Nephropathies (2017)

Origins and progresses of nephropathies are manifold and include inflammatory or non-inflammatory causes. The incidence of nephropathies increases all over the world, supported by the growing elderly population. Nowadays, there are about two million fatalities per year due to acute kidney injury (AKI).1 Clinical outcomes of AKI have not improved over the past 50 years.2 Renal tissue hypoperfusion and hypoxia are thought to be the main elements causing AKI and the progression to chronic kidney disease (CKD) and end-stage renal disease (ESRD).1 Moreover, renal disorders often coincide with systemic diseases like hypertension, which also has a high mortality, or with diabetes. Up to date, there is less opportunity to prevent or predict the development of renal diseases and less is known about drugs for an effective therapy. To develop therapeutic targets against nephropathies, gaining a deeper understanding of their pathophysiological mechanisms remains a current issue. This review will give a short overview of the latest reports and strategies published in Acta Physiologica to combat kidney diseases. Nephropathies can occur in the glomeruli or in the interstitial room in the kidney. Irregularities of the immune system can cause glomerulonephritis, for example the development of autoantibodies or the disease appears in systemic diseases like diabetes mellitus. An interstitial nephritis can, for instance, be induced by drugs, viruses, bacteria or autoantibodies. One can further distinguish between different sources of nephropathies: examples for congenital nephropathies are Bartter′s syndrome, Fanconi syndrome and renal tubulary acidosis. Grill et al. analysed the role of a basolateral chloride channel, called ClC-Kb, in the context of Bartter′s syndrome type 3 in ClC-K2-deficient mice. They found that ClC-Kb has a mandatory role in renal salt reabsorption and concentrating ability.3 Contrast dye-induced acute kidney injury is attended by a reduced glomerular filtration rate (GFR) and is the third most common cause of renal failure that is hospital acquired. Patzak et al. analysed the impact of diadenosine pentaphosphate (Ap5A) in contrast dye-induced AKI. They found that Ap5A is responsible for constriction of afferent perfused arterioles and thereby reduces the GFR in mice.4 AKI is characterized by the rapidly progressing loss of renal function within hours to days. The pathomechanisms are multiple as follows: (i) renal ischaemia and reperfusion injury (IRI) cause renal tubular and endothelial cell necrosis, apoptosis and inflammation, (ii) sepsis-induced organ dysfunction, (iii) nephrotoxic substances like radio-contrast dyes, chemotherapeutics, heavy metals, but also antibiotics and non-steroidal anti-inflammatory drugs and (iv) further organ failures like hepatic malfunction or even multi-organ failure5, 2 AKI often leads to retention of metabolic waste products and ranges from a decreased GFR to complete loss of renal function.2, 5 Current treatments focus on avoiding the potential injury due to nephrotoxic drugs or intravenous contrast agents and on providing supportive care. Identifying biomarkers or the development of tools for early diagnosis of AKI therefore is the most promising therapeutic concept to combat AKI and subsequent damage. Currently, AKI diagnosis is based on the elevation of serum creatinine and this happens in a very late stage of kidney injury. Due to this, there is an urgent need to identify and establish suitable early markers of kidney dysfunction. Pozzoli et al. report current issues in prediction and early diagnosis of AKI, ranging from the identification of biomarkers to the development of prediction models. Neutrophil gelatinase-associated lipocalin (NGAL) and Cystatin-C, both derived from serum plasma or urine, are two promising biomarkers for early detection (within hours) of AKI. In several independent studies, NGAL is described as a powerful early biomarker for AKI and NGAL tests are already available for diagnostic clinical use in Europe. Cystatin-C is a potent marker of the GFR and compared to serum creatinine, Cystatin-C is less influenced by body weight, age and gender.6 A new, non-invasive in vivo option to assess renal tissue oxygenation in terms of AKI is now under examination: it is so called blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) for the kidney.1 Paramagnetic properties of deoxyhaemoglobin are measured with BOLD-MRI. An increased deoxyhaemoglobin concentration in blood decreases proton relaxation time, and this is characteristic for pathophysiological intrarenal oxygenation. Moreover, Rueth et al. elucidated and quantified the impact of post-translational modifications on renal pathophysiology. Albumin was used as a ‘proof of concept’ protein, as albumin is the most abundant plasma protein and transports and detoxifies hydrophobic uraemic toxins in the kidney. Albumin, isolated from patients with chronic kidney disease, shows guanidinylations at five different lysine sites, whereas albumin from healthy donors was not post-translationally modified.7 AKI patients have a higher risk of CKD and for ESRD, depending on the underlying pathophysiological circumstances.5 Hypertension and diabetes mellitus, among other factors, play a crucial role during the development of CKD.8 In a high number of diabetic patients, accumulation of the basal membrane and renal glomeruli is observed, in combination with a decrease in the GFR and the development of hypoxia. Hypoxia also contributes to the infiltration of immune cells. The reactive oxygen species (ROS) level might determine renal oxygenation, as well as markers of inflammation.9 Diabetic nephropathy progresses with glomerular hypertrophy, inflammation of glomeruli and interstitial areas, apoptosis-induced reduction in cell number and ECM accumulation. Two experimental works raise hope to become potential therapeutic targets in CKD. Wada and Makino et al. investigated major pathways of modified intracellular metabolism that influence diabetic nephropathy development and their potential as therapeutic target: hyperglycaemia goes along with the formation of advanced glycation end products (AGE). The receptors for AGE (RAGE) play a role in signalling of inflammation and oxidative stress and the AGE-RAGE system might become a novel therapeutic target.10 Neymeyer et al. elucidated the role of annexin A1 (AnxA1) and the convenient formyl peptide receptor 2 (FPR2) in an animal model of renal fibrosis in CKD. The main sources for AnxA1 and FPR2 in rats suffering from CKD are found to be renal fibroblasts and activation of AnxA1 signalling induced antifibrotic effects. The AnxA1/FPR2 system therefore potentially provides a target for antifibrotic therapy in CKD patients.11 CKD and diabetes are major causes for ESRD, demanding dialysis therapy or kidney transplantation. Therapies for CKD to decelerate the development of ESRD should consist of a decrease in blood pressure and the protection against tissue damage.8 In terms of hypertension and regulation of renal blood flow, the renin angiotensine aldosterone system (RAAS) is of great importance. Angiotensin-converting enzyme (ACE) inhibitors decrease blood pressure, and for diabetes-induced kidney damage, ACE inhibitors reduce proteinuria. On the other side, it is well known that a treatment of pregnant women with ACE inhibitors can negatively influence foetal growth and development, that growth is reduced and anuria and hypotension occur. As childbirth after the age of 35 increases, while the onset of diabetes type 2 occurs at an earlier age, the usage of ACE inhibitors during pregnancy increases. Hansell and Palm describe that the lack of angiotensinogen II can cause accumulation of the matrix component hyaluronan due to the disappearance of hyaluronidase. Hyaluronan then potentially contributes to the histological and functional defects in fetopathy.12 The analysis of pathophysiological pathways in the context of the RAAS and its role in nephropathies sets a focus on the signalling molecule adenosine and its receptors as targets for therapy. Adenosine is a regulator of manifold physiological circumstances. In short, adenosine modulates the release of renin and thereby the activity of the RAAS, the GFR and renal vascular tone and is a critical regulator of tubuloglomerular feedback (TGF).2 Adenosine levels increase during pathological conditions in the kidney, for example impaired renal perfusion, hypoxia and increased ATP consumption.2 Besides a function in the central nervous system, purinergic receptors play an important role in nephropathies. One can distinguish between three families of purinergic receptors: (i) P1 receptors that recognize the ligand adenosine and are G-protein-coupled receptors, (ii) P2X receptors that are ATP-guided ion channel receptors and (iii) P2Y receptors that represent a group of metabotropic receptors that recognize nucleotides like ATP, ADP, UTP and UDP and also belong to the G-protein-coupled receptors. To characterize the pathophysiological mechanisms of nephropathies, there is research ongoing in the wide field of purinergic receptors. A broad overview about classes of adenosine receptors (P1) and their role in the renal environment and their potential therapeutic benefit is given by Yap and Lee.2 Adenosine is considered to be protective in response to IRI and is produced in the renal environment. In ischaemic tissues, intracellular adenosine levels increase 100-fold. The extracellular amount of adenosine is much lower, due to a short half-life. Extracellular adenosine increases via enzymatic phosphohydrolysis of ATP in the extracellular space or via release during hypoxic conditions inflammation or acute injury.13 Extracellular adenosine is known to be a regulator of immune cell activation: investigations revealed that the adenosine 2a subtype receptor (A2aAR) has anti-inflammatory functions in terms of AKI. The A2aAR receptor is expressed on renal cells as well as hematopoietic cells like dendritic cells and macrophages, which make up the most prominent population of immune cells in the kidney interstitium and are known to orchestrate inflammation following IRI13 and systemic inflammation.2 A study from Persson et al. reports that chronic stimulation of A2aAR prevented proteinuria in diabetic rats with an effect 10-fold higher than in healthy animals. Glomerular damage and infiltration of immune cells were also prevented through anti-inflammatory mechanisms due to chronic A2aAR stimulation while oxidative stress or renal oxygen metabolism was not affected.9 Adenosine can modulate the RAAS. The secretion of renin gets reduced due to activation of A1 adenosine receptor (A1AR) by adenosine.14 A1AR has protective functions in nephrotoxic AKI and contrast dye-induced nephropathy by reversing vascular constriction and inducing natriuresis and diuresis.2 Adenosine is a vasoconstrictor of renal vasculature and mediator of renal autoregulation when binding to A1AR and via TGF, and adenosine binding to A2AR causes renal vasodilation. Maintenance of salt and water homoeostasis is realized by the TGF that is provoked by a release of adenosine due to an increase in NaCl delivery to the macula densa.15 In accordance with this, Kim et al. described that deficiency of A1AR is associated with abolished TGF responses in mice with mixed genetic background.16 Unless there are many factors controlling TGF responsiveness, oxidative stress in the macula densa is shown to be essential for TGF. Vasoconstriction in the arterioles occurs once TGF is activated and the generation of NO and O2− in the macula densa increases. Interestingly, hypertension has an effect on regulation of TGF in the macula densa. In healthy mice, more NO than O2− is generated by the macula densa and NO is the main player of controlling the TGF response. Once hypertension is induced in mice O2− is the more dominant player in the TGF response control.15 Hypertension often causes tubulointerstitial inflammation. Franco et al. report that P2 purinergic receptors might play a role in the development of salt-sensitive hypertension as well as angiotensin II-induced hypertension, which also leads to the salt-sensitive form.17 The usage of inflammatory modulators leads to a lower risk for hypertension. The P2Y2 receptor was found to be involved in the development of lithium-induced polyuria. Diabetes insipidus is characterized by polyuria, natriuresis and kaliuresis, because the kidney gets resistant to arginine vasopressin (AVP). Unfortunately, nephrogenic diabetes insipidus (NDI) can be a side effect in the treatment of bipolar disorders with lithium occurring in about 40% of lithium-treated patients. To date, lithium is a very potent drug not only against bipolar disorders, but also chronic neurodegenerative diseases and even stroke or ischaemia.18 After P2Y2 receptor deletion, mice were much more resistant to the lithium-induced development of NDI, due to changes in PGE2 signalling and a reduced EP3 receptor protein abundance in the kidney. Unless P2Y2 is a promising target to treat lithium-induced NDI, so far there are no P2Y2-blocking agents available. Sometimes, only a single kidney is diseased. The increase in activity of one kidney as a result of a disease of the contralateral kidney is called reno-renal reflex. The excretion of water and sodium rises in the healthy kidney. The regulatory mechanism is still unclear, but there is evidence that bradykinin as a mediator might play a role in the initiation of excitation of the sympathetic nervous system. Interestingly, Barry et al. reported that there was an increase in activity of the renal sympathetic nerve in the contralateral kidney as well as a decrease in sodium excretion as a result of an intrarenal infusion of bradykinin into the ipsilateral kidney in terms of an intact innervation of these kidneys.19 The manifold causes and symptoms of nephropathies make it often difficult to deal with nephropathies in terms of diagnosis and treatment. Studies to predict and early diagnose AKI and to treat AKI and CKD in order to prevent the establishment of ESRD will be an ongoing challenging task in the future. None. AW, SR and RM were supported by BMBF grant FKZ 031A303A and BMBF grant FKZ 01EK1612B.