Chronic Renal Failure

What is Chronic Renal Failure?
Chronic Renal Failure is rarely reversible and leads to progressive decline in kidney function in the small scale is a normal process for every human being as we get older, but this does not cause disorder or to cause symptoms because it is still within the bounds of the fair that can be tolerated kidneys and the body. But by various causes can occur where the decrease in renal function abnormalities occur in a fast / progressive could result in many complaints from mild to severe, the condition is called chronic renal failure (CKD) or Chronic renal failure (CRF).

By definition, there are several differences between the experts / specialists in writing the definition of this disease. Scopes can be defined differently, there is a define based on what happens in the kidneys, cause and effect on the kidneys and the human body, or a combination of one or two components. Overall it was not wrong because the experts (doctors) in the whole world has agreed on the mechanism of occurrence of this disease, only the disclosure of just how different. According to the authors, Chronic renal failure is a condition / disease in which renal function progressively declined, causing irreversible variety of disorders and symptoms that interfere with and harm. For the record, the boundary where the decline in kidney function had begun to cause the onset of symptoms for the owner of the kidney is of 75-85%, which means that complaints / symptoms would appear / clear if renal function was below 25%
The different stages of chronic kidney disease form a continuum in time; prior to February 2002, no uniform classification of the stages of chronic kidney disease existed. At that time, K/DOQI published a classification of the stages of chronic kidney disease, as follows:

* Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2)
* Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)
* Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2)
* Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2)
* Stage 5: Kidney failure (GFR <15 mL/min/1.73 m2 or dialysis) In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities in imaging tests, should also be present in establishing a diagnosis of stage 1 and stage 2 chronic kidney disease. The K/DOQI definition and the classification of chronic kidney disease allow better communication and intervention at the different stages. Pathophysiology Approximately 1 million nephrons are present in each kidney, each contributing to the total GFR. Regardless of the etiology of renal injury, with progressive destruction of nephrons, the kidney has an innate ability to maintain GFR by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons. This nephron adaptability allows for continued normal clearance of plasma solutes so that substances such as urea and creatinine start to show significant increases in plasma levels only after total GFR has decreased to 50%, when the renal reserve has been exhausted. The plasma creatinine value will approximately double with a 50% reduction in GFR. A rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the reference range, actually represents a loss of 50% of functioning nephron mass. The residual nephron hyperfiltration and hypertrophy, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive renal dysfunction. This is believed to occur because of increased glomerular capillary pressure, which damages the capillaries and leads initially to focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. This hypothesis has been based on studies of five-sixths nephrectomized rats, which develop lesions that are identical to those observed in humans with chronic kidney disease. Factors other than the underlying disease process and glomerular hypertension that may cause progressive renal injury include the following: * Systemic hypertension * Acute insults from nephrotoxins or decreased perfusion * Proteinuria * Increased renal ammoniagenesis with interstitial injury * Hyperlipidemia * Hyperphosphatemia with calcium phosphate deposition * Decreased levels of nitrous oxide * Smoking The biologic process of aging initiates various structural and functional changes within the kidney. Renal mass progressively declines with advancing age. Glomerulosclerosis leads to a decrease in renal weight. Histologic examination is notable for a decrease in glomerular number of as much as 30-50% by age 70 years. Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the renal medulla. Juxtamedullary glomeruli see a shunting of blood from the afferent to efferent arterioles, resulting in redistribution of blood flow favoring the renal medulla. These anatomical and functional changes in renal vasculature appear to contribute to an age-related decrease in renal blood flow. Renal hemodynamic measurements in aged human and animals suggest that altered functional response of the renal vasculature may be an underlying factor in diminished renal blood flow and increased filtration noted with progressive renal aging. The vasodilatory response is blunted in the elderly when compared to younger patients. However, the vasoconstrictor response to intrarenal angiotensin is identical in both young and older human subjects. A blunted vasodilatory capacity with appropriate vasoconstrictor response may indicate that the aged kidney is in a state of vasodilatation to compensate for the underlyingsclerotic damage. Given the histologic evidence for nephronal senescence with age, a decline in the GFR is expected. However, a wide variation in the rate of decline in the GFR is reported because of measurement methods, race, gender, genetic variance, and other risk factors for renal dysfunction. Because of these anatomical and physiological changes, elderly patients with chronic kidney disease may behave differently, in terms of progression and response to pharmacological treatment, than younger patients Clinical Patients with chronic kidney disease stages 1-3 (GFR >30 mL/min) are generally asymptomatic and do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangement. Generally, these disturbances clinically manifest with chronic kidney disease stages 4-5 (GFR <30 mL/min). Uremic manifestations in patients with chronic kidney disease stage 5 are believed to be primarily secondary to an accumulation of toxins, the identity of which is generally not known.

The ability to maintain potassium (K) excretion at near normal levels is generally maintained in chronic kidney disease patients as long as both aldosterone secretion and distal flow are maintained. Another defense against potassium retention in patients with chronic kidney disease is increased potassium excretion in the GI tract, which also is under control of aldosterone.

Therefore, hypercalsemia usually develops when the GFR falls to less than 20-25 mL/min because of the decreased ability of the kidneys to excrete potassium. It can be observed sooner in patients who ingest a potassium-rich diet or if serum aldosterone levels are low, such as in type IV renal tubular acidosis commonly observed in people with diabetes or with use of angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs). Hyperkalemia in chronic kidney disease can be aggravated by an extracellular shift of potassium, such as that occurs in the setting of acidemia or from lack of insulin. Hypokalemia is uncommon but can develop among patients with very poor intake of potassium, gastrointestinal or urinary loss of potassium, diarrhea, or diuretic use.

Metabolic acidosis often is mixed, normal anion gap and increased anion gap, the latter observed generally with chronic kidney disease stage 5 but with the anion gap generally not higher than 20 mEq/L. In chronic kidney disease, the kidneys are unable to produce enough ammonia in the proximal tubules to excrete the endogenous acid into the urine in the form of ammonium. In chronic kidney disease stage 5, accumulation of phosphates, sulphates, and other organic anions are the cause of the increase in anion gap. Metabolic acidosis has been shown to have deleterious effects on protein balance, leading to a negative nitrogen balance, increased protein degradation, increased essential amino acid oxidation, reduced albumin synthesis, and a lack of adaptation to a low protein diet. Hence, this is associated with protein-energy malnutrition, loss of lean body mass, and muscle weakness. The mechanism for reducing protein may include effects on ATP-dependent ubiquitin proteasomes and increased activityofbranchedchain keto acid dehydrogenases.
In the NHANES III prevalence study, hypoalbuminemia (a marker of protein-energy malnutrition and a powerful predictive marker of mortality in dialysis patients as well as in the general population) was independently associated with low bicarbonate as well as the inflammatory marker C reactive protein. Metabolic acidosis is a factor in the development of renal osteodystrophy, as bone acts as a buffer for excess acid, with resultant loss of mineral. Acidosis may interfere with vitamin D metabolism, and patients who are persistently more acidotic are more likely to have osteomalacia or low-turnover bone disease.

The evidence for the benefits and risks of correcting metabolic acidosis is very limited, with no randomized controlled trials in pre-ESRD patients, none in children, and only 3 small trials in dialysis patients. These trials suggest that there may be some beneficial effects on both protein metabolism and bone metabolism, but the trials were underpowered to provide robust evidence. Experts recommend alkali therapy to maintain the serum bicarbonate concentration above 22 mEq/L.

Inflammation and hemostasis may increase the risk of kidney function decline, but prospective studies are lacking. The Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort, observed markers of inflammation and hemostasis in 14,854 middle-aged adults.2 The risk for decreased kidney function associated with the inflammatory and hemostasis markers was examined, using data from 1787 cases of chronic kidney disease (CKD) that developed between 1987 and 2004.

After adjustments for various factors, such as demographics smoking, blood pressure, diabetes, lipid levels, prior myocardial infarction (MI), antihypertensive use, and alcohol use, the above study revealed that the risk for chronic kidney disease rose with increasing quartiles of white blood cell (WBC) count, fibrinogen, von Willebrand factor, and factor VIIIc. The investigators found a strong inverse association between serum albumin level and chronic kidney disease risk. The study's findings suggested that inflammation and hemostasis are antecedent pathways for chronic kidney disease.

Salt and water handling by the kidney is altered in patients with chronic kidney disease. Extracellular volume expansion and total-body volume overload results from failure of sodium and free water excretion. This generally becomes clinically manifested when the GFR falls to less than 10-15 mL/min, when compensatory mechanisms have become exhausted. As kidney function declines further, sodium retention and extracellular volume expansion lead to peripheral and, not uncommonly, pulmonary edema and hypertension. At a higher GFR, excess sodium and water intake could result in a similar picture if the ingested amounts of sodium and water exceed the available potential for compensatory excretion.

Normochromic normocytic anemia principally develops from decreased renal synthesis of erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell (RBC) production. It starts early in the course of disease and becomes more severe as the GFR progressively decreases with the availability of less viable renal mass. No reticulocyte response occurs. RBC survival is decreased, and tendency of bleeding is increased from the uremia-induced platelet dysfunction. Other causes of anemia in chronic kidney disease patients include chronic blood loss, secondary hyperparathyroidism, inflammation, nutritional deficiency, and accumulation of inhibitors of erythropoiesis.

Anemia is associated with fatigue, reduced exercise capacity, impaired cognitive and immune function, and reduced quality of life. Anemia is also associated with the development of cardiovascular disease, the new onset of heart failure, or the development of more severe heart failure. Anemia is associated with increased cardiovascular mortality.

Renal bone disease is a common complication of chronic kidney disease and results in both 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: (1) high turnover bone disease due to high parathyroid hormone (PTH) levels; (2a) low turnover bone disease (adynamic bone disease); (2b) defective mineralization (osteomalacia); (3) mixed disease; and (4) beta-2-microglobulin associated bone disease.

Secondary hyperparathyroidism develops because of hyperphosphatemia, hypocalcemia, decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D, or calcitriol), intrinsic alteration in the parathyroid gland that give rises to increased PTH secretion as well as increased parathyroid growth, and skeletal resistance to PTH.

* Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to PTH synthesis and secretion.
* Phosphate retention begins in early chronic kidney disease; when the GFR falls, less phosphate is filtered and excreted, but serum levels do not rise initially because of increased PTH secretion, which increases renal excretion. As the GFR falls toward chronic kidney disease stages 4-5, hyperphosphatemia develops from the inability of the kidneys to excrete the excess dietary intake. Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min. Increased phosphate concentration also effects PTH concentration by its direct effect on parathyroid gland (posttranscriptional effect).
* Hypocalcemia develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels and possibly from calcium binding to elevated serum levels of phosphate.
* Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been demonstrated to independently trigger PTH synthesis and secretion. As these stimuli persist in chronic kidney disease, particularly in the more advanced stages, PTH secretion becomes maladaptive and the parathyroid glands, which initially hypertrophy, become hyperplastic. The persistently elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate.
* If serum levels of PTH remain elevated, a high bone turnover lesion, known as osteitis fibrosa, develops. This is one of several bone lesions, which as a group are commonly known as renal osteodystrophy. These lesions develop in patients with severe chronic kidney disease and are common in those with ESRD.
* The prevalence of adynamic bone disease in the United States has increased, and it has been described before the initiation of dialysis in some cases. The pathogenesis of adynamic bone disease is not well defined, but several factors may contribute, including high calcium load, use of vitamin D sterols, increasing age, previous corticosteroid therapy, peritoneal dialysis, and increased level of N-terminally truncated PTH fragments. Low turnover osteomalacia in the setting of chronic kidney disease is associated with aluminum accumulation and is markedly less common. Dialysis-related amyloidosis from beta-2-microglobulin accumulation in patients who have required chronic dialysis for at least 8-10 years is another form of bone disease that manifests with cysts at the ends of long bones.

Other manifestations of uremia in ESRD, many of which are more likely in patients who are inadequately dialyzed, include the following:

* Pericarditis - Can be complicated by cardiac tamponade, possibly resulting in death.
* Encephalopathy - Can progress to coma and death
* Peripheral neuropathy
* Restless leg syndrome
* GI symptoms - Anorexia, nausea, vomiting, diarrhea
* Skin manifestations - Dry skin, pruritus, ecchymosis
* Fatigue, increased somnolence, failure to thrive
* Malnutrition
* Erectile dysfunction, decreased libido, amenorrhea
* Platelet dysfunction with tendency to bleeding

Physical

The physical examination often is not very helpful but may reveal findings characteristic of the condition underlying chronic kidney disease (eg, lupus, severe arteriosclerosis, hypertension) or complications of chronic kidney disease (eg, anemia, bleeding diathesis, pericarditis).
Causes

* Vascular disease - Renal artery stenosis, cytoplasmic pattern antineutrophil cytoplasmic antibody (C-ANCA)–positive and perinuclear pattern antineutrophil cytoplasmic antibody (P-ANCA)–positive vasculitides, antineutrophil cytoplasmic antibody (ANCA)–negative vasculitides, atheroemboli, hypertensive nephrosclerosis, renal vein thrombosis
* Primary glomerular disease - Membranous nephropathy, immunoglobulin A (IgA) nephropathy, focal and segmental glomerulosclerosis (FSGS), minimal change disease, membranoproliferative glomerulonephritis, rapidly progressive (crescentic) glomerulonephritis
* Secondary glomerular disease - Diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, scleroderma, Goodpasture syndrome, Wegener granulomatosis, mixed cryoglobulinemia, postinfectious glomerulonephritis, endocarditis, hepatitis B and C, syphilis, human immunodeficiency virus (HIV), parasitic infection, heroin use, gold, penicillamine, amyloidosis, light chain deposition disease, neoplasia, thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), Henoch-Schönlein purpura, Alport syndrome, reflux nephropathy
* Tubulointerstitial disease - Drugs (eg, sulfa, allopurinol), infection (viral, bacterial, parasitic), Sjögren syndrome, chronic hypokalemia, chronic hypercalcemia, sarcoidosis, multiple myeloma cast nephropathy, heavy metals, radiation nephritis, polycystic kidneys, cystinosis
* Urinary tract obstruction - Urolithiasis, benign prostatic hypertrophy, tumors, retroperitoneal fibrosis, urethral stricture, neurogenic bladder

Laboratory findings:
the diagnosis of renal failure is made by documenting elevations of the BUN and serum creatinine concentrations. further evaluation is needed to differentiate between acute and chronic renal failure. evidence of previously elevated BUN and creatinine, abnormal prior urinalyses, and stable but abnormal serum creatinine on successive days is most consistent with a chronic process.