Nephropathy: New aspects of mechanisms, diagnosis and therapy (2018)

Nephropathy denotes a loss of kidney function as a result of renal disease or kidney damage. In general this can be caused by inflammation or non-inflammatory causes. Non-inflammatory processes leading to nephropathy are for example a decreased glomerular flow rate (GFR), exposure to renal toxins (eg drugs) and renal trauma. Acute kidney injuries (AKI) occur global and are a common challenge in hospitals. One out of five patients develops AKI during its clinical stay.1, 2 AKI is potentially life-threatening, associated with elevated short-term morbidity and mortality and can lead to chronic kidney diseases (CKD) and cardiovascular events.3 To prevent or attenuate the outcome of AKI, a fast diagnosis and identification of the cause is necessary. Measuring the level of creatine in the serum and monitoring the output of urine is the current standard diagnosis for AKI.3, 4 However, the evaluation of creatine levels without a comparative value is problematic. In these cases the “Kidney Disease: Improving Globular Outcome Acute Kidney Injury Work Group” provided a guideline for the back-calculation of a baseline creatine serum level. Nevertheless, Kork et al found out that a diagnosis of AKI without a measured baseline creatine level in surrogate patients is not feasible. Therefore, additional diagnostic tools for AKI, for example specific biomarkers, are needed. Schrezenmeier et al summarized six important biomarkers of AKI discussing their advantages and disadvantages, clinical performance and possible follow-up studies. A leading problem in finding the perfect biomarker and by that establishing a new standard for diagnosing AKI is the shortcoming and heterogeneous definition of AKI. In addition the described biomarkers are not entirely specific for AKI.3 Another useful diagnostic tool could be the measurement of albumin-containing vesicles in the urine.5 This is because of a newly investigated way of albumin to pass the glomerular filtration barrier in addition to the classical paracellular way. Thereby albumin enters the podocyte in a vesicle via endocytosis and is released from the apical part of the cell. In contrast to paracellular albumin, where 90% is reabsorbed in the tubulus, there is no evidence that transcellularly entered albumin is removed from the urine.5 It is possible that transcytosis of albumin induces a deleterious inflammatory response and a deterioration of podocyte function leading to an increase of glomerular albumin permeability. Measuring albumin-containing vesicles in the urine could therefore be a beneficial diagnostic method for the early phase of a compromised glomerular barrier function, which is one of multiple causes for AKI.5 To understand glomerular barrier function and proteinuria in more detail, Siegerist et al established a microscope-based method to monitor dynamics of glomerular barrier functions during induction of podocyte injury in zebrafish larvae. They demonstrate that the zebrafish larva is an optimal animal model for studying glomerular barrier function and proteinuria in vivo and in 4D.6 The mouse represents another animal model for nephropathy. Mice with reduced renal mass (RRM) fed a high-salt diet have a 35% lower GFR and a twofold higher albumin excretion compared to sham-operated mice fed a normal- or a high-salt diet.7 In contrast to human CKD and a rat RRM model these mice have a normal blood pressure and minimal renal damage. Zhao et al found that the high-salt diet in combination with RRM induces renal oxidative stress which leads to an outward eutrophic remodelling of the efferent arterioles with an increase in luminal diameter up to 30%. They hypothesize that this enlargement of the diameter may prevent glomerular hypertension and barotrauma and by that leading to less glomerular or renal damage. An increased intake of salt is associated with a damage of the kidney, though not scientifically confirmed.8 However, the nephropathy Batter's syndrome is characterized by a hereditary salt-loss, hypokalaemia, metabolic alkalosis and secondary hyperaldosteronism owing to genetic mutations of transport molecules mediating the tubular reabsorption of ions from the tubule lumen.9 In case of Batter's syndrome type 3 mutations of the CLCNKB gene encoding the ClC-Kb Cl− channel are the cause of this disease.9 The homologue of the human Cl− channel ClC-Kb is the ClC-K2 in rodents. ClCKb and ClC-K2 are kidney-specific and mainly located in the basolateral membrane of the thick ascending limb of Henle's loop (TAL) cells suggesting they may be crucial for normal TAL Cl reabsorption. In addition ClCKb and ClC-K2 are expressed along the tubular system, including the distal convoluted tubule (DCT).10 Using ClC-K2 deficient mice Grill et al could show that ClC-K2 exclusively facilitates basolateral Cl exit and salt reabsorption in the DCT. For TAL an additional and alternative Cl transepithelial pathway exists, most likely via ClC-K1. In addition they were able to demonstrate that the kidney pathophysiology of ClC-K2 deficient mice resembles that of patients with Batter's syndrome type 3 and are therefore a suitable model.10 Besides Cl, Na and water are also reabsorbed by the kidney. In the proximal tubule claudin-2, a tight junction protein, forms paracellular channels for small cations and water. In most cases transcellular transport of solutes and water occurs through distinct and independent pathways. Rosenthal et al11 found out that the claudin-2 mediated transport of cations and water is coupled and that they share a common pore. Besides claudins, cations are also transported by cation channel receptors like members of the transient receptor potential (TRP) cation channel receptor family. Marko et al reviewed four members of this cation channel receptor family, namely TRP vanilloid 1 receptor (TRPV1), TRP vanilloid 4 receptor (TRPV4), TRP subfamily C member 6 (TRPC6) and TRP melastatin (TRPM2). All of these have been studied in knock-out animal models and play a role in renal physiology. In addition, they seem to be involved in hypertension, obesity and diabetes, the leading causes of nephrosis. TRPV1 for example is found to be renoprotective after ischaemic AKI. The manipulation of these TRP members could be a strategy to treat or even prevent the harmful effects of subsequent diseases like AKI and CKD.12 New therapeutical strategies like this and novel innovations are indispensable to fight nephropathy. This is underlined for example by the increased mortality rate for CKD (36.9% from 1990 to 2013).13 CKD is often followed by chronic heart failure (chronic renocardiac syndrome, cRCS) where multiple systems of a complex network are disturbed including the renin-angiotensin system (RAS), the sympathetic nerve system (SNS), a systemic inflammatory state and imbalance between nitric oxide (NO) and reactive oxygen species (ROS).14 Oosterhuis et al tested the effect of five common drugs affecting one of the systems involved in CKD and cRCS alone and in different combinations (Losartan [RAS], Pyrrolidinedithiocarbamate [inflammation], Metoprolol [SNS], Molsidomine and Tempol [NO/ROS balance]). Individual and combined treatment show similar effects in limiting cardiac fibrosis. That indicates that in the heart a single factor for example, activation of the RAS, prompted activation of the other systems. In case of the kidney, RAS and the other systems are not redundant. Combined treatment preserved renal structure better than RAS inhibitors alone or the combination of modulation of inflammation and NO/ROS balance. In addition to find new strategies to treat kidney diseases common therapies must be validated and optimized, for example the use of antioxidant therapies in ischaemia-reperfusion injury (IRI). IRI is a common cause of AKI and characterized by a decreased GFR and renal blood flow (RBF), oxidative stress, renal parenchymal damage and ongoing renal injury. A study showed that accumulated H2O2 in IRI, which is caused by a reduced catalase activity, can buffer Angiotensin II-mediated vasocontraction. That may protect RBF after IRI. Because of that the use of antioxidant therapies in IRI has to be carefully evaluated to keep the renal-protective character of H2O2.15 In contrast to IRI which is characterized by apoptosis or necrosis of tubular epithelial cells, sepsis-induced AKI (SI-AKI) is characterized by healthy or reversibly injured renal tubular epithelial cells.16 In intensive care settings, more than 50% of the patients suffer from AKI, where the most common cause is sepsis.2 The underlying mechanisms are unknown. Anderberg et al summarized the role of the Toll-like receptor 4 (TLR4) in SI-AKI. TLR4 is the main sensor of gram-negative bacteria and leads to activation of the innate immune system and pro-inflammatory response. Studies showed that TLR4 stimulation can cause renal injury and dysfunction and that the blocking of the TLR4-signalling in various sepsis models alleviate or abolish SI-AKI. AKI-characteristic GFR reduction and impaired tubular function are also detected when TLR4 is activated. However, the role of TLR4 in SI-AKI is still unknown. Nevertheless, for the treatment of AKI in human gram-negative sepsis TLR4 is an interesting target.2 Another part of the innate immune system, the human complement system (CS), is also associated with renal diseases. One example is the atypical haemolytic uraemic syndrome which in a lot of cases is caused by mutations in one or more regulators of the CS. The role of the CS in kidney diseases has been reviewed by Reuter et al.17 In addition to mutations for example in genes for the CS, the kidney can be injured in multiple ways by many drugs. One nephrotoxic drug is the chemotherapeutic substance cisplatin. Why and how cisplatin harms the kidney is not fully understood but renal hypoxia and the hypoxia-inducible factors (Hifs) seem to play a big role.18 Fähling et al found out that in mice chronic cisplatin treatment likely provokes episodic hypoxia which induces both Hif and its functional inhibitor Fih. Because of its nephrotoxic effect cisplatin is used to induce renal failure in animal models to study nephropathy. Abdulla and coworkers showed that renal bradykinin B1 and B2 receptors which are activated by renal failure, induced by cisplatin, affect the high- and low-pressure baroreflex regulation of the renal sympathetic nerve activity (RSNA). B2 receptors modulate afferent information delivered to neural pathways involved in high-pressure baroreceptor regulation of the RSNA. B1 receptors are required for facilitating the renal sympatho-inhibitory response to volume expansion. In a state of renal injury or inflammation B1 and B2 receptors seem to be important for modulating the sensory input to the brain to determine the effectiveness of the low-pressure cardiopulmonary reflex.19 Neurohumoral dysfunction leading to sympathetic overactivity, baroreflex dysfunction and chronically elevated circulating vasopressin are characteristic of CKD. The mechanism underlying neurohumoral dysfunction is still poorly understood. Underwood et al reviewed the possibility that uraemic toxins are drivers of neurohumoral dysfunction in CKD. Among others this thesis is supported by renal failure patients who show reduced sympathetic activity as well as improved cardiac baroreflex sensitivity after intensive haemodialysis. Their review summarizes several potential mechanisms by which uraemia might drive neurohumoral dysfunction in CKD. One possibility is that uraemic toxin induced stimulation of ROS production, inhibition of NOS activity and activation of pro-inflammatory pathways. They also consider that uraemic toxins may act synergistically with other sympathoexcitatory factors, especially Ang II, to increase sympathetic drive.20 Uraemia and other renal failure injuries are treated by haemodialysis (HD) or haemodiafiltration (HDF). These methods are limited because they cannot fully replace renal function in patients, as they do not prevent toxin accumulation like protein-bound indoxyl sulphate (IS).21 Enhancing the ionic strength by increasing Na+ concentration leads to more free fraction of IS which could be removed by HD or HDF. It should be noted that Na+ levels higher than the physiological one can cause haemolysis. Krieter et al designed a HDF with an increased plasma ionic strength (IPIS) and a diffuser to filter the used hypertonic NaCl solution. By using in vitro studies and an established animal model appropriate Na+ concentrations were selected and a clinical pilot study on maintenance patients was carried out as proof of principle. HDF-IPIS obtained the highest removal of IS compared to HD and HFD. However, further studies are needed to increase the effectiveness of HDF-IPIS as well as to confirm the better outcome for patients treated with this method.21 Despite new findings and extensive research, nephropathy is still a worldwide occurring problem, especially in hospitals.2, 22, 23 Further studies to understand, diagnose and treat this heterogeneous field of renal diseases are necessary and important for patients, society and public health care. There is no conflict of interest to declare. Bundesministerium für Bildung und Forschung (BMBF) iPS-Profiler, FKZ: 01EK1612B; BMBF SysToxChip FKZ: 031A303A.