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The major cause of the failure to excrete enough acid is diminished renal ammonia production and excretion. Before this stage, serum chloride initially rises as theserum bicarbonate level falls. High serum parathormone levels and extracellular fluid volume lead to proximal tubular acidosis but do not seem to fully account for the early hyperchloremic metabolic acidosis of CRF.

Htn- is due to retention of NaCl, inappropriately high renin levels for the status of expended extracellular fluid volume, sympathetic stimulation via afferent renalreflexes, and impaired renal endothelial function with deficient nitric oxide andenhanced endothelin production. Due to hypertension, there are lesion to theafferent and efferent arterioles decreasing the effectiveness of the filtration of

blood in the glomerular that leads to the decrease capability of the kidney to properly excrete waste products

Heart failure is common and is due to sodium and water retention, acid-base

changes, hypocalcemia and hyperparathyroidism, hypertension, anemia, coronaryartery disease, and diastolic dysfunction secondary to increased myocardialfibrosis with oxalate and urate deposition and myocardial calcification. Uremiaitself may also impair myocyte function.

In the gastrointestinal tract, anorexia and morning vomiting are common.In severe uremia, gastrointestinal bleeding may occur secondary to plateletdysfunction and diffuse mucosal erosions throughout the gut.

Pruritus is a common and troublesome complication of uremia that is only

partially explained by hyperparathyroidism and a high Ca P product withincreased microscopic calcification of subcutaneous tissues.

The restless legs syndrome is a manifestation of sensory peripheral neuropathy.

Progressively more severe normochromic, normocytic anemia develops as theGFR and renal erythropoietin secretion decrease.In most patients, the hematocrit reaches about 20 to 25% by the time that ESRDdevelops.

It now appears that some families have a genetic predisposition not only for essential hypertension and diabetes mellitus but also for the development of renaldisease secondary to these systemic diseases.

Physical ExamOn physical examination, signs of hypertensiv e (left ventricular hypertrophy andhypertensive retinopathy) or diabetic disease (peripheral neuropathy, diabeticretinopathy) are important.

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hyperkalemia usually develops when the GFR falls to less than 20-25 mL/min becauseof the decreased ability of the kidneys to excrete potassium. Hyperkalemia in chronickidney disease can be aggravated by an extracellular shift of potassium.

Salt and water handling abnormalitiesSalt and water handling by the kidney is altered in chronic kidney disease.Extracellular volume expansion and total-body volume overload results from failureof sodium and free water excretion. This generally becomes clinically manifest whenthe GFR falls to less than 10-15 mL/min, when compensatory mechanisms havebecome exhausted.As kidney function declines further, sodium retention and extracellular volumeexpansion lead to peripheral edema and, not uncommonly, pulmonary edema andhypertension. At a higher GFR, excess sodium and water intake could result in a similarpicture if the ingested amounts of sodium and water exceed the available potential forcompensatory excretion.

AnemiaNormochromic normocytic anemia principally develops from decreased renalsynthesis of erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell (RBC) production. It starts early in the course of disease and becomesmore severe as the GFR progressively decreases with the availability of less viablerenal mass.No reticulocyte response occurs. RBC survival is decreased, and tendency of bleeding isincreased from the uremia-induced platelet dysfunction

Bone diseaseRenal bone disease is a common complication of chronic kidney disease. It results inboth skeletal complications (eg, abnormality of bone turnover, mineralization, linear

growth) and extraskeletal complications (eg, vascular or soft tissue calcification).Different types of bone disease occur with chronic kidney disease, as follows:High-turnover bone disease due to high parathyroid hormone (PTH) levelsLow-turnover bone disease (adynamic bone disease)Defective mineralization (osteomalacia)Mixed diseaseBeta-2-microglobulin associated bone disease

Chronic kidney disease mineral and bone disorder (CKD-MBD) involves biochemicalabnormalities, (ie, serum phosphorus, PTH, and vitamin D levels) related to bonemetabolism.

Hypocalcemia develops primarily from decreased intestinal calcium absorptionbecause of low plasma calcitriol levels and possibly from calcium binding to elevatedserum levels of phosphate.Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all beendemonstrated to independently trigger PTH synthesis and secretion. As these stimulipersist in chronic kidney disease, particularly in the more advanced stages, PTHsecretion becomes maladaptive and the parathyroid glands, which initially hypertrophy,

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become hyperplastic. The persistently elevated PTH levels exacerbatehyperphosphatemia from bone resorption of phosphate.

Hyponatremia commonly occurs in both acute and chronic renal failure,

because the kidneys cannot maximally excrete excess ingested or infusedwater. Hyponatremia is not very common in nephrotic syndrome unlessassociated with a substantial decrease in glomerular filtration rate (GFR);however, with severe hypoalbuminemia of