Diabetic Kidney Disease Flashcards
Diabetic Kidney Disease
Epidemiology
DKD is the most common primary diagnosis for patients who start dialysis (~50%)
Diabetic Kidney Disease
Epidemiology
60%: classic DKD (large kidneys, proteinuria > 1 g/d, ± diabetic retinopathy)
25% to 30%: another primary kidney disease in addition to DKD
Diabetic Kidney Disease
Epidemiology
10% to 15%: atypical presentation with ischemic nephropathy (low level proteinuria)
Diabetic Kidney Disease
Epidemiology
Kidney diseases in diabetic patients who present with ESRD:
Cumulative prevalence of proteinuria is ~50% to 60% at 25 years after diagnosis of diabetes.
Cumulative prevalence of progression to ESRD is ~60% at 5 years after onset of proteinuria.
Cumulative prevalence of proteinuria and progression to ESRD are similar for DM types 1 and 2.
Diabetic Kidney Disease
Risks for the Development of DKD and Progression
Unmodifiable risks:
Genetic susceptibility:
Family history of predisposition to abnormal sodium handling and hypertension
Genotypes: angiotensin-converting enzyme (ACE), angiotensin II type 2-receptor, aldose reductase
Diabetic Kidney Disease
Risks for the Development of DKD and Progression
Unmodifiable risks:
Genetic susceptibility:
Ethnicity: Blacks, Hispanics, Pima Indians with DM type 2
Gender: Caucasian males and African American females
Age: possibly early onset
Duration of DM
Modifiable risks: hypertension, early glomerular hyperfiltration, prolonged uncontrolled hyperglycemia, obesity, tobacco smoking, use of oral contraceptives
Diabetic Kidney Disease
Clinical Manifestations
Albuminuria:
Moderate increase in albuminuria may predict high risk for eventual DKD
Diabetic Kidney Disease
Clinical Manifestations
The American Diabetes Association recommends screening for microalbuminuria in:
All patients with DM type 2 at the time of diagnosis and annually thereafter
All patients with DM type 1 five years after the diagnosis and annually thereafter
Diabetic Kidney Disease
Clinical Manifestations
(Microscopic) Hematuria:
May occur with DKD
Red blood cell casts may be present, but other glomerular diseases must be ruled out.
Diabetic Kidney Disease
Clinical Manifestations
Morbidities and mortality:
Increasing albuminuria and decreasing GFR correlate with cardiovascular and renal events in patients with DM type 2.
Mortality among diabetics with ESRD is 1.5 to 2.0-fold greater compared to non-diabetics
Diabetic Kidney Disease
Natural History
Proposed scheme of DKD stages for type 1 DM (less reliable for type 2 DKD):
Pre-DKD: 0 to 5 years since disease onset: glomerular hyperfiltration, renal hypertrophy
Diabetic Kidney Disease
Natural History
Incipient DKD: 5 to 15 years
Microalbuminuria (30 to 300 mg/24 h or overnight albuminuria at 20 to 200 μg/min in at least two of three consecutive nonketotic sterile urine samples) occurs in 20% to 30% of patients, less than 50% of whom will progress to overt nephropathy, hypertension.
Diabetic Kidney Disease
Natural History
Incipient DKD: 5 to 15 years
Structural changes: mesangial expansion, moderate glomerular basement thickening, arteriolar hyalinosis
Diabetic Kidney Disease
Natural History
Overt DKD: 15 to 25 years:
Proteinuria (>300 mg albuminuria/24 hours or overnight albuminuria > 200 μg/min—when severely increased albuminuria occurs, the majority will progress to ESRD), nephrotic syndrome, reduced glomerular filtration
Diabetic Kidney Disease
Natural History
Overt DKD: 15 to 25 years:
Structural changes: severe glomerular basement membrane thickening, mesangial nodules (Kimmelstiel–Wilson lesions), tubulointerstitial fibrosis
Diabetic Kidney Disease
Natural History
ESRD > 25 years: 4% to 17% at 20 years from time of diagnosis of type 1 DM
Diabetic Kidney Disease
Pathogenesis
Hyperglycemia:
Enhances matrix production, glycation of matrix proteins, formation of advanced glycation end (AGE) products
Stimulates VEGF, endothelial injury
Increases expression of transforming growth factor β (TGF-β)
Diabetic Kidney Disease
Pathogenesis
Advanced glycation end products:
AGE crosslinking with collagen
AGE:AGE receptor interaction (AGE:RAGE) leads to oxidative stress, activation of protein kinase C (PKC)
Diabetic Kidney Disease
Pathogenesis
Activation of PKC pathway leading to:
Endothelial dysfunction with decreased NO production
Increased expression of ET1, VEGF, NFκB, and plasminogen activator inhibitor-1 (PAI-1) leading to tissue inflammatory response, TMA, vascular injury
Diabetic Kidney Disease
Pathogenesis
Polyol pathway (via aldose reductase): thought to contribute to diabetic complications including diabetic cataracts, neuropathy, hyperfiltration, albuminuria. Use of aldose reductase inhibitors have been disappointing due to hypersensitivity reactions and liver abnormalities.
Diabetic Kidney Disease
Pathogenesis
Accumulation of N-acetylglucosamine via hexosamine pathway: N-acetyleglucosamine may lead to increased synthesis of TGF-β1, PAI-1.
Diabetic Kidney Disease
Pathogenesis
Prorenin activation of mitogen-activated protein kinases
Reduction of nephrin expression presumably via angiotensin II
Diabetic Kidney Disease
Pathogenesis
Systemic hypertension
Metabolic stress leading to mitochondrial dysfunction (which may lead to type B lactic acidosis observed in patients with diabetic ketoacidosis)
Diabetic Kidney Disease
Pathogenesis
Structural Changes
Gross structural changes: kidney weight increases by ~15% due to glomerular hypertrophy and hyperfiltration
Diabetic Kidney Disease
Pathogenesis
Histopathology
Glomerular basement thickening (up to three times normal)
Diabetic Kidney Disease
Pathogenesis
Histopathology
Mesangial expansion:
Due in part to hyperglycemia induced increased matrix production or glycation of matrix proteins, AGE crosslinking with collagen, and decreased matrix degredation.
Mild to severe diffuse mesangial expansion without nodules
Diabetic Kidney Disease
Pathogenesis
Histopathology
Nodular glomerular intercapillary lesions (Kimmelstiel–Wilson lesion):
Associated with mesangiolysis and capillary microaneurysms
Differential diagnoses of nodular glomerulosclerosis: dysproteinemias (e.g., amyloidosis and monoclonal Ig deposition diseases, and immunotactoid GN), fibronectin glomerulopathy, collagen III glomerulopathy, chronic hypoxic/ischemic conditions, chronic MPGN, or idiopathic.
Diabetic Kidney Disease
Pathogenesis
Histopathology
Nodular glomerular intercapillary lesions (Kimmelstiel–Wilson lesion):
Patients with Kimmelstiel–Wilson lesions are more likely to have diabetic retinopathy (DR) and worse kidney function.
Diabetic Kidney Disease
Pathogenesis
Histopathology
Advanced diabetic sclerosis
Vascular lesions including hyalinization of both afferent and efferent arterioles, pathognomonic for diabetic nephropathy, and arterial intimal fibrosis.
Diabetic Kidney Disease
Indications for Kidney Biopsy in Patients with DM
Absence of DR (particularly in DM type 1). Note, however, the absence of DR in DM type 2 does not exclude DKD.
Diabetic Kidney Disease
Indications for Kidney Biopsy in Patients with DM
NOTE
Patients with DM type 1 and DKD almost always have other evidence of diabetic microvascular disease (i.e., DR, neuropathy), but the converse is not true (i.e., not all patients with DR have DKD)
Diabetic Kidney Disease
Indications for Kidney Biopsy in Patients with DM
DR is present in only ~50% to 65% of patients with DM type 2 and DKD. Albeit the absence of DR does not exclude DKD, patients without DR have a high likelihood of having a non-diabetic glomerular disease.
Diabetic Kidney Disease
Indications for Kidney Biopsy in Patients with DM
Acute onset of proteinuria, particularly if less than 5 years from diagnosis in DM type 1
Presence of active urinary sediment (e.g., red blood cell casts) or significant hematuria (gross hematuria)
Diabetic Kidney Disease
Indications for Kidney Biopsy in Patients with DM
Rapid decline in kidney function
Presence of extrarenal manifestations and/or positive serologies suggestive of another glomerular disease (e.g., positive ANCA, hypocomplementemia)
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Maintain hemoglobin A1C ~7% for both DM types 1 and 2
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise
Glucose Control
Renal dose adjustments for pharmacologic therapy:
Metformin: contraindicated for eGFR < 30 mL/min/1.73 m2.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Dipeptidyl peptidase-4 inhibitors:
Linagliptin: no dose adjustment
Saxagliptin: half-dose adjustment for creatinine clearance < 50 mL/min
Sitagliptin, alogliptin: half-dose adjustment for creatinine clearance 30 to 50 mL/min; quarter-dose adjustment for creatinine clearance < 30 mL/min
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Reduction in rates of development of microalbuminuria
Partial reversal of glomerular hypertrophy and hyperfiltration
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Rationale: Protective effects of intensive glycemic control:
Stabilization or decrease protein excretion in patients with albuminuria after apparent normoglycemia > 2 years
Slowing of GFR decline
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Rationale: Protective effects of intensive glycemic control:
Successful pancreas transplantation leads to stabilization of glomerular structure at 5-year follow-up and significant reversal of DKD histopathologic changes at 10 year.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Data:
Studies indicating that strict glycemic control decreased risk for microalbuminuria:
Diabetes Control and Complications Trial (DCCT) (DM type 1): 9-year follow-up, intensive therapy group with mean A1C of 7% had a 35% to 45% lower risk for development of microalbuminuria compared with control group (mean A1C 9%); Renoprotection persists even after return to less intensive therapy, a phenomenon known as “legacy effect.” This is presumably due to the effect of euglycemia on long-lasting modification of transcription of genes responsible for DKD.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Data:
Kumamoto study, DM type 2: 60% rate reduction of microalbuminuria in relatively young non-obese DM type 2 patients in intensive group (mean A1C 7%) compared with conventional therapy group (mean A1C 9.4%)
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Data:
U.K. Prospective Diabetes Study (UKPDS), DM type 2: A1C ~7.0% versus 7.9%
Relative risk reduction for development of microalbuminuria
Ten-year follow-up after study ended still revealed 24% lower risk of microvascular disease and myocardial infarction. All-cause mortality also remained reduced and attributed to “legacy effect.”
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Data:
U.K. Prospective Diabetes Study (UKPDS), DM type 2: A1C ~7.0% versus 7.9%
Relative risk reduction for development of microalbuminuria
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Data:
Ten-year follow-up after study ended still revealed 24% lower risk of microvascular disease and myocardial infarction. All-cause mortality also remained reduced and attributed to “legacy effect.”
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Data:
Strict glycemic control: effects on cardiovascular disease (CVD):
Action in Diabetes and Vascular Disease, Perindopril and Indapamide Controlled Evaluation (ADVANCE): intensive control (A1C 6.5% vs. 7.3%) resulted in a 10% relative reduction in combined outcome of major macrovascular and microvascularly events, primarily as a consequence of a 21% relative reduction in nephropathy.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Data:
Action to Control Cardiovascular Risk in Diabetes (ACCORD): very tight control (A1C 6.5% vs. 7.5%) had higher mortality, up by 22%, p = 0.04.
Veterans Affairs Diabetes Trial (VADT): A1C 6.9% versus 8.4%: no difference in reduction in cardiovascular deaths or events at 7.5-year follow-up
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Glucose Control
Data:
NOTE
In patients with long-standing DM and known CVD, current data do not support strict glycemic control in reducing risk for further CVD events or mortality.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Hypertension occurs in ~40% of DM type 1 and 70% of type 2.
Higher BP is associated with both development and progression of DKD.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Progressive lowering of BP to 120 mm Hg was associated with improved renal and patient survival. However, SBP < 120 mm Hg or DBP < 70 mm Hg, are poorly tolerated and associated with increased incidence of myocardial infarction and mortality. The latter is thought to reflect reduced coronary perfusion during diastole, particularly in patients with underlying coronary artery disease (Irbesartan Diabetic Nephropathy Trial (IDNT)).
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Recommendations (JNC 8):
Maintain SBP < 140 mm Hg and DBP < 90 mm Hg
If DKD is present, one antihypertensive agent should include ACEI or ARB.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
ACEI versus ARB:
RAAS inhibition with either ACEI or ARB confers renoprotection in patients with DKD independent of BP control via both intraglomerular hemodynamic and nonhemodynamic (i.e., antiproliferative and antifibrotic) effects of angiotensin II.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
RAAS inhibition also blocks aldosterone, thus its effects on sodium retention, potassium and magnesium wasting, and tissue inflammation and fibrosis. 40% to 50% of patients on ACEI or ARB develop “aldosterone escape” by 12 months of therapy. Aldosterone antagonism may be added if safely tolerated.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Data on DM type 1:
ACEI reduces the risk of progression from microalbuminuria to overt nephropathy.
In normotensives with microalbuminuria, ACEI leads to a 60% reduction in progression to macroalbuminuria and 3 times likelihood in regression to normoalbuminuria.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Data on DM type 1:
Captopril treatment in patients with macroalbuminuria or overt nephropathy reduces albuminuria and GFR decline and delays onset of kidney failure.
Insufficient data for ARB, but expected to be similar to ACEI.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Data on DM type 2:
Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study (IRMA 2) trial: Irbesartan reduces progression to overt DKD by 70% in hypertensive type 2 patients over 2-year follow-up.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Data on DM type 2:
Microalbuminuria Reduction with Valsartan in Patients with Type 2 DM (MARVAL) trial: daily valsartan 80 mg reduces urinary albumin excretion better than amlodipine (44% vs. 8%)
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Data on DM type 2:
IDNT and the Reduction in Endpoints in NIDDM with the AII Antagonist Losartan (RENAAL) trials: DM type 2 with macroalbuminuria and reduced GFR, ARBs reduce proteinuria and composite end points of death, dialysis, and doubling of serum creatinine.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Data on DM type 2:
NOTE
In contrast to DM type 1, data on efficacy of ACEI in type 2 DKD are not as robust.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Recommendations:
DM types 1 and 2: Use ACEI or ARB in normotensive patients with albuminuria ≥ 30 mg/g Cr who are at high risk for DKD or its progression
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Recommendations:
High risk for DKD or its progression is defined as having increasing albuminuria in the microalbuminuria range, macroalbuminuria, declining GFR, increasing BP, presence of DR, elevated lipids and/or uric acid concentrations, or family history of HTN, macrovascular disease, or DKD.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Recommendations:
In patients with microalbuminuria range and without high risks, follow-up without RAAS inhibition may be appropriate.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Recommendations:
In patients with macroalbuminuria without retinopathy, especially if present within 10 years of diagnosis of DM, consider evaluation for nondiabetic kidney disease.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Special notes regarding RAAS inhibition:
Combination therapy of RAAS inhibition in DKD: not advised due to unacceptable increase in adverse events (i.e., impaired kidney function and hyperkalemia). Additionally, there was no significant benefit in primary end point (progression of kidney disease), mortality, or cardiovascular events: Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Blood Pressure Control
Special notes regarding RAAS inhibition:
Aliskiren (renin inhibitor): should not be used in combination with either ACEI or ARB due to increased risk of stroke and adverse events (i.e., hyperkalemia, hypotension, and ESRD or death due to kidney disease)—Aliskiren Trial in Type 2 Diabetes Using Cardio–Renal Endpoints (ALTITUDE).
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Lipid Management
“Lowering low-density lipoprotein cholesterol (LDL-C) with statin-based therapies reduces risk of major atherosclerotic events, but not all-cause mortality in patients with CKD including those with DM.”
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Lipid Management
Recommendations:
Use of lipid-lowering agents (statins or statin/ezetimibe combination) is recommended to reduce risk of major atherosclerotic events in patients with diabetes and CKD including kidney transplant recipients. There is no evidence to suggest improvement in kidney disease outcomes with statin therapy.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Lipid Management
Initiating statin in patients with diabetes who are about to receive or already receiving dialysis is not recommended. Statins provide little or no benefit in death rates due to CVD events in dialysis patients with diabetes and appear to increase risk of hemorrhagic stroke:
A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis (AURORA) revealed no significant benefit on primary cardiovascular outcome (cardiac death or nonfatal MI and fatal or nonfatal stroke); Risk of hemorrhagic stroke increased by greater than fivefold. Twofold increased hemorrhagic stroke risk also noted in Die Deutsche Diabetes Dialyse Studie (4D).
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Lipid Management
Initiating statin in patients with diabetes who are about to receive or already receiving dialysis is not recommended. Statins provide little or no benefit in death rates due to CVD events in dialysis patients with diabetes and appear to increase risk of hemorrhagic stroke:
Study of Heart and Renal Protection (SHARP) trial (combined simvastatin 20 mg/ezetimibe 10 mg): no significant reduction in primary outcome of major atherosclerotic events in over 3,000 patients on dialysis.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Lipid Management
Other data not yet incorporated into practice guidelines (confirmatory data still needed):
Veterans Affairs High-density Lipoprotein Intervention Trial (VA-HIT): gemfibrozil reduces the risk of major cardiovascular events (fatal coronary heart disease, nonfatal MI, and stroke) by 42% in a post hoc analysis of 297 individuals with eGFR < 75 mL/min/1.73 m2 and diabetes.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Lipid Management
Other data not yet incorporated into practice guidelines (confirmatory data still needed):
Diabetes Atherosclerosis Intervention Study (DAIS) and Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: fenofibrate lowered the risk of developing new onset microalbuminuria.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Other Therapeutic Candidates
Peroxisome proliferator-activated receptor γ (PPAR) agonists:
PPARγ modulates numerous effectors of ECM accumulation.
Thiazolidinediones (TZD) are PPARγ agonists.
TZDs prevent increase in TGF-β and ECM and inhibit mesangial cell and fibroblast proliferation in vitro.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Other Therapeutic Candidates
Peroxisome proliferator-activated receptor γ (PPAR) agonists:
TZD + ARB losartan may confer better renoprotection than ARB alone, although safety of using TZD needs to be addressed:
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Other Therapeutic Candidates
Peroxisome proliferator-activated receptor γ (PPAR) agonists:
Prior concerns for coronary artery disease with rosiglitazone (Avandia) but recent trial revealed no increased risk of myocardial infarction;
Concerns for possible association with bladder cancer with pioglitazone (Actos).
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Other Therapeutic Candidates
AGE-targeted therapies:
Aminoguanidine blocks AGE formation and improves mesangial matrix expansion and albuminuria, but its use is limited by side effects.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Other Therapeutic Candidates
AGE-targeted therapies:
Pyridoxamine dihydrochloride (pyridorin), a derivative of vitamin B6 and potent inhibitor of AGE formation has been shown slow DKD progression, but only in patients with relatively preserved kidney function (i.e., baseline SCr 1.3 to 1.9 mg/dL).
Phenacylthiazolium bromide may be able to cleave AGE-derived protein cross-links.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Other Therapeutic Candidates
Other potential medical interventions:
Anti-TGF-β agent: pirfenidone has been shown to be renoprotective in mice.
Inhibitor of protein kinase C, β-isoform: ruboxistaurin
Small study suggests reduction of albuminuria and eGFR decline.
Efficacy in DR is being studied.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Other Therapeutic Candidates
Other potential medical interventions:
Pentoxifylline 1,200 mg/d, a nonspecific phosphodiesterase inhibitor commonly used to treat occlusive peripheral vascular disease, has been shown to improve eGFR decline and albuminuria in patients with DM2, DKD stages 3 to 4 at 24-month follow-up.
Diabetic Kidney Disease
Management (KDIGO 2012 Unless Specified Otherwise)
Other Considerations in the Management of DKD
Nonmedical strategies to slow down progression of DKD:
smoking cessation, weight loss
Autonomic neuropathy exacerbates uremic symptoms.
