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Contents lists available at ScienceDirect

Disease-a-Month
journal homepage: [Link]/locate/disamonth

Diabetic Kidney Disease

Anna Gaddy, MD a,∗, Mohamed Elrggal, MD b, Hector Madariaga, MD c,
Adam Kelly, MD a, Edgar Lerma, MD d, Gates Colbert, MD e
a
Division of Nephrology, Medical College of Wisconsin, 8700 Watertown Plank Road Milwaukee, WI 53226, USA
b
Nephrology Department, Kidney and Urology Center, Alexandria, Egypt
c
Lahey Hospital & Medical Center, Burlington, MA 01805, USA
d
Section of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
e
Division of Nephrology, Texas A&M University College of Medicine in Dallas, Dallas, TX 75246, USA

a r t i c l e i n f o a b s t r a c t

Article history: Diabetic kidney disease is a leading cause of kidney failure worldwide and is easily de-
Available online xxx tectable with screening examination. Diabetes causes hyperfiltration and activation of the
renin-angiotensin aldosterone system by hemodynamic changes within the nephron, which
Keywords:
perpetuates damaging physiology. Diagnosis is often clinical after detection of heavy pro-
Diabetes
teinuria in a patient with diabetes,but can be confirmed by observation of histologic stages
CKD
SGLT2i on kidney biopsy. Mainstays of treatment include angiotensin conversion or receptor block-
Hypertension ade, mineralocorticoid receptor blockade, and tight glucose control. Newer agents favored
Nephropathy in diabetic kidney disease are sodium glucose-cotransporters and glucagon-like peptide 1
receptor agonists, both for glycemic control and for various methods of reversing damaging
physiology.
© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI
training, and similar technologies.

Diagnosis

Unfortunately, diabetes continues to be very prevalent worldwide particularly in developing countries. It is estimated
that it affects 530 million adults in the entire world with a prevalence of 10.5 % among adults 20–79 years-old.1 The lead-
ing cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States of America continues
to be diabetes. Though the diagnosis of diabetic kidney disease is confirmed by a kidney biopsy, most patients do not un-
dergo this procedure, given the risk of performing a kidney biopsy and also because in most cases, DKD is believed to be
highly clinically suspicious. With the current better treatments now available for diabetes control and DKD treatment, many
patients are able to remain stable and live with CKD without needing a kidney transplant or kidney replacement therapy.
These therapeutic options make early detection more important than ever.
Screening for DKD is recommended in all patients with diabetes to detect abnormal glomerular filtration rate (eGFR)
or the presence of albuminuria. Spot urine collections are sufficient for screening and monitoring and from the patients’
perspective, this appears to be the more convenient approach. Though 24-hr urine collection would provide valuable in-
formation and is considered the gold standard, its applicability in clinical practice is difficult for patients. eGFR needs to
be calculated with a race-free creatinine-based equation such as the Chronic Kidney Epidemiology Collaboration (CKD-EPI)

∗
Corresponding author at: Division of Nephrology, Medical College of Wisconsin, 8700 Watertown Plank Road Milwaukee, WI 53226, USA.
E-mail address: agaddy@[Link] (A. Gaddy).

[Link]
0011-5029/© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Please cite this article as: A. Gaddy, M. Elrggal, H. Madariaga et al., Diabetic kidney disease, Disease-a-Month, [Link]
org/10.1016/[Link].2024.101848
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Fig. 1. Classic nodular kidney disease by light microscopy. Courtesy of Alexander Gallan, MD.

Table 1
Classification of diabetic kidney disease based on histopathologic characteristics.

International renal pathology society classification Type of histologic changes

Class I -Isolated glomerular basement membrane thickening

-Mild changes by light microscopy
Class II (a or b) Mesangial Expansion -Mild (a) or severe (b) mesangial expansion
Class III Nodular Sclerosis -One or more glomeruli with nodular increase in mesangial matrix (Kimmelstiel-Wilson)
not meeting criteria for Class IV
Class IV Advanced Diabetic Glomerulosclerosis ->50 % global glomerulosclerosis with other clinical or pathologic evidence that
sclerosis is attributable to diabetic nephropathy

equation.2 Despite the fact that these tools appear to be easy and low cost, it has remained difficult to implement these
interventions and DKD remains undetected as demonstrated in several studies. For instance, the Danish Adult Diabetes Reg-
istry, showed that only 85 % of patients with diabetes were screened for albuminuria in a 2-year period.3
Diagnosis of DKD usually is suspected based on laboratory values and urinalysis. The main components for diagnosis are:

- Persistent albuminuria of >30 mg/g, confirmed with 2 or 3 samples with concurrent evidence of diabetic retinopathy.
Other forms of CKD need to be ruled out. Moreover, albuminuria is not required to diagnose DKD as a small percentage
of patients present without microalbuminuria and have histological findings consistent with DKD4
- Decreased eGFR, of <60ml/min/1.73 m2 for >3 months using a race-free creatinine-based formula
- Absence of other etiologies of CKD

This highlights the importance in obtaining autoimmune markers of glomerulonephritis, taking a review for culprit med-
ications, and workup for structural causes of CKD if clinically suspicious. Diabetic kidney disease is likely to be underdiag-
nosed as mentioned previously- autopsy studies of patients with diabetes indicate that pathologic changes can occur even
in the absence of albuminuria or decreased eGFR.5 The Italian multi-center Renal Insufficiency And Cardiovascular Events
(RIACE) study of >15,0 0 0 participants with type 2 diabetes mellitus suggesting that patients with albuminuria had microvas-
cular complications (cerebrovascular and peripheral vascular events) and patients without microalbuminuria with decreased
eGFR had a more macrovascular phenotype (associated with coronary events).6
On the other hand, all kidney disease in diabetic patients is not necessarily DKD: a study of the Cleveland Clinic Kidney
Biopsy Epidemiology Project found that of 1242 biopsies undertaken in patients with diabetes, 63 % had findings consistent
with other pathologies and 53 % had these other pathologies without concurrent pathognomonic diabetic kidney disease
changes.5 In this group without DKD, 24 % had FSGS, 8 % had IgA nephropathy, 7 % had antineutrophil cytoplasmic antibody
vasculitis, and 5 % had membranous nephropathy. This finding echoes that of at least one smaller study and provides a valu-
able list of factors positively associated with non-diabetic kidney disease: absence of retinopathy (adjusted odds ratio [aOR],
3.98;, lower A1c level (<7 % vs≥7 %) (aOR, 3.08), higher eGFR (≥60 vs<60 mL/min/1.73m2) (aOR, 2.39, microalbuminuria
(<300 vs macroalbuminuria≥300 [mg/g]) (aOR; 2.94), and lower UPCR (<3 vs ≥ 3 mg/mg) (aOR; 1.8). Figs. 1 and 2.
When present, diabetic kidney disease can be classified according to the International Renal Pathology Society consensus
classification system7 which categorizes diabetic nephropathy into progressive stages of kidney damage based on character-
istic histologic criteria: Table 1.

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Fig. 2. Various factors increase filtration pressure in diabetic kidney disease, including afferent (left) and efferent (right) mediators.

The pathological features in type 2 DM vary even within the disease: for example, one study of 31 subjects with di-
abetic kidney disease found that patients without albuminuria had typical glomerular changes much less commonly than
did patients with micro or macroalbuminuria. Mesangial expansion was increasingly common with degree of albuminuria.
3 of 8 patients without albuminuria had predominantly interstitial or vascular changes.8 This may reflect a spectrum of
heterogeneity or simply the frequently comorbid nature of DM2 with other kidney-damaging conditions. Clearly, although
albuminuria is a marker for kidney disease, it cannot predict long term outcomes and is not specific to DKD. Given the
global burden of CKD, research has been focusing on identifying those individuals at high risk of developing DKD.
In the search for biomarkers, serum stromal cell-derived factor-1 (SDF-1), a CXC chemokine widely expressed in different
tissues induced by hypoxia-inducible factor 1 and which regulates stem cell function, has been shown potential indicator for
DKD in patients with type 2 diabetes in a small biopsy-compared study.9 Urinary biomarkers as well as microRNAs (miRNS)
have been reported to be useful, however they have not been clinically validated.10 Future research is required into this field
as a combination of plasma and urine biomarkers would help with prevention strategies, early diagnosis and treatment of
DKD.
Genome-wide association studies (GWAS) have been performed without single gene variants with convincing effect but
one major study did find that alleles with increased risk of high body mass index and DM2 were associated with risk of
DKD.11 In DM1 - association study, two single nucleotide polymorphisms in the SORBS1 gene were strongly associated with
nephropathy.12 This gene codes the protein sorbin, which is differentially upregulated in glomeruli of a rat model of diabetic
kidney disease and is thought to be involved in the stress and fibrosis response.13
Prognostic imaging and biomarkers for DKD are under investigation as well. The iBEAT (Biomarker Enterprise to Attack
DKD) study is attempting to identify patients at risk from a cohort of patients with DM2 with the use of imaging measure-
ments derived from magnetic resonance imaging (MRI) and ultrasound of the kidneys. Kidney biopsy will be performed,
and a range of biomarkers will be collected as well as serial laboratory parameters over a course of three years. The over-
all aim of the study is to determine the utility of imaging studies as an aid in prognostication as well as to understand
underlying pathogenesis of diabetic kidney disease.14 Already, data from ancillary studies has been used to propose novel
histopathological classes of disease within patients with DKD.15

Pathophysiology

The basic pathophysiology of diabetic kidney disease– glomerular hyperfiltration and hypertension resulting from
hyperglycemia- has been established for decades.16 Over time, these consequences propagate the kidney damage seen clin-
ically in patients with persistently high blood glucose levels. The hyperfiltration mechanism can be worsened by amino
acids, such as high protein intake, or as a result of hormonally- induced changes with high levels of glucagon.17 In these
scenarios, the afferent arteriole becomes dilated and transmits increased pressure into the glomerulus. Other factors such

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as nitric oxide, insulin resistance, natriuretic peptides, and prostanoids induce reduced resistance in the afferent arterioles18
which contributes to an increased glomerular hydrostatic pressure. In addition, activation of the renin angiotensin aldos-
terone system (RAAS) is a potent trigger for hyperfiltration as exaggerated pressure is forced on the glomerulus. Angiotensin
II produced within the kidney constricts the efferent arteriole and leads to a higher back pressure. The net effect results in
an imbalance between both sides of the glomerular vascular tones, increasing glomerular filtration pressure and prompts
hyperfiltration. Over years and decades, the increased filtration and pressure lead to glomerular hypertrophy, resulting in
premature death and drop out. This is reflected clinically in the classic presentation of reduced glomerular filtration rate
only after many years of measurable albuminuria.19
At the same time, Inflammation and fibrosis within the glomerulus occur. These two mechanisms of glomerular injury
that are so profound that they can be seen by light microscopy of a kidney biopsy tissue as hallmark lesions of diabetes.
Hyperglycemia leads to both of these injuries through a series of pathways. Angiotensin II, primarily thought of as a hemo-
dynamic mediator, also stimulates expression of proinflammatory and profibrotic mediators which lead to barotrauma At
the same time, altered intracellular glucose metabolism results in generation of advanced glycation end products (AGEs),
reactive oxygen species, and activation of protein kinase C and Janus kinase (JAK)-signal transducer.20 Glomerular podocytes
that are exposed to these AGEs increase nuclear factor KB (NF-κ B)-associated upregulation of messenger RNA expression for
a variety of mediators that are proinflammatory. Inside the podocytes and endothelial cells, the AGEs bind to the receptor
for AGE (RAGE),and produce inflammation via the nucleotide-binding oligomerization domain-like receptor pyrin domain
containing 3 (NLRP3) inflammasome.21 Taking all of these expressions together, NF-κ B and NLRP3 induce expression and
activation of the interleukins (IL0, IL-1B and IL-18.22 ) Additionally, AGEs increase expression of serum amyloid A that per-
petuates a feed-forward cycle of inflammation. The signaling of the intracellular mediators lead to ongoing proinflammatory
mediator release, immune cell recruitment, and eventually profibrotic factors.23 In the extracellular space of the glomerulus,
AGEs result in disruption of the basement membrane and extracellular matrix, driving mesangial expansion and glomeru-
losclerosis.
In summary, the accumulation of AGEs triggers both intracellular and extracellular processes that lead to severe changes
in glomerular hemodynamics, resulting in glomerular hypertension, proteinuria, progressive glomerulosclerosis, and inter-
stitial fibrosis. The longstanding recommendations of pharmacological RAAS blockade (discussed further in Management,
below) are a result of partial understanding of this cascade of damage.
Newer clinical approaches to managing DKD focus on other mechanisms of damage. For example, the kidneys normally
filter approximately 120–180 gs of glucose from plasma each day but typically <0.5 gs are excreted in the urine. Glucose
is freely filtered in the glomerulus and then reabsorbed in the proximal convoluted tubule (PCT). The maximum kidney
glucose resorptive capacity (TmG) is calculated at 375 mg/min and glucose is filtered at 125 mg/min or 180 mg/day, in
the average healthy human with normal estimated glomerular filtration rate (eGFR). As a result, glucosuria occurs when
glycemia exceeds 180 mg/dL and this phenomenon develops because the filtered glucose load exceeds the TmG leading to
glucosuria.
Glucose cannot be reabsorbed through the walls of the proximal convoluted tubule (PCT), and so requires cotransporters
present in the PCT for transmission. The sodium glucose cotransporters, SGLT1 and SGLT2 are members of the SLC5 gene
family, a subdivision of sodium cotransporters. SGLT1 is predominantly expressed in the small intestine and to a lesser
extent in the kidneys, particularly in the cortex, whereas SGLT2 is present exclusively in the kidney cortex.24 SGLT2 is
present in the first and second segment (S1 and S2) of the PCT and is responsible for 90 % of glucose reabsorption. SGLT1
is mostly present in the luminal membrane of the S3 segment.25 This cotransporter in S1 has a high capacity/low affinity
whereas in S2 and S3, it has high-affinity and low-capacity glucose/galactose co-transporter. The basolateral Na/K ATPase
provides a low-sodium intracellular environment which drives the downhill transportation of one sodium and one glucose
molecule despite the uphill glucose gradient at the apical membrane of the PCT. The ratios of sodium to glucose cotransport
inside the cell are 1;1 and 2;1 for SGLT2 and SGLT1, respectively,26 which subsequently is then transferred into the blood
by the glucose transporters, GLUT1 and GLUT2 on the basolateral membrane of the PCT.
In an illustration of this phenomena, newly primetime SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists
(GLP1 RAs) can prevent diabetic kidney progression independent of their glucose lower effects.26 , 27 SGLT2is prevent glucose
reabsorption into the PCT which is thought to ameliorate some of the aforementioned inflammatory effects. In previous
models of diabetes, SGLT2 inhibition suppresses hyperglycemia-induced reactive oxygen species (ROS) and AGE formation in
the PCT cells and consequently decreases tubulointerstitial inflammation and fibrosis28 Glucagon-Like Peptide GLP-1 Ras also
downregulate proinflammatory pathways29 and this class may further prevent oxidative stress by inhibition of nicotinamide
adenine dinucleotide phosphatase oxidase through cyclic adenosine monophosphate-dependent protein kinase A activation
and upregulation of heme-oxygenase-1 (HO-1).30 These two drug classes will be discussed extensively later in this review,
but their unexpectedly profound clinical benefit in the diabetic kidney highlights that we have much left to learn about the
pathophysiology of this disease.
The timeline and sequence of glomerular and interstitial injury can be well mapped out for Type I DM. Type II DM affects
the kidney in a less well-defined manner as there are competing etiologies for CKD and patients with DM II have shown
to have a wide variety of histologic kidney lesions.31 Surprisingly, it is not clear whether incidence of DKD is higher in
Type 2 DM or in Type 1 DM. As mild hyperglycemia is a relatively asymptomatic state, many patients go years without the
screening tests necessary to make a diagnosis. Consequently, the timeframe of development for hyperglycemia, and possibly
HTN, in Type 2 DM is poorly characterized compared to Type 1. Autopsy studies have shown that in up to 20 % of patients

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Fig. 3. Classes of medication used in diabetic kidney disease in the domains impacted.

with diagnosed Type 2 DM, diagnostic DKD lesions are seen even without a decline eGFR or albuminuria, which suggests
that the true prevalence of DKD is underestimated.4

Management

Cornerstones of management of diabetic kidney disease include blood glucose management to prevent ongoing damage
as well as management of concurrent resultant hypertension. It is important to not only understand the threshold goals
for both parameters, but also to prioritize agents which provide benefit in more than one domain of management. When
possible, it is preferable to select hypertension and hyperglycemia treatments which have kidney protective mechanisms. To
that end, we will discuss specific classes of medication across each applicable domain as depicted in Fig. 3.

Glycemic control in DKD

Management of glycemic control in DKD is important to minimize risk of microvascular and macrovascular complications
of diabetes. Hyperglycemia leads to elevated levels of downstream metabolites of glycolysis which drives pathogenesis,32
and metabolites such as Advanced Glycation End Products (AGEPs) and polyols directly activate pro-inflammatory and pro-
fibrotic pathways which cause kidney dysfunction in DKD. Thus, awareness and management of hyperglycemia is paramount.
KDIGO 2022 DM in CKD guidelines recommend monitoring glycemic control by hemoglobin A1c (HA1c) measurement
and continuous glucose monitors (CGM’s). Prolonged exposure to elevated blood glucose levels, increases risk of diabetic
complications. A Cochrane review comparing standard of care to intensive HA1c targets found that intensive glycemic con-
trol delayed onset of moderate albuminuria and decrease risk of non-fatal myocardial infarction with moderate level of
evidence.34 An individual target of <8 % or <6.5 % is recommended based on patient goals, demographics, characteristics. A
relatively healthy, young patient with a CGM and on diabetic agents less prone to hypoglycemia may opt for the <6.5 % tar-
get. In comparison, an elderly patient with multiple comorbidities, shorter life expectancy, monitoring sugars by fingerstick,
and on glycemic medications prone to hypoglycemia, may opt for the <8 % HA1c as their risk of hypoglycemia is higher and
long-term benefits from tighter control would not be seen in their shorter remaining lifespan.
Management of diabetes of DKD follows a comprehensive approach of nonpharmacologic and pharmacologic treatment
to minimize hyperglycemia. There are several lifestyle recommendations to lower HA1c including eating at least 0.8 g/kg
of protein daily, dietary restriction of salt to <2 gs daily, and meeting weekly moderate-intensity exercise goals. First line

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medications for glycemic control in DKD are metformin (Glucophage) and SGLT2i. metformin (Glucophage) has a similar
reduction of HA1c to insulin and sulfonylureas with a decreased risk of hypoglycemia. SGLT2i’s can lower HA1c around
∼1 %, similarly has a low risk of hypoglycemia, and have extensive kidney and cardiovascular benefits which are expanded
upon below.35 Beyond first line medications, there is strong evidence supporting GLP1 RAs use in DKD. GLP1 RA’s effectively
lower HA1c, decrease weight, decrease risk of cardiovascular outcomes, decrease progression of albuminuria, and slow eGFR
decline – this will be discussed in greater depth ahead.

Blood pressure control in DKD

HTN and CKD often coexist and reinforce one another. HTN can lead to vascular remodeling of the kidney vasculature
and glomerulus causing hyperfiltration, perfusion auto-regulation dysfunction, proteinuria from podocyte dysfunction, and
ultimately, nephrosclerosis.36 RAAS is activated in HTN and CKD with several consequences. Angiotensin-II mediated effer-
ent arteriole vasoconstriction increases intra-glomerular filtration pressures causing glomerular damage. AII and Aldosterone
both have pro-inflammatory and pro-fibrotic kidney effects. Additionally, AII increases sodium reabsorption in the proxi-
mal tubule and collecting duct. This increase leads to extracellular volume expansion which further elevates BP, increases
vessel stiffness, and leads to sympathetic nervous system (SNS) activation. SNS activation increases peripheral vascular resis-
tance, vascular remodeling, and further activates RAAS. Additionally, endothelial dysfunction, oxidative stress, and increased
endothelin levels in CKD further drive BP elevation. HTN in CKD clinically manifests with elevated risk of adverse cardiovas-
cular and kidney outcomes and an overall increase in mortality.
While the importance of BP control in CKD is established, the exact BP targets are not clear. KDIGO 2021 Blood Pressure
Guidelines has a relatively weak 2B recommendation to target a systolic blood pressure of <120 mm Hg in patients with
high BP and CKD.37 This recommendation is based on subgroup analysis showing a non-significant decrease in cardiovascular
events and mortality in a 2600 patient CKD cohort within the SPRINT trial. In the CKD subgroup, there was a HR 0.82
(CI 0.63–1.07) in the intensive BP treatment group. Findings from the SPRINT trial suggest risk reduction of cardiovascular
outcomes is proportional to systolic blood pressure reduction.
Evidence is less clear on blood pressure management in DKD. Although the SPRINT trial had a sizable number of CKD
patients, it excluded patients with diabetes.38 The ACCORD trial included patients with diabetes and found a reduction
in stroke events in the intensive treatment group, but no other cardiovascular or kidney treatment benefits.39 ACCORD
also did not include many CKD patients: only 1/3 of patients had microalbuminuria and G2 CKD based on eGFR. Several
meta -analyses pooling ACCORD, SPRINT, among other studies show cardiovascular risk reduction with a more intensive BP
goal in subgroups of patients with CKD and diabetes patients.40 However, the study design of these papers and included
trials are very heterogeneous making interpretation difficult. One meta-analysis including CKD and DM2 patients found that
cardiovascular outcomes depended on baseline BP rather than reduction target.41

Angiotensin converting enzyme inhibitor (ACE) & angiotensin receptor blockers (ARB) in DKD

A cornerstone of diabetic kidney disease management is blockade of the Renin-Angiotensin-Aldosterone-System (RAAS).

As discussed above, RAAS activation drives hemodynamic, inflammatory, and oxidative kidney changes that lead to kid-
ney dysfunction in DKD. Angiotensin-Converting Enzyme inhibitors (ACEs) and Angiotensin-Receptor Blockers (ARBs) are
first-line agents to inhibit RAAS. ACE-Is inhibit the Angiotensin-Converting-Enzyme which facilitates Angiotensin I’s trans-
formation to Angiotensin II. ARBs block the Angiotensin-Receptor I which facilitates AII’s pro-inflammatory effects. AII is
free to bind to the unblocked Angiotensin-Receptor II whose anti-inflammatory properties are thought to be kidney pro-
tective. Lastly, both RAAS inhibitors decrease production of aldosterone which has a role in sodium homeostasis, potassium
excretion, and organ-specific fibrosis.
There are several downstream effects of this blockade which are beneficial for prevention of DKD.42 Prevention of AII me-
diated efferent renal artery vasoconstriction decreases intra-glomerular pressures. AII mediates TGF-B upregulation among
other pro-inflammatory enzymes that drive glomerular, mesangial, and renal endothelial fibrosis. It also contributes to hy-
perinsulinemia by inhibiting GLUT4 translocation in skeletal muscle and desensitizing insulin receptors in mouse models.
Additionally, ACE-i’s block bradykinin breakdown which has vasodilatory downstream effects. This bradykinin inhibition,
which is not seen with ARBs, commonly causes cough in patients and can rarely lead to angioedema.
Both ACE and ARBs have been extensively studied in DKD. Studies have consistently shown reduction in blood pres-
sure, proteinuria, cardiovascular outcomes, and kidney outcomes such as decline in eGFR, ESKD incidence. KDIGO 2022 DKD
guidelines33 have a 1B recommendation to initiate and titrate ACE-I or ARBs to the highest approved dose tolerated in
patients with CKD, diabetes, HTN, and albuminuria.
This strong recommendation is based on several seminal studies. In Lewis et al’s 1993 study of Captopril vs placebo in
insulin-dependent diabetic patients (DM1 and DM2) with moderate albuminuria >500 mg per 24 h,43 found a 43 % risk
reduction in incidence of doubling of serum creatinine and a 46 % risk reduction in the kidney composite outcome of death,
dialysis, or kidney transplant. The IRMA-2 (irbesartan (Avapro) in Patients with Type 2 Diabetes and Microalbuminuria)44
and INNOVATION (Incipient to Overt: Angiotensin II Blocker, telmisartan (Micardis) (Micardis), Investigations on Type 2 Di-
abetic Nephropathy)45 found a 68 % and 66 % relative risk reduction of progression to overt nephropathy, respectively, in
patients with type 2 diabetes, CKD, moderate albuminuria, and HTN treated with ARB compared to placebo.

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Clinical benefits of RAASi were further seen in the RENAAL (Effects of Losartan on Renal and Cardiovascular Outcomes in
Patients with Type 2 Diabetes and Nephropathy) and IDNT (Reno protective Effect of the Angiotensin-Receptor Antagonist
irbesartan (Avapro) in Patients with Nephropathy Due to Type 2 Diabetes) trials in 2001.46 , 47 In RENAAL, patients with DM2
and CKD (serum creatinine of 1.3–3) with UACR >300mg/g or >500mg/day were randomized to losartan or placebo. It
found a 16 % risk reduction of the primary outcome: a composite of events including kidney death, dialysis, and doubling
of serum creatinine. Proteinuria decreased over 40 %, as well. In IDNT, patients with DM2, HTN, UACR >900 mg/day, and
serum creatinine 1–3 were randomized to receive irbesartan (Avapro), amlodipine, or placebo. A 20 % risk reduction in the
primary composite outcome of death of any cause, ESKD, and doubling of serum creatinine. Proteinuria was decreased in
the irbesartan (Avapro) group.
Both IRMA, INNOVATION, RENAAL and IDNT found decreased progression of CKD independent of the blood pressure
lowering effects of losartan and irbesartan (Avapro). While KDIGO does not recommend RAASi in for patients with DKD
without HTN, there are established cardiovascular benefits of ACEi/ARB use in this population48 even if there is limited
evidence of kidney-protective effects. Although some clinicians may opt to discontinue RAASi in advanced disease to protect
glomerular function, the STOP-ACE trial found no difference in rate of ESKD progression in patients with CKD-IV and CKD-
V who were either continued on ACE/ARB or discontinued.49 Additional observational research has shown increased CKD
progression, cardiovascular events, and mortality in patients whose ACE/ARB was discontinued compared to those continued
on the medication.50 As such there is compelling evidence to continue RAASi as long as possible to maximize the kidney
and cardiovascular protection they offer.
Comparisons between ACE-I and ARB medications have shown similar efficacy. A large meta-analysis of RAASi in CKD
(not exclusive to DKD) found similar kidney and cardiovascular benefits but only found a mortality reduction in ACE-I use.51
KDIGO recommends maximizing ACE and ARB efficacy by titrating to maximally approved or tolerated doses. Dual RAAS
blockade with ACE and ARBs simultaneously has no cardiovascular nor kidney benefits while increasing rates of AKI and
hyperkalemia52 and as such is not recommended.

MRA use in DKD

Despite ACE-I or ARB use, about half of patients with DKD continue to have elevated plasma aldosterone.53 Known as
“aldosterone escape” or “aldosterone breakthrough” in this situation, elevated plasma aldosterone has numerous pathologic
effects. Aldosterone-mediated activation of the kidney mineralocorticoid receptor increases distal tubule sodium reabsorp-
tion contributing to extracellular volume expansion and HTN. Mineralocorticoid activation in numerous tissues including the
kidney, heart, and immune cells causes activation of pro-inflammatory cell signaling pathways. Chronic aldosterone release
causes fibrosis in heart and kidney tissue contributing to both heart and kidney failure.
The addition of mineralocorticoid-receptor-antagonists (MRAs) to RAAS-i with ACE/ARBs has been studied to block al-
dosterone breakthrough and decrease DKD progression. While steroidal MRA’s (s-MRAs) spironolactone (Aldactone) and
eplerenone have an established role in heart failure, HTN, and primary hyperaldosteronism, their benefit in DKD is negligi-
ble. S-MRAs may reduce proteinuria in mild-moderate CKD, but do increase rates of hyperkalemia and AKI, without change
in eGFR or rate of ESKD.54 S-MRA’s also come with many side effects due to their lack of mineralocorticoid specificity. Acti-
vation of estrogen, progesterone, and glucocorticoid receptors causing symptoms like gynecomastia and sexual dysfunction
are the most frequently encountered. Accordingly, KDIGO guidelines only recommend the use of nonsteroidal MRA’s (s-MRA)
for management of DKD.
This attention to non-steroidal MRA’s (ns-MRA’s) in DKD has been a recent development as the first agent was approved
for use only in 2021. Ns-MRA’s are specific to the mineralocorticoid receptor, thus reducing the off-target side-effects seen
in spironolactone (Aldactone) and eplerenone. Two large RCT’s, FIGARO and FIDELIO, provide evidence of the benefit of ns-
MRA, Finerenone, in DKD. FIGARO55 studied patients with CKD and DM2 already on maximally tolerated RAAS inhibition
with the addition of Finerenone vs placebo. The primary cardiovascular composite outcome (cardiac death, MI, CVA, and
heart failure hospitalization) was significantly lower in the Finerenone group: 12.4 % vs 14.2 % HR 0.87 (CI 0.76–0.98). A
reduction in systolic blood pressure was seen. The secondary kidney composite outcome measuring incidence of <40 %
reduction of eGFR and ESKD had a HR of 0.87 (0.76–1.01). FIDELIO56 had a similar population with slightly more advanced
CKD, DM2, on maximally tolerated RAAS inhibition and randomized to Finerenone or placebo. The Finerenone group had a
significantly lower kidney composite outcome (kidney failure, death from kidney cause, and sustained decrease >40 % eGFR)
with a HR 0.82 (0.73–0.93). Finerenone lead to a sustained reduction in albuminuria and slight reduction in systolic blood
pressure. A combined analysis of both studies found both a significant reduction in cardiovascular and kidney composite
outcomes.57
Finerenone is not the only ns-MRA that may have use in DKD. Esaxerenone was randomized with placebo in a phase
III trial conducted in a population with DM2, CKD, and HTN on maximally tolerated RAAS-i.58 The Esaxerenone group had
a significant reduction in the primary endpoint of albuminuria “remission” (a return to <30mg/g cr and >30 % reduction
in UACR from baseline) with a HR 5.13 (3.27–8.04) that was sustained over a 52-week period. Overall, there was a > 50 %
reduction in albuminuria and a 10 % reduction in eGFR compared to placebo. Apararenone has completed a 28-week phase
II dose response RCT in patients with mild CKD, DM2 which found a ∼50 % reduction in albuminuria and slight decrease
in eGFR.59 Both studies found minimal impact on serum potassium levels and low rates of trial discontinuation due to
elevated K. Although neither trial reported clinical outcomes such as kidney failure, there was a strong association between

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>30 % reduction in UACR and relevant clinical outcomes such as ESKD and doubling of serum creatinine.60 Additionally,
the MIRACLE trial studied the addition of Balcinrenon, a non-steroidal selective mineralocorticoid modulator with partial
antagonist activity, to patients on an SGLT2-I in a population with heart failure and DKD.61 There was no change in the
primary composite endpoint of UACR reduction; however, the study was underpowered.
The development of an aldosterone synthase inhibitor is an idea under much scrutiny, to curtail aldosterone breakthrough
at the source. This is a difficult prospect, as aldosterone synthase has much structural homology with 11β hydroxylase and
cortisol synthesis could be affected as a result. However, several such drugs are under development and recently, BI-690517A
completed phase II RCT in a population with CKD on RAAS inhibition.62 Two-thirds of participants had DM2. Patients were
first randomized to either receive empagliflozin or placebo in an initial run-in period, then subsequently randomized to
receive BI-690,517 or placebo. There was approximately a 40 % reduction in the primary outcome of UACR in patients who
received 10 or 20 mg of BI-690,517. Trends suggest Empagliflozin may slightly enhance the kidney protective effects of BI-
690,517, as well. Slight reduction in eGFR and blood pressure were also seen. The rate of hyperkalemia ranged from 10
to 18 % and 4 % of patients were discontinued due to persistent hyperkalemia. It remains to be seen whether blockade
of aldosterone production is more beneficial overall than blockade of receptor. Several putative mechanisms - namely that
cortisol plays a role in mineralocorticoid-activated kidney damage and will not be blocked by these medications- suggest
that this may not be the case. Another concern is the adrenal insufficiency- rare in Phase 2 trials- that may emerge in larger
clinical trials. Therefore, Phase 3 trials will be important for this class of drug.63
Hyperkalemia is frequently seen in patients treated for DKD. Diabetes can lead to RTA-IV which elevates serum potas-
sium, and more on management of RTA is detailed below. RAAS inhibitors, MRA’s, and aldosterone synthase inhibitors all
increase serum potassium levels by blocking aldosterone-mediated potassium excretion. Hyperkalemia was frequently en-
countered with the addition of spironolactone (Aldactone) to patients RAAS-I, so to allow for mechanistic study of the
beneficial effect of finerenone, a run-in period was used in FIDELIO to prevent randomization of patients prone to hyper-
kalemia. As a result, very few patients in the FIDELIO or FIGARO trials were removed from the trial due to hyperkalemia
(∼1 %.) Unfortunately, outside of clinical trials, hyperkalemia often leads to discontinuation of these medications. In pa-
tients with mild hyperkalemia and CKD, discontinuation of ACE/ARB increases mortality without any kidney benefit. Several
observational studies show increased risk of cardiovascular risk in patients whose RAAS inhibition was discontinued due
to hyperkalemia.49 Potassium binders can effectively lower serum potassium in CKD patients. Large clinical trials featuring
patiromer64 and sodium zirconium65 have both been shown to maintain normokalemia safely and effectively for up to a
year.

Sodium glucose cotransporter 2 inhibitors (SGLT2i)

The development of diabetic kidney disease is a complex process as described above, including many pathways of in-
flammation and fibrosis downstream of hyperglycemia- mediated hyperfiltration and aberrant vasoactivity. The SGLT2i class
has recently been shown to have multifaceted benefits in patients with DKD. First and most obviously, tight glucose control
is important in patients with DKD and SGLT2i provide glycemic benefit by increasing excretion of glucose in the urine. This
medication class was approved for glycemic control in diabetic patients in the mid 2010s but not generally thought to be a
good choice for patients with CKD given that the effect is dependent on filtration of glucose. Indeed, the CREDENCE trial of
canagliflozin in patients with DKD, treatment with canagliflozin resulted in an HA1c decrease of <0.3 %.66
More importantly, SGLT2is prevent diabetic kidney progression independent of glucose lowering effects. After diabetes
approval, randomized controlled trials (RCTs) of SGLT2is were undertaken to evaluate the effect on cardiovascular outcomes,
which noted decreased albuminuria and creatinine but did not include sufficient numbers of patients with kidney disease to
provide power. A meta-analysis of these cardiovascular RCTs combined kidney outcome data and found that over the time
course of 2–3 years, treatment with SGLT2i reduced the risk of end stage kidney disease by 35 % consistently across all
trials in patients with diabetic kidney disease.27 Though more variable across trials, the risk of combined substantial loss of
kidney function, end-stage kidney disease, and death due to cardiovascular or kidney disease was decreased by 29 % overall.
Importantly, the risk of AKI was also significantly and substantially (by 25 %) decreased in patients treated with SGLT2i.
This is an important caveat given that the risk of AKI is a theoretical concern with SGLT2i due to their hemodynamic
effect outlined below. Another critical observation of this analysis was that the benefit of treatment on these outcomes was
significant (though potentially less substantial) across all eGFR subgroups. As the glucose-lowering efficacy of these drugs is
attenuated at lower eGFR, this finding is important to guide clinical use but also lends credence to the idea that the benefit
of this class is not solely attributable to better glycemic control.
Subsequently, the results of this meta-analysis have been reinforced with the publication of DAPA-CKD in which patients
with proteinuria and eGFR as low as 25mL/min/1.73 m2 had dramatic improvement in risk of adverse kidney outcomes,
regardless of whether they were diabetic or not. Overall, the risk of eGFR decline by 50 %, ESKD, or death from kidney or
cardiovascular causes was significantly lower in the SGLT2i group with a hazard ratio of 0.61 and the trial was stopped early
due to this efficacy.67 The 2023 RCT EMPA-KIDNEY found similar result in patients with eGFR as low as 20mL/min/1.73 m2
regardless of diabetic kidney disease.68
The mechanisms responsible for this robust benefit are not completely understood but there are several mechanisms with
reasonable evidence. SGLT2is prevent glucose reabsorption into the PCT - As mentioned in the pathophysiology section, the
glomerular hemodynamic changes which occur because of hyperfiltration are mitigated with treatment. This decrease in

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glomerular filtration pressure -similar to the effect of RAS blockade- is responsible for the slight decrease in eGFR seen
when initiating either drug, but it is worth noting that the effects of SGLT2i seem to be consistent regardless of baseline use
of RAS blockade. The prevention of glucose reuptake also is thought to ameliorate some of the aforementioned inflammatory
causes of DKD. In previous models of diabetes, SGLT2 inhibition suppresses hyperglycemia-induced reactive oxygen species
(ROS) and AGE formation in the PCT cells and consequently decreases tubulointerstitial inflammation and fibrosis.68
As discussed previously, SGLT2 inhibitors work by inhibiting sodium reabsorption in the proximal convoluted tubules,
leading to natriuresis and osmotic diuresis. This mechanism results in a reduction of plasma volume and blood pressure,
giving these drugs its early hypotensive effect69 and may act by suppressing sympathetic nerve activity long term.70 As
such, SGLT2i influence blood pressure (BP). Three recent meta-analyses provide insights into the effects of SGLT2 inhibitors
on blood pressure reduction. The network meta-analysis by Tsapas et al. compared the effects of 21 glucose-lowering drugs,
including SGLT2 inhibitors, on body weight and blood pressure across 424 trials with 276,336 patients.71 The study particu-
larly focused on the impacts of these drugs on both systolic and diastolic BP in adults with type 2 diabetes. SGLT2 inhibitors
(empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) were highly effective in reducing both body weight and systolic
BP, with reductions sustained over 52 weeks. The largest placebo-subtracted reductions were evident with canagliflozin and
empagliflozin. Change in diastolic blood pressure was reported in 191 studies (142, 591 patients). Empagliflozin was the most
efficacious agent compared with placebo, followed by dapagliflozin.
Teo et al. performed another meta-analysis of 111 randomized controlled trials involving 104,304 patients, including
diabetic and non-diabetic populations, to assess the BP-lowering effects of SGLT2 inhibitors.72 In diabetic patients, SGLT2
inhibitors reduced systolic BP by 3.46 mmHg compared to placebo. However, the effect was not significant in non-diabetic
patients. Ren and Chen conducted a third meta-analysis to assess the hypotensive effects of SGLT2 inhibitors in patients
with essential hypertension and prehypertension. This study included nine trials with 2450 participants.73 SGLT2 inhibitors
lowered systolic and diastolic BP by an average of 5.04 and 1.67 mmHg respectively compared to placebo. More significant
reductions in blood pressure were observed at higher doses of SGLT2 inhibitors.
These meta-analyses confirm that SGLT2 inhibitors contribute to modest yet meaningful reductions in both systolic
and diastolic blood pressure, particularly in diabetic and hypertensive populations. At times, the mild nature of the anti-
hypertensive effect can be a benefit of the SGLT2i class, when patients have residual proteinuria, but blood pressure is
already controlled.
More impressive findings were seen in Japan, where the SACRA Study investigated changes in blood pressure with em-
pagliflozin plus existing antihypertensive therapy in adult patients with type 2 diabetes mellitus and uncontrolled nocturnal
hypertension.74 At 12 weeks, reductions in systolic blood pressure with empagliflozin were significantly greater than with
placebo across various settings: daytime (−9.5 mm Hg), 24-hour (−7.7 mm Hg), morning home (−7.5 mm Hg), and clinic
(−8.6 mm Hg). This is the greatest reduction in blood pressure reported in any trial with SGLT2 inhibitors. Empagliflozin,
but not placebo, also significantly reduced nighttime systolic blood pressure compared to baseline (−6.3 mm Hg), although
the between-group difference in the change from baseline was not statistically significant (−4.3 mm Hg; P = 0.159).
It is worth noting that modest blood pressure effect of SGLT2i was demonstrated in patients with CKD, even those pa-
tients without diabetes. The CREDENCE trial evaluated the effect of canagliflozin on kidney outcomes in patients with type 2
diabetes and CKD.66 Patients receiving active treatment with canagliflozin experienced an average reduction of 3.30 mmHg
in systolic blood pressure, while the decrease in diastolic blood pressure was minimal, at 0.95 mmHg compared to placebo.
The DAPA-CKD trial assessed the efficacy of dapagliflozin in reducing the progression of CKD and preventing cardiovascular
events in patients with and without type 2 diabetes.67 In a pre-specified post-hoc analysis of the DAPA-CKD trial, partici-
pants receiving dapagliflozin showed a significant 3.6 mmHg (95 % CI 2.8–4.4 mmHg) reduction in systolic blood pressure
after 2 weeks of treatment. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg
(0.6–1.4 mmHg). This effect was sustained throughout the trial, with similar reductions observed in both patients with and
without type 2 diabetes. Similarly, The EMPA-KIDNEY trial explored the use of empagliflozin to prevent kidney disease pro-
gression and cardiovascular death in patients with CKD, both with and without diabetes and found the average difference
in systolic blood pressure between the empagliflozin group and the placebo group was 2.6 ± 0.3 mmHg75
In conclusion, major kidney trials, including CREDENCE, DAPA-CKD, and EMPA-KIDNEY, consistently demonstrate that
SGLT2 inhibitors lead to modest but meaningful reductions in systolic blood pressure in patients with CKD, regardless of
diabetes status (Table 2). Canagliflozin, dapagliflozin, and empagliflozin each showed reductions in systolic blood pressure
ranging from 2.6 to 3.6 mmHg, while effects on diastolic blood pressure were minimal.

Glucagon-Like peptide 1 receptor agonists (GLP1 RAs)

Proglucose genes in L cells in the small intestine produce GLP-1, which binds to its specific receptor expressed in sev-
eral tissues. Its main effect is stimulating glucose-dependent insulin release from pancreatic islets. In patients with type 2
diabetes mellitus, impaired insulin response is inhibited by a reduction in postprandial GLP-1 secretion. GLP-1 also slows
gastric emptying and inhibits glucagon release after meals. Naturally, GLP-1 has a very short half-life of 1–2 min due to
N-terminal degradation by enzyme dipeptidyl peptidase 4 (DPP-4). This pathway has been harnessed to treat diabetes with
FDA approval of GLP-RAs in the early 2010s. These synthetic GLP1 receptor agonists are resistant to its degradation by this
enzyme facilitating a longer half-life. Weight loss is common with these therapies due to the effects of GLP-1 on slowing

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Table 2
Systolic and diastolic blood pressure reduction reported in major SGLT2 inhibitors trials. (SBP: systolic blood pressure, DBP: diastolic blood pressure, CVOT:
cardiovascular outcome trials, HF: heart failure, n/r: not reported.).

Trial name Agent Mean SBP reduction Mean DBP reduction

(mmHg) (mmHg)

Kidney outcome trials CREDENCE Canagliflozin 3.3 0.95

DAPA-CKD Dapagliflozin 3.6 1
EMPA-KIDNEY Empagliflozin 2.6 0.5
CVOT CANVAS Canagliflozin 3.93 1.39
DECLARE-TIMI 58 Dapagliflozin 2.7 0.7
SCORED Sotagliflozin 2.44 0.8
HF trials DAPA-HF Dapagliflozin 1.27 n/r
EMPEROR-REDUCED Empagliflozin 0.7 n/r
EMPEROR-Preserved Empagliflozin 1.2 n/r

gastric emptying and resultant early satiety. Nausea and vomiting are very common side effects which typically attenuate
over time.76
GLP-1 therapies are safe in patients with eGFR of >15mL/min/1.73 m2. In patients with CKD 5 or those who receive
dialysis, cautious use has been recommended, and safe use has been demonstrated in several small trials.77 Due to the risk
of hypoglycemia, these agents should not be used with dipeptidyl peptidase (DPP-4) inhibitors. However, there is emerging
evidence that, like SGLT2i, the benefits of GLP1-RAs may be more than simply glucose-lowering. Emerging evidence has
shown that medications in this class have a protective kidney and cardiovascular effects.
The REWIND trial evaluated dulaglutide vs placebo and included patients with diabetes and cardiovascular disease with a
median follow up of 5.4 years, and it showed a reduction in the composite clinical microvascular outcome (first occurrence
of retinopathy therapy or kidney outcomes such as microalbuminuria, defined as >33.9 mg/mmol, sustained >30 % decline
in eGFR or chronic kidney replacement therapy outcome) in the dulaglutide group. This effect was primarily driven by fewer
composite kidney outcomes.78 In the FLOW trial, a randomized placebo-controlled trial of semaglutide in over 3500 adults
with DM2 and CKD, semaglutide reduced kidney events (a composite of kidney failure onset, >50 % reduction in eGFR from
baseline and kidney/cardiovascular-related mortality) over a median follow up of 3.4 years.79 Furthermore, it also attenuated
the annual decline in eGFR in comparison to placebo, with a mean difference in slope of 1.16 mL/min/1.73 m2 per year.
The PRECIDENTD is an ongoing clinical trial which plans to enroll at least 90 0 0 patients with established type 2 diabetes
mellitus and cardiovascular disease or at high risk of heart disease, will randomize in a 1:1 allocation to sodium-glucose
cotransporter-2 inhibitor (SGLT21) or GLP-1 RA. Primary outcomes include the composite number of total episodes of car-
diovascular events (myocardial infarction, arterial revascularization, stroke, hospitalization for heart failure, development of
ESKD, kidney transplantation and mortality). Patients will be followed up for over 5 years. These results are sorely needed
as clinicians weigh their options in a patient with DKD- particularly as medication prices and availability are limiting factors
with these two classes.
Overall, findings support the use of semaglutide in patients with DKD. In fact, the 2024 KDIGO CKD guidelines recom-
mend a GLP-1 agonist as a 1B recommendation in adults with type 2 diabetes and CKD who have not achieved adequate
glycemic targets despite the use of SGLT2 or metformin (Glucophage).80 Other GLP-1 agonists include exenatide and lixise-
natide, however it should be noted that these agents are excreted by the kidneys and should be avoided in patients with
eGFR of 30 mL/min/1.73 m2.81

Management of renal tubular acidosis

Renal tubular acidosis or hypoaldosteronism (Type IV RTA) should be considered in patients with diabetes, persistent hy-
perkalemia, mild hyperchloremic metabolic acidosis when there is not an obvious cause of kidney disease or prior exposure
to potassium-sparing diuretics or potassium supplements. Type IV RTA is the only type of RTA that features hyperkalemia; it
is very common and unfortunately underdiagnosed.82 One of the most common causes of hypoaldosteronism is hyporenine-
mic hypoaldosteronism, angiotensin II inhibition, trimethoprim-sulfamethoxazole and heparin. These patients typically do
not experience any symptoms consistent with primary adrenal insufficiency.
Hyporeninemic hypoaldosteronism is typically seen in elderly patients with mild to moderate kidney dysfunction in the
setting of DKD or in those with chronic interstitial nephritis. Low plasma renin activity is usually encountered due to a
conversion defect of prorenin, a precursor of renin.83 Increase in atrial natriuretic peptide and volume expansion also plays
a role in its pathophysiology. Diagnosis requires ruling other etiologies such as prior use of anti-inflammatory non-steroidal
(NSAIDs), ACEIs/ARBs, beta blockers, calcineurin inhibitors and HIV infection as well as other genetic disorders such as
pseudo hypoaldosteronism type 1 and type 2. Low plasma renin activity, low serum aldosterone concentration and nor-
mal serum cortisol concentration is generally encountered in cases of Type IV RTA. Treatment options include low dietary
potassium, loop and thiazide-type diuretics and fludrocortisone to control hyperkalemia. Concomitant hypertension, unfor-
tunately, prevents many patients from using fludrocortisone.

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New Frontiers

The pipeline for new medications and combination therapy for DKD is the most prolific space that the Nephrology world
has seen in decades. The focus of researchers and pharmaceutical companies focus on three relative strategies: the efficacy of
currently approved medications and getting kidney specific outcomes measured, new drugs in existing and new mechanisms
of action, and estimating combination therapy of traditional with newer medication approvals. We will discuss studies and
drugs that are ongoing in these categories below.
Verinurad is a human uric acid transporter (URAT1) inhibitor known to decrease serum uric acid(sUA) levels and that may
reduce albuminuria. In a Phase 2a study, treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio
(UACR) at 12 weeks by 39 % among patients with Type 2 diabetes mellitus, hyperuricemia and albuminuria. In SAPPHIRE a
Phase 2b, randomized, placebo-controlled Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and
hyperuRicEmia will examine the effect of verinurad + allopurinol on albuminuria and eGFR slope among patients with CKD
and hyperuricemia.84 It is proposed this could be an add on treatment for those with DKD and high uric acid levels.
Tirzepatide may be the first of a new generation of antidiabetic and weight-correcting drugs. Tirzepatide is a twincretin
recently approved by the FDA to improve glycemic control in type 2 diabetes mellitus (DM2) and under another brand name
for weight management. More specifically, tirzepatide is an agonist of both the glucose-dependent insulinotropic polypeptide
(GIP) and the glucagon-like peptide-1 (GLP1) receptors. In a post hoc analysis of the SURPASS-4 trial, tirzepatide decreased
albuminuria and total eGFR slopes and almost cut in half the risk of a composite kidney endpoint (eGFR decline ≥40 %,kid-
ney death, kidney failure or new-onset macroalbuminuria) in participants with Type II DM and cardiovascular risk when
compared with insulin glargine comparator.85 Further applications of tirzepatide are ongoing in the obesity space, but cur-
rently there are not actively recruiting trials looking at CKD or DKD population outcomes specifically. Hopefully these other
obesity trials will recruit enough CKD patients to give meaningful insights into the hope this drug class can help CKD and
albuminuria progression. Trials to watch for outcomes include: SURPASS-CVOT and SURMOUNT-MMO.
The MOSAIC study evaluated whether selonsertib attenuated kidney function decline in patients with diabetic kid-
ney disease.86 Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor that reduces inflammation, apoptosis, and
fibrosis. The study included 310 patients who were randomized to placebo (68 % male, mean age 65 years, mean
baseline eGFR 35 ml/min/1.73 m2). Mean difference between selonsertib and placebo eGFR slopes at week 84 was
1.20 ml/min/1.73 m2/year (95 % CI, −0.41 to 2.81; P = 0.14). Kidney clinical events occurred in 17 % (26/154) of patients
randomized to selonsertib and 12 % (19/156) of those randomized to placebo (difference 4.7 %; 95 % CI, −6.3 % to 15.9 %).
Unfortunately, more patients in the selonsertib arm had the composite kidney clinical events and the most common event
was AKI. One subgroup finding showed that patients with lower eGFR did the best. As lower eGFR patients are associated
with a heightened inflammatory state, it is possible that selonsertib is more effective in those with more advanced CKD. As
of this writing there are No active trials with selonsertib registered with [Link], but future hypothesis trials are
suggested.
Pentoxifylline (PTX) is a medication that has been on the US market since 1984 for use for lower extremity vessel disease.
Recent data suggest that PTX, when added to usual care in patients with DKD, is associated with lower albuminuria and
reduced inflammation, as evidenced by lower levels of inflammatory cytokines. Together, these endpoints may lead to longer
term delay in diabetic kidney disease progression. “Pentoxifylline in Diabetic Kidney Disease” (PTXRx) is a study ongoing at
forty Veteran’s Affairs hospitals across the nation to determine whether or not PTX can prevent worsening of kidney disease
and delay death in patients with DKD.87 Primary endpoint is set at time to ESKD or kidney death. Current enrollment goal is
set around 2500 patients and expected completion in 2028. Is an old drug applied to a different patient population capable
of the new leaders of SGLT2i, nsMRA, or GLP1? We will wait and see on this trial for the end of the decade.
Another possible pathway under study is that of Interleukin-33 (IL-33). It has been documented that chronic inflam-
mation impairs biologic activities which reduce cellular activities, including the cardiorenal pathophysiological connection.
It is believed that IL-33 is overly expressed cytokine in patients with CKD and leads to disease progression by overacti-
vation of the immune system.88 Research models have shown with a new molecule named tozorakimab, a high affinity
IL-33-neutralizing immunoglobulin G1 monoclonal antibody, that glomerular endothelial immune-pathology effects could
be normalized. Currently there is an ongoing FRONTIER-1 phase 2b trial that will use tozorakimab in patients with 500+
diabetic kidney disease to monitor for long term outcomes.89 Primary outcome is percent change in UACR and secondary
outcomes with monitoring UACR and safety events.
A seemingly obvious metric that should be achieved by most practitioners, involves following the repeated guidelines
of multiarmed screening and therapy of healthcare that already exists to us. Measuring blood pressure, following blood
testing, checking urine albumin levels is low cost and easily performed. Prescribing appropriate patients on the correct anti-
hyperglycemic regimen, using highest tolerated RAASis, and adding a SGLT2i or nonsteroidal MRA are care plans that should
be as backbone DKD therapy in the 2020 s and beyond. Yet, following and prescribing these therapy plans has not yielded
large implementation in the United States or the World. One study which included patients from Brazil, France, Germany,
and the USA showed RAASi prescriptions varied from 52 to 81 % and less than half of patients achieved systolic BP levels
lower than 130 mmHg (except Brazil at a modest 57 %).90 In diabetic patients specifically, <10 % of patients were on target
for achieving guideline BP, appropriate RAASi, dietary management, and HbA1c. Gregg et al. published that in the Veterans
Affairs database, of 174,443 patients with CKD, DM2, and ASCVD who visited a primary care clinic in 2020, only 20,024
(11.5 %) were prescribed an SGLT2i.91 This is a dismally low percentage of patients that would have profound benefit given

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their risk factors. If practitioners would practice along the guidelines already established, our outcomes have a much better
chance of slowing and preventing the aggressive nature of DKD. Even without newer agents and techniques, we have the
tools today to make a major impact on our patients’ lives if we can spread education and awareness now.

Data availability

Data will be made available on request.

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