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Diabetic NephropathyDiabetic Nephropathy
OutlineOutline
Introduction of diabetic nephropathy Introduction of diabetic nephropathy Manifestations of diabetic nephropathyManifestations of diabetic nephropathy Staging of diabetic nephropathyStaging of diabetic nephropathy MicroalbuminuriaMicroalbuminuria Diagnosis of diabetic nephropathyDiagnosis of diabetic nephropathy Treatment of diabetic nephropathyTreatment of diabetic nephropathy
The leading cause of end-stage renal disease The leading cause of end-stage renal disease Diabetic nephropathy- Diabetic nephropathy-
→ → 30~40% 30~40% type 1 DMtype 1 DM vs. 20% vs. 20% type 2 DMtype 2 DM after years after years
Majority of diabetic p’ts with Majority of diabetic p’ts with ESRDESRD→→Type 2 DM Type 2 DM Prevalence of type 2 DM >> type 1DM (10~15x)Prevalence of type 2 DM >> type 1DM (10~15x)
Introduction ofIntroduction of
Diabetic nephropathyDiabetic nephropathy
→→5 stages5 stages Clinical and morphologic featuresClinical and morphologic features→→Similar in Similar in type 1 DMtype 1 DM and and type 2 DMtype 2 DM
Glomerular hypertension and hyperfiltrationGlomerular hypertension and hyperfiltration are the earliest renal abnormalitiesare the earliest renal abnormalities
Course of GFR change: more variable in Course of GFR change: more variable in type 2 DMtype 2 DM
→ → GFR decline: 5~10cc/min/year GFR decline: 5~10cc/min/year (1~20 cc/min/year in type 2 DM)(1~20 cc/min/year in type 2 DM)
Manifestations ofManifestations of
Diabetic nephropathyDiabetic nephropathy
DM nephropathy stagesDM nephropathy stages Stage 1:hyperfiltration phaseStage 1:hyperfiltration phase Stage 2:silent phaseStage 2:silent phase Stage 3:microalbuminuria phaseStage 3:microalbuminuria phase Stage 4:macroalbuminuria phaseStage 4:macroalbuminuria phase Stage 5:ESRDStage 5:ESRD
Describes the renal hypertrophy and Describes the renal hypertrophy and hyperfiltration that present at the time of hyperfiltration that present at the time of diagnosis of type 1 DM .diagnosis of type 1 DM .
GFR and UAER- elevated by 20-40%GFR and UAER- elevated by 20-40%(UAER: urine albumin excretion rate)(UAER: urine albumin excretion rate)
→→ GFR and UAER↓while insulin therapyGFR and UAER↓while insulin therapy
Stage of Diabetic nephropathy
Stage 1-Hyperfiltration phase
Clinically silent (GFR↑)Clinically silent (GFR↑) Early histologic change (GBM/Matrix ↑)Early histologic change (GBM/Matrix ↑) Hyperfiltration related to Hyperfiltration related to
Degree of hyperglycemia (Degree of hyperglycemia (up to 250 mg/dLup to 250 mg/dL), ), higher levels of glycemia- GFR↓higher levels of glycemia- GFR↓
Better glucose control- hyperfiltration↓Better glucose control- hyperfiltration↓
Typically lasts for Typically lasts for 5-15 years 5-15 years
Stage of Diabetic nephropathy
Stage 2- Silent phase
Incipient nephropathyIncipient nephropathy Occurs after Occurs after 6 -15 years6 -15 years of diabetes of diabetes UAER: 30-300mg/dUAER: 30-300mg/d Always Always small but detectable BP↑small but detectable BP↑ Impairment of nocturnal BP “dipping”Impairment of nocturnal BP “dipping”
GFR is elevated or reduced into normal GFR is elevated or reduced into normal rangerange
Initial hyperfiltration Initial hyperfiltration greater greater subsequent rate of decline in GFR subsequent rate of decline in GFR
Stage of Diabetic nephropathy
Stage 3- Microalbuminuria phase
24Hr BP Profile in Hypertension 24Hr BP Profile in Hypertension (Dipper vs non-dipper)(Dipper vs non-dipper)
Blood pressure (mm Hg)
7:00 11:00 15:00 19:0 23:00 3:00 7:00
Sleep
Dipper
Non-dipper
Time of day
175
135
115
95
75
55
155
Established or overt nephropahtyEstablished or overt nephropahty CharacteristicsCharacteristics
Clear histologic changesClear histologic changes HTN- established in most patientsHTN- established in most patients
Proteinuria→ increase 15~40 % per yearProteinuria→ increase 15~40 % per year GFR decline→10(2~20)mL/min per yearGFR decline→10(2~20)mL/min per year
The rate of decline in GFR is correlated with The rate of decline in GFR is correlated with blood pressure levelsblood pressure levels
Microscopic hematuriaMicroscopic hematuria: 66% of patient: 66% of patient
Stage of Diabetic nephropathy
Stage 4- Macroalbuminuria phase
Macroproteinuric phaseMacroproteinuric phase→ → a steady decline in renal functiona steady decline in renal function
GFR↓(about 1 mL/min↓per month)GFR↓(about 1 mL/min↓per month) A plot of the reciprocal of the serum A plot of the reciprocal of the serum
creatinine level against timecreatinine level against time usually yields a straight line and allows usually yields a straight line and allows
prediction of the rate of deteriorationprediction of the rate of deterioration
Stage of Diabetic nephropathy
Stage 4- Macroalbuminuria phase
ESRD developed inESRD developed in 50% of type 1 diabetic patient with overt 50% of type 1 diabetic patient with overt
nephropathy within nephropathy within 10 years10 years Within a median of Within a median of 7 years7 years from the from the
development of persistent proteinuria development of persistent proteinuria
Stage of Diabetic nephropathy
Stage 5- ESRD
Accurate measurement of UAERAccurate measurement of UAER→→Identification of incipient “early” nephropahtyIdentification of incipient “early” nephropahty→→Modify the natural history of DMNModify the natural history of DMN Normal urine contains some albuminNormal urine contains some albumin
< 30 mg/day< 30 mg/day
The importance of
Microalbuminuria
Sample: overnight urineSample: overnight urine Microalbiminuria (MicroA): Microalbiminuria (MicroA):
30mg/day< UAER <300mg/day30mg/day< UAER <300mg/day
Persistent microA: Persistent microA: MicroA found inMicroA found in 2/3 2/3 consecutive urine samples consecutive urine samples
within within 3-6 months3-6 months DM DM < 6 years< 6 years: other causes should be : other causes should be
suspectedsuspected
Diagnosis of
Microalbuminuria
ScreeningScreening An early morning urine sampleAn early morning urine sample Screening recommendationsScreening recommendations
Type 1 DM: Age >12 y/o, DM Dx >5 yearsType 1 DM: Age >12 y/o, DM Dx >5 years Type 2 DM: At diagnosisType 2 DM: At diagnosis
Both: Annually until 70 y/oBoth: Annually until 70 y/o
Screening of
Microalbuminuria
Microalbiminuria Microalbiminuria
The predictive value of overt DMNThe predictive value of overt DMN A marker of overt nephropathy risk in type 1 DM A marker of overt nephropathy risk in type 1 DM
patients.patients. Type 1 DM> 15 years with microA: 28% developed Type 1 DM> 15 years with microA: 28% developed
overt DMN within 10 years. overt DMN within 10 years.
Systemic hypertensionSystemic hypertension A significant relationship between BP and urine A significant relationship between BP and urine
albumin excretion rate(UAE).albumin excretion rate(UAE).
Microalbiminuria Microalbiminuria
Diabetic retinopathyDiabetic retinopathy Type 1 DM patients: strong association Type 1 DM patients: strong association
between UAE and DMR.between UAE and DMR. Close ophthalmologic monitoring advised.Close ophthalmologic monitoring advised.
Atherosclerosis:Atherosclerosis: DM patients with overt DMN: increased risk DM patients with overt DMN: increased risk
of CV mortality.of CV mortality. Micro A: potentially atherogenic changesMicro A: potentially atherogenic changes
Screening for Screening for microalbuminuria microalbuminuria
1) Measurement of albumin:creatinine 1) Measurement of albumin:creatinine ratio in random spot collectionratio in random spot collection
2) 24-hour collection with creatinine, 2) 24-hour collection with creatinine, allowing the simultaneous measurement allowing the simultaneous measurement of creatinine clearanceof creatinine clearance
3) Timed (eg, 4-hour or overnight 3) Timed (eg, 4-hour or overnight collection). collection).
Albuminuria thresholds for 3 Albuminuria thresholds for 3 common tests of diabetic common tests of diabetic nephropathynephropathy
Category Albumin:creatinine ratio, spot collection (μg/mg)
24-h creatinine collection
(mg/24h)
Albuminuria, timed collection
(μg/min)
Normal <30 <30 <20
Microalbuminuria 30-299 30-299 20-199
Clinical albuminuria (macroalbuminuria)
≥300 ≥300 ≥200
Using a specific assay for albumin is a Using a specific assay for albumin is a more sensitive technique. The normal rate more sensitive technique. The normal rate of albumin excretion is less than 20 of albumin excretion is less than 20 mg/day (15 µg/min); persistent albumin mg/day (15 µg/min); persistent albumin excretion between 30 and 300 mg/day (20 excretion between 30 and 300 mg/day (20 to 200 µg/min) is called microalbuminuria to 200 µg/min) is called microalbuminuria and, in patients with diabetes (particularly and, in patients with diabetes (particularly type 1 diabetes), is usually indicative of type 1 diabetes), is usually indicative of diabetic nephropathydiabetic nephropathy
Although the 24-hour urine collection was Although the 24-hour urine collection was previously the gold standard for the previously the gold standard for the detection of microalbuminuria , it has detection of microalbuminuria , it has been suggested that screening can be been suggested that screening can be more simply achieved by a timed urine more simply achieved by a timed urine collection or an early morning specimen collection or an early morning specimen to minimize changes in urine volume that to minimize changes in urine volume that occur during the day . occur during the day .
Microalbuminuria is unlikely if the albumin Microalbuminuria is unlikely if the albumin excretion rate is below 20 µg/min in a excretion rate is below 20 µg/min in a timed collection or if the urine albumin timed collection or if the urine albumin concentration is less than 20 to 30 mg/L in concentration is less than 20 to 30 mg/L in a random specimen. Higher values a random specimen. Higher values (particularly those just above this range) (particularly those just above this range) may represent false positive results, and may represent false positive results, and should be confirmed by repeated should be confirmed by repeated measurementsmeasurements
There are also a variety of semiquantitative There are also a variety of semiquantitative dipsticks, such as Clinitek Microalbumin dipsticks, such as Clinitek Microalbumin Dipsticks and Micral-Test II test strips, which Dipsticks and Micral-Test II test strips, which can be used to test for microalbuminuria if can be used to test for microalbuminuria if the urine albumin excretion cannot be directly the urine albumin excretion cannot be directly measured. The reported sensitivity and measured. The reported sensitivity and specificity of these tests range from 80 to 97 specificity of these tests range from 80 to 97 percent and 33 to 80 percent, respectivelypercent and 33 to 80 percent, respectively
Albumin-to-creatinine ratio — The effect Albumin-to-creatinine ratio — The effect of volume can be avoided entirely by of volume can be avoided entirely by calculation of the albumin-to-creatinine calculation of the albumin-to-creatinine ratio in an untimed urine specimen. A ratio in an untimed urine specimen. A value above 30 mg/g (or 0.03 mg/mg) value above 30 mg/g (or 0.03 mg/mg) suggests that albumin excretion is above suggests that albumin excretion is above 30 mg/day and therefore that 30 mg/day and therefore that microalbuminuria is probably present microalbuminuria is probably present
Patients who progress from Patients who progress from normoalbuminuria to microalbuminuria or normoalbuminuria to microalbuminuria or microalbuminuria to macroalbuminuria microalbuminuria to macroalbuminuria are more likely to have higher are more likely to have higher hemoglobin A1c (A1C) values and a hemoglobin A1c (A1C) values and a higher blood pressure than higher blood pressure than nonprogressors nonprogressors
. Patients with type 1 diabetes almost always . Patients with type 1 diabetes almost always have a blood pressure of less than 130/80 mmHg have a blood pressure of less than 130/80 mmHg if albumin excretion is normal or only slightly if albumin excretion is normal or only slightly increased [23]. The blood pressure usually increased [23]. The blood pressure usually begins to rise within the normal range in the third begins to rise within the normal range in the third year after the onset of microalbuminuria [36]; the year after the onset of microalbuminuria [36]; the incidence of overt hypertension is approximately incidence of overt hypertension is approximately 15 to 25 percent in all patients with 15 to 25 percent in all patients with microalbuminuria and much higher as the patient microalbuminuria and much higher as the patient progresses to overt nephropathyprogresses to overt nephropathy
RecommendationsRecommendations
Type 2 diabetes — Progression from Type 2 diabetes — Progression from microalbuminuria to overt nephropathy microalbuminuria to overt nephropathy within a 10 year period occurs in 20 to 40 within a 10 year period occurs in 20 to 40 percent of Caucasian patients with type 2 percent of Caucasian patients with type 2 (non-insulin-dependent) diabetes [3,43,44]. (non-insulin-dependent) diabetes [3,43,44]. Risk factors contributing to progression Risk factors contributing to progression include hyperglycemia, hypertension, include hyperglycemia, hypertension, ethnicity, and cigarette smoking ethnicity, and cigarette smoking
Screening can be deferred for five years Screening can be deferred for five years after the onset of disease in type 1 after the onset of disease in type 1 diabetes because microalbuminuria is diabetes because microalbuminuria is uncommon before this time. If not found uncommon before this time. If not found at the initial screen, yearly screening is at the initial screen, yearly screening is recommended for microalbuminuria. recommended for microalbuminuria.
Use of the albumin-to-creatinine ratio in an Use of the albumin-to-creatinine ratio in an untimed urinary sample is recommended untimed urinary sample is recommended as the preferred screening strategy for all as the preferred screening strategy for all diabetic patients. An elevated ratio should diabetic patients. An elevated ratio should be confirmed with at least two additional be confirmed with at least two additional tests performed over the subsequent 3 to 6 tests performed over the subsequent 3 to 6 months, with confirmation of the diagnosis months, with confirmation of the diagnosis requiring at least 2 of 3 positive samplesrequiring at least 2 of 3 positive samples
— — We recommend that an albumin-to-We recommend that an albumin-to-creatinine ratio be measured yearly in creatinine ratio be measured yearly in patients with type 2 diabetes [50]. An patients with type 2 diabetes [50]. An elevated ratio should be confirmed with elevated ratio should be confirmed with at least two additional tests performed at least two additional tests performed over the subsequent 3 to 6 months, with over the subsequent 3 to 6 months, with confirmation of the diagnosis requiring at confirmation of the diagnosis requiring at least 2 of 3 positive samples [50]. least 2 of 3 positive samples [50].
MicroalbuminuriaMicroalbuminuria
Microalbuminuria
Monitor Creatinine
Investigate forOther Renal
Disease
Screen forHeart Disease
Screen forVascular Disease
Screen forEye Disease
OptimizeLipids
OptimizeGlucose
DiscourageSmoking
OptimizeBP
Usually depend on clinical grounds without a Usually depend on clinical grounds without a renal biopsyrenal biopsy
Supportive clues areSupportive clues are 1.DM hx >10 years1.DM hx >10 years 2.Presence of normal or enlarged kidneys2.Presence of normal or enlarged kidneys 3.Evidence of proliferative diabetic retinopathy3.Evidence of proliferative diabetic retinopathy 4.A bland urinary sediment.4.A bland urinary sediment. 5.Typical DM nephropathy course 5.Typical DM nephropathy course
Retinopathy is found in Retinopathy is found in 90 and 60 percent90 and 60 percent of patients with type of patients with type 1 DM and type 2 DDM, respectively, who develop nephropathy1 DM and type 2 DDM, respectively, who develop nephropathy
Diagnosis ofDiagnosis of
Diabetic nephropathyDiabetic nephropathy
““Typical Typical ““ overt overt nephropathynephropathy
Type 1 DM for > 10 yearsType 1 DM for > 10 years RetinopathyRetinopathy Previous microalbuminuriaPrevious microalbuminuria No macroscopic hematuriaNo macroscopic hematuria No RBC castsNo RBC casts Normal renal echoNormal renal echo
No Biopsy
““AtypicalAtypical““ proteinuria proteinuria
Type 1 DM for <10 yearsType 1 DM for <10 years No retinopathyNo retinopathy Nephrotic range proteinuria without Nephrotic range proteinuria without
previous microalbiminuriaprevious microalbiminuria Macroscopic hematuriaMacroscopic hematuria Red cell castsRed cell casts
Renal biopsy
The earliest morphologic abnormalities in The earliest morphologic abnormalities in diabetic nephropathy:diabetic nephropathy: Thickening of the glomerular basement Thickening of the glomerular basement
membrane (membrane (GBMGBM)) ExpansionExpansion of the mesangium due to of the mesangium due to
accumulation of extracellular accumulation of extracellular matrixmatrix. . With timeWith time
matrix accumulation becomes diffuse and is matrix accumulation becomes diffuse and is evident as eosinophilic, periodic acid Schiff (+) evident as eosinophilic, periodic acid Schiff (+) glomerulosclerosis on biopsyglomerulosclerosis on biopsy
Pathologic change ofPathologic change of
Diabetic nephropathyDiabetic nephropathy
Laboratory tests to order Laboratory tests to order at the initial diagnosis of at the initial diagnosis of diabetes diabetes
Type 1 Fasting plasma glucose OR random plasma glucose A1C Fasting lipid profile: total cholesterol, HDL, LDL, triglycerides Serum creatinine in adults; in children if proteinuria is present* Urinalysis: ketones, protein,* sediment Thyroid-stimulating hormone (TSH)
Type 2 Fasting plasma glucose OR random plasma glucose A1C Fasting lipid profile: total cholesterol, HDL, LDL, triglycerides Serum creatinine* Urinalysis: ketones, glucose, protein,* microalbuminuria,* sediment; culture if abnormal microscopic findings or symptoms of infection are present
Type 2Type 2
· Fasting plasma glucose OR random plasma · Fasting plasma glucose OR random plasma glucose glucose
· A1C · A1C · Fasting lipid profile: total cholesterol, HDL, LDL, · Fasting lipid profile: total cholesterol, HDL, LDL,
triglycerides triglycerides · Serum creatinine* · Serum creatinine* · Urinalysis: ketones, glucose, protein,* · Urinalysis: ketones, glucose, protein,*
microalbuminuria,* sediment; culture if abnormal microalbuminuria,* sediment; culture if abnormal microscopic findings or symptoms of infection are microscopic findings or symptoms of infection are present present
Test (specimen or method)
Units Purpose Benefits Limitations
Urinalysis (dipstick)
Varies with component subtest
Screening test for a variety of systemic diseases, renal diseases, and disorders of the urinary tract
Morphometric and biochemical analysis of urine components
Widely available
Measures specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood, leukocyte esterase, nitrite, urobilinogen, WBCs, RBCs, casts, and bacteremia
Assesses presence of crystals
Result may be altered by contaminated reagent strips, reading a strip at the wrong time, exercise
Specimen volume <2 mL may limit the number of subtests that can be performed
Microalbuminuria (24 h urine, timed overnight 10 h urine collection, spot AM urine after initial voiding)
mg/L or mg/24 h
Spot collections:
μg albumin/mg creatinine
Detects small amounts of albumin
Result predicts development of proteinuria (progression of diabetic nephropathy)
Result strongly supports a diagnosis of diabetic nephropathy
Creatinine clearance may be measured from the same urine specimen
Measures lower concentrations of albumin than can be detected by dipstick methods
Usually sent to a reference laboratory
UAE may decline 30-50% at night
Result may be altered by exercise, pregnancy, fever, inflammatory disorders, urinary tract infection, urinary tract bleeding, or benign postural proteinuria
Proteinuria, quantitative (24 h urine)
mg/24 h Follow-up assessment of proteinuria and diabetic nephropathy
Readily available Requires vigilant oversight of specimen collection
Check with laboratory regarding need for refrigeration or preservative
Result may be altered by intrinsic variation in proteinuria, x-ray contrast media,* tolbutamine, antibiotics
Creatinine (serum or plasma)
mg/dL Result can be used to calculate to calculate approximate GFR and should be measured at least annually in all patients with diabetes1,<4
Readily available; most commonly ordered test of renal function
Moderate changes in GFR may not be detected
Should not be used alone as a measure of kidney function, but to estimate GFR and stage the level of chronic kidney disease 4
Result may be altered by meat ingestion, pregnancy, muscular disorders, hyperthyroidism, cephalosporin antibiotics, corticosteroids, cimetidine, other drugs