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
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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)
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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