C‐reactive protein as a prognostic marker for advanced renal cell carcinoma treated with sunitinib

Objectives: To investigate the prognostic role of C‐reactive protein in patients with advanced renal cell carcinoma treated with sunitinib. Methods: A total of 41 consecutive patients with advanced clear‐cell renal cell carcinoma treated with sunitinib between December 2008 and August 2011 were included in this study. Logistic regression analysis estimated the relative importance of non‐tumor variables, including C‐reactive protein, and selected adverse events as predictive factors for sunitinib responses. Results: Overall, 11 patients (26.8%) showed a partial response and 10 patients (24.4%) had stable disease. On univariate analysis, Memorial Sloan‐Kettering Cancer Center non‐poor risk, normal C‐reactive protein, hand–foot skin reaction, altered taste, fatigue and leukopenia were significantly correlated with objective responses (P = 0.020, 0.001, 0.006, 0.006, 0.023 and 0.037, respectively). On multivariate analysis, normal C‐reactive protein was independently associated with objective response (P = 0.016). Patients with a normal level of C‐reactive protein (≤0.30 mg/dL) had a significantly higher partial response plus stable disease rate (84.6% vs 35.7%, P = 0.002) and significantly longer progression‐free survival (median 19.0 vs 6.0 months, P = 0.036) than patients with an elevated level of C‐reactive protein. Conclusions: C‐reactive protein is an independent prognostic indicator for patients with advanced renal cell carcinoma treated with sunitinib.     

Inhibition of growth by calcitriol in a proximal tubular cell line (OK)

Calcitriol has been shown to inhibit (i) cell proliferationof renal carcinoma cell lines and of cultured adult human mesangialcells in vitro, and (ii) renal compensatory growth in vivo.In the present study we examined the effects of calcitriol onDNA synthesis and cell replication in an immortalized cell lineshowing the phenotypic characteristics of proximal tubular cells(opossum kidney, OK cells). The viability of OK cells was notaffected by calcitriol (Trypan-blue exclusion, LDH and K⁺ release),but the cells did not convert ³H-25(OH)₂ to 3H-1,25(OH)₂D3.In the log growth phase, calcitriol (but not alternative vitaminD metabolites) caused dose-dependent (1012 to 10^–6 M)inhibition of radiothymidine incorporation. Inhibition was calciumdependent, i.e. it was more pronounced at the lower nominalcalcium concentration in tissue culture media (0.9 versus 1.8mmol/l) and amplified by coincubation with nifedipine (I µM).Inhibition of DNA synthesis was paralleled by inhibition ofcell replication (growth curve) under basal conditions and afterstimulation with EGF (10 ng/ml). In conclusion, calcitriol inhibitsproliferation of proximal tubular cells which normally express1-alpha- hydroxylase activity.     

Tamm-Horsfall protein as a marker of tubular maturation

Tamm-Horsfall protein (THP), a glycoprotein with a molecular weight of 95 kilodaltons, is produced and secreted in the ascending loop of Henle. To evaluate the measurement of THP in the assessment of fetal renal development and function, we stained fetal kidney sections for THP and measured THP concentrations in 129 amniotic fluid samples from healthy pregnancies, together with other parameters such as transferrin, albumin, α₁- and β₂-microglobulin. After the 16th week of gestation THP could be detected immunohistochemically in the distal tubular cells, but was not consistently detected by sandwich enzyme immunoassay until after the 20th week of gestation (detection limit 50 ng/ml). Between the 15th and 19th week of gestation THP was only detected occasionally, but after the 20th week of gestation the concentration increased significantly reaching levels of 0.4 – 4 mg/l at term. The THP concentration was lower in samples taken directly before birth than in the corresponding first urine after birth, indicating that THP is produced from the fetal kidney only and does not pass the placental barrier. This pattern was different from other proteins studied. Transferrin and albumin were significantly lower in the first urine voided, microglobulins remained unchanged, and the creatinine concentration increased. This indicates that maternal to fetal exchange or transport is likely for most of the other proteins. Measurement of THP concentrations, in addition to other proteins in the amniotic fluid, can improve fetal renal assessment, but because the range of THP concentrations is wide accurate predictions are still not possible. Received April 5, 1994; received in revised form September 1995; accepted October 20, 1995     

霉酚酸酯用于肝移植术后慢性肾功能损害患者的疗效分析

目的 探讨肝移植术后慢性肾功能损害患者在减少钙调磷酸酶抑制剂(calcineurin inhibitors,CNIs)的基础上联合霉酚酸酯(mycophenolate mofeil,MMF)的临床疗效.方法 对我院28例术前肾功能正常,术后发生慢性肾功能损害的患者在减少CNIs的基础上联合MMF治疗,观察患者肾功能指标的变化,记录相关的不良事件.结果 除1例患者因严重骨髓抑制而停用MMF外,其余27例患者随访30.8个月,期间肾功能均得到一定程度改善.治疗1个月、12个月时患者血清肌酐水平[分别为(124.30±28.27)μmol/L和(119.71±31.36)μmol/L]较治疗前[(134.26±27.25) μmol/L]下降.治疗1个月、6个月、12个月时肌酐清除率、肾小球滤过率较转换治疗前升高,差异均有统计学意义(P＜0.05).治疗期间1例(3.7％)发生急性排斥反应.无巨细胞病毒感染或肿瘤复发发生.5例(18.5％)发生轻度消化道症状(腹胀、腹泻),2例(7.4％)发生缺血性胆管炎.结论 肝移植术后慢性肾功能损害患者转换MMF联合低剂量CNIs免疫抑制方案,可以改善和稳定肾功能,并不增加排斥和感染的发生率.     

Microscopic hematuria as a screening marker for urinary tract malignancies

BACKGROUND: Although a mass screening urinalysis is a widely accepted procedure, it has not yet been shown if microhematuria is an appropriate and useful screening marker for urologic malignancies. METHODS: (1) The incidence of hematuria was studied in 113 patients with renal cell carcinoma (RCC), 185 with bladder carcinoma and 51 with renal pelvic or ureteral carcinoma. The association of the T stage with the intensity of hematuria in each malignancy was also examined. (2) In 823 asymptomatic adults with microhematuria, the prevalence of these malignancies was studied retrospectively to find the positive predictive value (PPV). RESULTS: (1) The incidence of hematuria was 35% for RCC, including gross and microhematuria. Advanced RCC (T3 and T4) were diagnosed more frequently in the gross hematuria group than in the microhematuria and no hematuria groups. In contrast, the incidence of hematuria was 94% for urothelial carcinomas either in the upper urinary tract or in the bladder. There was no significant difference in the T stage nor grade between the gross hematuria group and the microhematuria group. (2) Regarding asymptomatic microhematuria, the PPV was 1.7% (14 cases) for bladder carcinoma, 0.4% (3 cases) for ureteral/renal pelvic carcinoma and 0.2% (2 cases) for RCC. In men aged 50 years or older, PPV was 6.2% for urothelial carcinomas. In 14 cases of bladder carcinoma, 3 cases showed muscle invasion. CONCLUSIONS: Microhematuria is an appropriate screening marker for urothelial carcinomas, particularly in elderly men, but not for RCC. However, it is unlikely that a mass screening urinalysis using a single voided urine sample would contribute to earlier detection of bladder carcinoma.     

Medullary cystic disease and tubular basement membrane changes: clinicopathological characteristics of four patients

We describe herein the clinicopathological characteristics of four members of a family in which about half of the generation was affected by chronic renal failure after middle age. The inheritance was considered to be an autosomal dominant pattern. Clinically, neither sensorineural deafness nor ocular abnormalities were evident. In addition, there was neither hypokalemia nor hypercalcemia causing deterioration of renal function. Radiological examination revealed no cystic formation in the kidneys in any patients, although in two of them the examination was performed at the time of endstage renal disease. Histological examination showed chronic tubulo-interstitial damage with periglomerular fibrosis. On electron microscopy, characteristic but nonspecific thickening and lamination of tubular basement membrane were noted in all patients, while glomerular basement membrane was unremarkable in all patients. These findings suggest that our patients had medullary cystic disease. Demonstration of lamination and thickening of the tubular basement membrane by electron microscopy may be useful for the diagnosis of medullary cystic disease with undetectable cyst formation. Received: December 1, 1999 / Accepted: October 16, 2000     

An association of tubular dysfunction, cortical macrocysts and chronic kidney disease

We present an unusual combination of kidney disorders in a boy born to consanguineous parents. He presented in the first year of life with dehydration and urosepsis and was subsequently found to have hyposthenuria and distal renal tubular acidosis, with normal appearance of the kidneys, by ultrasound examination. By 4 years of age he had developed multiple large cysts in both kidneys, and his nephropathy eventually progressed so that at 17 years of age he is approaching end-stage renal disease (ESRD). The association of initial tubular dysfunction followed by the development of multiple cysts may represent a new form of kidney disease.     

Fatty acids carried on albumin modulate proximal tubular cell fibronectin production: a role for protein kinase C.

BACKGROUND: Proteinuric renal disease is associated with accumulation of tubulointerstitial matrix proteins. Human proximal tubular cells (PTCs) produce fibronectin in response to serum proteins but not albumin alone. It has been suggested that renal toxicity of filtered albumin depends on its lipid moiety. We therefore investigated the functional consequences of different fatty acids (FAs) carried on human albumin after exposure to human PTCs in culture. METHODS: Confluent human PTCs were exposed to recombinant human serum albumin (rHSA) or palmitate (P)-, stearate (S)-, oleate (O)-, and linoleate (L)-complexed rHSA. In all experimental conditions, test media contained 1 mg/ml rHSA alone or carrying 100 mmol FAs. Mitogenic response was assessed by [(3)H]thymidine incorporation. Cell culture supernatants were assayed for fibronectin. Protein kinase C (PKC) activity was assessed in cell lysates. RESULTS: Apical exposure to rHSA alone or the O-rHSA complex stimulated a significant increase in [(3)H]thymidine incorporation, whereas the L-rHSA complex was markedly inhibitory to human PTC growth. The L-rHSA complex was associated with severe cytotoxicity as assessed by lactate dehydrogenase release. Among all conditions, O-rHSA was the only test media that significantly increased fibronectin levels over control conditions (150.1+/-10.6% over control, P<0.05, n=3). Pre-treatment of PTCs with PKC inhibitors before O-rHSA exposure resulted in a dose-dependent decrease in fibronectin secretion. O-rHSA activated PKC significantly compared with controls. CONCLUSIONS: We conclude that rHSA has a mitogenic effect on human PTCs, but fibronectin secretion was only induced by O-complexed rHSA and the O-rHSA effect was mediated via PKC activation. Involvement of PKC signal transduction pathway may be a novel therapeutic target for ameliorating proteinuria-induced tubular injury.     

Transforming growth factor-beta-induced alpha-smooth muscle cell actin expression in renal proximal tubular cells is regulated by p38beta mitogen-activated protein kinase, extracellular signal-regulated protein kinase1,2 and the Smad signalling during epithelial-myofibroblast transdifferentiation.

BACKGROUND: Transforming growth factor-beta (TGFbeta)-induced epithelial-myofibroblast transdifferentiation is a central mechanism contributing to the pathogenesis of progressive tubulo-interstitial fibrosis. We wanted to dissect the role of extracellular signal-regulated protein kinase (ERK1,2), p38 mitogen-activated protein kinase (p38 MAPK) and the receptor-regulated Smad proteins in the regulation of alpha-smooth muscle cell actin (alphaSMA) expression, a hallmark of myofibroblast formation, induced by TGFbeta in renal proximal tubular cells. METHODS: Activation of signalling molecules was assessed by western blotting using phospho-specific antibodies. To specifically interfere with signalling cascades, porcine proximal tubular cells (LLC-PK/AT1) were infected with recombinant replication-deficient adenoviruses. In other experiments, specific kinase inhibitors were used. The alphaSMA synthesis was assessed by western blotting or immunofluorescent staining of cellular alphaSMA. To assess the regulation of the alphaSMA promoter, tubular cells were transiently transfected with a 785 bp alphaSMA promoter-luciferase reporter construct and vectors interfering with the Smad pathway. RESULTS: Blocking ERK1,2 activation with PD98059 or p38 MAPK with SB 203580 potently inhibited the TGFbeta-induced alphaSMA synthesis in renal tubular cells. Adenoviral expression of dominant negative (DN) p38beta but not of p38alpha potently inhibited alphaSMA expression. Furthermore, adenoviral expression of DN MKK6b but not of DN MKK3b caused a substantial inhibition of the TGFbeta effect, confirming the role of p38beta in the regulation of TGFbeta-induced alphaSMA expression. Finally, inhibiting the Smad pathway with adenovirally delivered Smad7 and DN Smad3 also blocked TGFbeta-induced alphaSMA synthesis. CONCLUSION: TGFbeta-induced alphaSMA expression is regulated by the coordinated activation of a complex system of parallel MAPK and Smad signalling pathways in renal proximal tubular cells during epithelial-mesenchymal transdifferentiation.     

Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in children with chronic kidney disease

Very few biomarkers exist for monitoring chronic kidney disease (CKD). We have recently shown that serum neutrophil gelatinase-associated lipocalin (NGAL) represents a novel biomarker for early identification of acute kidney injury. In this study, we hypothesized that serum NGAL may also represent a biomarker for the quantitation of CKD. Forty-five children with CKD stages 2–4 were prospectively recruited for measurement of serum NGAL, serum cystatin C, glomerular filtration rate (GFR) by Ioversol clearance, and estimated GFR (eGFR) by Schwartz formula. Serum NGAL significantly correlated with cystatin C (r=0.74, P<0.000). Both NGAL and cystatin C significantly correlated with measured GFR (r=0.62, P<0.000; and r=0.71, P<0.000, respectively) as well as with eGFR (r=0.66, P<0.000 and r=0.59, P<0.000, respectively). At GFR levels of ≥30 ml/min per 1.73 m², serum NGAL, cystatin C, and eGFR were all significantly correlated with measured GFR. However, in subjects with lower GFRs (<30 ml/min per 1.73 m²), serum NGAL levels correlated best with measured GFR (r=0.62), followed by cystatin C (r=0.41). We conclude that (a) both serum NGAL and cystatin C may prove useful in the quantitation of CKD, and (b) by correlation analysis, NGAL outperforms cystatin C and eGFR at lower levels of measured GFR.     

Stone necklace of urinary tract presenting as renal failure: One stage management

We describe three cases with bilateral extensive involvement of both upper and lower urinary tract with calculi presenting in renal failure. The management of these patients in a single operative session and rendering them stone free is discussed. Modern endourologic techniques have made it possible to treat patients with such an extensive involvement of the urinary tract with stone disease with minimum morbidity.     

Early-onset chronic renal failure as a presentation of infantile nephropathic cystinosis

We report an 18-month-old girl who presented in chronic renal failure after an illness characterised by protracted diarrhoea, poor weight gain and anaemia. There were no symptoms and signs suggestive of a renal Fanconi syndrome, but a diagnosis of nephropathic cystinosis was suggested by renal biopsy and confirmed by an elevated leucocyte cystine concentration. We suggest that the diagnosis of cystinosis should be considered in any child with chronic renal failure of unknown aetiology.     

Primary signet-ring cell carcinoma of the urinary bladder inducing renal failure

A case of primary signet-ring cell carcinoma of the urinary bladder that was found to have induced renal failure is the second such case reported in the world. Primary signet-ring cell carcinoma of the urinary bladder is a rare histologic variant of adenocarcinoma. The patient died of distant metastasis 8 months after undergoing total cystectomy. The neoplasm had a high stage at diagnosis, so the prognosis was very poor. To improve the prognosis, earlier diagnosis and establishing a regimen of chemotherapy is necessary.     

Significance of platelet distribution width as a severity marker of erectile dysfunction

Mean platelet volume (MPV) and Platelet distribution width (PDW) are potential markers in platelet activation. In present study, we aimed to evaluate MPV and PDW as potential severity markers for those patients who are complaining erectile dysfunction (ED). A total of 358 participants were enrolled in this study. The whole cohort was asked to complete the International Index of Erectile Function‐5 (IIEF‐5) questionnaire. The participants were classified into 3 groups: control group (n = 120), mild ED (n = 118) and severe ED (n = 120). We found in our cohort MPV and PDW were significantly higher in both mild ED group and severe ED group than control group (9.24 ± 0.70 and 9.71 ± 0.80 versus 8.56 ± 0.62 for MPV; 14.48 ± 1.29 and 14.98 ± 1.60 versus 12.86 ± 1.13 for PDW respectively). The MPV and PDW increased as the disease progressed. In the mild and severe ED groups, a significant inverse correlation was detected between the mean values of IIEF‐5 score and PDW. Furthermore, in the receiver operating characteristic curve analysis, the area under the curve of the MPV and PDW to predict severe ED was 0.818 and 0.848 respectively. Our study establishes a dose‐dependent association between the PDW and ED. Therefore, the PDW can serve as a potential marker for predicting the severity of ED.     

Clear cell adenocarcinoma of the urinary bladder inducing acute renal failure

We report a case of clear cell adenocarcinoma of the urinary bladder. A 59-year-old male was referred to our hospital complaining of oliguria, left lower abdominal pain and loss of appetite. Ultrasonography revealed bilateral hydroureteronephrosis and obstructions at the ureterovesical junction. Magnetic resonance imaging demonstrated an invasive irregular tumor located in the posterior wall of the urinary bladder and urinary infiltration to the left retroperitoneal space.The clinical diagnosis was acute post renal failure due to bilateral ureteral obstructions from an invasive bladder tumor. After we performed bilateral percutaneous nephrostomy, the patient underwent trans urethral biopsy of the bladder tumor, which showed clear cell adenocarcinoma extending from the submucosa to the muscular layer, histopathologically. The patient died of metastatic disease 8 months after diagnosis. To our knowledge, the present case is the 23rd to be reported and demonstrates the shortest survival period in the related literature.     

Enzymuria and low molecular weight protein excretion as the differentiating marker of complications in the early post kidney transplantation period

Renal function in the early post-transplantation period depends largely on factors affecting the kidney prior to implantation. Function of the graft may be also disturbed by the most common complications of the early post-operative period such as acute graft rejection (AGR), acute tubular necrosis (ATN) and may be modified by nephrotoxic action of cyclosporine A (CsA). Evaluation of excretion of enzymes and low molecular weight proteins (LMWP) may help in the differentiation of these complications. Aim Comparison of the urinary excretion of markers of tubular injury in patients with AGR, ATN, or patients with stable graft function (SGF) was made and differences between groups and correlations between markers and cold ischemia time (CIT), warm ischemia time (WIT) and blood trough level of cyclosporine A (CsA₀) were determined. Material and methods In 60 cadaveric renal allograft recipients in the early post-transplantation period urinary excretion of N-acetyl-β-d-glucosaminidase (NAG) and B isoenzyme (NAG-B), alanylaminopeptidase (AAP), γ-glutamyltransferase (GGT), α and π isoenzymes of glutathione S-transferase (α-GST, π-GST), retinol binding protein (RBP) and β2- microglobulin (β2M), were analyzed. Results NAG and NAB-B activities were higher in ATN (P<0.05, P<0.01) and in AGR (P<0.005, P<0.02) than in SGF. Excretion of π-GST was higher in AGR than in SGF (P<0.0002) or ATN (P<0.007). CIT and WIT in patients with ATN were higher (P<0.05) than in SGF group. In ATN patients, correlations of CIT with RBP (P<0.05) and π-GST (P<0.05), and WIT with RBP (P<0.05), and π-GST (P<0.001) were found. Conclusions High urinary NAG and NAG B excretion characterizes ATN and AGR patients. Evaluating urinary excretion of π-GST may be helpful in differentiating AGR from ATN. However, taking into account ischemia time is necessary in interpreting the π-GST value in early post transplant period.