Renal tubular dysfunction

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. 

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. 

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. 

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. 

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. 

Hjq)onatremia is rare, and persistent hyponatremia very rare in patients taking cisplatin (162). In a detailed description of the biochemical abnormalities that can result from renal tubular dysfunction after cisplatin therapy, it was noted that hypocalciuria is more common than hypomagnesemia, and that there tends to be a state of reduced serum bicarbonate. The most severe renal tubular damage caused by cisplatin is characterized by hypocalciuria, total body magnesium deficiency, and hypokalemic metabolic alkalosis (163). 

Transient renal tubular dysfunction has been reported in a patient with asthma requiring mechanical ventilation who received sevoflurane for 9 days (36). Soda hme was not used, and the cumulative dose was 298 MAC-hours. Serum and urinary inorganic fluoride concentrations reached maximum concentrations of 71 and 2047 pmoPl respectively. Markers of renal tubular injury were also greatly raised (urinary A-acetyl-beta-o-glucosaminidase and beta2-microglobulin). However, urine volume, creatinine clearance, and serum creatinine and urea concentrations were unaffected. 

Ishikawa M, Miyazaki M, Ohta Y. Transient renal tubular dysfunction in a patient with severe asthmatic attack treated with sevoflurane. J Anesth 2001 15(l) 49-52. 

Renal tubular dysfunction and hjrpophosphatemia occurred in a patient who was taking both stavudine and lamivudine (4). 

The acceptance by nephrologists of urinary enzyme activity as a measure of renal tubular dysfunction has been limited for several reasons. Paramount among these has been the difficulty to establish correlations between specific disease states and the presence or absence of enzymuria. In addition, a relationship between the severity of cellular injury and the magnitude or cellular source of the enzymuria has been difficult to establish. For example, enzymes that appear in the urine may originate from lysosomes, the brush-border membrane, and/or the cytoplasm of the cells. Moreover, various factors that alter urinary enzyme activity are independent of cellular integrity, i.e., urinary pH, osmolarity, and the presences of various enzyme inhibitors or activators [160]. 

Funai N, Shimamoto Y, Matsuzaki M, Watanabe M, Tokioka T, Sueoka E, et al. Hyperkalaemia with renal tubular dysfunction by sulfamethoxazole-trimethoprim for Pneumocystis carinii pneumonia in patients with lymphoid malignancy. Haematologia. 1993 25(2) 137-41. 

Renal tubular dysfunction is described in animals but human expression in unclear [12]. Most use of mTOR inhibitors is in conjunction with lowered doses of calcineurin inhibitors since it is known that these two drug classes have a potent drug-drug interaction leading to enhanced renal dysfunction compared to the calcineurin inhibitor alone [782]. This may be explained by inhibition of drug efflux pump P-glycoprotein since both siroiimus and the calcineurin inhibitors are competitive substrates [783, 784]. 

The LMW protein, (32-microglobulin, which is considered to be a more sensitive indicator of Cd-induced renal tubular dysfunction, was measured in an epidemiological study in 3,178 inhabitants over 50 years of... 

The epidemiological study reported by the Japan Environment Agency in 1989 failed to detect any renal tubular dysfunction among 7,196 persons in the Cd non-poUuted areas, while in 202 persons among 13,570 (1.5% ) of the Cd-poUuted areas, proximal renal tubular dysfunction was seen [88]. 

Data from a 7-year follow-up study in another Cd-polluted area (Nagasaki) showed that, in both men and women, serum p2-microglobulin and creatinine, as well as urinary total protein and p2-microglobulin were significantly related to mortality independent of age as assessed by the Cox s proportional hazards model [111]. In advanced cases, the excess mortality of subjects with Cd-induced renal tubular dysfunction might, to some extent, be ascribed to a reduction in GFR. 

Auto-antibodies against metallothionein can be determined in plasma by enzyme-linked immunosorbent assay. It was shown in an occupationally Cd-exposed group in China, that persons with elevated levels of antibodies against metallothionein in plasma displayed a greater sensitivity to developing renal tubular dysfunction - odds ratio 4.2 (95% Cl 1.2-14.5) [161]. In a group of Chinese type-2 diabetics with uri-... 

KidoT, Honda R, Yamada Y,Tsuritani I, Ishizaki M, Nogawa K. a,-microglobulin determination in urine for the early detection of renal tubular dysfunctions caused by exposure to cadmium.Toxicol Lett 1985 24 195-201. 

Harada T, Matsuo S, Hara K, Yoshimura S. The association between proximal renal tubular dysfunction and osteopenia using microdensitometry in subjects required observation in cadmium-polluted areas. Kankyo-Hoken Report (In Japanese) 1986 52 109-113. 

In the early stage of the disease, patients suffer from pains in the lumbar areas, shoulders, and eventually the entire body due to renal tubular dysfunction and decrease in the bone mass. In the later, more serious stage, patients may experience difficulty in mobility due to osteomalacia with severe pains, and may further experience spontaneous bone fracture caused by the slightest external pressure, such as coughing. Finally, patients waste away and eventually die due to significant weight loss. 

Renal tubular dysfunction with itai-itai disease is irreversible and progressive even if the cadmium exposure is reduced. There is no specific treatment for renal tubular dysfunction by chronic cadmium poisoning. Long-term administration of vitamin D could be useful in the treatment of osteomalacia however, its effectiveness is limited, and the reappearance of osteomalacia could be observed due to the latent renal tubular dysfunction. 

Lead is one of the systemic poisons, in that once absorbed into the circulation, it is distributed throughout the body where it causes serious health effects. Manifested effects of Pb poisoning include nausea, anorexia, and severe abdominal cramps, weight loss, anemia, renal tubular dysfunction, muscle aches, and joint pains. Lead can pass the placental barrier and may reach the fetus, resulting in miscarriages, abortions, and stillbirths. 

Aminoacidurias may be primary or secondary. Primary disease is due to an inherited enzyme defect, also called an inborn error of metabolism. The defect is located either in the pathway by which a specific amino acid is metabolized or in the specific renal tubular transport system by which the amino acid is reabsorbed. Secondary aminoaciduria is due to disease of an organ, such as the liver, which is an active site of amino acid metabolism, or to generalized renal tubular dysfunction, or to protein-energy malnutrition. Specific inborn errors of metabohsm are discussed in more detail in Chapter 55. 

Lindemann R. 1991. Congenital renal tubular dysfunction associated with maternal sniffing of organic solvents. Acta Pediatr Scand 80 882-884. 

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