Hypoxia -the culprit behind diabetic

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Hypoxia - the culprit behind diabetic kidney disease

Professor Per-Henrik Groop, MD DMSc FRCPE

Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, and

Folkhälsan Institute of Genetics, Helsinki, Finland, and Department of Diabetes, Central Clinical School, Monash

University, Melbourne, Australia

50^th Anniversary of the Finnish Society of Nephrology Helsinki 12.3.2020

Session II: The Future of Nephrology

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Outline of the talk

- Oxygen, diabetes and the kidney

- Hypoxia and diabetic kidney disease in T1D

- Hypoxia and kidney disease in experimental animals - Hypoxia and diabetic kidney disease in T2D

- Take home messages

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Oxygen, diabetes and the

kidney

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Intrarenal oxygen availability is the balance between supply, mainly dependent on renal blood flow (RBF), and demand,

determined by the basal metabolic demand and the energy- requiring tubular electrolyte transport

Oxygen tension (pO₂) is determined by the balance between oxygen (O₂) delivery and consumption (Q_O2).

O₂ is determined by blood flow and by O₂ extraction from the blood, whereas Q_O2 is affected by mitochondrial activity,

cellular Q_O2 and electrolyte transport

Oxygen supply and demand of the kidney…...

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Hyperglycemia results in increased oxygen consumption and decreased oxygen tension (pO₂) in the kidney

In diabetes the increased oxygen consumption is closely linked to glomerular hyperfiltration, oxidative stress, increased

mitochondrial leak respiration, and decreased tubular sodium transport efficiency

Reduced oxygen tension promotes alterations in gene expression that counteracts hypoxia and promotes cell survival and adaptation An adequate gene response is important to maintain tissue pO₂, and is mainly achieved by hypoxia-inducible transcription factors (HIFs)

Diabetes and oxygen consumption in the kidney…...

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HIFs consist of two subunits: an alpha-subunit that is continuously produced but rapidly degraded in the presence of oxygen, and a

constitutively expressed beta-subunit

In hypoxia, the alpha-subunit accumulates because of the lack of oxygen and form transcriptionally active heterodimers with the beta-subunit

The heterodimers bind to DNA to induce transcription of

hypoxia-responsive genes such as EPO, VEGF, HO-1, NO-synthase, COX-2, and PPAR alpha

HIF is inadequately activated in the hypoxic diabetic kidney

Hypoxia-inducible factors – the defense system

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Takiyama and Haneda. BioMed Research Internationa 2014l

Hypoxia-inducible factors (HIFs) and their regulation

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Hypoxia and diabetic kidney disease in

individuals with type 1 diabetes

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0,8 0,9 13,6

22,3

17,6

29,3

0 5 10 15 20 25 30 35

15/min 6/min

Baroreflex sensitivity (ms/mmHg)

Type 1 diabetics

**

† †

† † Breathing rate * group

interaction p=NS

NS

Healthy subjects

Surgically denervated subjects

Within groups **p<0.005, between groups ††p<0.005

Rosengård-Bärlund et al. Diabetologia 52, 1164-1172, 2009

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Autonomic and BRS abnormalities in patients with chronic mountain sickness

(chronic hypoxia)

Cerro de Pasco 4339m, Peru

…that are reversed with oxygen or descent to sea-level

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Oxygen saturation (SaO2) reduced at baseline in patients with type 1

diabetes

Control

Type 1 diabetes

P=0.001

Gordin et al. Acta Diabetologica 53, 439-357, 2016

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BRS increases after oxygen

administration in type 1 diabetes

Bernardi et al. Diabetologia 54, 2164-2173, 2011

Control (N=49) Type 1 diabetes

(N=98)

Luciano Bernardi

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Low SaO₂ present at rest… does a 1.5% difference matter?

SaO₂ (%): 98.7 ±0.1 vs 97.2 ± 0.1 p<0.001

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Low SaO₂ present at rest. Does a 1.5% difference matter?

YES it does! due to the dissociation curve of Hb, this implies a large difference in PO₂

SaO₂ (%): 98.7 ±0.1 vs 97.2 ± 0.1 p<0.001

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Decreased oxygen transport due to glycosylation of hemoglobin

P50 is the pressure value at which the red blood cells are fifty percent saturated with oxygen. The lower the P50, the higher is the affinity of Hb for oxygen and makes it difficult to release oxygen to the tissues

glucose

Solomon LR and Cohen K. Diabetes 38 (7), 881-886, 1989

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Glycosylation of basal membranes in the lungs leads to reduced DLCO that correlates with HbA1c

Wheatley et al. Eur J Appl Physiol 111, 567-578, 2011

Lung diffusion abnormalities

correlate with HbA

_1c

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Hypoxia and diabetic kidney disease in

experimental animals

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Franzén et al. Am J Physiol Renal Physiol 310, F807-9, 2016

Pronounced and persistent intrarenal hypoxia as early as 3 days after induction of diabetes in mice

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Total kidney oxygen consumption in rats with and without

administration of dinitrophenol (DNP), a mitochondial uncoupler

Dinitrophenol increases oxygen consumption and causes kidney hypoxia

Friederich-Persson et al. Hypertension 62 (5), 1-16, 2013

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Kidney hypoxia due to increased oxygen consumption induces kidney disease independently of hyperglycemia

and oxidative stress

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Dinitrophenol increased urinary protein excretion, kidney vimentin expression and infiltration of inflammatory cells

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Activation of Hypoxia-Inducible Factors prevents diabetic kidney disease

Nordquist et al. J Am Soc Nephrol 26, 328-338, 2015

Cobalt chloride activates HIFs

Tempol is a superoxide dismutase mimetic

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Activation of Hypoxia-Inducible Factors prevents diabetic kidney disease

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Activation of Hypoxia-Inducible Factors prevents diabetic kidney disease

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Hypoxia and diabetic kidney disease in

individuals with type 2 diabetes

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Empagliflozin is not indicated for the treatment of CKD.

Comparison of trials should be interpreted with caution due to differences in study design, populations and methodology

*Exploratory analyses; ^†Prespecified outcome; ^‡Accompanied by eGFR ≤45 ml/min/1.73 m²; ^§Nominal p-value eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; RRT, renal replacement therapy

1. Wanner C et al. N Engl J Med 2016;375:323; 2. Perkovic V et al. Lancet Diabetes Endocrinol 2018;6:691; 3. Mosenzon O et al. Lancet Diabetes Endocrinol2019;7:606;

4. Perkovic V et al. N Engl J Med 2019;380:2295

Similar patterns on kidney outcomes have been observed in SGLT2 inhibitor CV and cardio–renal outcomes trials

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EMPA-REG OUTCOME*¹ (empagliflozin)

Doubling of serum creatinine,^‡ RRT or death from

kidney causes

46%

p<0.001^§

CANVAS Program*² (canagliflozin)

Doubling of serum creatinine, ESKD or death from

kidney causes

47%

DECLARE-TIMI 58*³ (dapagliflozin)

≥40% decrease in eGFR to

<60 ml/min/1.73 m², ESKD or death from kidney causes

47%

p<0.0001

CREDENCE^†4 (canagliflozin)

ESKD (RRT or sustained eGFR <15 ml/min/1.73 m²), doubling of serum creatinine or

death from kidney causes

34%

p<0.001

HR 0.54

(95% CI 0.40, 0.75)

HR 0.53

(95% CI 0.33, 0.84)

HR 0.53

(95% CI 0.43, 0.66)

HR 0.66

(95% CI 0.53, 0.81)

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Empagliflozin attenuates glomerular hyperfiltration

Type 1 diabetes patients with hyperfiltration. Mean GFR recorded at baseline and after 8 weeks treatment with empagliflozin 25 mg QD

Cherney D et al. Circulation 129, 587-597, 2014 172.0

139.0

0 20 40 60 80 100 120 140 160 180 200

T1D-H (Euglycemia)

Mean GFR (ml/min/1.73 m2 )

Baseline Empagliflozin

*p<0.01

GFR reduced by

-33 ml/min/1.73 m²

Glomerular filtration rate

*

Type 1 Diabetes:

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Empagliflozin reduces intra-glomerular pressure

Skrtic M et al. Diabetologia 57, 2599-2602, 2014

Intra-glomerular pressure recorded at baseline and after 8 weeks treatment with empagliflozin 40

45 50 55 60 65 70 75 80

T1D-N T1D-H

Mean intra-glomerular pressure, euglycaemia, mm Hg

*

Glomerular pressure T1D-H (mmHg) ^Baseline ^EMPA ^{p value} Change from baseline

Euglycaemia (mmHg) 67.4 ± 5.4 61.0 ± 5.2 <0.0001 9.5%

Hyperglycaemia (mmHg) 69.3 ± 6.5 61.6 ± 6.3 <0.0001 11.1%

*p<0.0001

~6−8 mmHg

Glomerular hypertension

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Reduced hyperfiltration was mediated by effects on renal blood flow and vascular resistance

• Reduced renal blood flow (RBF) & increased renal vascular resistance (RVR) after empagliflozin treatment are consistent with afferent arteriole vasoconstriction

1641

1156

0 200 400 600 800 1000 1200 1400 1600 1800

RBF Mean RBV (ml/min/1.73 m2)

0.054

0.072

0 0,01 0,02 0,03 0,04 0,05 0,06 0,07 0,08

RVR

Mean RVR (mmHg/L/min)

*

* p<0.01

Patients with type 1 diabetes and hyperfiltration at baseline. RBV and RVR recorded in euglycaemic state.

RBF, renal blood flow; RVR, renal vascular resistance Cherney D et al. Circulation 2014;129:587

renal blood flow renal vascular resistance

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The “Tubular Hypothesis”

Heerspink et al. Circulation 134, 752-772, 2016

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Diabetes

⇡Renal blood flow Hyperfiltration

⇡Sodium handling in the proximal tubule

(90 % of oxygen consumption in the kidneys)

HYPOXIA

CKD

↑Oxygen consumption in cortex and medulla

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Diabetes

⇡Renal blood flow

Hyperfiltration

Less HYPOXIA

or NORMOXIA

Renal benefit

SGLT2 inhibitor

⇡Sodium handling in the proximal tubule

(90 % of oxygen consumption in the kidneys)

↓Oxygen consumption in cortex and medulla

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Take home messages

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• Intrarenal hypoxia causes kidney disease

• Patients with diabetes are hypoxic

• The defense mechanisms to cope with hypoxia are impaired in diabetes

• Hypoxia leads to abnormalities in the autonomic and vascular function that precede diabetic complications

• There are new promising modes of treatment to fight

hypoxia behind the door…..

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Thank you for your attention

per-henrik.groop@helsinki.fi www.finndiane.fi