diabetic nephropathy. outline introduction of diabetic nephropathy manifestations of diabetic...

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


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 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 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 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 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 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


““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


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

diabetic nephropathy. outline introduction of diabetic nephropathy manifestations of diabetic...

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