Diabetic Nephropathy & Chronic Renal Failure

8/10/2019 Diabetic Nephropathy & Chronic Renal Failure

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DIABETIC NEPHROPATHY &

CHRONIC RENAL FAILURE /

CHONIC KIDNEY DISEASE /including chronic gn


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0 2 5 11-23 13-25 15-27

Incipient Nephropathy

Predictors?

Hyperfiltration

MicroalbuminuriaRising BP

Poor glycemic contol

Onset

Of DM

Onset of Rising ESRD

Proteinuria S.Cr

HTN

Functional changesGFR increase (renal hypertrophy)

reversible albuminuria

increase kidney size

Structural changesincrease GBM thickening

Mesangial expansion

nodular (Kimmelstiel-Wilson) & diffuse forms of

intercapillary glomerulosclerosis

capsular drop lesion

fibrin cap lesion

IDDM, 30-40% DN

NIDDM, 10-20% DN


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Progression of nephropathy in type 2 diabetes. Following 10 years of stable renal function and normal UAE rate (300 mg/d),

declining glomerular filtration rate, and increased cardiovascular morbidity. With the onset of macroalbuminuria renal

function progressively declines, and ESRDs

eventually develop, requiring RRT with dialysis or transplantation. Diabetics with overt proteinuria have a higher risk of

dying from cardiovascular disease . The Journal of Clinical Investigation , Volume 116 Number 2 February 2006


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Remission/regression in diabetic and nondiabetic nephropathies. Changes in GFR during 47 years follow-up after

institution of singledrug or multidrug antiproteinuric treatment (based on renin-angiotensin system blockade) in patients

with diabetic nephropathy ,. or nondiabetic nephropathies as well as in a patient with systemic lupus erythematosus

and proteinuric chronic disease . Stabilization of GFR values (remission) was achieved after years of treatment and in

7 patients belonging to the REIN trial even positive GFR changes (regression) were found. DETAIL, Diabetics Exposed

to Telmisartan and Enalapril trial; DM, diabetic mellitus; SLE, systemic lupus erythematosus.The Journal of Clinical Investigation , Volume 116 Number 2 February 2006


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Schematic view of the possible roles of TGF- in diabetic nephropathy.

Reeves W B , Andreoli T E PNAS 2000;97:7667-7669

2000 by National Academy of Sciences


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.

Gnudi L et al. JASN 2007;18:2226-2232

2007 by American Society of Nephrology


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Correlation analysis in study population of urinary type IV collagen (ng/mg creatinine)

with A:C ratios (A: r= 0.12; NS when outlier at A:C ratio of 3,080 is excluded; r= 0.37,

P= 0.10 when outlier is included) and with RSC values (B: r= 0.62; P< 0.001).

Diabetes CareMay 2001 vol. 24 no. 5 914-918
http://care.diabetesjournals.org/content/24/5/914/F1.large.jpg


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Morphologic changes

Glomeruli: increase GBM thickening Mesangial expansion

nodular (Kimmelstiel-Wilson) & diffuse forms of intercapillaryglomerulosclerosis

capsular drop lesion

fibrin cap lesion Tubulointerstitium,& tubular functional defects

Interstitial scarring

Impaired tubular reabsorption of low MW proteins and albumin

Increased Na reabsorption leading to volume expansion

Hypercalciuria Impaired excretion of H & K ions

Vascular, hyaline thickening of the arteriolar wall

Glomerular haemodynamic changes Decreasing Pglom: ACE-I, ARB, low protein diet


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Transient microalbuminuria

Hyperglycemia

Hypertension

Congestive heart failure

Urinary tract infection

Excessive physical exercise

Albumin Excretion Rate / AER

Normal < 30 mg/day

Microalbuminuria 30-300 mg/d

Overt proteinuria AER> 300 mg/d


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Overt Diabetic Nephropathy

In early DN the albuminuria is secondary to a loss of theanionic charge barrier of the GCW

In established DN, the proteinuria is due to the presenceof an increased number of nonselective and large pores

The presence of persistent proteinuria heralds the overtphase of DN

>95% of patients with DN have D Retinopathy

Rate of decline in GFR has been reported as linear in agiven patient, but wide differing between patients

~ 1 ml/min per month, with 50% of patients reachingESRD ~ 7 years after the onset of proteinuria.

Recent reports suggest that is has slowed down ~10years


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Complication of DM

Microvascular

Retinopathy

Nephropathy

Macrovascular Peripheral vascular disease

Coronary artery disease

Cerebrovascular disease Diabetic neuropathy, incl. gastroparesis

Hyperkalemic RTA


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Syndrome X

Obesity

Decreased glucose tolerance, Insulin

resistance & hyperinsulinemia

Hypertension

Hyperlipidemia, esp triglycerides

Increased risk for atheroscerosis


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NIDDM

Patients on HD in a dialysis unit ~ 30-50%

because of NIDDM & diabetic nephropathy

Many patients with NIDDM will die of other

causes (cardiovascular) before reaching ESRD Natural history less well characterized

Heterogeneous group, with many comorbid

conditions, hypertension, obesity 10-20% incidence of DN, mostly after 10-20 y

Familial predisposition


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Management

Control of Diabetes, HbA1c


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CKD

Diabetic Nephropathy Hypertension

Glomerulonephritis

Acute

Rapidly Progressive GN

Chronic GN

Secondary GN ( Infections, Malignancies,

Autoimmune Ds,)

Drugs & Toxins

Hereditary : Alports, PCKD, . Congenital : VU Reflux

Obstructive Nephropathy


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CHRONIC KIDNEY DISEASE

CKD


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usg


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Signs & Symptoms

Edema

High Blood Pressure

Nocturia Frequency & Dysuria

Loin pain unrelated to movements

Hematuria

Proteinuria


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CRF & ESRD

Poor appetite. Nausea & vomiting

Insomnia & Restlessness

Labile mood swings Asthenia

Shortness of breath. Pulmonary edema. Metabolic acidosis

Cardiac arrhythmias. Hyperkalemia Hypertensive urgencies / emergencies

LVH

Anemia Malnutrition

Hyperphosphatemia Hyperparathyroidism


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KIDNEY DIDEASE

Prevalent in identifiable groups

Aging , > 50

DM

Hypertension

Cardiovascular disease, CVD

Family members

Herbal medicine (jamu), Analgetics


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RISK FACTORS(+)--- CHECK URINE & CR -----MCU

NORMAL HEMATURIA/PROTEINURIA

HIGH CR

RENAL US--------CRF/Hydronephrosis

ESTIMATE GFR / 24H U CCT

SPOT U Prot/Cr RATIO / 24H U Prot

IMMUNOLOGY SEROLOGY :C3,C4,ANA,ANCA

ETIOLOGY??? RENAL BIOPSY

DIAGNOSIS & PROGNOSIS

SPECIFIC THERAPY : STEROID, IMMURAN

CYCLOPHOSPHAMIDE, CYCLOSPORIN, MMF/CELLCEPT

STARTNONSPEC IFIC

THERAPYREGULAR

CHECKS

PREVENTIVE

ACTION

, a-dsDNA,

GBM-Ab


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Therapy CKD

Specific Therapy. depends on etiology &histopathology

Decrease proteinuria / albuminuria

Tightly control Blood Pressure < 125 / 75ACE-I, ARB, non-dihydropyridine-CCB,.

Tightly control Blood Sugar

Manage hyperlipidemia Stop smoking

Low protein diet 0.6 0.8 g /kg BW/day


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Manage Anemia and other co morbidities,

Manage Cardiovascular ds,

Complications of decreased kidneyfunction

Preparation for kidney failure and RRT

Initiation of RRT


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Progression of CKD

Mechanisms of ongoing renal injury Deposition IC, Ag, Ab, matrix, collagen, fibroblasts Intracapillary coagulation

Vascular necrosis

Hypertension & increased Pglom

Metabolic disturbances, e.g. DM, hyperlipidemia Continuous inflammation

Nephrocalcinosis ; dystrophic & metastatic

Loss of renal mass / nephrons

Ischemia; imbalance between renal energy demands and supply

Results in Glomerulosclerosis

Tubular atrophy

Interstitial fibrosis


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C t l h i


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Compensatory renal changes in

CKD

Hypertrophy of residual nephrons

Increased RBF per nephron, but

decreased total RBF

Increased Single Nephron GFR / SNGFR

Increased osmotic / solute load

Hyperfiltration

Increased intraglomerular pressure / Pglom


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## NEPHRONS

Pcap +flow

Glomerular Protein Glomerular

injury flux hyperfiltration

Glomerulosclerosis

## NEPHRONS


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Pattern of excretory adaptation

Increased filtered load; Cr, BUN Decreased tubular reabsorption; Na, H2O

Increased tubular secretion; K+, H+, Cr

Limitation of nephron adaptation

Magnitude

Time, ~response to intake / load, production Abrupt changes in intake / production may not be

tolerated

Trade off, expense to other systems E.g. to preserve P balancePTH increases


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VolumeUrine,

Uosm,

U(Na,K,H)
http://jasn.asnjournals.org/content/vol17/issue1/images/large/asn0010605660002.jpeg


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Multiple mechanisms of chronichypoxia in the kidney.

Mechanisms of hypoxia in the kidney of chronic kidneydisease include loss of peritubular capillaries (A),

Decreased oxygen diffusion from peritubular capillariesto tubular and interstitial cells as a result of fibrosis of thekidney (B),

Stagnation of peritubular capillary blood flow induced bysclerosis of "parent" glomeruli (C),

Decreased peritubular capillary blood flow as a result ofimbalance of vasoactive substances (D),

Inappropriate energy usage as a result of uncoupling ofmitochondrial respiration induced by oxidative stress (E),

Increased metabolic demands of tubular cells (F), and

Decreased oxygen delivery as a result of anemia (G).


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Treatment modalities that target chronichypoxia in the kidney

Improvement of anemia by EPO

Preservation of peritubular capillary blood flow byblockade of the renin-angiotensin system

Protection of the vascular endothelium

VEGF Dextran sulfate

Antioxidants to improve the efficiency of cellularrespiration

HIF-based therapy (hypoxia inducible factor) Prolyl hydroxylase inhibitors

Gene transfer of constitutively active HIF


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The Uremic Syndrome Nervous system

Impaired concentration, perceptual thinking, Peripheral neuropathy; primarily sensory, paresthesias, restless leg syndrome

Autonomic neuropathy; impaired baroreceptor function, orthostatic hypotension, impairedsweating

Uremic ancephalopathy

Hematology system Anemia is invariably present when renal function fall


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Cardiovascular system Cardiovascular disease is the leading cause of death in patients

with CKD stage 4-5 Accelerated Atherosclerosis / CAD

Hypertension, ~ 80% of all uremic patients

Pericarditis

Metabolic abnormalities Lipids; increase in tot. triglycerides, Lp(a), LDL, decrease HDL

Carbohydrate metabolism; insulin resistance, decreased needfor OAD / insulin in DM

High prolactin; galactorrhea

Men : testosteron is low, FSH / LH normal or high

Women: pg E2 & progesterone are low, FSH /LH normal orslightly elevated

Abnormalities of thyroid gland function test, normal TSH


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CKD stage 5 (ESRD / GGT)

DIALYSIS / Renal Replacement Therapy

Hemodialysis

Peritoneal Dialysis

Continues Renal Replacement Therapies

Kidney Transplant

Cadaver

Living related / unrelated

Documents

Diabetic Nephropathy & Chronic Renal Failure