Current insights into the Pathophysiology of kidney diseases

Chronic kidney disease (CKD) affects 700–800 million humans per year.¹ Damage to the kidney is often recognized late, although early diagnosis is essential for successful treatment. While acute kidney injury can often be effectively managed, CKD poses a challenge due to irreversible structural damage, compromising intrinsic kidney functions such as regulation of fluid, electrolyte, and acid–base balance, and the release of hormones into the blood, for example, renin and erythropoietin (Epo). The decrease in the glomerular filtration rate (GFR) and the increase in albumin in the urine are the most important markers in the diagnosis of kidney diseases. This article presents novel findings on kidney diseases, potential approaches for future therapies and new impacts in preventing and treating different stages of renal diseases, recently published in Acta Physiologica.

Early diagnosis of acute kidney injury (AKI) is of high importance for an adequate treatment. However, revealing early events in AKI is challenging, due to the absence of clear symptoms. Several urine- or blood-based markers for renal injury, fibrosis etc. have been suggested, with varying outcomes. In most forms of AKI, renal tissue hypoxia is an early marker. Hypoxia of the kidney tissue is also involved in the development of chronic and diabetic kidney disease. Kidney hypoxia often comes along with changes in kidney size. Cantow et al. analyzed in a magnetic resonance imaging (MRI)-based approach the connection between kidney size and renal tissue hypoxia. To achieve this, they used different interventions impairing renal tissue oxygenation, for example, occlusions and hypoxemia. MRI markers, kidney size, and their interactions were analyzed. In summary, observation of kidney size enables the interpretation of pathophysiological changes in kidney oxygenation. They conclude that monitoring of kidney size should always accompany MRI oximetry to gain essential information about renal disease levels, especially in acute changes in renal tissue oxygenation in AKI and its progression to CKD.²

Betrie et al. and Xu et al. focus on exploring preventive measures against AKI in ovine and rat models. Half of the patients with sepsis develop AKI and thereby have a higher morbidity and mortality. In ovine sepsis, hypoxia and renal medullary hypoperfusion is often followed by AKI, probably due to inflammation and oxidative stress. So far, there is a lack of specific renal-protective therapies available that focuses on the reduction of inflammation and the increased bioavailability of reactive oxygen and nitrogen species that appear in the kidneys. Betrie et al. investigated a possible protective effect of tempol on the development of AKI following sepsis. Tempol is a synthetic heterocyclic nitroxide that has a positive effect on reducing oxidative stress, increasing the bioavailability of nitric oxide and inhibiting inflammation. Following unilateral nephrectomy, sepsis was triggered by administration of Escherichia coli. Tempol had no effect in healthy sheep. Septic sheep that received tempol intravenously also showed no beneficial effect. However, renal arterial infusion of tempol prevented the onset of renal medullary hypoperfusion and hypoxia and thereby the development of AKI in septic sheep over 24 h. Oxidative and nitrosative stress markers were not affected, suggesting that oxidative stress displays no precondition to AKI development in ovine sepsis. The question arises but remains as to whether therapy with tempol could be of benefit in the case of established septic AKI.³

Exercise training is another strategy to prevent sepsis-associated organ dysfunction. Physical exercise upregulates the expression of muscle-derived R-spondin 3 (RSPO3), a secreted protein that showed a beneficial effect in murine models of mesenteric ischemia/ reperfusion injury and lung injury. Xu et al. investigated the effects of modulating the expression of RSPO3 by aerobic exercise on sepsis-associated AKI. One group of mice underwent treadmill training for 6 weeks. AKI was induced by intraperitoneal injection of lipopolysaccharide (LPS). Wild-type and RSPO3 knockout mice received RSPO3 intraperitoneal, followed by the same LPS treatment. Aerobic exercise caused an increase in RSPO3 expression in renal tissue. Supplemented and exercise-derived RSPO3 had a protective effect on LPS-induced renal endothelial hyperpermeability, inflammation and AKI. RSPO3 deletion aggravated the symptoms of AKI. Xu et al. found an inhibitory effect of RSPO3 on matrix metalloproteinases (MMPs), which are responsible for the disruption of the glycocalyx and tight junctions in LPS-induced renal AKI.⁴

As already mentioned, prevention of AKI is difficult, due to the complex pathogenesis and its complicated diagnosis. Zhou et al. investigated potential treatment options for AKI in a murine ischemia/reperfusion (IR) model. IR-induced AKI goes along with oxidative stress, because of damaged mitochondria, depletion of ATP and increased lipid peroxidation. Zhou et al. analyzed the potential role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in order to identify new treatment options. ADAMTS13 has already been associated with several diseases, for example, thrombotic microangiopathies, coronary heart disease and kidney diseases like renal failure and diabetic nephropathy. The effects of recombinant ADAMTS13 (rADAMTS13) on oxidative stress were investigated, focusing on antioxidant stress-enzyme activities and kidney function markers. They identified a number of positive effects of rADAMTS13 on IR-induced AKI: blood urea nitrogen and proteinuria were reduced, the activity of antioxidant stress enzymes was increased and reactive oxygen species (ROS) production was attenuated. On the molecular level ADAMTS13 caused the upregulation of nuclear factor-erythroid 2-related factor2 (Nrf2) and thereby upregulated the expression of, for example, heme oxygenase-1 (HO-1), a key cytoprotective enzyme. This may lead to the increasing antioxidant capacity of ADAMTS13 in ischemic kidneys and identifies rADAMTS13 as a potential future therapeutic option for the broad treatment of AKI.⁵

If AKI has developed, the GFR is increased in order to maintain kidney function.⁶ Up to a loss of 50% of the functional nephrons, full GFR can still be ensured, which is also often the reason for the late diagnosis of AKI. This phenomenon is called renal functional reserve (RFR). The GFR can also be increased by administering amino acids. In this context, Jufar et al. investigated the influence of amino acid administration on renal cortical and medullary oxygenation. They analyzed in sheep whether recruiting RFR induces renal medullary hypoxia or improves renal medullary oxygenation to find out whether RFR recruitment can be diagnostic or therapeutic. They observed an increase in mean renal oxygen delivery, renal oxygen consumption, GFR and oxygen tension of renal cortical and medullary tissue due to RFR recruitment. Jufar et al. propose RFR recruitment as biomarker for detecting clinical kidney dysfunctions or for prophylactic or therapeutic usage, for example, to increase GFR in kidney in nephropathies.⁷

Patients suffering from cancer often have reduced GFRs due to nephrotoxic therapeutic substances. However, a physiological healthy kidney is a key determinant for the treatment of cancer, as the kidney is of high priority for excretion of therapeutics. In their review, Claudel and Gandhi et al. speculate on a preferred method of measuring GFR for clinical treatment decisions, as there are no clear guidelines for cancer patients. They conducted a comprehensive survey of equations derived from creatinine and cystatin C, and synthesized novel methodologies for estimation. For patients in routine clinical practice Claudel and Gandhi propose the CKD-EPI (epidemiology) equation of 2009 and 2012. However, these equations are ethnicity-based. The authors recommend implementing the CKD-EPI equations of 2021 and complementing these with further studies to be able to make valid statements about cancer patients.⁸

Renal fibrosis is one of the main causes of CKD and lacks effective treatment strategies. Kresse et al. hypothesized that the EP₁ receptor is a promising target for prevention of fibrosis and examined the impact of PGE₂-EP₁ (Prostaglandin E₂) receptor on the kidney fibrosis pathogenesis. PGE₂ binds to the G-protein-coupled EP receptors. Inhibition of EP₁ with a specific receptor antagonist showed anti-fibrotic effects in UUO mice, Madin-Darby Canine Kidney cells, primary human renal fibroblasts and human fibrotic precision-cut kidney slices. Kresse and colleagues postulate a protective effect for EP1 receptor antagonism in both, early and late stage of renal fibrosis and highlight the potential usage of their findings for clinical care.⁹

Anemia is a severe side effect of advanced CKD, often due to Epo deficiency. It is, however, unclear, why Epo expression is lost during CKD. Hypoxia inducible factor 2 (HIF-2) induces kidney and liver Epo synthesis in healthy humans and patients suffering from a commonly observed anemia. Inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHIs) activate HIF-2 itself.^{10, 11} Kobayashi et al. analyzed in kidney fibrosis models whether Epo synthesis can be reactivated with HIF-PHIs. It is already described that liver Epo production in rodent models of CKD can be stimulated with pharmacologic HIF-PHI.¹² Kobayashi et al. found that HIF-PHI does not contribute to Epo transcription in interstitial myofibroblasts. However, HIF-PHI-stimulated Epo synthesis in fibrotic kidney is possible, but is limited to areas with preserved kidney architecture and a certain level of residual renal function.¹³

In this context, Dahl and colleagues analyzed the long-term fate of renal Epo-producing cells and whether they can be recruited repeatedly in healthy and damaged kidneys. Transcription of Epo under hypoxic conditions is followed by fibrotic tissue remodeling without Epo transcription. Their findings show that inactive Epo-producing cells can be reactivated via HIF stabilizing agent or a hypoxic stimulus in kidneys, indicating a persistent cell functionality of Epo-producing cells in normoxia and during fibrotic tissue remodeling.¹¹

In water balance disorders, for example, CKD and nephrogenic diabetes insipidus aquaporin-2 shuttling is dysregulated. Ernstsen et al. analyzed trafficking of renal aquaporin-2 in connection with acute pyelonephritis. They found that uropathogenic as well as nonpathogenic bacteria induce the plasma membrane targeting of aquaporin-2 in cell culture. They speculate that microbe-associated molecular patterns induce this effect. This suggestion is confirmed by the fact that aquaporin-2 membrane targeting as a result to uropathogenic bacterial lysates is independent of an increase in intracellular cAMP. Moreover, aquaporin-2 targeting was increased in the inner medullary collecting ducts in renal sections of a murine model of acute pyelonephritis due to pathogenic microbes, confirming a role of aquaporin-2 for the disease pattern.¹⁴

CKD often goes along with cardiovascular disease (CVD). This connection is referred to as cardiorenal syndrome (CRS), recently reviewed by van Ham et al. with focus on uremic toxins in CRS. The increase of plasma uremic toxin concentrations causes a reduction in kidney function and further make dialysis essential. Van Ham et al. highlight a lack of information regarding the molecular mechanisms of uremic toxin influence in cardiac diseases.¹

In another review, Boi et al. focus on mesangial tissues in healthy kidneys and in disease, especially for IgA nephropathy (IgAN) and diabetic kidney disease (DKD). They emphasize the many central functions of the mesangium in renal and systemic crosstalk communication. The mesangium reacts in a variety of ways to cytokines, growth factors and other signaling molecules and releases them. In glomerular disease, the mesangial matrix shows prolonged inflammation. TGF-β plays an important role in the development of fibrosis. Pathological mesangial matrix expansion likely appears due to the increased expression of collagen III that is also caused by TGF-β. Infiltrating neutrophils and macrophages and especially the complement system strongly interact with the mesangium.¹⁵

The mammalian target of rapamycin (mTOR) signaling pathway is important for the regulation of cell growth and metabolism and is a central player in renal diseases. mTOR functions in renal tubular ion handling, with mTOR complex 1 being responsible for nutrient transports in the proximal tubule and mTOR complex 2 in the collecting duct influencing Na + reabsorption and K+ excretion. In their review, Adella and de Baaij give a complex overview on mTOR signaling in the kidney tubule and in disease settings. They focus on how mTOR is involved in autosomal dominant polycystic and diabetic kidney disease and nephropathic cystinosis.¹⁶

While mTOR regulates growth and survival, renin-angiotensin-aldosterone system (RAS) is important for fluid and electrolyte balance. RAS is activated when ureteral obstruction occurs and this can lead to severe tissue remodeling and end-stage renal disease. Nagalakshmi et al. investigated whether the improvements observed after partial ureteral obstruction are due to the involvement of renin-forming cells or cells of the renin lineage.¹⁷ During persistent ureteral obstruction and release of obstruction renin cells exhibit dynamic changes. After ureteral obstruction renin levels increased. Lineage tracing showed that GFP labeled renin cells were present in renin producing juxtaglomerular cells, smooth muscle cells of renal arteries and the intra-glomerular mesangium. Ablation of renin cells impairs the reparative response and the ability of the kidney regeneration after the release of the obstruction. The authors speculate about a contribution of renin to the damage responses during the obstruction and a regenerative response of renin cells afterwards.¹⁷

Familial Hypomagnesia with Hypercalciuria and Nephrocalcinosis (FHHNC) is a rare kidney disease. Patients suffer from polyuria, polydipsia, enuresis and recurrent urinary tract infections. Electrolyte handling is impaired but patients only receive supporting dietary due to a lack of specific treatment options. An important factor that influences FHHNC mortality is calcium dysregulation. Kriuchkova et al. report the benefits of furosemide treatment in calcium transport in a murine model. They were able to confirm that furosemide reduced hypercalciuria, which might be of relevance for clinical FHHNC patients.¹⁸

The prevention and treatment of AKI and CKD is a highly relevant field of research. New insights into regulating substances, signaling pathways and potential therapeutics at the molecular level provide a comprehensive overview into the (patho)physiology and are fundamental for the development of new therapeutic agents.

Anika Westphal: Conceptualization; research; writing—original draft; writing—review and editing.

None.

The author declares no financial or other conflicts of interest that might bias this article.