Heterogeneity and Risk Prediction of Diabetic Kidney ... › files › 2017 › 10 ›...

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Heterogeneity and Risk Prediction of Diabetic Kidne y Disease

Amy Mottl MD, J. Charles Jennette, MD

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• Pathology

• Pathogenesis

• Epidemiology

• Pathologic features for clinical correlation

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Diabetic Glomerulosclerosis

K-W nodule

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Capillary aneurysm caused by mesangiolysis

K-W nodule

Capsular drop

Hyaline cap

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IgG Staining in Diabetic Glomerulosclerosis

Linear staining of GBMs and TBMs.

Variable staining of mesangial matrix.

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normal diabetes

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Diabetic Kidney Disease

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O’Shaughnessy, Hogan, Poulton, Falk, Singh, Nickeleit, Jennette. CJASN 2017;12:614-623

Temporal and Demographic Trends in Glomerular Disease Epidemiology in the Southeastern United States, 1986–2015

Among 21,374 patients (mean age =48.3±18.3 years ol d; 50.8% men;

56.8% white; 38.3% black; 2.8% Latino; 1.4% Asian; 0.8% other),the

frequency of diabetic glomerulosclerosis in renal b iopsy specimens

increased dramatically over three decades (5.5%, 11 .4%, and 19.1% of

diagnoses, respectively; P for trend <0.001).

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Temporal trends in the relative renal biopsy freque ncies of the most common glomerular disease subtypes, 1986–2015.

DKD Frequencies excluding DKD


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Relative renal biopsy diagnosis frequencies of the most common glomerular disease subtypes according to patient ag e category and typical

mode of clinical presentation.

DKD

Nephrotic Presentation Nephritic Presentation

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Absolute renal biopsy diagnosis frequencies of the most common glomerular disease subtypes according to patient ag e category


DKD

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Renal biopsy diagnosis frequencies of the most comm on glomerular disease subtypes according to patient age category stratified by sex

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DKD DKD

FSGSSLE

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Renal biopsy diagnosis frequencies of the most comm on glomerular disease subtypes according to patient age category stratified by race

DKDDKDFSGS

FSGS

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USA/Canada

Europe

Asia

Latin America

DKD

Glomerular Disease Frequencies by Race, Sex, and Region: Results from the International Kidney Biopsy Survey (IKBS). O'Shaughnessy, Hogan, Thompson, Coppo, Fogo, Jennette. Nephrol Dial Transplant 2017, in press.

Glomerular Disease Subtype Kidney Biopsy Frequencies, by Geographic Region

The higher risk for DKD in USA/Canada versus Europe, Latin America, or Asia may be driven by associations between unhealthy lifestyle, metabolic syndrome, and disease development.

>60K diagnoses, >40K glomerular disease diagnoses

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DKD DKD DKD

Glomerular Disease Subtype Kidney Biopsy Frequencie s, by Race, Comparing Regions of Ancestral Origin to USA/Canada

Glomerular Disease Frequencies by Race, Sex, and Region: Results from the International Kidney Biopsy Survey (IKBS). O'Shaughnessy, Hogan, Thompson, Coppo, Fogo, Jennette. Nephrol Dial Transplant 2017, in press.

Based on 42,603 renal biopsy diagnoses

DKD is a more frequent glomerular disease among whi tes in North America vs Europe (18% vs 6%, p<0.001); and more frequent among Latinos in USA/Ca mada vs Latin America (17% vs 4%, p<0.001)

>60K diagnoses, >40K glomerular disease diagnoses

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Glomerular Segmental Sclerosis and Extracapillary H ypercellularityPredict Poor Outcome in Diabetic Kidney Disease

Amy K. Mottl, Adil Gasim, Fernanda P. Schober, Yichun Hu,Askia Dunnon, Susan L. Hogan, J. Charles Jennette

Submitted to JASN, 2017

• Study Design and Population: Longitudinal, retrospective study of clinical, 109native kidney biopsies at the University of North Carolina (UNC) between 1995–2011with a pathologic diagnosis of diabetic glomerulosclerosis, and adequate clinical data.

• Pathology Review of Kidney Biopsy Specimens: Renal biopsy review carried outwithout knowledge of clinical outcomes.

• Statistical Analyses: Baseline demographic and clinical parameters and pathologiccharacteristics quantified using percentages for categorical variables and median andinterquartile ranges (IQR) for continuous variables. Univariate and multivariable riskmodels of ESRD with death as a competing risk were constructed to assess theassociation between clinical and pathologic variables and ESRD.

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Class IV DGSSegmental sclerosis

& adhesionSegmental sclerosis

with collapseExtracapillary

hypercellularity

Extracapillary hypercellularity

Extracapillary hypercellularity and arteriolar occlusion

EXHC and SS

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Changing clinical landscape of DKD

1988-1994 1999-2004 2005-2008 2009-2014P value

for trend

Any DKD 28 (24-33) 27 (23-31) 27 (23-31) 26 (23-30) 0.39

AlbuminuriaACR≥30ug/mg

21 (16-25) 19 (15-22) 18 (14-23) 16 (13-19) § <0.001

Macroalbuminuria 5.6 (2.8-8.4) 5.4 (3.1-7.7) 4.9 (2.8-7.1) 5.0 (3.6-6.6) 0.22

eGFR < 60 ml/min/1.73m2 9.2 (6.2-12.2) 11.6 (8.5-14.6)§ 11.8 (8.4-15.1) § 14.1 (11.3-17.0) § <0.001

eGFR < 30ml/min/1.73m2 1.0 (0.5-2.0) 1.7 (1.1-2.6) 1.8 (1.2-2.7) 2.7 (2.0-3.7) § 0.004

*All characteristics account for persistence except eGFR < 30ml/min/1.73m2

§Significantly different from prevalence in reference years 1988-1994

Afkarian, et al. JAMA 2016; 316(6): 602-610

Changing prevalence, % (95% CI) clinical characteristics* of DKD over past 20 years from NHANES.

Changing clinical landscape of DKD

Afkarian, et al. JAMA 2016; 316(6): 602-610

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Krolewski et al. Diabetes Care 2014; 37:226-234

eGFR decline as an EARLY prognostic tool

Characteristics

Normoalbuminuria Microalbuminuria

GFR change during follow-up GFR change during follow-up

Nondecliner Decliner P-value Nondecliner Decliner P-value

Renal FunctionBaseline eGFRFollow up eGFReGFR slope (%/yr)

113 (103-124)103 (93-115)

-1.3 (-2.1 to -0.7)

104 (91-117)61 (54-76)

-5.0 (-7.3 to -3.8)

<0.005116 (105-124)103 (89-116)

-1.5 (-2.1 to -0.7)

99 (80-111)59 (48-76)

-5.1 (-7.4 to -4.0)

<0.001

AER abnormalityBaseline AER (µg/min)Progression to MicroProgression to Macro

16 (12-22)17%

--

16 (12-22)54%

--

NS<0.001

57 (42-92)--

4%

94 (51-166)--

27%

<0.001

<0.001

Factors associated with rapid eGFR decline

Krolewski et al. Diabetes Care 2014; 37:226-234

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Pathogenetic factors in DKD

Atherosclerosis

Hypertension Hyperglycemia

DKD

Obesity

Genetics

Insulin Resistance

ATNATN

Acute kidney injury in DKD

Thakar CV et al. CJASN 2011; 6: 2567-72

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Correlations of pathology with clinical markers

eGFR ≥ 60ml/min/1.73m 2 eGFR < 60ml/min/1.73m 2

Urine Albumin:Creatinine Ratio

<30ug/mg 30-299ug/mg ≥300ug/mg <30ug/mg 30-299ug/mg ≥300ug/mg

??

Clinical DKD phenotype using currently available markers of renal disease.

Fioretto et al. Diabetologia 1996; 39: 1569-1576; Ekinci et al; Diabetes Care 2013 Nov;36(11):3620-6; Mottl et al; unpublished

Pathologic Classification of DKDTervaert et al. J Am Soc Nephrol. 2010 Apr;21(4):556-63

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Renal survival, free of ESRD, among diabetic patients with (A) renal biopsy and (B) pure DN according to pathologic glomerular classification.

Renal survival according to histology

Oh, et al. Diab Res Clin Prac 2012; 97: 418-424

Characteristic Mean (95% CI)

Age, years 52 (46, 62)

Male sex, n (%) 62(56.9%)

Black race, n (%) 53(48.6%)

Type 2 diabetes, n (%) 79(86.8%)

Diabetes duration, years 14.1 (9.7, 17.4)

Hemoglobin A1c, % 6.8 (6.2, 9.0)

Systolic blood pressure, mmHg 151 (134, 165)

Follow-up time, months 18.2 (5.5, 42.3)

eGFR, ml/min/1.73m2 22 (15, 37)

Urine protein*, gm/gm 4.5 (2.0, 8.1)

eGFR slope, ml/min/1.73m2/yr -3.3 (-14.2, 0.00)

ESRD during f/u, n (%) 59 (55.7%)

Time to ESRD, months 9.1 (3.0, 29.9)

Death during follow up, n (%) 28 (26.4%)

Time to death, months 22.9 (11.5, 43.6)

Risk Stratification by Pathologic Characteristics

in Clinical Biopsies (N=109)

Mottl, Gasim, Jennette, et al; in review, JASN

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Mottl, Gasim, Jennette, et al; in review, JASN

Pathologic predictors in clinical biopsies

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Stereologic analyses in early DKD

Histologic Predictors of GFR Decline

25 –

20 –

15 –

10 –

5 –

0 –

-50 -25 -20 -15 -10 -5 0 +5 +10 +15 +20 +25

# of patients

//25 –

20 –

15 –

10 –

5 –

0 –

-50 -25 -20 -15 -10 -5 0 +5 +10 +15 +20 +25//

MicroalbuminuricsMedian: -0.40 % GFR/yr

% GFR change from base line per year

ProteinuricsMedian: -1.80 % GFR/yr

Nosadini R et al. Diabetes 2000; 49:476-484

Median

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Nosadini et al. Diabetes 2000; 49: 476-484

Stereology as a prognosticator

Stereology as a prognosticator

Morphometric Variable

Hazard Ratios (95% CI) for ≥40% renal function loss

Unadjusted Adjusted*

Global glomerular sclerosis, %

1.08 (0.83, 1.41) 1.63 (1.21, 2.21)

Mean glomerular volume, x106 u3 1.32 (1.02, 1.70) 1.42 (1.02, 1.96)

GBM width, nm 1.53 (1.16, 2.0) 1.48 (1.05, 2.08)

Mesangial Fractional Volume per glom, %

1.84 (1.39, 2.42) 2.27 (1.58, 3.26)

Glomerular Filtration Surface Density, µ2/µ3 0.67 (0.48, 0.92) 0.62 (0.41, 0.94)

Nonpodocyte no. per glomerulus

1.46 (1.15, 1.87) 1.50 (1.10, 2.05)

Endothelial Fenestration, % 0.68 (0.50, 0.91) 0.68 (0.48, 0.95)

*Adjusted for baseline age, sex, diabetes duration, HbA1c, GFR

Fufaa et al. CJASN 2016; 11: 254-261

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Circulating TNF Receptors

Niewczas et al. JASN 2012; 23: 507-515

Heterogeneity and Risk Prediction of Diabetic Kidney ... › files › 2017 › 10 ›...

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