chronic renal failure

1. CHRONIC RENAL FAILURE(CRF)
Chronic renal failure is a syndrome characterised by progressive and
irreversible deterioration of renal function due to slow destruction of renal
parenchyma, eventually terminating in death when sufficient number of nephrons
have been damaged. Acidosis is the major problem in CRF with development of
biochemical azotaemia and clinical uraemia syndrome.
CKD is categorized by the level of kidney function, based on glomerular filtration
rate (GFR), into stages 1 to 5, with each increasing number indicating a more
advanced stage of the disease, as defined by a declining GFR. This classification
system from the National Kidney Foundation’s Kidney Dialysis Outcomes and
Quality Initiative (K/DOQI) also accounts for structural evidence of kidney
damage. CKD stage 5, previously referred to as end-stage renal disease (ESRD),
occurs when the GFR falls below 15 mL/min per 1.73 m2 body surface area. The
patient with stage 5 CKD requiring chronic dialysis or renal transplantation for
relief of uremic symptoms is said to have ESRD.
ETIOPATHOGENESIS:
All chronic nephropathies can lead to CRF. The diseases leading to CRF can
generally be classified into two major groups: those causing glomerular pathology,
and those causing tubulointerstitial pathology.Though this classification is useful
to facilitate study, the disease rarely remains confined to either glomeruli or
tubulointerstitial tissue alone. In the final stage of CRF, all parts of the nephron are
involved.
1. Diseases causing glomerular pathology. A number of glomerular diseases
associated with CRF have their pathogenesis in immune mechanisms . Glomerular
destruction results in changes in filtration process and leads to development of the
nephrotic syndrome characterised by proteinuria, hypoalbuminaemia and oedema.
The important examples of chronic glomerular diseases causing CRF are covered
under two headings: primary and systemic.
i) Primary glomerular pathology: The major cause of CRF is chronic
glomerulonephritis, usually initiated by various types of glomerulonephritis such

2. as membranous glomerulonephritis, membranoproliferative glomerulonephritis,
lipoid nephrosis (minimal change disease) and anti-glomerular basement
membrane nephritis.
ii) Systemic glomerular pathology: Certain conditions originate outside the renal
system but induce changes in the nephrons secondarily. Major examples of this
type are systemic lupus erythematosus, serum sickness nephritis and diabetic
nephropathy.
2. Diseases causing tubulointerstitial pathology. Damage to tubulointerstitial
tissues results in alterations in reabsorption and secretion of important constituents
leading to excretion of large volumes of dilute urine. Tubulointerstitial diseases
can be categorised according to initiating etiology into 4 groups: vascular,
infectious, toxic and obstructive.
i) Vascular causes: Long-standing primary or essential hypertension produces
characteristic changes in renal arteries and arterioles referred to as nephrosclerosis .
Nephrosclerosis causes progressive renal vascular occlusion terminating in
ischaemia and necrosis of renal tissue.
ii) Infectious causes: A good example of chronic renal infection causing CRF is
chronic pyelonephritis. The chronicity of process results in progressive damage to
increasing number of nephrons leading to CRF.
iii) Toxic causes: Some toxic substances induce slow tubular injury, eventually
culminating in CRF. The most common example is intake of high doses of
analgesics such as phenacetin, aspirin and acetaminophen (chronic
analgesicnephritis). Other substances that can cause CRF after prolonged exposure
are lead, cadmium and uranium.
iv) Obstructive causes: Chronic obstruction in the urinary tract leads to progressive
damage to the nephron due to fluid backpressure. The examples of this type of
chronic injury are stones, blood clots, tumours, strictures and enlarged prostate.
Regardless of the initiating cause, CRF evolves progressively through 4 stages:
1. Decreased renal reserve. At this stage, damage to renal parenchyma is
marginal and the kidneys remain functional. The GFR is about 50% of normal,
BUN and creatinine values are normal and the patients are usually asymptomatic
except at times of stress.
2. Renal insufficiency. At this stage, about 75% of functional renal parenchyma
has been destroyed. The GFR is about 25% of normal accompanied by elevation in

3. BUN and serum creatinine. Polyuria and nocturia occur due to tubulointerstitial
damage. Sudden stress may precipitate uraemic syndrome.
3. Renal failure. At this stage, about 90% of functional renal tissue has been
destroyed. The GFR is approximately 10% of normal. Tubular cells are essentially
nonfunctional. As a result, the regulation of sodium and water is lost resulting in
oedema, metabolic acidosis, hypocalcaemia, and signs and symptoms of uraemia.
4. End-stage kidney. The GFR at this stage is less than 5% of normal and results
in complex clinical picture of uraemic syndrome with progressive primary (renal)
and secondary systemic (extra-renal) symptoms.

5. CLINICAL FEATURES
Clinical manifestations of fullblown CRF culminating in uraemic syndrome are
described under 2 main headings: primary (renal) uraemic manifestations and
secondary (systemic or extra-renal) uraemic manifestations.
A. Primary uraemic (renal) manifestations: Primary symptoms of uraemia
develop when there is slow and progressive deterioration of renal function. The
resulting imbalances cause the following manifestations:
1. Metabolic acidosis: As a result of renal dysfunction, acidbase balance is
progressively lost. Excess of hydrogen ions occurs, while bicarbonate level
declines in the blood, resulting in metabolic acidosis. The clinical symptoms of
metabolic acidosis include: compensatory Kussmaul breathing, hyperkalaemia and
hypercalcaemia.
2. Hyperkalaemia: A decreased GFR results in excessive accumulation of
potassium in the blood since potassium is normally excreted mainly in the urine.
Hyperkalaemia is further worsened by metabolic acidosis. The clinical features of
hyperkalaemia are: cardiac arrhythmias, weakness, nausea, intestinal colic,
diarrhoea, muscular irritability and flaccid paralysis.
3. Sodium and water imbalance: As GFR declines, sodium and water cannot
pass sufficiently into Bowman’s capsule leading to their retention. Release of renin
from juxtaglomerular apparatus further aggravates sodium and water retention. The
main symptoms referable to sodium and water retention are: hypervolaemia and
circulatory overload with congestive heart failure.
4. Hyperuricaemia.: Decreased GFR results in excessive accumulation of uric
acid in the blood. Uric acid crystals may be deposited in joints and soft tissues
resulting in gout.
5. Azotaemia: The waste-products of protein metabolism fail to be excreted
resulting in elevation in the blood levels of urea, creatinine, phenols and
guanidines causing biochemical abnormality, azotaemia. The secondary
manifestations of uraemia are related to toxic effects of these metabolic waste-
products.
B. Secondary uraemic (extra-renal) manifestations: A number of extra-renal
systemic manifestations develop secondarily following fluid-electrolyte and acid-
base imbalances. These include the following:

6. 1. Anaemia: Decreased production of erythropoietin by diseased kidney results in
decline in erythropoiesis and
anaemia. Besides, gastrointestinal bleeding may further aggravate anaemia.
2. Integumentary system: Deposit of urinary pigment such as urochrome in the
skin causes sallow-yellow colour. The urea content in the sweat as well as in the
plasma rises. On evaporation of the perspiration, urea remains on the facial skin as
powdery ‘uraemic frost’.
3. Cardiovascular system: Fluid retention secondarily causes cardiovascular
symptoms such as increased workload on the heart due to the hypervolaemia and
eventually congestive heart failure.
4. Respiratory system: Hypervolaemia and heart failure cause pulmonary
congestion and pulmonary oedema
to back pressure. Radiologically, uraemic pneumonitis shows characteristic central,
butterfly-pattern of oedema and congestion in the chest radiograph.
5. Digestive system: Azotaemia directly induces mucosalmulcerations in the lining
of the stomach and intestines. Subsequent bleeding can aggravate the existing
anaemia. Gastrointestinal irritation may cause nausea, vomiting and diarrhoea.
6. Skeletal system: The skeletal manifestations of renal failure are referred to as
renal osteodystrophy .
Two major types of skeletal disorders may occur:
i) Osteomalacia occurs from deficiency of a form of vitamin D which is normally
activated by the kidney. Since vitamin D is essential for absorption of calcium, its
deficiency results in inadequate deposits of calcium in bone tissue.
ii) Osteitis fibrosa occurs due to elevated levels of parathormone. How
parathormone excess develops in CRF is complex. As the GFR is decreased,
increasing levels of phosphates accumulate in the extracellular fluid which, in turn,
cause decline in calcium levels. Decreased calcium level triggers the secretion of
parathormone which mobilizes calcium from bone and increases renal tubular
reabsorption of calcium thereby conserving it. However, if the process of
resorption of calcium phosphate from bone continues for sufficient time,
hypercalcaemia may be induced with deposits of excess calcium salts in joints an
and soft tissues and weakening of bones (renal osteodystrophy).
Diagnostic test results:

7. a. Creatinine clearance may range from 0 to 90 mL/min, refl ecting renal
impairment.
b. Blood tests typically show
(1) Elevated BUN and serum creatinine concentration.
(2) Reduced arterial pH and bicarbonate concentration.
(3) Reduced serum calcium level.
(4) Increased serum potassium and phosphate levels.
(5) Possible reduction in the serum sodium level.
(6) Normochromic, normocytic anemia (hematocrit 20% to 30%).
c. Urinalysis may reveal glycosuria, proteinuria, erythrocytes, leukocytes, and
casts. Specific gravity is fixed at 1.010.
d. Radiographic fi ndings. Kidney, ureter, and bladder radiography, IV
pyelography, renal scan,
renal arteriography, and nephrotomography may be performed. Typically, these
tests reveals mall kidneys (less than 8 cm in length).
Structural assessments of the kidney may be performed using a number of imaging
procedures, including:
• ultrasonography
• intravenous urography (IVU)
• plain abdominal radiography
• computed tomography (CT), magnetic resonance imaging (MRI) and magnetic
resonance angiography (MRA).
TREATMENT
1. Improve patient comfort and prolong life.
2. Treat systemic manifestations of CKD.
3. Correct body chemistry abnormalities.
NONPHARMACOLOGIC THERAPY
• A low-protein diet (0.6 to 0.75 g/kg/day) can delay progression of CKD in
patients with or without diabetes, although the benefit is relatively small.

8. Management of the CKD patient is generally conservative. Dietary measures and
fluid restriction relieve some symptoms of CKD and may increase patient comfort
and prolong life until dialysis or renal transplantation is required or available.
PHARMACOLOGICAL TREATMENT
1. Treatment of edema. Angiotensin-converting enzyme (ACE) inhibitors and
diuretics: may be given to manage edema and CHF and to increase urine output.
a. ACE inhibitors—captopril (Capoten®), enalapril (Vasotec®), lisinopril ,
fosinopril (Monopril®)—are widely used to delay progression of CKD because
they help preserve renal function and typically cause fewer adverse effects than
other antihypertensive agents. They also decrease proteinuria and nephrotic
syndrome.
b. Diuretics. An osmotic diuretic, a loop diuretic, or a thiazide-like diuretic may be
given.
(1) Osmotic and loop diuretics
(2) Thiazide-like diuretics. Metolazone (Zaroxolyn®) is the most commonly
used thiazide diuretic in CKD.
(a) Mechanism of action and therapeutic effect. Metolazone reduces the body’s
fluid and sodium volume by decreasing sodium reabsorption in the distal
convoluted tubule, thereby increasing urinary excretion of fl uid and sodium.
(b) Administration and dosage. Metolazone is given orally at 5 to 20 mg/day; the
doseis titrated to the patient’s needs. Due to its long half-life, metolazone may be
givenevery other day. Furosemide and metolazone act synergistically.
Combination use is common, and metolazone should be administered 30 mins
before furosemide to achieve the optimal diuretic effect.
(c) Precautions and monitoring effects
(i) Metolazone should not be given to patients with hypersensitivity to sulfonamide
derivatives, including thiazides.
(ii) To avoid nocturia, the daily dose should be given in the morning.
(iii) Metolazone may cause hematological reactions, such as agranulocytosis,
aplastic anemia, and thrombocytopenia.

9. (iv) Fluid volume depletion, hypokalemia, hyperuricemia, hyperglycemia, and
impaired glucose tolerance may occur during metolazone therapy.
(v) Metolazone may cause hypersensitivity reactions, including vasculitis and
pneumonitis.
(d) Significant interactions
(i) Diazoxide may potentiate the antihypertensive, hyperglycemic, and
hyperuricemic effects of metolazone.
(ii) Colestipol and cholestyramine decrease the absorption of metolazone.
2. Treatment of hypertension. Antihypertensive agents may be needed if blood
pressure becomes dangerously high as a result of edema and the high renin levels
that occur in CKD. Antihypertensive therapy should be initiated in the lowest
effective dose and titrated according to the patient’s needs.
a. ACE inhibitors—captopril, enalapril, lisinopril, fosinopril
b. Dihydropyridine calcium-channel blockers, including amlodipine
(Norvasc®) and felodipine (Plendil®), have similar eff ects and may be used
instead of ACE inhibitors.
c. βAdrenergic blockers, including propranolol and atenolol , reduce blood
pressure through various mechanisms.
d. Other antihypertensive agents are sometimes used in the treatment of CKD,
including (-adrenergic drugs, clonidine , and vasodilators, such as hydralazine .
3. Treatment of hyperphosphatemia :involves administration of a phosphate
binder, such as aluminum hydroxide or calcium carbonate.
4. Treatment of hypocalcemia:
a. Oral calcium salts.
b. Vitamin D
(1) Mechanism of action and therapeutic effect: Vitamin D promotes intestinal
calcium and phosphate absorption and utilization and, thus, increases the serum
calcium concentration.
(2) Choice of agent: For the treatment of hypocalcemia in CKD and other renal
disorders, calcitriol (Rocaltrol®) (vitamin D3, the active form of vitamin D) is the
preferred vitamin D supplement because of its greater effi cacy and relatively short
duration of action. Other single-entity preparations include dihydrotachysterol,
ergocalciferol (Calciferol®), doxercalciferol and paricalcitol .

10. (3) Administration and dosage: Calcitriol is given orally or via IV; the dose is
titrated to the patient’s needs (0.5 to 1.0 mg/day may be effective).
(4) Precautions and monitoring effects:
(a) Vitamin D administration may be dangerous in patients with renal failure and
must be used with extreme caution.
(b) Vitamin D toxicity may cause a wide range of signs and symptoms, including
headache, dizziness, ataxia, convulsions, psychosis, soft tissue calcification,
conjunctivitis, photophobia, tinnitus, nausea, diarrhea, pruritus, and muscle and
bone pain.
(c) Vitamin D has a narrow therapeutic index, necessitating frequent measurement
of BUN and serum urine calcium and potassium levels.
5. Treatment of other systemic manifestations of CKD
a. Treatment of anemia includes administration of iron (e.g., ferrous sulfate),
folate supplements, and epoetin alfa.
(1) Severe anemia may warrant transfusion with packed red blood cells.
(2) Epoetin alfa stimulates the production of red cell progenitors and the
production of hemoglobin. It also accelerates the release of reticulocytes from the
bone marrow.
(a) An initial dose of epoetin alfa is 50 to 100U/kg intravenously or
subcutaneously three times a week. The dose may be adjusted upward to elicit the
desired response.
(b) Epoetin alfa works best in patients with a hematocrit below 30%. During the
initial treatment, the hematocrit increases 1.0% to 3.5% in a 2-week period. The
target hematocrit is 33% to 35%. Maintenance doses are titrated based on
hematocrit after this level is reached.
(c) Epoetin alfa therapy should be temporarily stopped if hematocrit exceeds 36%.
Additional side effects include hypertension in up to 25% of patients. Headache
and malaise have been reported.
(d) The effects of epoetin alfa are dependent on a ready supply of iron for
hemoglobin synthesis. Patients who do not respond should have iron stores
checked. This includes serum iron, total iron-binding capacity, transferrin
saturation, and serum ferritin. Iron supplementation should be increased as
indicated.

11. (3) Darbepoetin (Aranesp®) is an epoetin alfa analogue. Its advantage is a
prolonged plasma half-life, thus allowing it to be administered once weekly or
biweekly.
(4) Intravenous iron products may be given to replete iron stores. Th is route is
preferred to oral supplementation due to low oral bioavailability and GI
intolerance. Iron dextran is commonly used; however, it is associated with
hypotension and anaphylaxis. Newer iron products include sodium ferric gluconate
and iron sucrose, which are better tolerated and can be infused more rapidly
compared to iron dextran. Patients with severe iron deficiency may receive up to a
total of 1 g of an iron preparation over several days. The rate of infusion depends
on the preparation used.
b. Treatment of GI disturbances
(1) Antiemetics help control nausea and vomiting.
(2) Docusate sodium or methylcellulose may be used to prevent constipation.
(3) Enemas may be given to remove blood from the GI tract.
c. Treatment of skin problems. An antipruritic agent, such as diphenhydramine
(Benadryl®), may be used to alleviate itching.
6. Management of body chemistry abnormalities
7. Dialysis: When CKD progresses to end-stage renal disease and no longer
responds to conservative measures, long-term dialysis or renal transplantation is
necessary to prolong life.
a. Hemodialysis: is the preferred dialysis method for patients with a reduced
peritoneal membrane, hypercatabolism, or acute hyperkalemia.
(1) This technique involves shunting of the patient’s blood through a dialysis
membrane containing unit for diffusion, osmosis, and ultrafiltration. The blood is
then returned to the patient’s circulation.
(2) Vascular access may be obtained via an arteriovenous fistula or an external
shunt.
(3) The procedure takes only 3 to 8 hrs; most patients need three treatments a
week. With proper training, patients can perform hemodialysis at home.

12. (4) The patient receives heparin during hemodialysis to prevent clotting.
(5) Various complications may arise, including clotting of the hemofilter,
hemorrhage, hepatitis, anemia, septicemia, cardiovascular problems, air embolism,
rapid shift s in fluid and electrolyte balance, itching, nausea, vomiting, headache,
seizures, and aluminum osteodystrophy.
b. Peritoneal dialysis is the preferred dialysis method for patients with bleeding
disorders and cardiovascular disease.
(1) The peritoneum is used as a semipermeable membrane. A plastic catheter
inserted in to the peritoneum provides access for the dialysate, which draws fluids,
wastes, and electrolytes across the peritoneal membrane by osmosis and diffusion.
(2) Peritoneal dialysis can be carried out in three different modes.
(a) Intermittent peritoneal dialysis :Is an automatic cycling mode lasting 8 to 10
hrs, performed three times a week. This mode allows nighttime treatment and is
appropriate for working patients.
(b) Continuous ambulatory peritoneal dialysis : is performed daily for 24 hrs
with four exchanges daily. The patient can remain active during the treatment.
(c) Continuous cyclic peritoneal dialysis : may be used if the other two modes
fail to improve creatinine clearance. Dialysis takes place at night; the last exchange
is retained in the peritoneal cavity during the day, then drained that evening.
(3) Advantages of peritoneal dialysis include a lack of serious complications,
retention of normal fluid and electrolyte balance, simplicity, reduced cost, patient
independence, and a reduced need (or no need) for heparin administration.
(4) Complications of peritoneal dialysis include hyperglycemia, constipation, and
inflammation or infection at the catheter site. Also, this method carries a high risk
of peritonitis.
8. Renal transplantation: This surgical procedure allows some patients with end-
stage renal disease to live normal and, in many cases, longer lives.
a. Histocompatibility must be tested to minimize the risk of transplant rejection
and failure. Human leukocyte antigen (HLA) type, mixed lymphocyte reactivity,
and blood group types are determined to assess histocompatibility.
b. Renal transplant material may be obtained from a living donor or a cadaver.

13. c. Three types of graft rejection can occur.
(1) Hyperacute (immediate) rejection results in graft loss within minutes to hours
after transplantation.
(a) Acute urine fl ow cessation and bluish or mottled kidney discoloration are
intraoperative signs of hyperacute rejection.
(b) Postoperative manifestations include kidney enlargement, fever, anuria, local
pain, sodium retention, and hypertension.
(c) Treatment for hyperacute rejection is immediate nephrectomy.
(2) Acute rejection may occur 4 to 60 days after transplantation.
(3) Chronic rejection occurs more than 60 days after transplantation.
(a) Signs and symptoms include low-grade fever, increased proteinuria, azotemia,
hypertension, oliguria, weight gain, and edema.
(b) Treatment may include alkylating agents, cyclosporine, antilymphocyte
globulin, and corticosteroids. In some cases, nephrectomy is necessary.
d. Complications include
(1) infection,diabetes, hepatitis, and leukopenia, resulting from immunosuppressive
therapy.
(2) hypertension, resulting from various causes.
(3) cancer (e.g., lymphoma, cutaneous malignancies, head and neck cancer,
leukemia, colon cancer).
(4) pancreatitis and mental and emotional disorders (e.g., suicidal tendencies,
severe depression, brought on by steroid therapy).