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org/ckd/#Treatment
Sultan Chaudhry
Chronic kidney disease (CKD)
Def inition
N Engl J Med. 2004 Sep 23;351(13):1296-305.
Lancet. 2012 Jan 14;379(9811):165-80.
Progressive loss of renal f unction over time; based on a gradual decline in the GFR and creatinine
clearance. The diagnosis of CKD requires the f ollowing:
1. Decline of kidney f unction f or 3 months or more AND
2. Evidence of kidney damage (e.g. albuminuria or abnormal biopsy) OR
GFR <60 mL/min/1.73 m
2
Each patient is classif ied into one of the f ollowing 5 stages of CKD because management and prognosis
varies according to the progression of damage.
Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m
2
)
Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m
2
)
Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m
2
)
Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m
2
)
Stage 5: Kidney failure (GFR <15 mL/min/1.73 m
2
or dialysis)
Etiology and pathogenesis
Annu Rev Pathol. 2011 Feb 28;6:395-423
Semin Nephrol. 2007 Mar;27(2):130-43
Semin Nephrol. 2002 Jan;22(1):17-26
Semin Nephrol. 2007 May;27(3):321-37
J Am Soc Nephrol. 2008 Apr;19(4):651-3
J Am Soc Nephrol. 2003 Jul;14(7 Suppl 2):S186-91.
Many causes of CKD exist, however, this chapter will f ocus on the most prevalent causes including
hypertension, diabetes, glomerulonephritis and urinary tract obstructions.
Hypert ension
Glomerular and vascular changes:
Elevated systemic blood pressures cause a hypertrophic response leading to intimal thickening
of the large and the small vasculature.
The mechanisms are compensatory at f irst, but later lead to glomerular damage
Global sclerosis ischemic injury to the nephrons causes death
Focal segmental sclerosis glomerular enlargement f or compensation of the loss of
nephrons in other areas of the kidney.
Interstitial nephritis:
The vascular and glomerular disease lead to tubular atrophy and an intense chronic interstitial
nephritis
The intense chronic interstitial nephritis is thought be secondary to immunologic
processes against ischemia-mediated antigen changes on the tubular epithelial cell
surf ace.
Chronically these changes lead to tubular and glomerular loss causing nephrons loss.
With the death of some nephrons, less are available to maintain the GFR.
Gradual decline in the GFR is noticed as the nephrons continue to die.
Diabet es diabet ic nephropat hy
Majority of the literature in the area is applied to the diabetic nephropathy patients based on data
hypothesized f rom the f indings in animal models.
Chronic hyperglycemiais thought to be the primary cause of diabetic nephropathy.
Unlike other tissues of the body, transmembrane glucose transporters (GLUT) receptors do
not f acilitate intracellular glucose transport in the kidneys.
This ef f ect is mediated via a number of mechanisms including (i) glomerular hyperf iltration, (ii)
direct ef f ects of hyperglycemia, and (iii) advanced glycosylation end products (AGE), and (iv)
cytokine secretion.
Glomerular hyperfiltration:
Glomerular hyperf iltration is mediated mainly via dilatation the af f erent arteriole leading to a
rise in the GFR and the renal blood f low.
This dilatation of the af f erent arteriole is mediated by a number of mechanisms in diabetic
nephropathy:
Hyperglycemia and high insulin-like growth f actor-1 (IGF-1) concentrations (observed in
diabetic patients) both are hypothesized to cause a rise in the GFR increasing renal
f low
Hyperf iltration of glucose leads to augmented sodium-glucose transport in the proximal
convoluted tubule causing enhanced sodium transport
Cause expansion of blood volume which leads to a rise in GFR
The rise in proximal reabsorption also leads to a reduced distal f luid delivery
which activates the tubuloglomerular f eedback with the renin-angiotensin system
which works to raise the GFR as well.
Hyperglycemia and AGE:
Hyperglycemia and AGE directly induce mesangial matrix production, cellular expansion and
apoptosis.
The two have also been shown to increase basement membrane permeability to albumin.
Cytokines:
Elevations in vascular endothelial growth f actor (VEGF), transf orming growth f actor beta
(TFG-), and prof ibrotic proteins increase damage to the nephrons at dif f erent levels; specif ic
mechanisms are unclear.

Glomerulonephrit is
Glomerular injury takes place via inf lammatory as well as non-inf lammatory mechanisms in dif f erent
types of glomerulonephritides.
Non-inflammatory injury:
Common examples of this include the podocytopathies; minimal change nephrotic
syndrome/focal segmental glomerulosclerosis (MCNS/FSGS) and membranous
nephropathy(MN)
A dramatic rise in the glomerular permeability without any evidence of inf lammation on
light microscopy.
Several cytokines such as IL-13 and members of the complement system C3, C5b-9 lead
to glomerular basement membrane thickening, as well as podocyte damage, apoptosis,
detachment and excretion in the urine. This induces glomerular sclerosis.
Inflammatory injury:
Common examples include post-streptococcal glomerulonephritis (GN),
membranoproliferative GN, Henoch-Schnlein purpura (HSP), systemic lupus
erythematosus (SLE), some f orms of rapidly progressive glomerulonephritis (RPGN), IgA
nephropathy, hemolytic uremic syndrome (HUS) and various vasculitides.
This inf lammatory injury has been f ound to be mediated by a number of mechanisms:
Some members of the complement system such as C5a have been implicated in
inf lammatory injury via inducing antibody deposition and activation and recruitment of
polymorphonuclear cells (PMNs); neutrophil, macrophage/monocyte, platelets and T-
cells.
These cells produce oxidants and proteases that cause f ibrin deposition, capillary wall
damage and produce proteinuria.
Unlike podocyte targeting in non-inf lammatory injury, disorders in which glomerular
endothelial and mesangial cells are principally involved exhibit a more dramatic response
to immune injury. This response is usually characterized by cell prolif eration and
phenotype change, as well as readily visible structural changes in the renal biopsy.
Post-Renal CKD: See Urology.
Pathophysiology
Nephrol Dial Transplant. 2002 May;17(5):723-31
Semin Neurol. 2011 Apr;31(2):139-43
Lancet. 2012 Jan 14;379(9811):165-80
Patients with stages 1-3 ([GFR] >30 mL/min) of CKD are generally asymptomatic; water/electrolyte
imbalances or endocrine/metabolic derangements are not clinically evident.
These disturbances manif est clinically in CKD stages 4-5 (GFR < 30 mL/min).
Sign/lab finding Symptoms Mechanism
Generalized edema Swelling Water retention due to a loss of GFR leading to sodium and f luid
retention. Fluid moves into the extravascular space, due to
increased hydrostatic pressure, causing pitting edema in the lower
extremity (f luid movement could also be due to hypoalbuminemia, in
some diseases, leading to a low oncotic pressure).
Pulmonary crackles Shortness
of breath
Fluid accumulation causes pulmonary edema and loss of air space
causing ventilation-perf usion mismatch. This leaves less area f or
oxygen dif f usion f orm the blood vessels.
Anemia Fatigue,
reduced
exercise
capacity,
and pallor
Erythropoietin (EPO), the major erythropoiesis stimulator, is
released f rom the kidneys; with renal f ailure, there is loss of EPO
release.
Weight loss Loss of
lean body
mass
Protein-energy malnutrition due to metabolic acidosis. Loss of
kidney f unction results in impaired H+ secretion f rom the body.
Hyperkalemia Malaise,
palpitations
Inability of the kidneys to secrete potassium in the urine leads to lif e
threatening arrhythmias.
Mechanisms of renal osteodystrophy
Hyperphosphatemia Damaged kidneys f ail to excrete phosphate.
Also secondary to high parathyroid hormone levels.
Hypocalcemia Thought to be secondary to low Vitamin D3 levels. In early stages of
CKD, low levels of calcitriol are due to hyperphosphatemia (negative
f eedback). In the later stages of CKD, low levels are hypothesized
to be due to decreased synthesis of 1-hydroxylase (enzyme that
converts calcif ediol to calcitriol in the kidneys).
Secondary and
tertiary
hyperparathyroidism
To compensate f or the low calcium due to low Vitamin D levels, the
parathyroid glands increase the parathyroid hormone secretion.
This leads to a high bone turnover, always attempting to normalize
the low calcium levels in the blood. Over time, this becomes
maladaptive leading to extraosseous calcif ication, and parathyroid
hyperplasia develops (tertiary hyperparathyroidism).
Complications of uremia
Urea and other toxins accumulate in the blood and cause lif e threatening issues.
Ecchymosis, GI
bleeding
Increased
tendency to
bleed and
ecchymosis
Uremia-induced platelet dysf unction
Pericardial f riction
rub
Chest pain,
malaise
Uremic pericarditis
Headaches,
conf usion,
coma
Uremic encephalopathy; adverse ef f ects of urea on the CNS.
Mechanisms unclear.
Treatment
Circulation. 2007 Jul 3;116(1):85-97.
Nat Rev Nephrol. 2011 Mar;7(3):128-3
Nephrol Dial Transplant. 2002 May;17(5):723-31
Lancet. 2012 Jan 14;379(9811):165-80.
Cardiovascular disease (CVD)is the leading cause of death in patients with CKD.
Reducing risk f actors f or development of CVD is benef icial.
E.g. treatment of hyperlipidemia, lif estyle and dietary changes
Tight blood pressure control:
Reducing damage due to the end organ ef f ects of hypertension on the kidney as well as the
heart.
Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor
blockers(ARBs) block the ef f ects of angiotensin II on (i) sodium and f luid retention, (ii)
vasoconstriction, (iii) stimulating ADH release, (iv) stimulating aldosterone release, and (v)
inducing a sympathetic response.
ACEIs and ARBs also slow down progression of proteinuria in patients with diabetic
CKD.
Diabetes management:
Tight glucose management slows the progression of vascular and heart disease.
Avoidance of IV contrast, NSAIDs, and nephrotoxic drugs:
These agents can potentially induce an acute kidney injury (AKI) on the underlying kidney
disease and theref ore exacerbate the baseline CKD.
Diet:
Mixed evidence exists whether dietary protein restriction is benef icial in slowing disease
progression.
Proteins af f ect the renal hemodynamics, raising the GFR, in hypothesized 2 ways.
Hormonal effects proteins cause secretion of glucagon, IGF-1 and kinins, all of which
have been shown to raise the GFR.
Tubuloglomerular effects high amino acid (AA) f iltration leads to increased AA and
hence the sodium uptake in the proximal convoluted tubule. A decreased sodium delivery
to the distal convoluted tubule leads to the rennin-angiotensin system activation via the
macula densa and these work to raise the GFR (mechanisms above)
Controlling hyperphosphatemia: Protein restriction also limits phosphorus consumption.
Hyperphosphatemia plays a major role in the progression of renal osteodystrophy. Phosphate
binders are used to reduce phosphate absorption through the GI tract.