Keywords
Diabetes - diabetic kidney disease - pathogenesis - treatment
Introduction
Diabetes mellitus (DM) manifests by polyuria, recurrent urinary tract infection, and
albumin loss in the urine (albuminuria/proteinuria). Acute renal failure is not an
uncommon complication, however, diabetic nephropathy (DN) or diabetic kidney disease
(DKD) has usually a chronic kidney disease (CKD) course, precipitating end-stage renal
disease (ESRD), increasing morbidity and mortality.[[1]],[[2]] The Kidney Disease Outcomes Quality Initiative clinical practice guidelines in
2007 suggested that the DKD term should replace DN to describe kidney involvement
in DM, whereas the biopsy-proven kidney disease due to DM is called diabetic glomerulopathy.[[3]] Understanding of the epidemiology, risk factors, natural history, and pathogenesis
of the disease should help practicing physicians recognize the rationale of contemporary
clinical practice guidelines and perhaps enhance adhering to them in day-to-day practice.
Hence, this narrative review aims to review these aspects concisely.
Materials and Methods
This is a narrative nonsystematic review of the updated literature on pathogenesis
and management of CKD. The review aims to provide an updated overview on the epidemiology,
pathogenesis, and current and emerging management strategies for DKD.
Nomenclature and Definitions
Nomenclature and Definitions
The DKD stages are as follows: first, glomerular hypertrophy and hyperfiltration,
manifesting as enlarged increases in the kidney, and increased glomerular filtration
rate (GFR); second, appearance of moderately albuminuria (30–300 mg/day) that later
becomes macroalbuminuria (>300 mg/day);[[4]] third, constant reduction of GFR; and finally, ESRD development.
Appropriate blood sugar control by hypoglycemic agents and hypertension control by
the renin–angiotensin–aldosterone system (RAAS) reduce albuminuria prevalence among
diabetics.[[5]] Some patients develop renal function deterioration without evidence of albuminuria,[[6]] especially in type 1 diabetic patients.[[7]] In 2020, the Italian Diabetes Society and the Italian Society of Nephrology addressed
in type 2 DM natural history a joint statement that describes two distinctive pathways
of DKD: a traditional albuminuric progressive renal impairment and nonalbuminuric
renal impairment pathway.[[8]] The main difference between the two entities is the presence of proteinuria at
the beginning of DKD and during its progression to CKD and ESRD. These observations
yielded that the nonalbuminuric pathway is due to tubulointerstitial and/or vascular
involvement that is mostly controlled by some factors such as dyslipidemia, high blood
pressure (BP), obesity, and aging.[[8]] DKD pathophysiology, new diabetes treatment approaches, and prevention strategies
of short- and long-term diabetes-induced kidney complications will be discussed and
updated.
Epidemiology
DM is the major cause of ESRD, for example, In the USA 47% and Malaysia >60% of ESRD
is due to DKD.[[9]] Approximately 23% of intensively treated and 36% of conventionally treated diabetic
patients have albuminuria after a mean follow-up of 24 years.[[10]] Another study noted that 38% developed albuminuria whereas 28% of type 2 diabetic
patients had renal impairment after a median of 15 years of follow-up. Furthermore,
it was reported that CKD prevalence was <30% to > 80% in diabetic patients,[[11]] however, DKD prevalence was changing significantly during the past decade.[[12]]
Diagnosis of Diabetic Kidney Disease
Diagnosis of Diabetic Kidney Disease
The main problem of diagnosing DKD is proving kidney disease's existence. Clinically,
the presence of albuminuria and/or GFR reduction is/are diagnostic for DKD. Recently,
urine albumin/creatinine ratio is commonly used to quantify albuminuria, although
24-h urine albumin content is still more informative when the urine is perfectly collected.
Two out of three high albumin/creatinine ratios (>30 g/g) of urine spots over 3–6
months are considered diagnostic. Conditions such as vigorous exercise, fever, hematuria,
urinary tract infection, and congestive heart failure may cause albuminuria. Hence,
3–6-month period is recommended to confirm diabetes-induced albuminuria in diabetic
patients.[[13]] It is recommended that GFR calculation and proteinuria should be checked at least
once per year after 5 years of type 1 DM and at type 2 DM diagnosis.[[14]] Persistent determined estimated GFR (eGFR) by the CKD epidemiology collaboration
equation of <60 mL/min/1.73 m2 is considered diagnostic for diabetes-induced CKD.
Renal biopsy is not recommended by many authors to diagnose DKD, however, it may be
needed if other causes of CKD rather than DKD are suspected. A short history of diabetes,
no evidence of diabetic retinopathy, particularly in DM type 2 patients, active urinary
sediments, rapidly progressive albuminuria, sudden-onset nephrotic syndrome and/or
abrupt GFR reduction, plus other signs and symptoms of other causes of kidney damage
are considered as indications for percutaneous renal biopsy in diabetic patients.[[14]] Approximately 6.5%–94% of renal biopsies that were done for diabetics revealed
DKD, and around 3%–83% were non-DKD, whereas 4%–45.5% were both DKD and non-DKD.[[15]] The varied ranges of biopsy results in diabetic patients can be due to the varied
renal biopsy indications and different DM prevalence.
Pathophysiology of Diabetic Kidney Disease
Pathophysiology of Diabetic Kidney Disease
DKD developments occur due to metabolic and/or hemodynamic disturbances. At early
DKD stages, the intraglomerular Bp increases, leading to higher GFR. These changes
increase the risk of DKD, promoting its progression [[Figure 1]].
Figure 1: Mechanisms of diabetic kidney disease
Hemodynamic pathways
Renin releases from granular cells (J-cells) of the renal juxtaglomerular apparatus
(JGA) in response to the singular or combined effect of the three factors that are
decreased sodium delivery to the distal convoluted tubule (DCT), reduced perfusion
pressure that can be detected by the baroreceptors in the afferent arteriole, and
the JGA stimulation by the sympathetic system via β1 adrenoreceptors. The main function
of the renin hormone is stimulation of angiotensin II formation. Angiotensin II increases
the total peripheral resistance, raising the systemic Bp. In the kidneys, angiotensin
II increases the vascular tone of both afferent and efferent, but its vasoconstriction
effect is more on the afferent arteriole, while it has more smooth muscle content.
However, the angiotensin II vasoconstrictor effect on the afferent is minimized by
the locally produced prostaglandins-kinins, thromboxane-2, and nitric oxide.
Proximal convoluted tubule (PCT) receives a massive amount of glucose in the filtrate,
leading to an increase of PCT reabsorptive power to glucose that couples with sodium
reabsorption, reducing sodium concentration into the DCT.[[16]] The decreased DCT filtrate sodium content and blood flow stimulate the J-cells
to excrete the renin hormone, increasing the intraglomerular pressure via the angiotensin
II effect.[[16]],[[17]] Additionally, endothelin-1 (ET-1) serum concentration is high in DM patients. ET-1
A and B receptor stimulation modulates renal vessel tone that affects filtration and
blood flow, enhancing DKD pathogenesis.[[18]] Increased glomerular hyperfiltration may be due to altered autoregulatory responses
of the afferent arterioles to the BP fluctuations[[19]] that are transmitted along to glomerular capillaries, resulting in glomerular sclerosis
and peritubular capillaries damage occur because of the persistent rise in intraglomerular
BP.[[20]]
Metabolic pathways
Damage to glomerular basement membrane due to increased intraglomerular BP and DM
increases glomerular protein leakage.[[20]] The presence of proteins in the nephron tubule enhances the formation of pro-inflammatory
and profibrotic factors, increasing kidney damage. Furthermore, hyperglycemia leads
to the accumulation of reactive oxygen species (ROS),[[21]] which cause mitochondrial malfunction and defect of pro-oxidant enzymes, such as
nicotinamide adenine dinucleotide phosphate oxidase,[[22]] increasing the risk of kidney damage. Additionally, ROS oxidize proteins, lipids,
and nucleic acids, producing metabolites that may ultimately cause significant kidney
damage.
Persistent hyperglycemia results in advanced glycation end-product formation and ROS,
activating intercellular signaling for pro-inflammatory and profibrotic gene expression,
increasing host mediators' formation that causes cell injury. Hyperglycemia causes
abnormal glucose metabolism and oxidative stress, leading to the activation of different
intracellular signaling pathways, which may have a role in DKD pathogenesis. One of
these pathways is a mitogen-activated protein kinase (MAPK). It was reported that
MAPK activation stimulates apoptosis and extracellular matrix production by the mesangial
cells.[[23]] Furthermore, hyperglycemia motivates Janus kinase-signal transducers and activators
of transcription (JAK-STAT) and nuclear factor-kappa B (NF-κB). These signals are
heavily engaged in the initiation of inflammatory reactions. Moreover, NF-κB encourages
molecule adhesion and pro-inflammatory cytokine expression (macrophage chemoattractant
protein-1, tissue necrosis factor-α, and interleukin-6) that contribute to DKD pathogenesis.[[24]] The kallikrein–kinin system is also activated by persistent hyperglycemia, encouraging
an inflammatory process by generating bradykinins such as kallistatin (an endogenous
tissue kallikrein inhibitor), leading to glomerulosclerosis, and tubulointerstitial
injury.[[25]]
Severe hyperglycemia causes a massive amount of glucose delivery to the nephron, requiring
more energy and oxygen consumption to reduce glucose loss in urine by upgrading the
activity of sodium–glucose cotransport function.[[26]] Additionally, hyperglycemia stimulates the mitochondrial uncoupling process, increasing
the oxidative stress, and the releasing of hypoxia-inducing factor (HIF), increasing
oxygen and energy consumption that promotes tubular epithelial cell damage.[[27]] The oxygen delivery to the kidney tubular system in DKD is decreased mostly due
to loss of peritubular capillaries and interstitial fibrosis.[[28]] However, it is difficult to demonstrate that hypoxia alone precipitates DKD progression.
Hence, HIF release inhibition can be claimed as a modality to prevent renal tubular
damage and prevent DKD.
Autophagy (self-killing) process abnormality is also reported in DKD pathogenesis.[[29]] Autophagy is a body self-mechanism by which the damaged proteins and organelles
are cleared, and it recycles intracellular resources in response to conditions such
as nutrient deficiency.[[29]] Mammalian target of rapamycin complex 1 (mTORC1) has a role, by inhibiting Unc-51-like
kinase 1 activity that stimulates autophagy in diabetics.[[30]],[[31]] It is noted that inhibition of mTORC1 by rapamycin decreases the risk of DKD in
diabetic mice.[[31]] Additionally, DKD epigenetic modifications affect gene expression without alteration
of DNA sequence. DM induces epigenetic variations such as DNA methylation, histone
modification, chromatin conformational changes, and altered expressions of noncoding
RNAs.[[32]] It is reported that in a mouse study, an aberrant DNA methylation in the mesangial
cells of type 2 diabetic mice was combined with an increase of transforming growth
factor-β (TGF-β) expression and formation.[[33]] Interestingly, it was documented that epigenetic changes act as “metabolic memory,”
mediating the persistent long-term expression of diabetes-related genes and phenotypes
that were induced by hyperglycemia, which might persist even after hyperglycemia control,[[32]] increasing the risk of DKD.
The main histological feature of the DKD is mesangial cell hypertrophy and matrix
accumulation that is mediated by the TGF-β system.[[34]] TGF-β production is increased in high blood sugar and angiotensin II milieu by
the mesangial cell, increasing glomerular extracellular mesangial matrix production
and reducing the production of matrix metalloproteinases which controls extracellular
matrix normal structure via old tissue lysis.[[34]]
Hyperglycemia causes glucose catabolism via nonglycolytic pathways such as the polyol
pathway, increasing oxidative stress via protein kinase C (PKC) activation. The activated
PKC lowers endothelial nitric oxide synthase (eNOS) formation and increases ET-1 and
vascular endothelial growth factor (VEGF) levels, encouraging endothelial instability
and cytokine production. The high VEGF and low eNOS stimulate vascular proliferation
and endothelial permeability in DND.[[35]] A balance between angiopoietins 1 and 2 is essential to control the endothelial
function, preventing endothelial proliferation in DKD.[[36]]
Macrophages are activated by hyperglycemic stress, high angiotensin II, oxidized low-density
lipoproteins, and other glycolysis end-products in DM. Furthermore, macrophage migration
increases into the glomeruli and the kidney interstitium in diabetic patients. These
changes have a significant link with DND progression.[[37]] Furthermore, the activated macrophages produce tumor necrosis factor-alpha, a pleiotropic
cytokine that promotes more damage and DKD progression.[[37]] TGF-beta and plasminogen activator inhibitor 1 production increases due to the
metabolism of the excess glucose by the hexosamine pathway.[[38]] Injury of PCT by abnormal glycolysis end-products, albuminuria, increased TGF-beta,
and high angiotensin II cause pericyte conversion into myofibroblasts, producing more
collagen and fibronectin deposition in the kidney interstitium.[[19]] Inhibition of these pathways can reduce and prevent DKD development.
Therapeutic Strategies of Diabetic Kidney Disease
Therapeutic Strategies of Diabetic Kidney Disease
DKD is a progressive disease, but good control of blood sugar targeting normal glycated
hemoglobin and Bp control targeting ≤120/80 mmHg are essential to limit the DND development
and progression. Furthermore, hyperlipidemia, cardiovascular (CV), and cerebrovascular
complications of DM must be addressed and treated promptly to improve the long-term
DM outcome [[Table 1]].
Table 1: Current and emerging therapeutic strategies for diabetic kidney disease
Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers
Renin–angiotensin–aldosterone system inhibitors (RAASis) are recently the most common
agents are used to control the Bp in diabetic patients. The RAASis reduce intraglomerular
pressure and glomerular hyperfiltration.[[39]] Furthermore, they amend the oxidative stress of angiotensin II, inflammation, and
fibrosis,[[40]] hence hypothetically, RAASis may completely pause the DKD progression to ESRD.
The decent effectiveness of the RAASis was proven in the management of DKD by various
randomized studies such as the Collaborative (captopril), RENAAL (losartan), and IDNT
(irbesartan) studies which reported that serum creatinine doubling, ESRD, and mortality
rates are decreased.[[21]] However, it was observed that the kidney outcome improvement is beyond to be attributed
only to the RAASis lowering Bp effect.[[21]]
Dual angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker
(ARB) therapies were proven more effective than a singular group agent in controlling
the Bp, and in the prevention of proteinuria deterioration. However, the long-term
DKN outcome was not changed, and the risk of acute renal failure and hyperkalemia
is increased.[[41]] The nonsteroidal mineralocorticoid receptor antagonists such as apararenone, esaxerenone,
and finerenone are potent and selective to inhibit mineralocorticoid receptors than
the steroidal mineralocorticoid receptor antagonists (spironolactone and eplerenone),
decreasing the risk of hyperkalemia when they are used with RAASis.[[42]] It was reported that in type 2 DM patients, adding esaxerenone to ACEi or ARB significantly
decreases the proteinuria,[[43]] but the combination is initially associated with dose-dependent eGFR reduction,
which is improved during 12 weeks of the treatment.[[43]] It is reported that adding finerenone to ACEi or ARBs improves proteinuria, and
decreases the risk of a long-term eGFR decline, ESRD, and death from renal diabetic-related
diseases.[[44]]
Sodium–glucose cotransporter-2 inhibitors
Sodium–glucose cotransporter-2 (SGLT2) proteins are present in the PCT of the kidneys.
The SGLT2 proteins are transporters that concern with 90% of the filtered glucose
reabsorption in PCT, therefore, inhibiting this mechanism by SGLT2 inhibitors will
effectively help in DM control.[[45]] SGLT2 inhibitors reduce and even may prevent ESRD.[[46]] It was noted that empagliflozin reduces cardiovascular system (CVS) morbidity and
mortality in type 2 diabetes,[[47]] and decreases the risk of DKD and its progression to ESRD.[[48]] A similar effect was reported with canagliflozin,[[48]] and dapagliflozin.[[49]]
Although the exact mechanisms of SGLT2 inhibitors' effect to prevent DKD and its progression
are not clearly understood, their sodium reabsorption inhibitory effect in the PCT,
which increases filtrate sodium content into the densa macula, activating a feedback
mechanism. The tubule-interstitial feedback mechanism causes afferent renal arteriole
vasoconstriction which reduces renal blood flow, and the intraglomerular Bp.[[50]] This hypothetical assumption is supported by the significant reduction of eGFR
in type 1 diabetics who are treated with empagliflozin.[[51]]
PCT cell needs more energy and oxygen consumption in hyperglycemic status. SGLT2 inhibitors
modulate the oxygen and energy requirements by inhibiting the sodium–glucose cotransport
system, producing better renoprotection. The possible explanation of the renoprotective
effect is due to oxygen demand reduction that is resulted from the mitochondrial uncoupling
process impairment by SGLT2 in the PCT epithelial cells. Furthermore, empagliflozin's
renoprotective role in both proteinuric and nonproteinuric DKD patients may be due
to its promoting effect on the production of ketone bodies, which block the mTORC1
pathway in PCT cells,[[52]] reducing the autophagy. Additionally, it was reported that chronic SGLT2 inhibitor
(ipragliflozin) administration reduces significantly the accumulation of Krebs cycle
intermediates, and also impairs the increased oxidative stress in the kidneys of diabetic
patients.[[53]] Moreover, SGLT2 reduces oxidative stress, improves cortical hypoxia, and promotes
vascular remodeling via attenuation of renal capillary injury and fibrosis by a VEGF-dependent
pathway in diabetic mice.[[53]],[[54]] Furthermore, recently, it is reported that type 2 DM patients had atherosclerotic
CV disease, ertugliflozin minimizes the risk for the prespecified renal vascular DM
effects, and it preserves the eGFR and decreases urine albumin creatinine ratio.[[55]]
It has been claimed recently that there is not a significant protective effect of
dapagliflozin on the renal and CV with advanced CKD. The U.S. Food and Drug Administration
(FDA) on May 3 approved dapagliflozin (Farxiga) oral tablets to reduce the risk of
kidney function decline, kidney failure, cardiovascular death and hospitalization
for heart failure in adults with chronic kidney disease (CKD) who are at risk of disease
progression. This announcement comes after the FDA approved dapagliflozin oral tablets
in 2020 for adults with heart failure with reduced ejection fraction to reduce the
risk of cardiovascular death and hospitalization for heart failure.
FDA approval was based on results from the DAPA-CKD trial, which involved 4,304 participants
and showed that dapagliflozin results in salutary effects on renal function and mortality
among patients with CKD, irrespective of diabetes mellitus status.
Glucagon-like peptide-1 receptor agonists
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion following food intake.
Analogs of GLP-1 such as liraglutide and semaglutide are utilized for type 2 DM therapy.
Liraglutide therapy is followed by lower rates of DND development and progression
than placebo.[[56]] Another study reported that in type 2 diabetic patients who had moderate-to-severe
CKD and had been treated with dulaglutide, eGFR decreased significantly compared with
insulin glargine over 52 weeks.[[57]] A randomized controlled trial of semaglutide is at present being conducted to assess
its long-term effects on eGFR decline rate, development of ESRD, and death from kidney
or CV events.
Anti-inflammatory agents
Pentoxifylline is a methylxanthine derivative that has a nonspecific phosphodiesterase
inhibitor with anti-inflammatory and antiproteinuric effects.[[58]] The combined therapy of RAAS blockades and pentoxifylline therapy for 2 years revealed
a reduction in albuminuria and eGFR decline in type 2 diabetic patients with Stage
III and IV CKD.[[59]] More randomized clinical trials are at present being performed to clarify the benefits
of adding pentoxifylline to delay the ESRD, and diminution of death risks that are
related to the renal cause.
JAK-STAT pathway activation that associates with the transmission of signals via cytokines
and chemokines, promoting different ranges of cellular damage responses in DKD patients.[[60]] A selective JAK-1 and JAK-2 inhibitor (baricitimab) therapy decreases albuminuria
and inflammatory biomarkers.[[61]] Furthermore, it was reported that C–C chemokine receptor type 2 inhibitor reduces
proteinuria in type 2 diabetics.[[62]] New research projects are required to assess the effects of these agents in delaying
and/or pausing the DKD progression.
It was suggested that several innate immune pathways have roles in DKD pathogenesis,
and alteration of these pathways may be a novel therapeutic method.[[63]] Complement C5a deposits were detected in DKD patients' renal biopsy tissues; additionally,
the usage of C5a inhibitor decreases glomerular and tubulointerstitial damage in db/db
mice.[[64]] Toll-like receptor 4 is activated by lipid and glucose metabolism intermediate
products, causing an inflammatory reaction via NF-κB signaling.[[65]] Hence, blocking these pathways can affect the outcome of DKD pathogenesis and progression
of DKD theoretically, therefore, new research projects are urged to investigate this
assumption.
Anti-oxidant
Activation of cellular anti-oxidant pathways such as NF-erythroid-2-related factor
2 (Nrf-2). Nrf-2 is a transcription factor that regulates the expression of several
antioxidant and cytoprotective genes that can inhibit the oxidation stress due to
hyperglycemia and hypoxia. Modulating the Nrf-2 effect seems a reasonable therapeutic
option to prevent and/or delay DKD development. During the oxidative stress, the Kelch-like
ECH-associated protein 1 (Keap-1) structure changes, dissociating Nrf-2 from the Keap-1/Nrf-2
complex. The free Nrf-2 translocates into the nucleus, inducing targeted genes transcription,
and the free Keap-1 negatively regulates the NF-κB kinase subunit β inhibitor, inactivating
the NF-κB pathway. Bardoxolone methyl stimulates the change of Keap-1 and simultaneously
acts as Nrf-2 inducer and NF-κB inhibitor.[[66]] It was observed that bardoxolone methyl increases the eGFR in type 2 DM and CKD
Stage IIIb and Stage IV patients,[[67]] however, it was reported that bardoxolone methyl administration in type 2 DM patients
increases the CV event risk.[[68]] Nevertheless, re-analysis revealed that the risk of CV event is more in patients
admitted with heart failure with high baseline B-type natriuretic peptide (BNP), and
the increased risk of CV events is not significantly related bardoxolone methyl therapy.[[69]] Another study reported that bardoxolone methyl therapy in type 2 DM patients had
Stage III and IV CKD, and they had not significant evidence of heart failure (BNP
<200 pg/mL) for 16 weeks did not result in serious adverse CV events.[[70]]
Apoptosis signal-regulating kinase inhibitor
Sustained oxidative stress leads to activation of ASK, inducing apoptosis, inflammation,
and fibrosis through downstream signaling pathway activation in DKD patients.[[71]] Preliminary data reported that a selective ASK-1 inhibitor (selonsertib) decreases
eGFR during the first 4 weeks, however, the eGFR drop is less during the 44 weeks
of the therapy.[[72]] Further studies are urged to investigate this agent more to evaluate its safety
and efficacy in preventing DKD.
Endothelin-1 receptors antagonists
It is reported that combining ET-1 A-receptor antagonists (avosentan and atrasentan)
with standard ARB regimens reduces proteinuria in DKD patients, but the fluid retention
side effect on long-term therapy increases the risk of CV events.[[73]] Despite the contradictory reports, adding a low dose of ET-1 antagonists was recommended
by some authors. Further research is needed to investigate the ET-1 receptor antagonists'
efficacy and safety in DKD therapy and prevention. However, it appears that fluid
retention is the major issue, and it must be closely monitored.
Other agents with therapeutic potentials
DKD progression is a manifestation of continuous kidney fibrosis, hence, stopping
the fibrosis reduces or even prevents ESRD development. Administration of antifibrotic
such as pirfenidone decreases TGF-β expression, amends mesangial matrix expansion,
and improves eGFR in diabetic db/db mice.[[74]],[[75]] However, further human clinical studies are required to prove the safety and efficacy
of this drug in diabetic patients with DKD.
Targeting the HIF is another modality that can be suggested. Administration of cobalt
nitrate as an activator for HIF improves albuminuria and tubulointerstitial damage
in diabetic rats.[[27]] HIF stabilizers are also known as HIF prolyl hydroxylase inhibitors (enarodustat)
are used for CKD-associated anemia therapy,[[76]] and some of them have illustrated a defensive property against DKD in preclinical
studies. It was illustrated that enarodustat offsets the renal metabolic changes,
inducing fatty acid and amino acid metabolism upregulation in the diabetic kidneys.
This upregulation reduces glutathione disulfide accumulation, leading to an increase
of glutathione/glutathione disulfide ratio, and glomerular hypertrophy improvement.[[77]]
Epigenetics has an essential role in the pathogenesis of DKD. It was noted that administration
of GSK-J4 (a histone demethylase) inhibitor reduces proteinuria, and ameliorates glomerular
expansion and tubulointerstitial injury in type 2 diabetic animals' model.[[78]] Finally, microRNAs are also likely novel therapeutics, but selective delivery and
avoidance of off-objective effects may be challenging issues.[[79]] Therefore, research projects are needed to determine the efficacy and safety of
these agents.
Conclusions
RAAS blockades are the preferred treatment for DKD, but their effects are not well
proven to prevent DKD from progressing to ESRD, even with the addition of newly available
agents. However, it appears that advances in our knowledge of DKD pathophysiology
have illuminated several points and given rise to new expectations for new therapies
and preventive measures. SGLT2 inhibitors, which have renoprotective effects, are
one of the proven promising agents. Other agents, such as antioxidatives, anti-inflammatory
agents, HIF stabilizers, and others, are promising novel therapeutic agents; however,
before they are approved for DKD therapy, further globalized human studies are needed
to determine their effects, benefits, and protection abilities.
Authors' contributions
Equal.
Compliance with ethical principles
No ethical approval is required for review articles type of study.
