Editorial

Diabetic Kidney Disease: An Update in Recent Clinical and Basic Research

Sydney C.W. Tang

Disclosures

Nephrol Dial Transplant. 2020;35(5):725-728. 

The continuously rising impact factor of Nephrology Dialysis Transplantation (NDT) is a clear sign of the high quality of the original papers that have been published over the last few years. This editorial discusses some of the landmark papers published in 2018. It should be noted that this selection is subjective and many more excellent articles in the field of diabetic kidney disease (DKD) were published in NDT during that period.

Proteinuria were used as a surrogate biomarker in many clinical trials of DKD. Residual albuminuria has a linear relationship with renal outcome; the higher the albuminuria, the greater the renal risk.

Minutolo et al.[1] reaffirmed proteinuria as a risk modifier in DKD in an observational study that evaluated cardiovascular (CV) and renal risks in diabetic versus non-diabetic CKD patients stratified by the level of proteinuria. Outcome measures of all-cause death, fatal and non-fatal CV death and end-stage renal disease (ESRD) were compared and there were several important findings. First, the cardiorenal risk of the non-proteinuric (<0.15 g/day) diabetes mellitus (DM) chronic kidney disease (CKD) cohort was not elevated when compared with their non-diabetic CKD counterparts, despite a higher risk profile. Patients in the DM CKD group were older, had higher body mass index and systolic blood pressure (BP) and had a more frequent history of CV disease. Second, when proteinuria was present (0.15–>1.0 g/day), CV events and all-cause mortality increased in the diabetic compared with non-diabetic patients with CKD, suggesting that risks conferred by DM are not absolute and are modulated by the presence of proteinuria. Finally, diabetes per se was not independently associated with the risk of ESRD, which was independently modified by the magnitude of proteinuria, such that the renal risk of diabetics and non-diabetics with CKD was comparable (Figure 1).[2]

Figure 1.

Absolute risks for ESRD in diabetic and non-diabetic CKD patients by proteinuria level (reproduced with permission from Oxford University Press [1]).

The prognosis of non-proteinuric DM CKD patients is unknown, as this cohort is usually excluded from clinical trials. Non-proteinuric patients with DM are now a well-recognized phenotype from those with incipient proteinuria.[3] Recent research has even suggested that progression to CKD as a result of DM involves various genetic susceptibility components.[4] Thus an automatic assumption of an elevated cardiorenal risk profile from diabetes may be outdated. The results herein suggest that proteinuria is a modulator of the attendant CV and renal risks in patients with DM CKD, whereas the non-proteinuric subgroup shares a similar prognosis comparable to non-diabetic CKD patients. Hence a variety of interactions are likely at play to modify the overall risk profile of a diabetic patient and future breakthroughs in therapy will rely on accurate dissection of predictors.

Among the pathogenetic pathways of DKD, renal inflammation plays a critical role in promoting and sustaining much of the chronic injury process.[5,6] Janus kinase–signal transducer and activator of transcription (JAK-STAT) signalling is one of the major pathways that transduce inflammatory signals in DKD.[7] The JAK-STAT pathway transmits signals from extracellular ligands, including cytokines, chemokines and growth factors, to the cell nucleus and induces a variety of pro-inflammatory responses.

Baricitinib is an oral, small-molecule inhibitor of the JAK family of protein tyrosine kinases that selectively inhibits JAK1 and JAK2 and has demonstrated clinical efficacy in chronic inflammatory conditions such as rheumatoid arthritis.[8] Tuttle et al.[9] performed a randomized, placebo-controlled, double-blind, Phase 2 trial at 40 sites in Japan, Mexico and the USA. Type 2 diabetics (n = 129) with a mean age of 63 years, estimated glomerular filtration rate (eGFR) of 45.0 ± 12.1 mL/min/1.73 m2 and median first morning urine albumin:creatinine ratio (UACR) of 820 mg/g were randomized to placebo or four different doses of baricitinib. At 4 mg daily, baricitinib decreased morning UACR by 41% at Week 24 compared with placebo [ratio to baseline 0.59 (95% confidence interval 0.38–0.93); P = 0.022]. These treatment-related reductions in 24-h UACR were mostly maintained after 4 weeks of washout. There was no appreciable change in serum creatinine, 24-h creatinine clearance and eGFR. Notably, there were significant reductions in inflammatory biomarkers >24 weeks, including urine C-X-C motif chemokine 10 (CXCL-10) and C-C motif ligand 2 (CCL2) and plasma-soluble tumour necrosis factor receptor 1 (TNFR1) and TNFR2, intercellular adhesion molecule 1 and serum amyloid A. There was no significant increase in adverse events except for anaemia in the treatment group.

This is the first randomized controlled trial (RCT) to demonstrate the anti-proteinuric effect of a JAK inhibitor on DKD, as reflected by dose-related reductions in JAK1- and JAK2-mediated inflammatory markers that have been linked to DKD pathophysiology. Among the measured cytokines, CCL2 (monocyte chemoattractant protein-1) and CXCL10 (Interferon γ-induced protein 10) were measured in urine, and urinary biomarkers appear to more closely track with inflammation in the kidney than with systemic inflammation.[10] These results support the plausibility that a reduction of local inflammation ameliorates DKD and suggests that baricitinib works, at least in part, via local anti-inflammatory effects in the diabetic kidney. In addition, reductions in soluble TNFR1 and TNFR2 are also in agreement with previous data.[11]

Apart from JAK-STAT activation, oxidative stress plays an independent role in the progression and severity of DN. Hyperglycaemia, activated transforming growth factor-β1 and advanced glycation end-products in the glomerular and tubular epithelial cells of the kidney all induce oxidative stress via generation of reactive oxygen species (ROS).[12]

Cluster of differentiation 36 (CD36), which belongs to a Class B scavenger receptor family, is a glycosylated surface receptor expressed in the plasma membrane and mitochondria of multiple cell types, including renal tubular cells, macrophages and endothelial cells. CD36 mediates oxidative stress injury in type 2 diabetes.[13] SS31 is a cell-permeable, mitochondrion-targeted antioxidant peptide that might be a therapeutic target against oxidative stress.

Hou et al.[14] investigated the therapeutic potential of SS31 against oxidative stress and examined whether SS31-induced renoprotection is CD36 dependent in db/db mice and high glucose (HG)-induced human kidney 2 (HK-2) cells. They showed that SS31, at 3 mg/kg/day intraperitoneally for 12 weeks versus saline control, alleviated proteinuria, glomerular hypertrophy and tubular injury and affected the creatinine level in db/db mice. SS31 suppressed oxidative stress, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, CD36 and nuclear factor κB p65 and activated manganese-dependent superoxide dismutase and catalase in db/db mice and HG-induced HK-2 cells.

ROS production is dependent mainly on NADPH oxidase activation.[15] Among the seven isoforms (Nox1–5, Duox1 and Duox2) of NADPH oxidase, Nox4 is localized mainly in renal mitochondria and is a key player in glucose-mediated ROS production.[16] NOX4 and p22phox messenger RNA and protein expression were increased remarkably in both db/db mice and in HG-treated HK-2 cells, and these increases were ameliorated by SS31 treatment, supporting the notion that SS31 reduces oxidative damage in the diabetic kidney by inhibiting NADPH oxidase–mediated ROS production. Therefore SS31 might have a therapeutic potential for DKD by inhibiting oxidative stress and downregulating CD36 expression.

Sodium–glucose co-transporter 2 inhibitor (SGLT2i) has emerged as the next most promising class of therapeutic agents for DKD following the angiotensin II receptor blockers.[17] The first encouraging report came from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) that showed reductions in the major CV outcomes of death from CV causes, non-fatal myocardial infarction and non-fatal stroke[18] and, serendipitously from the pre-specified component of the secondary microvascular outcomes of that trial, reductions in renal outcomes including incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal replacement therapy or death from renal disease) and incident albuminuria with empagliflozin.[19] On the other hand, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE)[20] was the first released trial designed to test the primary efficacy of canagliflozin on a composite of ESRD (dialysis, transplantation or a sustained eGFR <15 mL/min/1.73 m2), doubling of serum creatinine or death from renal or CV causes in patients with DKD. It was stopped early after interim analyses revealed that after a median follow-up of 2.62 years in 4401 patients, the relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group.

The mean baseline eGFR in CREDENCE was 56.2 mL/min/1.73 m2. And it remains unclear whether patients with lower eGFRs may benefit from SGLT2i. In a pooled analysis of 11 Phase 3 RCTs, Dekkers et al.[21] determined the least square mean changes in haemoglobin A1c (HbA1c), body weight, BP, eGFR and UACR >102 weeks in patients with type 2 diabetes and an eGFR of 12–<45 mL/min/1.73 m2 receiving placebo (n = 69) or two doses of dapagliflozin (n = 151). There was no significant change in HbA1c or eGFR, but dapagliflozin compared with placebo reduced UACR (by 47.1% for 5 mg and 38.4% for 10 mg), BP and body weight. These findings are in agreement with the same extraglycaemic benefits observed with empagliflozin.[22]

Collectively these recent data suggest that the cardiorenal protective effects of SGLT2i and their extraglycaemic effects at lower eGFRs (Stages 3b–4 CKD) are a class effect rather than a particular agent. These findings call for a large outcome trial in this population to confirm the long-term safety and efficacy in reducing adverse clinical endpoints. Whether this class of promising agents will feature an indication in the non-diabetic or non-CKD population requires further investigation.

In terms of novel treatment approaches for DKD, Skov-Jeppesen et al.[23] reported the outcome of a Phase 1 prospective, single-arm study using low-intensity shockwave therapy (LI-SWT) on eGFR and albuminuria in 14 patients with Stage 3 CKD and DM. The authors reported low adverse event rates except gross haematuria and non-sustained flank pain, with a trend of improvement in 6-month eGFR and a reduction of albuminuria (Figure 2).

Figure 2.

Set-up of LI-SWT treatment with the patient in the supine position and the shockwave source from a lithotripter beneath the table along the patient's lumbar region (reproduced with permission from Oxford University Press [23]).

LI-SWT is suggested as a novel modality to improve tissue vascularization and organ function, and shockwaves are biphasic acoustic waves of initial high-amplitude positive pressure followed by a tensile phase propagating three-dimensionally through various kinds of tissues.[24] At the cellular level, shockwaves provide a mechanical stimulus to the cytoskeleton and membrane-bound proteins[25] at an energy level that is much lower than lithotripsy. Clinical studies have shown that LI-SWT promotes angiogenesis, leading to regenerative effects in coronary artery disease,[26] musculoskeletal disorders, soft tissue wounds and even erectile dysfunction. At the molecular level, LI-SWT upregulates pro-angiogenic factors such as vascular endothelial growth factor and endothelial nitric oxide synthase (eNOS).[27] In diabetic eNOS knockout mice, shockwave-induced angiogenesis and wound healing are blunted, pointing to nitric oxide being the primary effector molecule of LI-SWT.[27]

This study is the first to suggest LI-SWT as a safe treatment modality with the potential for restoring renal function in DKD. Though encouraging, the results are limited, as no control group was applied, and the results did not demonstrate significant improvements of GFR and albuminuria.

LI-SWT is reminiscent of remote ischaemic preconditioning (RIPC), a brief, repeated, mild ischaemia–reperfusion injury induced in one organ that protects another organ from a subsequent episode of lethal ischaemia–reperfusion. In a meta-analysis of 33 RCTs, RIPC did not consistently reduce morbidity and mortality after cardiopulmonary bypass, although among patients who received volatile anaesthetics, RIPC decreased the incidence of AKI.[28]

An RCT (ClinicalTrials.gov identifier: NCT03445247) is currently under way in Taiwan to recruit 60 Stage 3 and 4 CKD patients with type 2 diabetes to be allocated to control or experimental groups in a 1:1 ratio.

This selection of five original research papers in DKD published in NDT in 2018 is subjective. Many more high-quality transplant papers were published in NDT during 2018, but I sought to cover a wide range of clinically important topics where considerable uncertainty existed before these papers appeared. As associate editor of NDT, I truly hope that these clinical research papers will enhance our knowledge and ultimately lead to better care and improved outcomes of our patients with DKD.

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