Background
Pathophysiology
Class | Biopsy findings |
---|---|
I | Thickening of glomerular basement membrane >430 nm in males ages 9 years and older, >395 nm in females ages 9 years and older |
II | Mild to severe expansion of mesangial extracellular material: width of interspace exceeds two mesangial cell nuclei in two or more glomerular lobules; also known as “diffuse diabetic glomerulosclerosis” |
III | Nodular sclerosis, Kimmelstiel-Wilson lesions: focal, lobular, mesangial lesions with acellular, hyaline/matrix core. Generally, these lesions indicate transition from early to later stages diabetic kidney disease |
IV | More than 50% global glomerulosclerosis attributed to diabetes: fibrotic lesions with a build-up of extracellular matrix proteins in the mesangial space. Presence indicates advanced diabetic kidney disease |
Other changes, lesions | Interstitial fibrosis and tubular atrophy; hyalinosis of the efferent, and possibly the afferent, arterioles; insudative lesions known as “capsular drop lesions” when found in Bowman’s capsule, as “hyalinized afferent and efferent arterioles when found in the afferent and efferent arterioles, and as fibrin cap lesions or hyalinosis when found in glomerular capillaries; “tip lesion” refers to abnormality in the tubuloglomerular junction, with atrophic tubules and no visible glomerular opening, and related to advanced DKD and macroalbuminuria |
Clinical manifestations
Diagnostic tools and laboratory practices for DKD
-
Stage A1, normal to mildly increased albuminuria: <30 mg/g (<3 mg/mmol) UACR in urine sample
-
Stage A3, severely increased albuminuria, macroalbuminuria: >300 mg/g (>30 mg/mmol) UACR; occurring ≥2 times, 3–6 months apart [21]
Treatments and medications
Drug class | Example(s) | Mechanism/action | Evidence of kidney protective effects | GFR range (ml/min/ 1.73m2) |
---|---|---|---|---|
Biguanides | Metformin | Reduces hepatic gluconeogenesis [38] | No | >30, lower dose if 30–45 |
Sulfonylureas | Glipizide Gliclazide Glimepiride Glyburide | Stimulates insulin secretion [39] | No | Varies by agent; generally >30 |
Sodium glucose transport protein-2 inhibitors (SGLT-2i) | Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin | Inhibits glucose reabsorption in the kidney thereby lowering blood glucose [40] | Yes (See Table 3, discussion) | Varies by agent; generally >20 |
Glucagon-like Peptide Receptor Agonist (GLP-1 RA) | Exenatide Exenatide ER Liraglutide Albiglutide Dulaglutide Semaglutide | Induces insulin secretion, reduces glucagon release, lowers hepatic gluconeogenesis, slows gastric emptying [50] | Yes (See Table 4, discussion) | Varies by agent; generally >15; Exenatide is contraindicated for GFR <30 or ESKD |
Insulin | Degludec Glargine Detemir NPH Aspart Lispro Glulisine Regular | No | No restriction by GFR, but doses usually must be reduced for GFR <30 | |
Dipeptidyl peptidase-4 (DPP4) inhibitors | Sitagliptin Alogliptin Linagliptin Vildagliptin | Prevent GLP-1 degradation, thereby lowering blood glucose [61] | No | Varies by agent; generally >30 except for linagliptin which can be used with lower GFR |
Thiazolidinediones | Pioglitazone | Nuclear transcription regulator and insulin sensitizer [62] | No | No restriction by GFR; watch for worsened fluid retention if eGFR <30 |
Study | Inclusion criteria | Participants | Kidney outcome(s) | HR (95% CI) or other as specified |
---|---|---|---|---|
Studies with at least one primary kidney outcome | ||||
CREDENCE [41] Feb 2014–Oct 2018 695 sites in 34 countries [42] | Adults with T2D, HbA1c 6.5% to 12.0%, age ≥30 yrs, eGFR (CKD-EPI) 30 to ≤90 AND UACR 300-5000, taking stable dose of ACEi or ARB for ≥4 weeks prior to randomization | N=2202 100 mg canagliflozin once daily N=2199 placebo once daily BL: mean age 63 yrs, 66% male, 67% white, mean HbA1c 8.3%, mean duration T2D 16 yrs, mean eGFR 56, median UACR 927 | A) Primary kidney composite outcome of ESKD (dialysis for ≥30 days or kidney transplantation or eGFR≤15), doubling of serum creatinine from BL sustained for ≥30 days, or death from kidney or CVD cause B) Secondary kidney composite outcome of ESKD, doubling of serum creatinine, or kidney death C) ESKD D) Doubling of serum creatinine E) Dialysis or kidney transplantation F) Kidney death G) ESKD, kidney- or CVD-related death Dialysis, kidney transplantation, or kidney death | A) 0.70 (0.59–0.82) B) 0.66 (0.53–0.81) C) 0.68 (0.54–0.86) D) 0.60 (0.48–0.76) E) 0.74 (0.55–1.00) F) – G) 0.73 (0.61–0.87) 0.72 (0.54–0.97) |
DAPA-CKD [43] Feb 2017–June 2020 386 sites in 21 countries | Adults with or without T2D, an eGFR of 25-75 AND a UACR of 200–5000, taking stable dose of ACEi or ARB >4 weeks prior to screening | N=2152 10mg dapagliflozin once daily N=2152 placebo once daily BL: mean age 62 yrs, 67% male, 53% white, 68% T2D, mean eGFR 43, 48% had UACR >1000 | A) Primary kidney composite outcome of decline of at least 50% in eGFR or death from kidney or CV cause in participants overall; B) Primary kidney composite outcome of decline of at least 50% in eGFR or death from kidney or CV cause in participants with T2D; C) Primary kidney composite outcome of decline of at least 50% in eGFR or death from kidney or CV cause in participants without T2D D) Secondary kidney outcomes: composite of sustained eGFR decline of at least 50%, ESKD, kidney death; Between-group difference in LS mean slope of eGFR from BL to month 30 | A) 0.61 (0.51–0.72) B) 0.64 (0.52–0.79) C) 0.50 (0.35–0.72) D) 0.56 (0.45–0.68) Difference = 0.93 mL/min/ 1.73m2/yr (0.61–1.25) |
Studies with kidney outcomes as secondary outcome(s) only | ||||
EMPA-REG OUTCOME [44] July 2010–April 2015 590 sites in 42 countries | Adults with T2D, HbA1c 7.0 to 10% if on antidiabetic therapy or 7 to 9% for drug naïve, age ≥18 yrs, established CVD or high risk for CVD, eGFR (MDRD) ≥30 | N=4685 empagliflozin (10 or 25 mg) once daily N=2333 placebo once daily BL: mean age 64.5 yrs, 70% male, 72% white, mean HbA1c 8.1% [45] | A) Incident or worsening nephropathy (UACR >300) B) Doubling of serum creatinine AND eGFR ≤45 C) Initiation of kidney replacement D) Composite outcome of incident or worsening nephropathy or CV-related death E) Progression to macroalbuminuria F) Composite of b + c + kidney-related death G) Incident albuminuria (UACR≥30) in those with normal albuminuria at BL | A) 0.61 (0.53–0.70) B) 0.56 (0.39–0.79) C) 0.45 (0.21–0.97) D) 0.61 (0.55–0.69) E) 0.62 (0.54–0.72) F) 0.54 (0.40–0.75) G) 0.95 (0.87–1.04) |
CANVAS, CANVAS-R [46] Dec 2009–Feb 2017 667 sites in 30 countries | Adults with T2D, HbA1c 7% to 10.5%, eGFR ≥30, age ≥30 yrs with symptomatic history of CVD, or age ≥50 yrs with 2+ risk factors for CVD | N=5795 canagliflozin (100 or 300 mg) N=4347 placebo BL: mean age 63.3 yrs, 64% male, 78% white, mean duration T2D=14 yrs, mean HbA1c 8.2% | A) Composite of progression of albuminuria (more than 30% increase in albuminuria), change from either normoalbuminuria to microalbuminuria or micro- to macroalbuminuria B) Regression of albuminuria C) Composite of 40% reduction in eGFR for at least 2 consecutive measures, need for kidney replacement therapy, and kidney-related death | A) 0.73 (0.67–0.79) B) 1.70 (1.51–1.91) C) 0.60 (0.47–0.77) |
DECLARE-TIMI 58 [47] April 2013–Sept 2018 882 sites, 33 countries | Adults with T2D, HbA1c 6.5% to 11.9%, age ≥40 yrs, creatinine clearance ≥60 ml/min, with multiple CVD risk factors or established CVD | N=8582 dapagliflozin (10 mg once daily) N=8578 placebo (once daily) BL: mean age 64 yrs, 63% male, 80% white, mean HbA1c 8.3%, median duration T2D 10.5 yrs, mean eGFR 85 | A) Composite of sustained decrease in eGFR (per CKD-EPI) of 40% or more to less than 60, new ESKD, or death from kidney or CV cause B) Sustained decrease in eGFR (per CKD-EPI) of 40% or more to less than 60, new ESKD, or death from kidney cause | A) 0.76 (0.67–0.87) B) 0.53 (0.43–0.66) |
VERTIS-CV [48] Nov 2013–Dec 2019 567 sites in 34 countries | Adults, with T2D and established atherosclerotic CVD, age ≥40 yrs, HbA1c 7.0% to 10.5%, BMI≥18 kg/m2, eGFR ≥30 | N=5499 5 or 15 mg ertugliflozin once daily N=2747 placebo once daily BL: mean age 64 yrs, 70% male, 88% white, mean HbA1c 8.2%, mean duration T2D 13 yrs, mean eGFR 76 | Composite of kidney death, kidney replacement therapy, or doubling of serum creatinine | 0.81 (0.63–1.04) |
EMPEROR REDUCED [49] March 2017–May 2020 520 sites in 20 countries | Adults with chronic heart failure and left ventricular ejection fraction <40%, age ≥18 yrs Note: Roughly 7 in 10 participants were taking MRAs at BL | N=1863 10 mg empagliflozin once daily N=1867 placebo once daily BL: mean age 67 yrs, 76% male, 70% white, 50% DM, mean eGFR 62 | A) Rate of decline in eGFR calculated per CKD-EPI equation B) Composite kidney outcome of chronic dialysis or kidney transplantation, profound & sustained reduction in eGFR | A) Between group difference=1.73 ml/min/1.73m2 (1.10–2.37) B) 0.50 (0.32–0.77) |
Study | Inclusion criteria | Participants | Kidney outcome | HR (95% CI) or other as specified |
---|---|---|---|---|
Studies with kidney outcomes as secondary outcome(s) only | ||||
LEADER [51] Aug 2010–Dec 2015 410 sites in 32 countries | Adults with T2D, age ≥50 yrs with established CVD, or age ≥60 yrs with CVD risk factors, HbA1c ≥7%, no GLP-1 RA or DPP-4i for 3 months prior to screening | N=4668 maximum 1.8mg liraglutide (as tolerated) once daily N=4672 placebo once daily BL: mean age 64 yrs, 64% male, 78% white, mean HbA1c 8.7%, mean duration T2D 13 yrs, mean eGFR (MDRD) 80, 26% had microalbuminuria, 11% had BL macroalbuminuria | A) Composite of new onset persistent macroalbuminuria, persistent doubling of serum creatine, kidney replacement therapy, death from kidney causes B) New onset persistent macroalbuminuria C) Persistent doubling of serum creatinine D) Kidney replacement therapy E) Death from kidney cause F) Decline in eGFR over 36 months G) Increase in UACR H) New onset microalbuminuria | A) 0.78 (0.67–0.92) B) 0.74 (0.60–0.91) C) 0.90 (0.67–1.20) D) 0.87 (0.61–1.25) E) 1.60 (0.52–4.90) F) Between group difference=1.02 (p=0.01) G) Between group difference=0.83 (p<0.001) H) 0.87 (0.83–0.93) |
REWIND [52] July 2011–Aug 2018 371 sites in 24 countries | Adults with T2D, age ≥50 with previous CVD event or with CVD risk factors, HbA1c ≤9.5% | N=4949 1.5mg dulaglutide once weekly N=4952 placebo once weekly BL: mean age 66 yrs, 54% male, 76% white, mean duration T2D 11 yrs, mean HbA1c 7.4%, mean eGFR 77 | A) Composite of development of macroalbuminuria (UACR>33.9 mg/mmol), sustained decline in eGFR ≥30%, or new chronic kidney replacement therapy B) Development of macroalbuminuria C) Sustained decline in eGFR ≥30% D) New chronic kidney replacement therapy | A) 0.85 (0.77–0.93) B) 0.77 (0.68–0.87) C) 0.89 (0.78–1.01) D) 0.75 (0.39–1.44) |
Harmony Outcomes [53] July 2015–March 2018 610 sites in 28 countries | Adults with T2D and established CVD, age ≥40 yrs, HbA1c >7%, eGFR (MDRD) ≥30, not using GLP-1 RA at screening | N=4731 30–50 mg albiglutide as tolerated once weekly N=4732 placebo once weekly BL: mean age 64 yrs, 70% male, 70% white, mean duration T2D 14 yrs, mean HbA1c 8.7%, mean eGFR 79 | Change in eGFR by treatment group | Mean eGFR difference=−1.11 (−1.84 to −0.39) at 8 months and -0.43 (−1.26 to 0.41) at 16 months. Figure 4 shows significant difference (no CI overlap) favoring albiglutide at 28 months but no numbers provided |
SUSTAIN-6 [54] Feb 2013–March 2016 230 sites in 20 countries | Adults with T2D, age ≥50 yrs with established CVD, heart failure (NYHA class II or III), or chronic kidney failure OR age ≥60 yrs with one or more CVD risk factors, HbA1c ≥7%, no use of DPP-4i within 30 days prior to screening or GLP-1 RA within 90 days prior to randomization | N=1648 0.5mg or 1.0 mg semaglutide once weekly N=1649 placebo once weekly BL: mean age 65 yrs, 61% male, 83% white, 30% eGFR>90, mean HbA1c 8.7%, mean T2D duration 14 yrs | A) New or worsening nephropathy B) Persistent macroalbuminuria C) Persistent doubling of serum creatinine and creatinine clearance per MDRD <45 D) Need for continuous kidney replacement therapy | A) 0.64 (0.46–-0.88) B) 0.54 (0.37–0.77) C) 1.28 (0.64–2.58) D) 0.91 (0.40–2.07) |
AMPLITUDE-O [55] April 2018–Dec 2020 344 sites in 28 countries | Adults with T2D, HbA1c >7%, age ≥18 yrs with history of CVD, OR males ≥50 yrs/females ≥55 yrs with eGFR (MDRD) 25.0 to 59.9 and ≥1 CV risk factor, no use of GLP-1 RA or DPP-4i within 3 months prior to screening | N=1359 initial dose 2mg efpeglenatide once weekly, titrated to 4mg or 6mg once daily to study end N=1358 6mg efpeglenatide once weekly N=1359 placebo once weekly BL: mean age 65 yrs, 67% male, 87% white, mean HbA1c 8.9%, mean eGFR 72, mean duration T2D 15 yrs, median UACR 28.3 | A) Incident macroalbuminuria B) Between-group difference in UACR C) LS mean difference in eGFR D) Decrease in eGFR≥40% for ≥30 days, ESKD, or all-cause death E) Composite of MACE, death from non-CV cause, hospitalization for heart failure, or occurrence of (A) | A) 0.68 (0.57–0.79) B) 0.68 (0.58–0.80) C) Lower by 21% (14–28%) D) Higher by 0.9 (0.3–1.50) E) 0.77 (0.57–1.02) F) 0.71 (0.59–0.87) |
ELIXA [56] June 2010–Feb 2015 829 sites in 49 countries [57] | Adults with T2D, HbA1c 5.5% to 11.0%, age≥30 yrs, with acute coronary syndrome (STEMI, non-STEMI, or unstable angina) <180 days before screening, HbA1c 5.5 to 11%, and eGFR (MDRD) ≥30, taking GLP-1 RA or DPP-4i during study | N=3034 10μg lixisenatide increased up to 20μg once daily N=3034 placebo once daily BL: mean age 60 yrs, 69% male, 75% white, mean duration T2D 9 yrs, mean HbA1c 7.7%, mean eGFR 76 | Percent change in UACR from BL to study week 108 (BL UACR and study week 108 data available for n=2830 placebo, n=2803 lixisenatide) | +34% placebo, +24% lixisenatide, p<0.01, adjusted for BL UACR, treatment, region, BL use of ACEi and ARB; +32% placebo, +26 lixisenatide, p=0.07, adjusted for BL and 3-month HbA1c |
EXSCEL [58] June 2010–April 2017 688 sites in 35 countries [59] | Adults with T2D, HbA1c 6.5% to 10.0%, age≥18 yrs, eGFR (MDRD) ≥30, range of CV risk factors, taking 0 to 3 oral glycemic control drugs or insulin with or without use of 1–2 oral glycemic drugs, never used GLP-1 RA | Propensity score matched N=572 placebo; N=572 exenatide once weekly +SGLT2i; N=575 exenatide once weekly; N=575 exenatide once weekly + SGLT2i BL: mean age 63 yrs, 62% male, 76% white, mean duration T2D 12 yrs, mean HbA1c 8% | Outcome comparisons between 1: placebo only with exenatide + SGLT2i, and 2: exenatide only with exenatide + SGLT2i: A) Change over time in eGFR (per MDRD) B) Composite of persistent 40% reduction in eGFR, kidney dialysis, or kidney transplant C) Composite of “B” plus new macroalbuminuria | A) (1) 1.94 (0.94–2.94); (2) 2.38 (1.40–3.35) B) (1) 0.32 (0.06–1.59); (2) 0.21 (0.05–0.97) C) (1) 0.43 (0.15–1.22); (2) 0.35 (0.13–0.98) |
AWARD 7 [60] July 2012–Dec 2016 99 sites in 9 countries | Adults with T2D and stage 3 or 4 CKD, age≥18 yrs, HbA1c 7.5% to 10.5%, taking insulin alone or with oral glucose control drug, taking maximum tolerated dose of ACEi or ARB, not taking GLP-1 RA or DPP-4i | N=192 1.5mg dulaglutide once weekly; N=190 0.75mg dulaglutide once weekly; N=194 insulin glargine once daily BL: mean age 65 yrs, 69% white, 52% male, mean HbA1c 8.6%, mean duration T2D 18 yrs, mean eGFR (CKD-EPI) by creatinine 36 (35 by cystatin C), median UACR = 214 for dulaglutide 1.5mg, = 234 for dulaglutide 0.75mg, = 196 for insulin glargine | Outcome comparisons between (1) insulin glargine vs dulaglutide 1.5mg, and (2) insulin glargine vs dulaglutide 0.75mg A) Change in eGFR per CKD-EPI creatinine B) Change in eGFR per CKD-EPI cystatin C C) UACR change from BL D) Change in eGFR per MDRD E) Kidney events of increase in serum creatinine >30% from BL, ESKD | A) Week 26 LS mean change (1): −0.1 (p<0.05), (2): −0.4 (p<0.05) Week 52 Change (1): −1.1 (ns), (2): −1.5 (ns) B) Week 26 LS mean change (1): 0.8 (p<0.05), (2): 1.1 (p<0.0001); Week 52 Change (1): −0.7 (p<0.05), (2): −0.7 (p<0.05) C) Week 26 Among those with BL macro-albuminuria, UACR decreased for dulaglutide 1.5mg vs insulin by 43.1% (p=0.008) at week 26 and decreased by 29% (p=0.02) at week 52; for dulaglutide 0.75mg, a decrease of 25.3% (no p-value provided) at week 26 and decrease of 12.3 (no p-value provided) at week 52; for those without BL macroalbuminuria, decrease of 0.4% at week 26 (ns) and decrease of 3.4 % (ns) at week 52 for dulaglutide 1.5mg; for dulaglutide 0.75mg, decrease of 18% (ns) at week 26 and decrease of 15.3% (ns) at week 52 D) Week 26 LS mean change (1): no change (p<0.05), (2): −0.2 (p<0.05); Week 52 change (1): −0.4 (p<0.05), (2) −1.3 (ns) E) Number of events Dulaglutide 1.5mg = 79 (41%); Dulaglutide 0.75mg = 73 (38%); Insulin = 91 (47%) |
Study | Inclusion criteria | Participants | Kidney outcome | HR (95% CI) or other as specified |
---|---|---|---|---|
Studies with at least one primary kidney outcome | ||||
FIDELIO DKD [63] Sept 2015–April 2020 978 sites in 48 countries | Adults with T2D and CKD (UACR 30 to <300 AND eGFR (CKD-EPI) 25 to <60 OR UACR 300-5000 AND eGFR 25 to <75), age ≥18 yrs, taking maximum tolerated dose of ACEi or ARB, serum potassium ≤4.8 mmol/L, HbA1c ≤12% | N=2833 finerenone, 10mg once daily titrated up to 20mg once daily as tolerated N=2841 placebo once daily BL: mean age 66 yrs, 70% male, 63% white, mean duration T2D 17 yrs, mean HbA1c 7.7%, mean eGFR 44, median UACR 852, mean serum potassium 4.37 mmol/L, 7% taking GLP-1 RA, 5% taking SGLT2i | Primary outcomes: A) Kidney composite of kidney failure (ESKD or eGFR <15), sustained decrease of ≥40% in eGFR from BL for ≥4 weeks, or kidney-related death B) Kidney failure C) ESKD D) eGFR <15 E) Sustained decrease of ≥40% in eGFR from BL for ≥4 weeks F) Kidney-related death Secondary outcomes G) Change in UACR from BL to study month 4 H) Composite of kidney failure, sustained decrease of ≥57% from BL eGFR for ≥4 weeks, or kidney-related death I) Sustained decrease of ≥57% from BL eGFR for ≥4 weeks | A) 0.82 (0.73–0.93) B) 0.87 (0.72–1.05) C) 0.86 (0.67–1.10) D) 0.82 (0.67–1.01) E) 0.81 (0.72–0.92) F) -- G) Between group difference=0.69 (0.66, 0.71) H) 0.76 (0.65, 0.90) A) I) 0.68 (0.55–0.82) |
Studies with kidney outcomes as secondary outcome(s) only | ||||
FIGARO DKD [64] Sept 2015–Feb 2021; NOTE: COVID-19 caused trial disruption for 29% of pts, and temporary interruption of trial regiment for 10% of pts 975 sites in 48 countries | Adults with T2D, age ≥18 yrs, HbA1c <12%, with either UACR 30 to <300 AND eGFR (per CKD-EPI) 25 to 90 OR UACR 300-5000 AND eGFR ≥60, taking ACEi or ARB at maximum tolerated dose, serum potassium ≤4.8 mmol/L at screening | N=3686 finerenone, 10mg once daily titrated up to 20mg per day as tolerated N=3666 placebo once daily BL: mean age 64 yrs, 69% male, 72% white, mean HbA1c 7.7%, mean eGFR 68, median UACR 308, 8% taking SGLT2i, and 8% taking GLP-1 RA at BL, with additional 16% and 11%, respectively, starting over study period | A) Composite of 1st occurrence of kidney failure (ESKD or sustained decrease in eGFR <15), sustained decrease of ≥40% from BL eGFR for ≥4 weeks, or kidney-related death B) 1st occurrence of kidney failure C) ESKD D) Sustained decrease in eGFR <15 E) sustained decrease of ≥40% from BL eGFR for ≥4 weeks F) kidney-related death G) Change in UACR from BL to study week 4 H) Composite of 1st occurrence of kidney failure, sustained decrease of ≥57% from BL eGFR for ≥4 weeks, or kidney-related death I) sustained decrease of ≥57% from BL eGFR for ≥4 weeks | B) 0.87 (0.76–1.01) C) 0.72 (0.49–1.05) D) 0.64 (0.41–0.995) E) 0.71 (0.43–1.16) F) 0.87 (0.75–1.00) G) – H) Between group difference=0.68 (0.65–0.70) I) 0.77 (0.60–0.99) J) 0.76 (0.58–1.00) |