and SPECT imaging of transplant rejection are reviewed by Grabner et al (2011).
[18F]FDG may have a role in detecting acute renal allograft rejection and following treatment response (Reuter et al., 2009 and 2010; Grabner et al., 2013a). Since [18F]FDG is extracted into urine, delayed PET scanning must be performed (Grabner et al., 2011). PET scan after just 67±15 min after [18F]FDG administration did not show any correlation with SUV and eGFR in kidney transplant recipients (Jadoul et al., 2016). A prospective study where PET scan was performed 201±18 min after administration compared cortical SUVs to histology based on biopsy; SUV threshold 1.6 provided 100% sensitivity and 50% specificity for acute rejection, while there were no group differences in eGFR; results suggest that [18F]FDG PET helps to avoid biopsies (Lovinfosse et al., 2016).
Measurement of renal perfusion could be used to study the viability of the transplant. Reduced perfusion in acute rejection can be detected with MRI (Wentland et al., 2009). In a pig model of acute rejection of renal allograft RBF, measured with [13N]NH4+ PET, was markedly reduced (Killion et al., 1993).
- PET imaging of the kidneys
- Atherosclerotic renal artery stenosis (ARAS)
- Circulatory system
- Inflammation and infection
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.
Flemming NB, Gallo LA, Forbes JM. Mitochondrial dysfunction and signaling in diabetic kidney disease: oxidative stress and beyond. Semin Nephrol. 2018; 38(2): 101-110. doi: 10.1016/j.semnephrol.2018.01.001.
Fogo AB, Cohen AH, Jennette JC, Bruijn JA, Colvin RB: Fundamentals of Renal Pathology. Springer, 2006. doi: 10.1007/978-0-387-31127-2.
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.
Haufe SE, Riedmüller K, Haberkorn U. Nuclear medicine procedures for the diagnosis of acute and chronic renal failure. Nephron Clin Pract. 2006; 103: c77-c84. doi: 10.1159/000091576.
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. http://urn.fi/URN: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.
Updated at: 2019-05-25
Created at: 2017-02-23
Written by: Vesa Oikonen