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Giuseppe PennoDipartimento di Medicina Clinica e SperimentaleUniversit di Pisa
La nefropatia diabetica
Inquadramento diagnostico della nefropatia diabetica
Dichiarazione esplicita di trasparenza delle fonti di finanziamentoe dei rapporti con soggetti portatori di interessi commerciali
Il sottoscritto Dr. Giuseppe Penno
in qualit diModeratore Relatore
ai sensi dellart. 3.3 sul Conflitto di Interessi, pag. 17 del Reg. Applicativo dellAccordo Stato-Regione del 5 novembre 2009,
dichiarache negli ultimi due anni ha avuto i seguenti rapporti anche di finanziamento con
soggetti portatori di interessi commerciali in campo sanitario:
AstraZeneca, Boerhinger Ingelheim, Eli-Lilly, Janssen, Merck Sharp & Dohme,
Novo Nordisk, Takeda
2 ottobre 2015
NAPOLI, 9 GIUGNO 2018
Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD
Key points
Albuminuria is a key marker ofkidney damage
Albuminuria indicates increased glomerular permeability Albuminuria can be categorised according to urine albumin-to-creatinine ratio or to
24-hour urine albumin excretion, as follows:
*Note that KDIGO 2012 guidelines recommend avoiding the terms microalbuminuria and macroalbuminuriaUACR, urine albumin-to-creatinine ratio
UACR (mg/g)24-hour UAE (mg/24 h)
Macroalbuminuria/severely increased*
>300>300A3
Microalbuminuria/moderately increased*
3030030300
A2
Normal to mildly increased
Estimated glomerular filtration rate is the most commonly used index of renal function
eGFR is generally reduced after widespread structural damage to the kidney It is categorised as follows:
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1
Kidney failure
KDIGO, Kidney Int Suppl 3: 1-150, 2013
Low riskModerate riskHigh riskVery high risk
Referral decision making by GFR and albuminuria. *Referring clinicians may wish to discuss with their nephrology service depending on local arrangements regarding monitoring or referring.
Kidney Disease: Improving Global Outcomes (KDIGO) classification
KDIGO, Kidney Int Suppl 3: 1-150, 2013
Kidney Disease: Improving Global Outcomes (KDIGO) classification
GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year).
Low riskModerate riskHigh riskVery high risk
l Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD
l Albuminuria and eGFR: clinicalcourse (and epidemiology) of DKD
Key points
Schematic presentation of the different clinical courses of diabetic kidney disease (DKD)
Boger CA et al., PLOS Genetics, 8: e1002989, 2012 (modified)
Normoalbuminuria
Normal GFR
Normoalbuminuria
Normal GFR
0 5 10 15 20Duration of diabetes (years)
Increased GFR (hyperfiltration)
Reduced GFR ESRD
crosstalk between the two channels
Normoalbuminuria
Microalbuminuria
Macroalbuminuria
Normal GFR
30-59 ml/min/1.73 m217.1%Normo 73.1%
Micro22.2%
Macro4.7%
60-89 ml/min/1.73 m251.7%
90 ml/min/1.73 m229.6%
62.5%12.0%
6.7%
17.1%
1.7%
No CKD
CKD stage 1
CKD stage 2
CKD stage 3
CKD stages 4/5
Approximately 40% of patientswith T2DM show signs of CKD (stages 1-5)
Approximately 20% of patientswith T2DM show signs of renalfailure (eGFR
Severe(A3)
Mild(A2)
Normal(A1)
15-29
30-44
45-59
60-89
>90
Albuminuria
Stage 2
Stage 1Stage 0(no CKD)
62.5%
Stage 3
Stage 4
Stage 5
Stage 1-2albuminuric phenotype
18.7%
Penno G et al. J Hypertens 29: 1802-1809, 2011
Renal dysfunction is common in patients with T2DMThe RIACE Study: 15,773 patients with T2DM
eGFRml/min/1.73 m2
Distribution of markers of CKD in RIACE and in NHANES participants with DM, hypertension, self-reported cardiovascular disease, & obesity, 20112014
Data Source: National Health and Nutrition Examination Survey (NHANES), 20112014 participants age 20 & older. Single-sample estimates of eGFR & ACR; eGFR calculated using the CKD-EPI equation. Abbreviations: ACR, urine albumin/creatinine ratio; BMI, body mass index; CKD, chronic kidney disease; SR CVD, self-reported cardiovascular disease; eGFR, estimated glomerular filtration rate; HTN, hypertension.
USRDS - 2016 Annual Data Report, Vol 1, CKD, Ch 1
10.6%
8.2%
18.7%
RIACE, Italy
De Cosmo S, et al., The AMD-Annals Study Group. Nephrol Dial Transplant, 29: 657-662, 2014
Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetes
Clinical features of 120,903 patients with type 2 diabetes: whole sample and divided according to the presence/absence of albuminuria or low eGFR
10.6% 18.7% 8.2%62.5%
Diabetic Kidney Disease (DKD)
Thomas MC et al., Nature Reviews / Disease Primers, 1: 1-19, 2015
The prevalence of CKD in different populations with type 2 diabetes
*Adjusted for age, sex, and race/ethnicity. p-values are for trendUACR, urine albumin-to-creatinine ratio
Prevalent cases of diabetic kidney disease in the United States accounting for persistence
Clinical manifestations of Kidney Disease among US Adults with Diabetes, 1988-2014
p=0.39 p
p=0.001 p=0.15p
l Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD
l Albuminuria and eGFR: clinicalcourse (and epidemiology) of DKD
l Albuminuria and eGFR in the KDIGO guidelines
Key points
KDIGO, Kidney Int Suppl 3: 1-150, 2013
Kidney Disease: Improving Global Outcomes (KDIGO) classification
KDIGO, Kidney Int Suppl 3: 1-150, 2013
Kidney Disease: Improving Global Outcomes (KDIGO) classification
Matsushita K et al, JAMA 307: 1941-1951, 2012
Distribution of estimated GFRData from 1.1 million adults from 25 general population cohorts,
7 high-risk cohorts (of vascular disease), and 13 CKD cohorts
Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular FiltrationRate
Matsushita K et al, JAMA 307: 1941-1951, 2012
Reclassification across estimated GFR categories
Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular FiltrationRate
Matsushita K et al, JAMA 307: 1941-1951, 2012
Net reclassification improvements for all-cause mortality, cardiovascular mortality, and ESRD
Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular FiltrationRate
KDIGO, Kidney Int Suppl 3: 1-150, 2013
Kidney Disease: Improving Global Outcomes (KDIGO) classification
l Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD
l Albuminuria and eGFR: clinicalcourse (and epidemiology) of DKD
l Albuminuria and eGFR in the KDIGO guidelines
l Albuminuria and eGFR for DKD monitoring
Key points
Normal AERn. 2,729 (75%)
Micro-albuminurian. 438 (12%)
Macro-albuminurian. 475 (13%)
Regressedn. 102
Persistentn. 336
Persistentn. 364
Regressedn. 111
23.3% 23.4%
The Finnish Diabetic Nephropathy Study
Study subjects (n. 3,642)
Men: 50.7%; Age: 37.4 11.9; BMI: 25.1 3.5
6.9 years follow-up
Jansson F et al., EASD, September 2016
The Finnish Diabetic Nephropathy Study
Jansson F et al., EASD, September 2016
0%
10%
20%
30%
40%
50%
0 5 10 15
Incidence of first ever CVD event by albuminuria status (n=3,449)
Time (years)
NORMO
MICRO
MACRO
HR = 1 (reference)
HR = 2.28 (1.68-3.10)
HR = 4.46 (3.46-5.77)
The Finnish Diabetic Nephropathy Study
Jansson F et al., EASD, September 2016
0%
10%
20%
30%
40%
50%
0 5 10 15
MACRO -> MICRO/NORMO
MICRO -> NORMO
HR = 1 (reference)
HR = 1.15 (0.61-2.19)
HR = 2.28 (1.68-3.10)
HR = 2.70 (1.73-4.24)
HR = 4.46 (3.46-5.77)
Time (years)
Incidence of first ever CVD event by albuminuria status (n=3,449)
NORMO
MICRO
MACRO
The Finnish Diabetic Nephropathy Study
Jansson F et al., EASD, September 2016
MACRO -> MICRO/NORMO
MICRO -> NORMO
HR = 1 (reference)NORMO
MICRO
MACRO
0%
10%
20%
30%
40%
0 5 10 15
Total mortality
Time (years)
HR = 1.19 (0.58-2.43)
HR = 2.65 (1.94-3.63)
HR = 3.54 (2.33-5.36)
HR = 6.32 (4.91-8.13)
l Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD
l Albuminuria and eGFR: clinicalcourse (and epidemiology) of DKD
l Albuminuria and eGFR in the KDIGO guidelines
l Albuminuria and eGFR and DKD monitoring
l What the diagnosis of DKD implies
Key points
Thomas MC et al., Nature Reviews / Disease Primers, 1: 1-19, 2015
The strong association between DKD and increased incidence and prevalence of other diabetic complications
Impact of DKD on EASD/ADA Treatment Algorithm (Two-Drug Combibnations)
Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providers
Tong L and Adker S. Postgraduate Medicine Published online: 18 Apr 2018.
Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providers
Tong L and Adker S. Postgraduate Medicine Published online: 18 Apr 2018.
Role of lipids, glucose and BP on CVD and DKD. Solid blue lines = strong clinical evidence linking the treatment to end-organ benefit Blue
dotted lines = inadequate evidence to support a clear benefit on CV or DKD
Maqbool M et al., Seminars in Nephrology 38: 217-232, 2018
In type 2 diabetes with CVD and kidney disease, empagliflozin reduced mortality and hospitalization
Wanner C et al., Circulation 137: 119-129, 2018
Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD
Albuminuria and eGFR: clinical course (and epidemiology) of DKD
Albuminuria and eGFR in the KDIGO guidelines
Albuminuria and eGFR and DKD monitoring
What the diagnosis of DKD implies
What the stratification by DKD phenotypes implies
Key points
0
10
20
30
40
50
CKD stages 1-2
n. 2,949
No CKD
n. 9,865
Maj
or C
VD e
vent
s, %
794(26.9%)
1,756(17.8%)
Any CVD event by CKD phenotype
Chi square, p
Kidney Disease and Increased Mortality in Type 2 Diabetes
Distribuzione dellEURODIAB PCS risk score in base ai fenotipi di CKD
64.9
28.3
11.8
0
26.0
37.7
23.5
8.39.1
34.0
64.7
91.7
0
20
40
60
80
100
No CKD CKD stadi1-2
n. 53
CKD stadi 3Alb-n. 17
CKD stadi 3Alb+n. 12
Rischio basso Rischio alto
1-2n. 692
p
Sopr
avvi
venz
a cu
mul
ativ
a
Follow-up, anni
K-M: Log Rank test p
HR 4.58(1.69-12.42)
p=0.003
HR 2.77(0.97-7.94)
p=0.058
Sopr
avvi
venz
a cu
mul
ativ
a
Follow-up, anni
Ref
HR 2.57(1.11-5.94)
p=0.027
HR 95%CI p
Sesso (M) 1.52 0.77-3.01 0.225
EURODIAB risk scoreRischio bassoRischio intermedioRischio alto
13.35
11.74
---1.20-9.32
4.44-31.04
Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD
Albuminuria and eGFR: clinical course (and epidemiology) of DKD
Albuminuria and eGFR in the KDIGO guidelines
Albuminuria and eGFR and DKD monitoring
What the diagnosis of DKD implies
What the stratification by DKD phenotypes implies
The kidney biopsy and the biomarkers
Key points
Thomas MC et al., Nature Reviews / Disease Primers, 1: 1-19, 2015
Glomerulopathy in diabetes
Morphological and functional alterations to renal glomeruli are one of the hallmarks of diabetic kidney disease
Indicazioni alla biopsia renale
Indicata in pazienti con diabete nei quali esiste il sospetto della presenza di DKD differenti dalla nefropatia diabetica
Permette di classificare la DKD in tre categorie associate a diverse prospettive prognostiche:
1. nefropatia diabetica (ND)2. malattia renale non diabetica (NDRD, non-diabetic renal
disease)3. condizione mista caratterizzata da NDRD sovrapposta a
ND.
Indicazioni alla biopsia renale
Le indicazioni legate alla presentazione atipica del danno renale sono le seguenti:
SID. Position Statement sullAppropriatezza nella Prescrizione degli Esami Strumentali in Diabetologia; Esami strumentali per lo Screening della Nefropatia Diabetica
- proteinuria in range nefrosico o riduzione del GFR in assenza di RD- proteinuria in range nefrosico o riduzione del GFR in soggetti con durata del
diabete inferiore a 5 anni - ematuria (microscopica) isolata o presenza di sedimento urinario attivo;- insufficienza renale acuta (AKI)- sospetto di nefropatia associata ad altre malattie sistemiche (basso
complemento, ANCA, ANA, dsDNA, anticorpi anticardiolipina, ASLO, HIV, M-Spike suggestivi di malattie monoclonali, crioglobuline, HCV)
- mancanza della caratteristica cronologia della DKD (comparsa rapida di proteinuria senza progressione da micro- a macroalbuminuria, presentazione con sindrome nefrosica, progressivo rapido declino del GFR in pazienti con funzione renale precedentemente stabile)
- significativa riduzione del GFR (>30%) dopo trattamento con bloccanti del RAS
CKD in diabetes: diabetic kidney disease versusnondiabetic kidney disease
Anders HJ et al., Nature Review / Nephrology, 14: 361-377, 2018
Causes of CKD in patients with diabetes mellitus and the pathophysiology of DKD
Presumed site of origin of commonly associated biomarkers predictive of DKD
Colhoun HM and Marcovecchio L, Diabetologia, Online, 8 march 2018
Thank for your attention!
Diapositiva numero 1Diapositiva numero 2Diapositiva numero 3Albuminuria is a key marker ofkidney damageEstimated glomerular filtration rate is the most commonly used index of renal function Diapositiva numero 6Diapositiva numero 7Diapositiva numero 8Diapositiva numero 9Diapositiva numero 10Diapositiva numero 11Diapositiva numero 12Diapositiva numero 13Diapositiva numero 14Diapositiva numero 15Diapositiva numero 16Diapositiva numero 17Diapositiva numero 18Diapositiva numero 19Diapositiva numero 20Diapositiva numero 21Diapositiva numero 22Diapositiva numero 23Diapositiva numero 24Diapositiva numero 25Diapositiva numero 26 Diapositiva numero 30Diapositiva numero 31Diapositiva numero 32Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providersGlycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providersDiapositiva numero 35Diapositiva numero 36Diapositiva numero 37Diapositiva numero 38Diapositiva numero 39Diapositiva numero 40Diapositiva numero 41Diapositiva numero 42Diapositiva numero 43Diapositiva numero 44Diapositiva numero 45Diapositiva numero 46Diapositiva numero 47Diapositiva numero 48Diapositiva numero 49