CHRONIC KIDNEY DISEASE

1. Differentiate acute renal failure from chronic renal failure.

Acute kidney injury (AKI) is defined by the impairment of kidney filtration and
excretory function over days to weeks, resulting in the retention of nitrogenous and
other waste products normally cleared by the kidneys. AKI is not a single disease but,
rather, a designation for a heterogeneous group of conditions that share common
diagnostic features: specifically, an increase in serum creatinine (SCr) concentration
often associated with a reduction in urine volume. The causes of AKI have traditionally
been divided into three broad categories: prerenal azotemia, intrinsic renal parenchymal
disease, and postrenal obstruction.

Chronic kidney disease (CKD) encompasses a spectrum of pathophysiologic

processes associated with abnormal kidney function and a progressive decline in
glomerular filtration rate (GFR). The risk of CKD progression is closely linked to both
the GFR and the amount of albuminuria. The dispiriting term end-stage renal disease
represents a stage of CKD where the accumulation of toxins, fluid, and electrolytes
normally excreted by the kidneys leads to death unless the toxins are removed by renal
replacement therapy, using dialysis or kidney transplantation. The pathophysiology of
CKD involves two broad sets of mechanisms of damage: (1) initiating mechanisms
specific to the underlying etiology (e.g., abnormalities in kidney development or
integrity, immune complex deposition and inflammation in certain types of
glomerulonephritis, or toxin exposure in certain diseases of the renal tubules and
interstitium) and (2) hyperfiltration and hypertrophy of the remaining viable nephrons,
that are a common consequence following long-term reduction of renal mass,
irrespective of underlying etiology and lead to further decline in kidney function.

2. Short term effect of renal injury versus long term effect of renal injury.
➢ Short term: “Adaptive hyperfiltration”
○ Increase glomerular capillary pressure and flow
➢ Long term: “Maladaptive response”
○ Sclerosis

● The responses to reduction in nephron number are mediated by vasoactive

hormones, cytokines, and growth factors.
● Eventually, these short-term adaptations of hyperfiltration and hypertrophy to maintain
GFR become maladaptive as the increased pressure and flow within the nephron
predisposes to distortion of glomerular architecture, abnormal podocyte function, and
disruption of the filtration barrier leading to sclerosis and dropout of the remaining
nephrons.
 ● Increased intrarenal activity of the RAAS appears to contribute both to the initial
compensatory hyperfiltration and to the subsequent maladaptive hypertrophy and
sclerosis.
● This is why a reduction in renal mass from an isolated insult may lead to a
progressive decline in renal function over many years

3. Criteria for the diagnosis of chronic renal disease.

a. How to evaluate?

STEP 1: Evaluate if your Patient has CKD

● Evaluate Chronicity
○If GFR is <60 mL/min/1.73 m2 or with markers of kidney
damage, review PMH and previous measurements to determine
duration
■ If >3 months, CKD is confirmed
■ If not >3 months or unclear, CKD is not confirmed
(may have CKD, AKI or both; repeat test
accordingly)

STEP 2: Determine the Cause of CKD

● Evaluate the clinical context, including personal and family history,

social and environmental factors, medications, PE, lab measures,
imaging and pathologic diagnosis to determine the causes of kidney
disease

STEP 3: Determine the GFR

● Evaluation of GFR
○ Use serum creatinine and a GFR estimating equation for
initial assessment
○ Clinicians should:
■Use GFR estimating equation to derive GFR from
serum creatinine rather than relying on serum
creatinine alone
■ Understand the clinical settings where eGFR is less
accurate
○ Do actual clearance measurement (radionuclide GFR
scan)

STEP 4: Measure albinuminuria

● Dipstick testing
● 24-hour measurement
● Spot urine sampling

b. Causes of Chronic kidney disease?

● Diabetic nephropathy
● Glomerulonephritis
 ● Hypertension-associated CKD (including vascular and ischemic kidney
disease and primary glomerular disease with associated hypertension)
● Autosomal dominant polycystic kidney disease
● Other cystic and tubulointerstitial nephropathy

c. What are the methods to determine GFR?

1. Equation from the Modification of Diet in Renal Disease Study
Estimated GFR (mL/min per 1.73 m2) = 1.86 × (SCr )−1.154 × (age)−0.203
Multiply by 0.742 for women
Multiply by 1.21 for African ancestry

2. CKD-EPI Equation
GFR = 141 × min(SCr /κ, 1)a × max(SCr /κ, 1)–1.209 × 0.993Age
Multiply by 1.018 for women
Multiply by 1.159 for African ancestry where SCr is serum creatinine in
mg/dL, κ is 0.7 for females and 0.9 for males, a is –0.329 for females and –
0.411 for males, min indicates the minimum of SCr /κ or 1, and max indicates
the maximum of SCr /κ or 1.

d. How to measure albuminuria?

a. Dipstick Testing
● most commonly used
● Highly specific (97-100%)
● Not sensitive (32-46%)
● False negatives:
○ Diluted urine
○ Mild protein loss
● Useful only when urine protein exceeds 300-500 mg/day (or
albumin >10-20 mg/day)
● It is essential to know how much protein is excreted to predict
long-term prognosis.

b. 24-hour measurement
● gold standard; difficult to collect
● simultaneous urine creatinine
○ to assess completeness of collection
● Men: 19-26 mg/kg/day
● Women: 14-21 mg/kg/day

c. Spot Urine Sampling

● Protein-Creatinine Ratio: good correlation with 24-hour values
(r2=0.97)
○ ≤ 0.2 normal
○ ≥ 3.5 nephrotic range
 ● Albumin-Creatinine Ratio: Correlates well with 24-hour albumin
excretion
○ <30 mg/gm = normal
○ 30-300 mg/gm = microalbuminuria
○ >300 mg/gm = overt nephropathy

4. What is the effect of electrolytes, sodium and potassium on chronic renal losses?

Sodium and Water Homeostasis

● Total body Na+ and H2O increased
● Due to disruption of glomerulotubular balance
● ECFV expansion → HTN → accelerated nephron injury
○ Salt/water restriction
○ Loop diuretic +/- Metolazone: may be helpful in loop
diuretics resistance as well as use of higher doses loop
○ Dialysis: indicated in patients with intractable edema and
hypertension in advanced CKD
● Impaired renal conservation of Na+ & H2O
○ Filtered Na+ inadequately reclaimed → ECFV depletion →
Acute-on-Chronic renal failure
■ When an extrarenal cause for fluid loss is present,
these patients may be prone to ECFV depletion
because of the inability of the failing kidney to
reclaim filtered sodium adequately. Furthermore,
depletion of ECFV can further compromise kidney
function through underperfusion, or a “prerenal”
state, leading to acute-on-chronic kidney failure.
○ Cautious fluid repletion with normal saline
■ as well as holding or adjusting the diuretic dose may
return the ECFV to normal and restore renal
function to baseline.

Potassium Homeostasis
● Defense against hyperkalemia
○ Increase urinary K+ secretion – aldosterone dependent
○ Augmented K+ secretion in GI tract
● Precipitants of hyperkalemia
○ Increase intake, protein catabolism, hemolysis, hemorrhage
○ Metabolic acidosis, Blood transfusion of stored RBC
○ Drugs (ACEi, ARB, spironolactone)
● Hypokalemia in CKD
○ Very low K+ intake o Diuretic therapy
○ GI losses
○ Renal K+ wasting
 ○ Fanconi’s syndrome
○ Renal tubular acidosis (RTA)
○ Tubulointerstitial disease
○
5. Treatment and effect of metabolic acidosis.

Metabolic Acidosis
● ↓ ammonia production → ↓ protein excretion → Non-Anion-gap Acidosis
● With worsening renal function, the total urinary net daily acid excretion is usually
limited to 30–40 mmol, and the anions of retained organic acids can lead to Anion-
gap metabolic acidosis.
● Net effect: Net protein catabolism → malnutrition
● Start alkali supplementation when HCO3 falls <20-23 mmol/L
○Consider need for diuretic

6. Differentiate high bone turnover versus low bone turnover on chronic kidney disease.
➢ High bone turnover
○ With increased PTH levels
○ Osteitis fibrosa cystica-classic lesion of secondary HPT
○ Clinical manifestations:
■ Bone pain and fragility
■ Brown tumors
■ Compression syndromes
■ Erythropoietin resistance
■ Muscle weakness
■ Fibrosis of cardiac muscles
■ Constitutional symptoms
➢ Low bone turnover
○ with low or normal PTH levels
○ Adynamic bone disease
■ characterized by reduced bone volume & mineralization
■ may result from excessive suppression of PTH production, inflammation,
or both
■ Complications: ↑ incidence of fracture & bone pain and an association
with ↑ vascular & cardiac calcification

7. What are the complications of chronic kidney disease and its treatment?
a. Cardiovascular
Ischemic Vascular Disease
● Coronary, cerebrovascular and peripheral vascular
● Traditional “classic” risk factors:
○ HTN, hypervolemia, dyslipidemia, sympathetic overactivity,
hyperhomocysteinemia
● Non-traditional “CKD-related” risk factors:
 ○ Anemia, hyperphosphatemia, hyperparathyroidism, sleep apnea,
generalized inflammation
● Reduced Renal Function → “Inflammatory State” → Accelerated
vascular occlusive disease and rapid vascular calcification (with low
fetuin level) → “Attenuated Coronary Reserve”
○ Inflammatory State: High CRP, Low Albumin, Low fetuin
○ Attenuated Coronary Reserve: Low NO, Reactive O2 species,
Dialysis hypotension and hypovolemia

Heart Failure
● Causes of HF or even pulmonary edema:
○ myocardial ischemia
○ left ventricular hypertrophy o cardiomyopathy
○ salt and water retention
● Can be diastolic, systolic dysfunction, or both
● “low pressure” pulmonary edema
○ shortness of breath
○ CXR: “bat wing” distribution of alveolar edema fluid
○ absence of ECFV overload
○ normal pulmonary capillary wedge pressure (PCWP)
○ ↑ permeability of alveolar capillary membranes due to uremia

➔ Treatment: responds to dialysis

b. Hypertension
Hypertension and Left Ventricular Hypertrophy
● one of the most common complications of CKD
● usually develops early during the course of CKD and is associated
with adverse outcomes including LVH and a more rapid loss of renal
function
● Causes of absence of hypertension in CKD:
○ Salt-wasting nephropathy
○ Effect of antihypertensivesVolume depletion
○ Poor LV function
● “reverse causation” – low BP has worse prognosis than high BP

➔ Treatment
● Overall goals:
○ Slow progression of renal disease
○ Prevent extrarenal complications of HTN (CVD, stroke
● Targets:
○ 130/80 mmHg
○ CKD with DM or proteinuria >1 gm/d – 125/75 mmHg
● Agents:
 ○ Salt restriction & diuretics – first choice
○ ACEi, ARB - Slow rate of decline
○ Kaliuretic agents – to prevent hyperkalemia

c. Anemia
● A normocytic, normochromic anemia is observed as early as stage 3
CKD and is almost universal by stage 4.

● Adverse Pathophysiologic Consequences:

○ Decreased tissue O2 delivery & utilization
○ Increased Cardiac Output
○ Ventricular dilatation and hypertrophy

● Clinical Manifestations:
○ Fatigue, diminished exercise tolerance
○ Angina, Heart failure
○ Decreased cognition and mental acuity
○ Impaired defense against infection

➔ Treatment
● Recombinant EPO (Darbopoietin)
○ lessened the need for regular transfusions in severely anemic
CKD patients, thus dramatically reducing the incidence of
transfusion associated infections and iron overload as well as
prevents the development of alloantibodies that can sensitize the
patient to donor kidney antigens which makes renal transplant more
problematic.
● Iron supplements
● Folate and Vitamin B12
● Recommended Target Hgb concentration: 110-120 g/L

d. Neuromuscular

● Well recognized complications of CKD

○ CNS, peripheral, and autonomic neuropathy
○ abnormalities in muscle structure and function
● Subtle clinical manifestations of uremic neuromuscular disease
usually become evident at stage 3 CKD.
● Clinical Manifestations
○ Early stage: mild disturbances in memory and concentration,
sleep disturbances
○ Later stages: Neuromuscular irritability (hiccups, cramps, twitch)
○ Advanced untreated Kidney Failure: Asterixis, myoclonus,
seizures, coma
 ● Peripheral Neuropathy
○ usually becomes clinically evident at stage 4 CKD o sensory
nerves involved more than motor
○ lower extremities more than upper
○ distal parts of extremities more than proximal
● Restless Leg Syndrome
○ characterized by ill-defined sensations of sometimes debilitating
discomfort in the legs and feet relieved by frequent leg movement
● Evidence of peripheral neuropathy without another cause (diabetes
mellitus) is an indication for starting RRT.

➔ Treatment:
● Many of the complications described above will resolve with dialysis,
although subtle nonspecific abnormalities may persist.

e. Endocrinology( especially on blood sugar)

Impaired glucose metabolism

● Slow rate of blood glucose decline after a glucose load
● FBS usually normal or only slightly elevated
● Mild glucose intolerance does not require treatment

Elevated plasma insulin level

● Diminished renal degradation of insulin
● Reduction in insulin dose with worsening renal function
● Hypoglycemia
● Many anti-hyperglycemic agents, including the gliptins, require dose
reduction in renal failure; metformin and sulfonylureas are
contraindicated when the GFR is less than half of normal.
Treatment: anti-hyperglycemic with dose reduction

f. Hormonal
Women with CKD
● Low estrogen level
● Menstrual abnormalities
● Infertility and Inability to carry pregnancy to term
● when GFR 40 mL/min – high rate of spontaneous abortion; with
only 20% leading to live births
● Pregnancy may hasten progression of CKD

Treatment: Hormonal replacement therapy and estrogen therapy- receptor

modulating therapy
Men with CKD
● Low testosterone
 ● Sexual dysfunction
● Oligospermia
● Delayed sexual maturation in adolescents

Treatment: Dopamine agonist for increased prolactin, erythropoietin, clomiphene

citrate, zinc in deficient state, androgens

8. Treatment of chronic kidney disease.

● Optimized glucose control in diabetes mellitus
● Immunomodulatory agent for glomerulonephritis
● Reducing Intraglomerular Hypertension and Proteinuria
➔ Control of systemic and glomerular hypertension is important in slowing
the progression of CKD. 125/ 75 mm Hg as the target blood pressure in
proteinuric CKD patients.
➔ ACE inhibitors and ARBS inhibit the angiotensin- induced
vasoconstriction of the efferent arterioles of the glomerular
microcirculation.
● Control of Blood Glucose
➔ 5.0-7.2 mmol/liter (90-130 mg/dl)
➔ Hemoglobin A1c <7 %
● Protein Restriction 0.60 and 0.75 g/kg per day
● Medication dose adjustment
➔ Avoid metformin, meperidine and oral hypoglycemic agent eliminated by
the kidney, NSAID
● Preparation for Renal Replacement Therapy
● Kidney Transplantation