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Glucose is Not Always Sweet Diabetic Kidney Disease: 27
Can we Make it “SWEET” Again?

glomerular hypertension and hyperfiltration as seen In old subjects, however, too aggressive metabolic
in the initial phase of diabetic kidney disease, when control would offer no appreciable advantages in
the interaction between metabolic and haemody- terms of long-term prevention of complications and
namic perturbations plays an important role in the would expose the patient to potentially catastroph-
pathophysiologyof kidney disease. In both T1DM and ic consequences of hypoglycaemic episodes, that
T2DM, insulin resistance per secontributes to higher become more dangerous as chronic kidney disease
salt sensitivity, which closely associates with increase progresses. In those with concomitant renal vascu-
in blood pressure, albuminuria, and renal function de- lar disease -that will be the vast majority-, intensified
cline. blood pressure control and/or RAAS inhibitor therapy
might evenaccelerate renal disease progression and
In the early phase of diabetic kidney disease, insu- expose the patient to the risk of life-threatening hy-
lin resistance and the associated poor glycaemic potension episodes, during concomitant diseases of
control also associate with upregulation of the Na+/ other nature or dehydration, an event not uncommon
glucose transporter sGLT2 that in turns leads to an in the elderly. Compliance and treatment-related hy-
increase in proximal tubular salt (Na+) reabsorption perkalemia may also be a concernin those on dual
and secondary worsening of hyperfiltration through RAAS blockade. No evidence is available so far that
the physiologic action of the tubule-glomerular feed- combined ACE inhibitor and ARB therapy may offer
back system.
any advantage over single RAAS blockade in patients
The increased glucose reabsorption appears to also with type 2 diabetes with overt nephropathy, whereas
contributes to the interstitial inflammatory processes this approach might reasonably provide major reno-
that characterize the renaltubulo-interstitial changes. protection to younger patients with less advanced
renal disease. A response-driven approach titrated
Tubular damage occurs early during the disease as
suggested by presence of liver-type fatty acid-bind- to both efficacy and tolerability, and combined with
ing protein (L-FABP), a marker of tubulo-interstitial close monitoring and patient counselling, will be the
damage, in the urine; L-FABP has been shown to key component of effective intervention to minimise
correlates closely with renal dysfunction in diabetic harm in the frailest patients.
subjects. Novel recent treatment approaches have been trying
to target different aspects of the pathophysiology of
Increase exposure to elevated glucose levels results
in the activation of the local angiotensin-2 system CKD in diabetes, and their future use is tested on top
and growth factors (e.g. CTGF, TGFβ1) resulting in of current standard of care for metabolic control and
early tubular cells proliferation, tubular hypertrophy hypertension with RAAS inhibition.
and fibrosis.Tubular hypertrophy and glucose/Na+ The most promising treatments, currently under in-
hyper-reabsorption contribute to glomerular hyperfil- vestigations, have been investigating inflammation
tration in the initial stages of diabetic nephropathy. inhibitors (CCR2/CCR5 antagonist), oxidative stress
Hyperfiltration, in turns, participate with the glomer- inhibitors (allopurinol, Nox1-4 inhibitors, N-acetyl-
ular capillary dysregulation towards the development cysteine, Nrf2 activators), novel endothelin and al-
of glomerular hypertension. dosterone/renin receptor system inhibitors, vitamin
D activators, inhibitors of advanced glycation end
Diabetic nephropathy is known as an irreversible
disease and the current treatments are been able products (AGE) and their receptor (RAGE), Jak1-2 in-
to slow its progression; only one report suggest a hibitors, Transforming Growth Factor-α (TGF-α) and
reversibility of diabetic nephropathy(2) and hopefully Epidermal Growth Factor Receptor (“EGFR”) blockers,
future treatments will be able to improve the outcome phosphodiesterase inhibitors, Apoptosis Signal-regu-
of this devastating diabetic complication. lating Kinase 1 (ASK1) inhibitors, and TGFβ1 and CTGF
inhibitors.Tie-2 activators are currently being tested in
Diabetic kidney disease: current and future diabetic eye disease and might, in a near future, be
explored also in diabetic kidney disease.
treatments
In the past few years, many failures have charac-
The current treatment strategies are not sufficient to terized the search for new agents for the treatment
completely prevent progression of diabetic kidney of chronic kidney disease (CKD) in diabetes. One of
disease to ESRD. Intensive metabolic and haemody- the main problems is patients’ phenotype; despite we
namic control has proven to be efficacious in delaying can usually obtain a pretty clear phenotypic charac-
the progression of chronic kidney disease in diabe- terization in patients with T1DM, in the T2DM popu-
tes in younger and relatively uncomplicated subjects.
lation we encounter a huge phenotypic heterogene-

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