Acidosis Proximal tubular

Metabolic Acidosis and Alkalosis Tubular Acidosis Proximal Tubular Acidosis... 

Renal tubular acidosis (proximal) PO 5-10 mEq/kg/day in divided doses. 

Hereditary fructose intolerance is caused by an autosomal recessive hereditary defect of the enzyme fructose-l-phosphate aldolase. Whenever fructose is supplied, severe hypoglycaemia and functional disorders occur in the liver, kidneys and CNS. The prevalence is estimated at 1 20,000 births. As with galactose intolerance, the gene which codes aldolase B is also localized on chromosome 9. This enzyme defect causes fructose-l-phosphate to accumulate in the liver and tissue. The cleavage of fructose-1,6-biphosphate is only slightly compromised since the enzymes aldolase A and C are available for this process. The consumption of phosphate and ATP in the tissue results in various functional disorders (i.) inhibition of gluconeogenesis in the liver and kidneys, (2.) increase in lactate in the serum with metabolic acidosis, (3.) decrease in protein synthesis in the liver, and (4.) functional disorders of the proximal tubular cells with development of Fanconi s syndrome, (s. pp 593, 594) (193, 194, 196, 198)... 

Initially, most of the adverse effects seen with zidovudine use (in particular hematological effects) were attributed to interference with cellular DNA replication. However, DNA replication also occurs in mitochondria. Mitochondrial DNA encodes some of the enzymes used for oxidative phosphorylation. Only recently has it been hjrpothesized that inhibition of this pathway could lead to mitochondrial toxicity and be responsible for most of the toxicity seen with NRTIs, including polyneuropathy, myopathy, cardiomyopathy, steatosis, lactic acidosis, exocrine pancreas failure, bone marrow failure, and proximal tubular dysfunction (11). These adverse effects are also a compilation of the clinical features seen in several genetic mitochondrial cytopathies. 

The finding of a hyperchloremic metabohc acidosis in a patient without evidence of gastrointestinal bicarbonate losses and with no obvious pharmacological cause should prompt suspicion of an RTA. The presence of suggestive clinical (e.g., nephrocalcinosis in dRTA) or biochemical (e.g., hypophosphatemia and hypouricemia as a result of proximal tubular wasting in pRTA) features should also be considered. 

Nephrotoxicity is the principal dose-limiting side effect of intravenous cidofovir. Proximal tubular dysfunction includes proteinuria, azotemia, glycosuria, metabolic acidosis and, uncommonly, Fanconi s syndrome. Concomitant oral probenecid and saline prehydration reduce the risk of renal toxicity. 

Nephrotoxicity is the principal dose-limiting side effect of intravenous cidofovir. Proximal tubular dysfunction includes proteinuria, azotemia, glycosuria, and metabolic acidosis. Concomitant oral probenecid and saline prehydration reduce the risk of renal toxicity. On maintenance doses of 5 mg/kg every 2 weeks, up to 5Wo of patients develop proteinuria, 10-15% show an elevated serum creatinine, and 15-20% develop neutropenia. Anterior uveitis that is responsive to topical glucocorticoids and cycloplegia occur commonly and ocular hypotony occurs infrequently with intravenous cidofovir. Administration with food and pretreatment with antiemetics, antihistamines, and/or acetaminophen may improve tolerance. 

In patients with proximal tubular acidosis, the threshold is lowered and bicarbonate appears in the urine with relatively low levels of bicarbonate in the serum. The loss of bicarbonate in the urine leads to acidosis by reducing the alkaline reserve and by inhibiting distal hydrogen secretion. Thus, the distal tubules are flooded with urine rich in bicarbonate, which impairs hydrogen secretion. At least three mechanisms for bicarbonate reabsorption have been described in the proximal convoluted tubule. 

It is also believed that a fraction of HCO3 is reabsorbed independently of any form of excretion, whether it be carbonic anhydrase dependent or independent. Thus, proximal tubular acidosis could result from low carbonic anhydrase activity, ineffective diffusion of hydrogen ions, or a defect in the -independent reabsorption of bicarbonate. It is not known which distortion is responsible for proximal renal tubular acidosis. 

Patients with primary proximal tubular acidosis usually have stable serum HCO3 levels in spite of the reduced acid excretion. The compensatory mechanism is not known, but reduced endogenous acid production can probably be excluded. A more likely adaptation is the formation of additional bases at the expense of bone CaC03. Some patients with primary proximal acidosis present skeletal demineralization, reduced levels of CO3 in the hydroxyapatite crystals, and increased calcium losses in the feces. Patients with proximal renal acidosis are usually symptomless, and except in cases of acid overproduction, the prognosis is usually favorable. 

Two hereditary diseases, Fanconi s syndrome and Lowe s syndrome, are associated with tubular acidosis. The Fanconi syndrome is a multiple proximal tubular defect including interference with amino acid, glucose, and phosphate reabsorption. In most cases there is also acidosis that is proximal in origin, but the mechanism of the acidosis is unknown. Lowe s syndrome, or oculocerebrorenal syndrome, is transmitted in a sex-linked recessive fashion. Affected patients have the Fanconi syndrome and also mental retardation, cataracts, glaucoma, and hypotonia. 

Renal losses (e.g., proximal [Type II] renal tubular acidosis [RTA])... 

The normal UAG ranges from 0 to 5 mEq/L (mmol/L) and represents the presence of unmeasured urinary anions. In metabolic acidosis, the excretion of NH4+ and concurrent CP should increase markedly if renal acidification is intact. This results in UAG values from -20 to -50 mEq/L (mmol/L). This occurs because the urinary CP concentration now markedly exceeds the urinary Na+ and K+ concentrations. Diagnoses consistent with an excessively negative UAG include proximal (type 2) renal tubular acidosis, diarrhea, or administration of acetazo-lamide or hydrochloric acid (HC1). Excessively positive values of the UAG suggest a distal (type 1) renal tubular acidosis. 

Carbonic anhydrase inhibitors such as acetazolamide act in the proximal tubule. These drugs prevent the formation of H+ ions, which are transported out of the tubular epithelial cell in exchange for Na+ ions. These agents have limited clinical usefulness because they result in development of metabolic acidosis. 

Several heavy metals, particularly lead, are known to cause major adverse effects to the mammalian kidney, resulting in kidney function impairment. Adverse effects to the mammalian kidney caused by lead include lesions on the proximal tubule and Henle s loop, and the presence of lead inclusion bodies. The metal also is known to cause aminoaciduria, phosphaturia, glycosuria, and renal tubular acidosis. Workers associated with lead-smelting industries also have shown kidney cancer. 

Kidneys Dysfunction of the proximal tubule may occur as a late manifestation of Wilson s disease. Epithelial flattening, a loss of the brush-border membrane, mitochondrial anomalies and fatty cellular changes can be observed. These findings are, in turn, responsible for proteinuria with a predominance of hyperaminoaciduria (L. UzMAN et al., 1948). Enhanced calciuria and phosphat-uria may cause osteomalacia as well as hypoparathyroidism. (329, 344) Glucosuria and uricosuria, if present, are without clinical relevance. Due to decreased bicarbonate resorption, tubular acidosis may occur, with a tendency towards osteomalacia as well as the development of nephrocalcinosis and renal stones (in some 15% of cases). (344, 356, 392) The intensity of the copper deposits in the kidneys correlates closely with the cellular changes and functional disorders. The glomerular function is not compromised, with the result that substances normally excreted in the urine are not retained. 

Streptozocin is highly nephrotoxic, and renal function must be monitored carefuUy in all patients who are receiving it. Its effects include uremia, proteinuria, anuria, and proximal renal tubular acidosis (16). Uric acid nephropathy has also been reported (17). Adequate hydration has been recommended to reduce the risk of nephrotoxicity (18). 

Kay TD, Hogan PG, McLeod SE, Johnson DW. Severe irreversible proximal renal tubular acidosis and azotaemia secondary to cidofovir. Nephron 2000 86 348-349. 

Tacrolimus may induce tubular dysfunction characterized as an increased excretion of urinary enzymes, decreased urinary concentrating ability, increased fractional excretion of magnesium in the presence of hypomagnesemia, hyperkalemia, hyperuricemia and fubular acidosis [12,260,645,647,705,736,737. In vitro sfudies showed fhat TAC inhibit Na/K - ATPase in rat microdissected cortical collecting duct and medullary thick ascending limb [738], and that high TAC doses added to primary human proximal tubules cultures decreased cell proliferation after 72 hours of incubation... 

Besides hypoglycemia, D-fructose-induced renal acidification in the HFI defect involves a lowered hydrogen-ion secretory capacity of the proximal nephron, as evidenced by a 20 to 30% diminution in renal-tubular (T) reabsorption of bicarbonate (THCO3) and simultaneous occurrence, and persistence throughout D-fructose administration, of impaired tubular reabsorption of phosphate, cc-amino nitrogen, and uric acid. This abnormality of renal metabolism affects the renal cortex, which contains aldolase B, but does not affect the renal medulla. Thus, the abnormality may result from accumulation of D-fructose 1-phosphate in the renal cortex. The intimate, biochemical mechanism for renal, tubular acidosis is still unknown.164... 

In type II renal tubular acidosis there is a defect in the secretion of hydrogen ions by the proximal tubule. Because the proximal tubule is the major site of bicarbonate reabsorption (4000 mEq of bicarbonate per day as compared to 70 mEq in the distal tubule), the defect in secretion of hydrogen ions in this condition leads to the flooding of the distal tubule with bicarbonate. The capacity of hydrogen ions secreted by the distal tubule to buffer this massive efflux of bicarbonate is soon overwhelmed and, as a result, large quantities of bicarbonate are excreted in the urine. Much more bicarbonate needs to be administered in this condition to correct the acidosis than is necessary in type I renal tubular acidosis. In general, in renal tubular acidosis the impairment in hydrogen ion secretion leads to excretion of potassium ions in urine. 

O Gorman MA, Fivush B, Wise B, Colombani P, Burdick J, Schwarz KB. Proximal renal tubular acidosis secondary to FK 506 in pediatric liver transplant patients. Clin Transplant 1995 9 312-316. 

Ifosfamide in high doses for transplant causes a chronic, and often irreversible, renal toxicity. Proximal, and less commonly distal, tubules may be affected, with difficulties in Ca + and Mg + reabsorption, glycosuria, and renal tubular acidosis. Nephrotoxicity is correlated with the total dose of drug received and increases in frequency in children less than 5 years of age. The syndrome has been attributed to chloroacetaldehyde and/or acrolein excreted in the urine. 

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