Tubular dysfunction

The presence of protein in the urine is a marker of glomerular and tubular dysfunction and is recognized as an independent risk factor for the progression of CKD.8 Furthermore, the degree of proteinuria correlates with the risk for progression of CKD. An increase of 1 g of protein excretion per day is associated with a five-fold increase in the risk of progression of CKD, regardless of the cause of CKD.9 The mechanisms by which proteinuria potentiates CKD are discussed later. Microalbuminuria is also linked with vascular injury and increased cardiovascular mortality.10... 

Genitourinary Renal papillary necrosis, hematuria, hyposthenuria, proteinuria, nephritic syndrome, tubular dysfunction,... 

Hematuria, hyposthenuria (inability to concentrate urine maximally), tubular dysfunction, enuresis during early childhood, acute renal failure can also occur... 

Hydroxyurea is an oral drug that inhibits ribonucleotide reductase, which converts ribonucleotides into the deoxyribuon-cleotides used in DNA synthesis and repair. The time to peak concentrations of hydroxyurea is 1 to 2 hours after oral administration. Approximately 50% is degraded by the liver to form urea and respiratory carbon dioxide. The remainder is excreted by the kidney. The half-life ranges from 3.5 to 4.5 hours. Hydroxyurea has shown clinical activity in the treatment of chronic myelocytic leukemia, polycythemia vera, and thrombocytosis. The major side effects are myelo-suppression, nausea and vomiting, diarrhea, and constipation. Rash, mucositis, and renal tubular dysfunction occur rarely. 

Rat (Wistar) 2-4 mo ad lib (W) Renal 81 F 320 F (tubular dysfunction as indicated by 2-3-fold increase in urinary excretion of B2-microglobulin) Vyskocil et al. 1995 PbAc... 

Vyskocil A, Panci J, Tusl M, et al. 1989. Dose-related proximal tubular dysfunction in male rats chronically exposed to lead. J Appl Toxicol 9 395-400. 

Significant renal tubular dysfunction >100-200 mg/kg FW renal cortex >400-800 mg/kg DW 2, 3... 

The renal tubular dysfunction of galactosemia is very similar to that caused by, e.g., heavy metal poisoning in both cases it seems likely that the inhibition of enzyme systems prevents the cells of the renal tubule... 

In those patients who survive more than a few weeks, the effects of renal tubular dysfunction become more severe. Acidosis and hypo-phosphatemic rickets are prominent features. The urine is alkaline and gives a strong Rothera reaction. However, the ability to concentrate the urine is never lost and there is neither polydipsia nor polyuria. Aminoaciduria, hydroxyphenyluria, glucosuria, fructosuria, and proteinuria continue. The liver remains large and cirrhotic. Death finally occurs in liver failure, sometimes after several years. There is evidence that some children recover with no residual signs other than a large firm liver. 

Methoxyflurane (Penthmne) is the most potent inhala-tional agent available, but its high solubility in tissues limits its use as an induction anesthetic. Its pharmacological properties are similar to those of halothane with some notable exceptions. For example, since methoxyflurane does not depress cardiovascular reflexes, its direct myocardial depressant effect is partially offset by reflex tachycardia, so arterial blood pressure is better maintained. Also, the oxidative metabolism of methoxyflurane results in the production of oxalic acid and fluoride concentrations that approach the threshold of causing renal tubular dysfunction. Concern for nephrotoxicity has greatly restricted the use of methoxyflurane. 

Acute exposure to inorganic lead can cause reversible damage to the kidneys, manifested as tubular dysfunction. Chronic exposure to lead, however, causes permanent interstitial nephropathy, which involves tubular cell atrophy, pathological changes in the vasculature, and fibrosis. The most pronounced changes occur in the proximal tubules. Indeed, lead-protein complexes are seen as inclusion bodies in tubular cells, and the mitochondria in such cells have been shown to be altered with impaired oxidative phosphorylation. Clearly, this will influence the function of the proximal tubular cells in reabsorption and secretion of solutes and metabolites. Consequently, one indication of renal dysfunction is amino aciduria, glycosuria, and impairment of sodium reabsorption. 

Q13 Magnesium is a major intracellular cation which acts as a co-factor in many intracellular enzyme reactions. Plasma concentration is normally 2 mg dl-1. This ion is abundant in the diet, and hypomagnesaemia is relatively uncommon, unless there is malabsorption or excessive loss via the kidney. However, when present, hypomagnesaemia can lead to hypoparathyroidism. Adjustment to the levels of magnesium can shift the function of the parathyroid glands back to normal. Chronic alcoholism, malnutrition, malabsorption, renal tubular dysfunction and excessive use of diuretics, such as loop and thiazide diuretics, may lead to hypomagnesaemia. Symptoms of magnesium deficiency include depression, confusion, muscle weakness and sometimes convulsions. 

The other case history was an example of the complete opposite. Here, low urine concentrations were observed in spite of obvious excessive exposure and moderate cholinesterase decline. This was a 49-year-old agricultural sprayman whose techniques were atrocious and protection was minimal. In spite of these practices, however, urine concentrations were always below the 1-p.p.m. level of PNP. It was also noted that, although not drinking excessively, over an 80-day period he failed to concentrate his urine above isotonic levels, suggesting some underlying urinary concentration defect. Correction of his urine to osmotic levels observed in other spraymen would have raised his PNP level to 5 p.p.m. Subsequent evaluation confirmed the presence of proximal and distal renal tubular dysfunction. 

The renal toxicity associated with aldesleukin is dose-related. It manifests as uremia, oliguria, fluid retention, and pronounced renal tubular sodium reabsorption (77). No evidence of tubular dysfunction has been found. There is reduced renal plasma flow associated with reduced renal prostaglandin synthesis and increased plasma renin activity, which may explain the mechanism (84). 

A prerenal mechanism secondary to the vascular leak syndrome is commonly involved in the pathophysiology of acute renal insufficiency. In addition it has been suggested that a direct intrinsic intrarenal effect of aldesleukin with a higher than expected reduction in glomerular filtration rate or tubular dysfunction (85,89) is involved. Several isolated cases of acute interstitial or tubulointerstitial nephritis with predominant T lymphocjde infiltration of the kidneys (90-92) and the exacerbation of a subchnical IgA glomerulonephritis (93) suggested altered cell-mediated immunity. 

Heys SD, Eremin O, Franks CR, Broom J, Whiting PH. Lithium clearance measurements during recombinant interleukin 2 treatment tubular dysfunction in man. Ren Fail 1993 15(2) 195-201. 

Aminoglycoside-induced proximal tubular dysfunction, which causes some manifestations of Fanconi s syndrome, including electrolyte abnormalities, is rare. 

Schreiber S, Hamling J, Zehnter E, Howaldt S, Daerr W, Raedler A, Kruis W. Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate. Gut 1997 40(6) 761-6. 

In a few cases, gentamicin nephrotoxicity was associated with a Fanconi syndrome, with raised serum enzymes activities in the urine. Among these, murami-dase seemed to be especially useful in checking for proximal tubular dysfunction (30). 

Wu MS, Hong JJ, Lin JL, Yang CW, Chien HC. Multiple tubular dysfunction induced by mixed Chinese herbal medicines containing cadmium. Nephrol Dial Transplant 1996 ll(5) 867-70. 

Burk CD, Restaino I, Kaplan BS, Meadows AT. Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms tumor. J Pediatr 1990 117(2 Pt l) 331-5. 

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. 

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