Tubular Damage In Patients Research Articles

Renal hypouricemia is an ominous sign in patients with severe acute respiratory syndrome

Background: The purpose of this study is to determine the incidence and significance of hypouricemia in patients with severe acute respiratory syndrome (SARS). Pulmonary lesions in patients with SARS are thought to result from proinflammatory cytokine dysregulation. Acute renal failure has been reported in patients with SARS, but whether cytokines can injure renal tubules is unknown. Methods: Sixty patients diagnosed with SARS in Taiwan in April 2003 were studied. Patients were identified as hypouricemic when their serum uric acid (UA) level was less than 2.5 mg/dL (<149 μmol/L) within 15 days after fever onset. Urine UA and creatinine levels were available for 43 patients; the serum cytokines interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α) were measured in 16 patients. Results: Sixteen patients (26.7%) had hypouricemia (UA, 1.68 ± 0.52 mg/dL [100 ± 31 μmol/L]). No differences in age, sex, symptoms, vital signs, hemogram, or other biochemistry data existed between the hypouricemic and normouricemic groups. Fractional excretion (FE) of UA (FEUA) in 12 hypouricemic patients was 39.6% ± 23.4%, significantly greater than that of 31 normouricemic patients (16.4% ± 11.4%; P < 0.0001). After adjustments for age and sex, high FEUA was significantly associated with the lowest blood oxygenation (P = 0.001; r = −0.624). The number of catastrophic outcomes (endotracheal intubation and/or death) adjusted for older age and sex showed that hypouremic patients had an odds ratio of 10.57 (confidence interval, 2.33 to 47.98; P = 0.002). Kaplan-Meier curves for catastrophic outcome–free results showed significant differences between patients with normouricemia or hypouricemia (P = 0.01). Serum IL-8 levels correlated significantly with FEUA (P < 0.001; r = 0.785) and inversely with serum UA level (P = 0.044; r = −0.509); neither IL-6 nor TNF-α level showed such correlations. Conclusion: One fourth of patients with SARS developed hypouricemia, which might result from a defect in renal UA handling and was associated with a high serum IL-8 level. Renal hypouricemia is an ominous sign in patients with SARS.

Lipid peroxidation and its correlations with urinary levels of oxalate, citric acid, and osteopontin in patients with renal calcium oxalate stones

Objectives To determine whether lipid peroxidation plays a role in patients with calcium oxalate kidney stones and to determine the correlation of lipid peroxidation with tubular damage and the major urinary risk factors. We also used the isoenzymes of glutathione S-transferase (GST) to examine which parts of the renal tubules were injured in patients with renal stones. Methods This clinical study included two study groups. Group 1 included 32 normal volunteers, and group 2 included 32 patients with calcium oxalate kidney stones. A 24-hour urine sample was collected from each subject, and the levels of Ca, P, Mg, oxalate, citrate, N-acetyl-β-glucosaminidase (NAG), β-galactosidase (GAL), αGST, πGST, osteopontin (OPN), thiobarbituric acid-reactive substances (TBARS), and malondialdehyde (MDA) were examined. Results Hyperoxaluria, hypocitraturia, and low urinary OPN were the major abnormalities found in the patients with stones. Elevated urinary αGST, NAG, and GAL were also noted in the patients with stones; however, urinary πGST showed no statistically significant difference compared with the controls. Urinary TBARS and MDA had statistically significant correlations with αGST, GAL, NAG, Ca, and oxalate, but had no correlation with πGST, citrate, OPN, Mg, and P. Urinary citrate had a negative, linear, and statistically significant correlation with αGST, GAL, and NAG. Conclusions Lipid peroxidation correlated with hyperoxaluria and renal tubular damage, indicating that hyperoxaluria can induce tubular cell injury and that this injury may be due to the production of free radicals in patients with calcium oxalate stones. Renal tubular damage in patients with stones may be limited to the proximal tubules.

Partially reversible renal tubular damage in patients with obstructive jaundice

Decreased serum uric acid levels resulting from renal urate wasting have been occasionally encountered in jaundiced patients. However, in these cases, there are no data concerning the underlying renal tubular defects. In the present study, we investigated the renal tubular function in 35 patients with obstructive jaundice of various severity and causes (11 with lithiasis, 17 with carcinoma, and 7 with intrahepatic cholestasis). A detailed study of the renal tubular function was performed. Beyond the conventional methods, 1H-NMR spectroscopy of urine was used to evaluate noninvasively renal damage by the characteristic perturbation in the excretion pattern of low-molecular weight endogenous metabolites. On admission, patients with obstructive jaundice had significantly lower serum uric acid and phosphate levels and higher bile acid concentrations compared with 40 age- and sex-matched controls. Serum uric acid levels presented a negative correlation with the total and direct bilirubin as well as the fractional excretion of uric acid. Furthermore, a great number of the patients studied developed one or more proximal tubular dysfunction manifestations beyond uricosuria, such as renal glucosuria, phosphaturia, and increased excretion of α1-microglobulin. 1H-NMR spectroscopy of the urine showed decreased levels of citrate and hippurate and increased levels of 3-hydroxybutyrate and acetate. In 12 patients partial or complete remission of jaundice was followed by an improvement of the proximal renal tubular damage. In conclusion, obstructive jaundice can cause a partially reversible generalized proximal tubular dysfunction. (HEPATOLOGY 2001;33;1365-1369.)

A review on urinary proteins in outflow disease of the upper urinary tract

Introduction: No review articles on outflow disease of the upper urinary tract discuss urinary protein excretion. Discussion: Following acute partial and/or complete ureteral obstruction (UO) or chronic partial UO, α-1-microglobulin excretion is significantly higher than in the reference population or patients with proven renal dilatation without obstruction, but is not found to be diagnostic for these conditions as such. Chronic partial UO is followed first by a destructive and then by a steady-state phase in renal damage. The observed increase in tubular proteinuria during the destructive phase correlates with the decrease in absolute dimercaptosuccinic acid (DMSA) uptake. If the destructive phase is not followed by a stable phase, a mixed tubular and glomerular proteinuria is seen. Urinary α-1-microglobulin excretion is found to be diagnostically useful in vesico-ureteral reflux (VUR) patients, increases with higher intravesical–intrapyelic pressure, correlates with the decrease in absolute DMSA uptake or with urinary epidermal growth factor excretion (both markers of the number of functioning nephrons) and predicts the outcome after treatment. Conclusion: α-1-Microglobulin is useful in the detection of renal tubular damage in patients with outflow disease of the upper tract, is diagnostic for VUR but is not so for ureteral obstruction.

Serum levels of IgG antibodies against Tamm-Horsfall protein and urinary excretion of NAG and alpha-1-microglobulin as possible markers for tubular damage in patients with a continent ileal reservoir for urinary diversion.

Serum IgG antibodies against Tamm-Horsfall protein and urinary excretion of NAG and alpha-1-microglobulin were measured in 26 patients with a Kock reservoir for continent urinary diversion or orthotopic bladder reconstruction in order to detect any signs of tubular damage. None of these markers for tubular damage was correlated to the postoperative observation time ranging between 2 and 16 years. No correlation was found between these markers and signs of renal scarring or upper urinary tract dilatation as judged from urographies. A positive correlation was demonstrated between NAG excretion and antibodies against Tamm-Horsfall protein. The annual reduction in GFR was increased in patients with elevated alpha-1-microglobulin excretion but not in patients with elevated titres of antibodies against Tamm-Horsfall protein or increased NAG excretion. Patients with previous or present reflux nipple problems had elevated excretion of alpha-1-microglobulin. Regular determinations of alpha-1-microglobulin excretion appear to be of value in the follow-up of these patients.

Urinary beta 2-microglobulin as a marker for vesicoureteral reflux.

To determine whether urinary beta 2-microglobulin (beta 2 M) excretion would be elevated in patients with severity of vesicoureteral reflux, urinary beta 2 M/creatinine (Cr) ratios were measured on random urine samples in 56 children with various grades of reflux. Results were compared with ratios of 39 nonrefluxing patients matched for age and gender. Patients with evidence of renal insufficiency or urinary tract infection were excluded. Bladder urine was obtained at the time of the vesicoureterogram. Reflux was graded using the International Reflux Classification System. The mean urinary beta 2 M/Cr ratio was higher in the refluxing group (1.82 +/- 0.6 micrograms/mg Cr) than in the nonrefluxing control group (0.54 +/- 0.09 microgram/mg Cr. P < 0.01). When the mean urinary beta 2 M/Cr ratios were compared for each grade of reflux with the nonrefluxing control group, patients with grade IV and V reflux had significantly higher urinary beta 2 M/Cr values than the nonrefluxing patients (2.83 +/- 0.71 micrograms/mg Cr and 4.61 +/- 0.65 micrograms/mg Cr, P < 0.001, respectively). No patient with grade I, II, or III reflux had a urinary beta 2 M/Cr ratio above 0.92 microgram/mg Cr. Statistical analysis revealed no significant differences among the mean beta 2 M/Cr ratio for grade I (0.53 +/- 0.08), II (0.51 +/- 0.09), or III (0.59 +/- 0.17) refluxers or the nonrefluxing controls. Therefore, urinary beta 2 M/Cr ratios are increased in children with a high grade of reflux. Such values may be useful in the early detection of tubular damage in patients with vesicoureteral reflux.

Serum concentration and urinary excretion of beta 2-microglobulin and microalbuminuria in familial Mediterranean fever.

Familial Mediterranean fever is characterised by recurrent and self limited attacks of fever and polyserositis and its devastating complication is the development of renal amyloidosis. In order to detect the presence of early glomerular and tubular damage in patients with familial Mediterranean fever and to assess the possible role of beta 2-microglobulin in the inflammatory attacks of this disease, serum and urine beta 2-microglobulin concentrations and microalbuminuria were evaluated in these patients. A total of 20 patients with familial Mediterranean fever were studied on and off colchicine treatment; seven of these patients developed a familial Mediterranean fever attack when they were off treatment. During the familial Mediterranean fever attacks serum beta 2-microglobulin concentrations decreased, whereas fractional excretion of beta 2-microglobulin, urine beta 2-microglobulin creatinine, and urine albumin/creatinine ratios increased. We conclude that glomerular and tubular functions deteriorate during the attacks. Further studies are needed to discover the effector(s) causing these transient glomerular and tubular disorders.

Relationship between markers of endothelial dysfunction, oxidant injury and tubular damage in patients with insulin-dependent diabetes mellitus.

1. Diabetic nephropathy is a serious microvascular complication in patients with insulin-dependent diabetes mellitus, resulting in end-stage renal disease in 30-45% of such patients. Despite intensive investigation, the pathophysiology of diabetic renal disease has not been fully elucidated. However, several clinical and experimental studies have suggested that endothelial dysfunction and free-radical activity may be important factors. 2. Forty normotensive patients with insulin-dependent diabetes mellitus of between 10 and 20 years duration with persistent normoalbuminuria (albumin excretion < 30 mg/day) and normal renal function were investigated for markers of endothelial dysfunction (plasma von Willebrand factor, soluble thrombomodulin and angiotensin-converting enzyme activity), free oxygen radical generation (erythrocytic superoxide dismutase and glutathione peroxidase) and oxidant injury (serum malondialdehyde). Glomerular proteinuria (albuminuria, transferrinuria), tubular proteinuria (retinol-binding protein) and tubular enzymuria (N-acetyl glucosaminidase and leucine aminopeptidase) were also measured. 3. Patients were divided into two groups. Group 1 comprised 21 patients with elevated markers of endothelial dysfunction, and group 2 comprised 19 patients with normal levels of plasma von Willebrand factor, soluble thrombomodulin and angiotensin-converting enzyme activity. Thirty-eight healthy subjects matched for age and sex acted as controls. 4. Groups 1 and 2 were similar in age, sex, body weight, duration of diabetes mellitus and recent glycaemic control. Serum cholesterol, serum creatinine and glomerular proteinuria were similar in the three groups. Group 1 patients had significantly increased oxidant injury, tubular enzymuria and proteinuria compared with group 2 patients and control subjects (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in urinary retinol binding protein excretion and other indices of renal tubular damage in patients with non-insulin dependent diabetes

Changes in urine retinol binding protein (RBP, M r 21 000) excretion and other indices of renal tubular damage were investigated in the patients with non-insulin dependent diabetes mellitus (NIDDM). Changes in urine RBP excretion were well paralleled with those of urine NAG excretion. In RBP-negative patients, the subjects with hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg) showed higher β 2-microglobulin ( β 2-MG) excretion and albumin (Alb) Cr ratios than normotensive ones. In addition, both urine β 2-MG excretions and Alb Cr ratios were significantly increased in RBP-positive patients. The measurement of urine RBP excretion may have an additional role in the diagnosis of renal tubular dysfunction in diabetic patients.

Renal Tubular Damage After Renal Stone Treatment

50 patients were studied with respect to renal tubular damage related to open operative, percutaneous and extracorporeal shock wave treatment of renal stones. Preoperative and postoperative urinary N-acetyl-glucosaminidase (NAG) levels were measured as a marker of renal damage. There was no significant evidence of renal tubular damage in patients who underwent a conventional or percutaneous nephrolithotomy; urinary NAG excretion was significantly increased after ischaemic surgery. After extracorporeal shock wave lithotripsy (ESWL) serum NAG levels increased, probably because a damage of the white blood cells in cutaneous and renal circulation, but a slight increase of urinary NAG excretion could suggest a mild renal tubular damage especially in case of more than 2,000 shocks.

Renal tubular damage after renal stone treatment.

50 patients were studied with respect to renal tubular damage related to open operative, percutaneous and extracorporeal shock wave treatment of renal stones. Preoperative and postoperative urinary N-acetyl-glucosaminidase (NAG) levels were measured as a marker of renal damage. There was no significant evidence of renal tubular damage in patients who underwent a conventional or percutaneous nephrolithotomy; urinary NAG excretion was significantly increased after ischaemic surgery. After extracorporeal shock wave lithotripsy (ESWL) serum NAG levels increased, probably because a damage of the white blood cells in cutaneous and renal circulation, but a slight increase of urinary NAG excretion could suggest a mild renal tubular damage especially in case of more than 2,000 shocks.

Renal tubular damage in patients with alcoholic liver disease

Renal tubular damage in patients with alcoholic liver disease

Enhancement of methotrexate nephrotoxicity after cisplatin therapy.

We measured urinary levels of total protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase-binding protein in ten children with osteogenic sarcoma who were receiving combination chemotherapy that included 12 doses of methotrexate (12 g/m2). Analysis of the changes in these sensitive markers of renal tubular damage permitted detection of subclinical methotrexate-induced nephrotoxicity. In the absence of cisplatin, methotrexate therapy was associated with significant but transient increases in each of the four markers. Irreversible nephrotoxicity, indicated by persistent rises in NAG and alanine aminopeptidase as well as increased serum creatinine levels, was associated with doses of methotrexate that followed the administration of cisplatin (400 mg/m2). The biphasic pattern of total protein and NAG excretion observed in all patients suggests more than one mechanism of methotrexate-induced nephrotoxicity. Monitoring renal tubular damage in patients who are receiving methotrexate in combined-drug regimens would provide useful information for scheduling nephrotoxic drugs in clinical trials.

Tubular damage in patients with hypokalaemia

Severe hypokalaemia is occasionally associated with gross changes in renal tubular function. We have looked for lesser degrees of renal tubular damage in unselected patients with hypokalaemia by measuring the urine excretion of total protein, albumin, the low molecular mass protein β 2-microglobulin (B2M) and two enzymes, N-acetyl-glucosaminidase (NAG) and alanine aminopeptidase (AAP). The frequency of abnormal values for these tests separately (compared with matched patients without hypokalaemia) was 39–56%. Many patients had an abnormal value for more than one of the tests, but this was at least partly due to chance association rather than to an underlying common mechanism for the several abnormalities. The frequency of abnormal values was greatest in the patients with the lowest plasma potassium concentrations, but not all of these patients had abnormal values for even one of the tests. Repeated measurements during treatment with potassium supplements showed that the tubular damage resolved in some patients but more slowly than the hypokalaemia. These results demonstrate that renal tubular damage is common amongst patients with hypokalaemia and is probably a consequence of the hypokalaemia in most of them. The measurements allow detection of patients whose tissues (at least the kidney) are adversely affected by the hypokalaemia, but the clinical usefulness of this information is yet to be established.

Increased Urinary Excretion of Renal Enzymes in Idiopathic Calcium Oxalate Nephrolithiasis

Urinary excretion of gamma-glutamyl transpeptidase, angiotensin I converting enzyme, beta-galactosidase and N-acetyl-beta-glucosaminidase was evaluated in 30 patients with idiopathic calcium oxalate urolithiasis. Higher than normal values were observed and the excretory enzyme pattern suggested tubular damage in patients with stones. A parallel study in the rat showed that an oxalate surcharge can promote increased urinary excretion of these enzymes. It is known that urothelium injury may enhance crystal adhesion. If the damage is primary it may be viewed as a promoting factor. If it is secondary it may be considered a factor capable of increasing salt precipitation.