CKD

KIDNEY DIDEASE
Prevalent in identifiable groups
Aging , > 50 DM Hypertension Cardiovascular disease, CVD Family members Herbal medicine (jamu), Analgetics

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

Figure 69.5A Antihypertensive regimens in chronic kidney disease (CKD). a, Algorithm 1: Initial antihypertensive therapy. *Assumes nonpharmacologic therapy to control blood pressure (BP) is in place (see text) and that the patient does not have renovascular hypertension, congestive heart failure, ischemic heart disease, or hypertensive urgency. This approach focuses on BP control in proteinuric nephropathies, but is also appropriate for hypertensive nephrosclerosis, polycystic kidney disease, and interstitial nephropathies. The suggestion to add a diuretic before an angiotensin receptor blocker (ARB) is arbitrary but can be justified by the evidence that a diuretic increases the antihypertensive effect of an angiotensin-converting enzyme (ACE) inhibitor, is often needed in chronic kidney disease to control fluid retention, is inexpensive, and may increase the renoprotective effects of the ACE inhibitor, ARB, or the combination. Emphasize salt restriction in autosomal dominant polycystic kidney disease rather than diuretic therapy, which may promote cyst growth. Details of diuretic therapy were discussed previously.

Figure 69.5B Antihypertensive regimens in chronic kidney disease (CKD).. b, Algorithm 2: Recommended therapy if algorithm 1 fails to control BP. *Diltiazem and verapamil sustained-release preparations are recommended. Clonidine recommended for individuals receiving insulin because it does not greatly affect glucoregulation and for those who have difficulty with a -blocker (e.g., bronchospasm, cardiac conduction). The -blocker/clonidine combination is usually well tolerated, but may cause bradycardia.

Therapy CKD
Specific Therapy. depends on etiology & histopathology Decrease proteinuria / albuminuria Tightly control Blood Pressure < 125 / 75 ACE-I, ARB, non-dihydropyridine-CCB,. Tightly control Blood Sugar Manage hyperlipidemia Stop smoking Low protein diet 0.6 0.8 g /kg BW/day

 Manage Anemia and other co morbidities, Manage Cardiovascular ds, Complications of decreased kidney function Preparation for kidney failure and RRT Initiation of RRT

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

## NEPHRONS

Pcap +flow

Glomerular injury

Protein flux

Glomerular hyperfiltration

Glomerulosclerosis ## NEPHRONS

 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 balance PTH increases

Volume Urine, Uosm, U(Na,K,H)

 Multiple mechanisms of chronic hypoxia in the kidney.

Mechanisms of hypoxia in the kidney of chronic kidney disease include loss of peritubular capillaries (A), Decreased oxygen diffusion from peritubular capillaries to tubular and interstitial cells as a result of fibrosis of the kidney (B), Stagnation of peritubular capillary blood flow induced by sclerosis of "parent" glomeruli (C), Decreased peritubular capillary blood flow as a result of imbalance of vasoactive substances (D), Inappropriate energy usage as a result of uncoupling of mitochondrial respiration induced by oxidative stress (E), Increased metabolic demands of tubular cells (F), and Decreased oxygen delivery as a result of anemia (G).

 Treatment modalities that target chronic hypoxia in the kidney

Improvement of anemia by EPO Preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system Protection of the vascular endothelium
VEGF Dextran sulfate

Antioxidants to improve the efficiency of cellular respiration HIF-based therapy (hypoxia inducible factor)
Prolyl hydroxylase inhibitors Gene transfer of constitutively active HIF

Intact nephron hypothesis

Using experimental animals; urine from each kidney was collected seperately

Before K1 K2 GFR NH3 excr NH3 excr/100mlGFR 50 49 100 50 51 100

After K1 55 66 120 K2 14 25 121

End K2 24 40 167 K1 removed

K2 was partially removed

Conclusion -Normal renal tissue undergoes hypertrophy to compensate for loss of functioning nephrons -Normal tubules adapt, increase in function as other tubules are lost -Diseased nephrons / tubules adapt in the same way ~ increase NH3 excr / 100mlGFR -Even diseased nephrons can increase their GFR

The Uremic Syndrome

Nervous system
Impaired concentration, perceptual thinking, Peripheral neuropathy; primarily sensory, paresthesias, restless leg syndrome Autonomic neuropathy; impaired baroreceptor function, orthostatic hypotension, impaired sweating Uremic encephalopathy Anemia is invariably present when renal function fall <30%
Decreased RBC survival, response to EPO, Deficiencies of Fe, B12, folate, aluminium overload Blood loss Hyper PTH Inflammation malnutrition Bone marrow fibrosis Inadequate dialysis Prolonged BT & abnormal platelet function PF3 concentration are generally low, impaired aggregability Reduced von Willebrands factor HMW multimers Uremic toxins & PTH Impaired Ab response to viral Ag (not to bacterial) Decreased T-cells Cutaneous anergy

Hematology system

Bleeding diathesis: easy bruising, slow clotting

Immune function

 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 need for 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 or slightly elevated Abnormalities of thyroid gland function test, normal TSH

Figure 72.2 Relationship between hemoglobin (Hb) and estimated glomerular filtration rate (GFR). Data are from a cross-sectional survey of individuals randomly selected from the general U.S. population (NHANES III). Results and 95% confidence interval are shown for males (a) and females (b) at each estimated GFR interval.

Clinical manifestation: musculoskeletal symptoms pruritus metastatic calcification, vascular calcification & calcifilaxis

Peripheral neuropathy e.g..: sensory loss, paresthesias, motor function loss Autonomic neuropathy e.g. : orthostatic hypotension, arrhytmia, gastroparesis Sleep disorders. Restless legs Syndrome