Chronic Renal Failure

Chronic renal failure is defined as gradual, irreversible nephron loss. This leads to Glomerular hyper filtration, a compensatory mechanism with nephron GFR which leads to glomerular sclerosis.



Chronic renal failure is characterized by a gradual and sustained decline in renal clearance or glomerular filtration rate (GFR), leading to the accumulation of urea and other chemicals in the blood. There is no widely established definition. Based on limited data on healthy ageing, the Kidney Disease Improving Global Outcomes (KDIGO) statement has defined a GFR of <60 mL/minute/1.73 m2 as indicative of chronic kidney disease. This corresponds to serum creatinine concentration >137 micromol/L in men and >104 micromol/L in women. KDIGO further classifies people with low GFR as follows: GFR 30 mL/minute to 60 mL/minute as stage 3; GFR 15 mL/minute to 30 mL/minute as stage 4; and GFR <15 mL/minute or a need for dialysis as stage 5 chronic kidney disease. By contrast, the term chronic renal failure usually excludes people treated with dialysis or transplantation, for whom the term end-stage renal disease (ESRD) is commonly used.

Also found in chronic renal failure when there is accumulation of nitrogenous wastes is azotemia and uremia. In Azotemia there is (increased BUN) AT 30-35% GFR. Azotemia is an elevation of blood urea nitrogen (BUN) (reference range, 8-20 mg/dL) and serum creatinine (normal value, 0.7-1.4 mg/dL) level. Uremia manifests at <20% normal excretory capacity. Pathogenesis of uremia is caused by retention of nitrogenous wastes, increased intracellular retention of Na+ and water, decreased intracellular K+, decreased levels of hormones and other mediators produced by the kidney. Uremia causes a decrease in basal body temperature (probably due to decreased activity of Na+/K+ ATPase activity), slowed glucose metabolism, and diminished lipoprotein lipase activity with accelerated atherosclerosis. Uremia is also associated with suppressed immunity probably due to leukocyte suppression by uremic toxins. Up to 25% of patients with uremia have peptic ulcer disease perhaps as a consequence of secondary hyperparathyroidism. Women with uremia have low estrogen levels characterized by amenorrhea and their inability to carry a pregnancy to term. Similarly in men there is a low testosterone level which may lead to impotence. While uric acid can be precipitated at high concentrations, especially in the joints, and thus cause gout, sufficiently high concentrations of uric acid are only rarely achieved in renal failure. The reabsorption of Na and water is inhibited in renal failure by a variety of factors such as natriuretic hormone, PTH and vanadate (inhibits Na+/K+ ATPase). The extracellular volume expands if there is an excess of NaCl and water ( Hypervolemia ). This results in formation of edemas, most dangerously pulmonary edema. Congestive heart failure also forms due to volume and salt overload. Inhibition of Na+/K+ ATPase causes reduced Na reabsorption in the kidney. Additionally, the intracellular K concentration falls in cells in diverse tissues and the cells depolarize. The intracellular concentration of Na rises and impairs 3Na+/Ca2+ exchange and thus intracellular Ca2+ also rises. The consequences of depolarization are abnormal neuromuscular excitability, cellular accumulation of Cl- and cell swelling. The increased Ca2+ causes vasoconstriction as well as increased release of hormones (gastrin, insulin etc.) and increased hormonal effects (e.g. epinephrine)

Reduced NaCl reabsorption in the ascending limb also compromises the concentrating mechanism. The large supply of volume and NaCl from parts of the proximal nephron promotes the reabsorption of Na distally and aids in the excretion of K+ and H+ in the distal nephron and in the collecting duct. Despite a diminishing GFR, Na and water balance is well maintained by increased fractional excretion of Na+ and a normal response to thirst (compensated renal insufficiency). Thus, the plasma Na+ concentration is typically normal, and hypervolemia is infrequent unless dietary intake of Na+ or water is very restricted or excessive. Disorders occur only when GFR has fallen to less than a quarter of normal level. However, this compensation is carried out at the expense of the regulatory range, in that the damaged kidney is inadequately able to increase the excretion of water, Na+, K+, H+, Phosphate etc. Heart failure can occur from Na and water overload, particularly in patients with decreased cardiac reserve.

For substances whose secretion is controlled mainly through distal nephron secretion (e.g. K+), adaptation usually maintains plasma levels at normal until renal failure is advanced. Hyperkalemia is a serious problem in CRF in patients whose GFR has fallen below 5ml/min. K-sparing diuretics, ACE inhibitors, β-blockers, NSAIDs, cyclosporine, tacrolimus, or angiotensin II receptor blockers may raise plasma K levels in patients with less advanced renal failure. Patients with Diabetes Mellitus may have a syndrome of hyporeninemic hypoaldosteronism (also termed type IV renal tubular acidosis) is a condition in which lack of renin production by the kidney diminishes the levels of angiotensin II and therefore impairs aldosterone secretion. As a result, affected patients are unable to compensate for the falling GFR by enhancing their aldosterone mediated potassium transport and have relative difficulty handling potassium. This difficulty is usually manifested as extreme hyperkalemia even before the GFR is diminished to 5ml/min.

Abnormalities of Ca2+, phosphate, parathyroid hormone (PTH), vitamin D metabolism, and renal osteodystrophy can occur. Decreased renal production of calcitriol contributes to hypocalcemia as normally it stimulates the absorption of calcium and phosphate in the gut. Decreased renal excretion of phosphate results in hyperphosphatemia. When the solubility is exceeded, phosphate combines with with Ca2+ to form poorly soluble calcium phosphate which is then deposited in the joints and skin causing joint pains or pruritus respectively. Forming this complex also reduces concentrations of Ca2+. This stimulates PTH release mobilizing calcium phosphate from bone resulting in osteomalacia.

Secondary hyperparathyroidism is common and can develop in renal failure before abnormalities in Ca2+ or phosphate concentrations occur. For this reason, monitoring PTH in patients with moderate CKD, even before hyperphosphatemia occurs, has been recommended.Renal osteodystrophy (abnormal bone mineralization resulting from hyperparathyroidism, calcitriol deficiency, elevated serum phosphate, or low or normal serum Ca2+) usually takes the form of increased bone turnover due to hyperparathyroid bone disease (osteitis fibrosa) but can also involve decreased bone turnover due to adynamic bone disease (with increased parathyroid suppression) or osteomalacia (demineralization of bone). Calcitriol deficiency may cause osteopenia or osteomalacia. Moderate metabolic acidosis (plasma HCO3- content 15 to 20 mmol/L) and renal anemia (due to impaired renal production of erythropoietin) are also characteristic. The metabolic acidosis results due to the diminished capacity to excrete acids and generate buffers. The fall in Ph in these patients can usually be corrected by administering 2-3g of sodium bicarbonate by mouth daily. The anemia of CKD is normochromic-normocytic, with hematocrit of 20 to 30% (35 to 50% in patients with polycystic kidney disease). It is usually caused by deficient erythropoietin production due to a reduction of functional renal mass. Other causes include deficiencies of iron, folate, and vitamin B12. The anemia may also arise by bone marrow suppressive effects of uremic poisons and bone marrow fibrosis due to elevated PTH.

Causes, incidence, and risk factors

Chronic renal failure is usually caused by diabetic nephropathy, followed by hypertensive nephroangiosclerosis and various primary and secondary glomerulopathies. Metabolic syndrome in which hypertension and type 2 diabetes are present, is a large and growing cause of renal damage. Chronic kidney disease (CKD) slowly gets worse over time. In the early stages, there may be no symptoms. The loss of function usually takes months or years to occur. It may be so slow that symptoms do not appear until kidney function is less than one-tenth of normal. The final stage of chronic kidney disease is called end-stage renal disease (ESRD). At this stage, the kidneys are no longer able to remove enough wastes and excess fluids from the body. The patient needs dialysis or a kidney transplant. Many other diseases and conditions can damage the kidneys, including Autoimmune disorders (such as systemic lupus erythematosus and scleroderma), Birth defects of the kidneys (such as polycystic kidney disease), Certain toxic chemicals, Glomerulonephritis, Injury or trauma, Kidney stones and infection, Problems with the arteries leading to or inside the kidneys, Some pain medications and other drugs (such as cancer drugs), Reflux nephropathy (in which the kidneys are damaged by the backward flow of urine into the kidneys) and Other kidney diseases. Chronic kidney disease leads to a buildup of fluid and waste products in the body. This condition affects most body systems and functions, including Blood pressure control, (increased production of renin promotes, whilst reduction inhibits the development of hypertension. As there is death of renin producing cells there is hypertension due to the remaining renin producing cells overproducing renin. Prostaglandins on the other hand cause vasodilation and therefore a fall of blood pressure.) Red blood cell production (due to impaired production of erythropoietin), Vitamin D and bone health (due to reduced calcitriol production) The reduced consumption of fatty acids by the kidney contributes to hyperlipidemia, and reduced gluconeogenesis will lead to hypoglycemia.

Symptoms

Patients with mildly diminished renal reserve are asymptomatic. Even patients with mild to moderate renal insufficiency may have no symptoms despite elevated BUN and creatinine. Nocturia is often noted, principally due to a failure to concentrate the urine. Lassitude, fatigue, anorexia, and decreased mental acuity often are the earliest manifestations of uremia. With more severe renal insufficiency (eg, creatinine clearance < 10 mL/min for patients without diabetes and < 15 mL/min for those with diabetes), neuromuscular symptoms may be present, including coarse muscular twitches, peripheral sensory and motor neuropathies, muscle cramps, hyperreflexia, and seizures (usually the result of hypertensive or metabolic encephalopathy). Anorexia, nausea, vomiting, weight loss, stomatitis, and an unpleasant taste in the mouth are almost uniformly present. The skin may be yellow-brown. Occasionally, urea from sweat crystallizes on the skin (uremic frost). Pruritus may be especially uncomfortable. Undernutrition leading to generalized tissue wasting is a prominent feature of chronic uremia. In advanced CKD, pericarditis and GI ulceration and bleeding are common. Hypertension is present in > 80% of patients with advanced CKD, is usually related to hypervolemia, and is occasionally the result of activation of the renin-angiotensin-aldosterone system. Heart failure caused by hypertension or coronary artery disease and renal retention of Na and water may lead to dependent edema.

Signs and tests

High blood pressure is almost always present during all stages of chronic kidney disease. A nervous system exam may show signs of nerve damage. The health care provider may hear abnormal heart or lung sounds when listening with a stethoscope. A urinalysis may show protein or other changes. These changes may appear 6 months to 10 or more years before symptoms appear. Causes of chronic kidney disease may be seen on: Abdominal CT scan, Abdominal MRI, Abdominal ultrasound, Kidney biopsy, Kidney scan, Kidney ultrasound. This disease may also change the results of the following tests; Erythropoietin, PTH, Bone density AND vitamin D tests. Complications Anemia, Bleeding from the stomach or intestines, Bone, joint, and muscle pain, Changes in blood sugar, Damage to nerves of the legs and arms (peripheral neuropathy), Heart and blood vessel complications, Fluid buildup around the lungs (pleural effusion), Liver damage or failure, Weakening of the bones and increased risk of fractures. Prognosis Progression of CKD is predicted in most cases by the degree of proteinuria. Patients with nephrotic-range proteinuria (> 3 g/24 h or urine protein/creatinine > 3) usually have a poorer prognosis and progress to renal failure more rapidly. Progression may occur even if the underlying disorder is not active. In patients with urine protein < 1.5 g/24 h, progression usually occurs more slowly if at all. Hypertension is associated with more rapid progression as well.

Prevention and treatment

Treating the condition that is causing the problem may help prevent or delay chronic kidney disease. People who have diabetes should control their blood sugar and blood pressure levels and should not smoke. There is no cure for chronic kidney disease. Untreated, it usually worsens to end-stage renal disease. Lifelong treatment may control the symptoms of chronic kidney disease. Other treatments may include: Control of diet, the use of special medicines called phosphate binders, to help prevent phosphorous levels from becoming too high. Treatment for anemia, such as extra iron in the diet, iron pills, iron through a vein (intravenous iron) special shots of a medicine called erythropoietin, and blood transfusions, Extra calcium and vitamin D can also be recommended. Kidney transplantation can also be considered in serious cases, and also Dialysis; is initiated when GFR reaches ≤ 10 mL/min in a patient without diabetes or ≤ 15 mL/min in a patient with diabetes. Patients with uremic symptoms (e.g. anorexia, vomiting, weight loss, pericarditis, pleuritis) or fluid overload who have no other conditions that would explain these symptoms should be started on dialysis even if GFR has not reached these levels. Other indications for dialysis in chronic kidney disease include hyperkalemia that causes ECG changes or that is persistent (K > 6 mmol/L) despite dietary restriction, heart failure poorly controlled with drugs, and metabolic acidosis that is difficult to control.

Links
http://clinicalevidence.bmj.com/x/systematic-review/2004/overview.html http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001503/ http://www.merckmanuals.com/professional/genitourinary_disorders/renal_failure/chronic_kidney_disease.html