Various Causes of Acute Renal Failure

The cause and/or precipitating factor of acute renal failure (ARF) is always responsible for the effectiveness of therapy and supportive care techniques including hemodialysis. A rapid loss of renal function is exhibited through elevated levels of serum creatinine and blood urea due to fall in the clearance of these nitrogenous wastes by the kidneys in all cases of ARF. It has been observed that a loss of 50% of glomerular filtration rate (GFR) leads to significant elevation of the level of creatinine in the blood with a decrease in the urine output (oliguria). There could be three types of causes and implicating factors of acute renal failure: 1) Pre-renal, 2) Renal and 3) Post-renal. In pre-renal type ARF causes are the physiological factors or conditions which lead to poor renal perfusion and severe impairment of renal function. Hemorrhage in gastrointestinal tract (stomach and intestines) and other internal spaces, sepsis, hepatic failure (liver failure), over compliance of antihypertensive drugs or non-steroidal anti-inflammatory drugs (NSAID), arterial or venous thrombosis and intra-vascular hemolysis due to transfusion reactions, are the major pre-renal causes of ARF.

Acute tubular necrosis (ATN), rapidly progressive glomerulonephritis (RPGN), post infection glomerulonephritis and interstitial nephritis are some major renal causes of ARF. Pre-renal factors and use of nephrotoxic drugs may also be associated cause of ATN. Some viral infections, drugs, multiple myeloma, lymphoma and granuloma may cause interstitial nephritis leading to renal type ARF.

Post-renal type ARF is caused by intra-tubular obstruction due to fibrosis, stones or tumors. Every case of acute renal failure needs urgent investigations to establish the cause and efficient mode of supportive care and line of treatment. A comprehensive physical examination is required to look for possible causes of ARF and planning the investigations to classify the type of ARF. By timely diagnosis and treatment, renal function could be restored in majority of cases of pre-renal type acute renal failure.

Nephrotic Syndrome and its Serious Effects

Urine examination shows critical abnormalities in nephrotic syndrome. The urine may froth if passed in a container or if shaken in a test tube. The dipstick test always shows extensive excretion of protein in urine. Total excretion of protein per day should be measured in 24-hour's collection of urine. The nephrotic syndrome is the consequence of prolonged massive proteinuria (excretion of protein in urine). The proteinuria exceeds 3.5 g/24-hours in adults or 50 mg/kg body-weight in children. Nephrotic syndrome is characterized by proteinuria, hematuria (blood in urine), hypertension (high blood pressure), oliguria (low output of urine per day), edema (swelling: apparently suborbital puffy eyes) and diminished renal function. Urine may be brown or red. Sodium (Na⁺) retention, increased circulating blood volume and hypertension (high blood pressure) may lead to cardiomegaly (enlargement of heart). Nephrotic syndrome is usually characterized by insidious onset of massive edema, proteinuria, hypoalbuminemia (low level of albumin in blood) and hyperlipidemia (high level of cholesterol in blood). There could be massive retention of sodium (Na⁺) and a tendency to excessive potassium (K⁺) loss. Serious ill effect of the nephrotic syndrome could be a tendency towards hypercoagulability (blood clotting disorder) which may lead to venous or arterial thrombosis and embolism. Susceptibility to chest (lung) infections may increase due to decreased immunoglobulins' level in blood. Serum calcium (Ca⁺⁺) level could be low as this is related to the level of albumin in blood. Dysfunction of proximal tubules of kidneys may cause glycosuria (excretion of glucose/sugar in urine) or aminoaciduria.

Amyloidosis: Causes and Detection

Amyloidosis or deposition of amyloid in vital organs could be labeled as chronic pathological state. Amyloid is an abnormal protein derivative and amyloidosis is characterized by extracellular accumulation of this abnormal protein, which could be detected with Congo-Red staining during histological examination of biopsies/tissues. Genesis of amyloid is associated with B-cell (B Lymphocytes) and Plasma-cell disorders or chronic infections like tuberculosis. Renal (kidney) involvement in amyloidosis may affect all compartments of kidneys. Renal glomeruli, extraglomerular blood vessels, uriniferous tubules and even interstitium could be severely affected leading to impairment of renal function and can cause renal failure. Amyloid could be composed of one or more proteins out of around two dozen different monotypic polypeptides, including immunoglobulin light chains (AL type amyloid), immunoglobulin heavy chains (AH type amyloid), amyloid-A-protein (AA type amyloid), prealbumin, b-2 microglobulin, b-amyloid protein, islet amyloid polypeptide, procalcitonin, cystatin-C, apolipoprotein A-1 or A-2, gelsolin, lysozymes etc. Immunoglobulin light chains type (AL type) and amyloid-A-protein (AA type) amyloid mostly affect the kidneys. Almost all the patients with amyloidosis of kidneys have proteinuria (excretion of proteins in urine; >3g/day) and around 70% also have diminished renal function. On electron microscopy amyloid could be resolved as approximately 10 nm thick non branching and randomly arranged fibrils as illustrated in Figure-1.

Figure-1: Electron micrograph showing randomly arranged non-branching fibrils of amyloid in the mesangial area of a renal glomerulus. Original magnification 36000x.

Amyloid-A-protein type (AA type) amyloidosis is most often associated with chronic inflammatory diseases like tuberculosis, osteoarthritis, or rheumatoid arthritis. Some viral infections can also boost amyloidosis. Production of amyloidogenic light chains is associated with B-cell lymphoma, multiple myeloma or plasma-cell dyscrasia. AL and AA type amyloid have identical physicochemical properties. On renal biopsy evaluation we find acidophilic deposits which stain weakly with Periodic acid Schiff's stain or Silver stain. Amyloid stains bright red with Congo-Red stain and shows apple green birefringence by polarized light microscopy. Amyloid deposits could be revealed in the mesangium and peripheral capillary wall of renal glomerulus depending on the chronicity of the disease process. In advanced stages of amyloidosis, the amyloid deposits could be detected in arteries and interstitial tissue of kidneys in addition to glomeruli, by conventional methods and electron microscopy.

IgA Nephropathy as a cause of End Stage Renal Disease

There are a variety of causes of end stage renal disease (ESRD) in teenagers and adults. Immunoglobulin-A (IgA) nephropathy could be a cause of end stage renal disease (ESRD) in around 25% of cases. There are five types of immunoglobulins in our body for protection against microorganisms and IgA provides defence at mucous membranes. Colostrum and breast milk are rich sources of IgA and protect us during infancy through breast-feeding. However, later in life, chronic mucosal inflammation (inflammation of respiratory, oral, or gastrointestinal mucous membranes) may lead to IgA-nephropathy (IgAN). Viral (including HIV), bacterial, yeast and parasitic infections have been found to be associated with IgAN. Environmental and food antigens have also been implicated in IgAN as these may mimic molecular structure of microbial antigens and lead to excessive IgA production, aggregation and breakdown of mucosal barrier. Patients affected by IgAN may present with hematuria (blood in urine) and/or proteinuria (protein in urine) with or without rise in serum creatinine. The most common initial symptom in children is microscopic hematuria. Some adults may present with acute or chronic renal failure.

IgA nephropathy is a common nephropathy, which could be detected on renal (kidney) biopsy evaluation through light and fluorescence microscopy. However, electron microscopic study of renal biopsy acts as a diagnostic adjunct as the location of immune complexes in the renal glomerulus could be pronounced on electron micrographs. Figures 1 and 2 are the electron micrographs from a proven case of IgAN, illustrating mesangial deposits of IgA.

Figure-1: Electron micrograph of an area of glomerulus of a case of IgAN showing electron dense deposits (D) in the mesangial (Mes) area. Glomerular basement membrane (GBM), capillary lumen (CL), podocyte or epithelial cell (EpC) and urinary space (US) are also exhibited; Original Magnification 4600x.

Figure-2: Electron micrograph of an area of glomerulus of a case of IgAN showing electron dense deposits (D) in the mesangial (Mes) area. Glomerular basement membrane (GBM), capillary lumen (CL), podocyte or epithelial cell (EpC) and urinary space (US) are also exhibited; Original Magnification 6000x.

The pathology of IgAN may be variable depending on underlying cause. Mesangioproliferative glomerulonephritis is the most common pattern in many renal biopsies; however, glomeruli may appear normal on light microscopy in some of the cases. Renal biopsies in a few cases may also show crescent formation in occasional glomeruli. Diagnosis of IgA nephropathy is established by direct immunofluorescence technique on renal biopsies and the pattern may be dominant or co-dominant for IgA staining. The incidence of ESRD has been found to be high in patients presenting with >1g/day proteinuria with increased level of serum creatinine as compared to those having proteinuria <1g/day with increased level of serum creatinine. Pathogenesis of IgAN is very complex. A variety of underlying diseases including hepato-biliary disease can be associated with IgA nephropathy. Defective detection and clearance by liver of polymeric immune complexes of IgA (IgA1) due to abnormal galactosylation of O-linked glycans is probably the major cause of IgAN in addition to loss of mucosal barrier and chronic mucosal inflammation. Recurrent tonsillitis may also lead to IgA nephropathy and tonsillectomy may be helpful in these cases to remove the mucosal foci of infection. Optimal treatment of tonsillitis and other oromucosal infections with antibiotics along with conventional treatment of IgAN would be helpful to put brakes on the progression of IgA nephropathy. Patients with acute or chronic renal failure due to advanced stage of IgAN may need hemodialysis or renal transplantation. Use of anti-oxidants and fish oil as food supplements in some cases of IgA nephropathy have been found beneficial.

Urea Synthesis and Clearing: Role of Liver and Kidneys

The proteins we eat contain about 20% nitrogen. A person consuming around 100g proteins daily will excrete about 17g of nitrogen daily in the form of urea. In man and other vertebrate animals the major excretory product of protein metabolism is urea, and they are classified as ureotelic animals. Birds and reptiles excrete the waste nitrogen in the form of relatively insoluble uric acid as the end product of nitrogen metabolism and are called uricotelic animals. Urea is synthesized in liver and is released into the blood and cleared by kidneys in the urine.
Urea synthesis in the liver involves five enzymes: (1) Carbamoyl phosphate synthetase 2) Ornithine carbamoyl transferase (3) Argininosuccinate synthetase (4) Argininosuccinate lyase and (5) Arginase. Deficiency in any of these enzymes may lead to metabolic disorder. The sole function of urea cycle is to convert the ammonia to non-toxic compound urea. All metabolic disorders of urea synthesis cause ammonia intoxication. Catabolism of amino acids in the most of cells produces ammonia. Considerable quantity of ammonia is produced by intestinal bacteria from the dietary proteins and from the urea present in cellular fluids secreted into the gastrointestinal tract. The ammonia produced in the intestine is absorbed into the portal venous blood and is promptly removed by the liver, where urea is synthesized from the ammonia. At first step, carbamoyl phosphate is produced by condensation of one molecule each of ammonia, carbon dioxide and phosphate, under the action of intramitochondrial carbamoyl phosphate synthetase-1 (CPS-1) in the presence of Mg⁺⁺ and N-acetyl glutamate. Now citrulline is formed from the carbamoyl phosphate by union of carbamoyl phosphate and ornithine under the action of another intramitochondrial enzyme called ornithine carbamoyl transferase. The rest of the steps in the urea synthesis take place in cytosol. Citrulline diffuses out from the mitochondrial membrane into the cytosol, where it is linked with aspartate to form argininosuccinate under the action of enzyme argininosuccinate synthetase in the presence of Mg⁺⁺ ions and ATP. There after the cleavage of argininosuccinate to arginine and fumarate is catalyzed by argininosuccinate lyase. The final step in the urea synthesis is the hydrolysis of arginine to urea and ornithine. Ornithine from the cytosol enters the mitochondria and is recycled in urea synthesis. Though other body tissues also exhibit the presence of urea synthesis enzymes but the physiologic contribution of extrahepatic urea synthesis is very low. Urea produced by the hepatic cells enters the blood and is excreted in the urine by the kidneys. Low level of blood/plasma urea and respiratory alkalosis are indicative of urea cycle disorders. Free "Human Body Maps"