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

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

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.

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:

1. Anaemia: Decreased production of erythropoietin by diseased kidney results in decline in erythropoiesis andanaemia. 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 oedemato 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:

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 inpatients with or without diabetes, although the benefit is relatively small.

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.

(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, fosinoprilb. 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 .

(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.

(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.

(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.

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).