Uninephrectomy increases kidney beta2-microglobulin: can it play a role in the progression of kidney damage?

Beta2-microglobulin (beta2M) is highly accumulated by the kidneys of normal rats. The aim of this study was to verify if uninephrectomy can modify the renal uptake of labeled beta2M. For this purpose the radioactivity of plasma and those of the remaining kidney, liver and urine have been measured in uninephrectomized rats (NX) and in controls (C) at different times after the injection as i.v. bolus of 131I-beta2M. The experiments were performed in 114 Sprague-Dawley male rats. Fifty seven animals underwent right nephrectomy, the other animals being the C. NX and their C were divided in 3 groups, studied 2, 4 and 6 weeks after nephrectomy, respectively. Part of the animals were sacrificed 12 min after the injection of labeled beta2M (peak-time, i.e. time of highest kidney accumulation of 131I-beta2M in the normal rat) and part 10 min later. The results demonstrate that: - uninephrectomy increases plasma retention of 131I-beta2M - kidney uptake (total and per gram) is always higher in NX - liver uptake (much lower than that of kidney) is not influenced by uninephrectomy - urine excretion of radioactivity is minimal in both NX and C. The behavior of beta2M is similar to that we previously observed with alpha1-microglobulin and lysozyme. The higher kidney content of some low mw proteins after uninephrectomy could play a role in the progressive reduction of renal function determined by the reduction of renal mass.     

What is the role of decorin in diabetic kidney disease?

The small proteoglycan decorin may intercept the activity of the TGF-beta system. Decorin administration has been advocated as potential therapy in renal fibrotic diseases, because of the findings of a relative deficiency of decorin and a relative excess of TGF-beta in acute glomerulonephritis. Does a similar situation pertain in diabetic kidney disease? Activation of TGF-beta seems to be crucial to tissue injury in diabetic nephropathy, but until recently it has not been established whether decorin plays any role in the manifestations of this disease. We review evidence that a surfeit rather than a deficit in decorin expression exists in diabetic renal disease, and that there exists a negative feed-back loop whereby TGF-beta1 induces down-regulation of decorin expression. Rat and mouse mesangial cells as well as mouse proximal tubular cells in culture exhibit increased decorin mRNA levels in high ambient glucose. Decorin mRNA level in the kidney of streptozotocin-induced diabetes in mice is rapidly and significantly increased following the induction of diabetes. Thus, the available evidence suggests that renal decorin is not deficient in this disorder and hence decorin supplementation does not seem to be warranted. Rather, interception of the effects of TGF-beta seems to be an approach most likely to yield beneficial results in diabetic nephropathy.     

Can bisphosphonates play a role in the treatment of children with chronic kidney disease?

In patients with chronic kidney disease (CKD) renal osteodystrophy, in the form of either low- or high-turnover bone disease, is quite common. While renal transplantation is expected to reverse renal osteodystrophy, long-term treatment with glucocorticoids before and/or after transplantation may lead to osteoporosis instead. Osteoporosis is defined as a skeletal disease with low bone mineral density, microarchitectural deterioration, and concomitant fragility. In adults, bisphosphonates are widely used to treat osteoporosis and other diseases associated with excessive bone resorption. In pediatric CKD patients the efficacy and safety of these drugs have not yet been addressed adequately and thus no evidence-based recommendations regarding the optimal type of bisphosphonate, dosage, or duration of therapy are available. Furthermore, while in adults the determination of areal bone mineral density is sufficient to diagnose osteoporosis, this is not the case in children. Instead, in pediatric patients, careful morphological assessment of bone structure and formation is required. Indeed, data from studies with uremic rats indicated that bisphosphonates, via a deceleration of bone turnover, have the potential not only to aggravate pre-existing adynamic bone disease, but also to impair longitudinal growth. Thus, the widespread use of bisphosphonates in children with CKD should be discouraged until the risks and benefits have been carefully elucidated in clinical trials.     

Developmental expression of c-kit protooncogene in the rat testis

IntroductionInmammalianembryos,thegermcelllinebeginswithprimordialgermcelIs,andinmales,primordialgermcellsbecomegono-cytes,thece1lprecursorsofthespermatogoni-a.ThedevelopmentofanormaltestisdependsupontheproliferationofprimordialgermcellsandtheiraggregationwithSertolicellprecur-sorsLl:.Theseeventshavebeenshowntobeassociatedwiththeexpressionofthec-kitProtooncogenemappedtothe"whitespottinglocus(W)~ofthemouse[2,3j.Thec-kitPro-tooncogeneencodesatransmembranetyrosinekinasereceptor(4,5).Thestructu…     

Treatment of pulmonary hypertension in the general adult intensive care unit: a role for oral sildenafil?

Use of inhaled nitric oxide for treatment of pulmonary hypertensionin adult critical illness is limited by its mode of deliveryand high costs, prompting evaluation of alternative therapies.We report the use of oral sildenafil in a patient with severesecondary pulmonary hypertension and right ventricular dysfunction.Following reduction in mean pulmonary artery pressure and pulmonaryvascular resistance with inhaled nitric oxide, crossover tosildenafil therapy maintained control of pulmonary hypertension,facilitating discontinuation of respiratory and cardiovascularorgan support. The relative pulmonary vascular specificity oforal sildenafil, and its low cost, makes it an attractive therapeuticalternative to inhaled nitric oxide, and warrants further study.     

Cardioprotective role of statins in chronic kidney disease: do we have the answer?

The observational study by Szummer et al. shows that patients with advanced chronic kidney disease (CKD) are treated less with statins after myocardial infarction, even though statins benefit survival in CKD classes 1-4. The study's limitations are obvious, but such a population may be more representative. The results indicate that statins should be used more frequently after myocardial infarction in CKD classes lower than 5, a conclusion supported by the recently presented Study of Heart and Renal Protection (SHARP).     

Altered expression of farnesyl pyrophosphate synthase in prostate cancer: evidence for a role of the mevalonate pathway in disease progression?

Background

Preclinical studies demonstrated effects of drugs inhibiting the mevalonate pathway including nitrogen-containing bisphosphonates (N-BPs) and statins on tumor growth and progression. The exact role of this pathway in prostate cancer (PC) has not been identified yet. Herein, we evaluate the expression of farnesyl pyrophosphate synthase (FPPS), the key enzyme of the mevalonate pathway, in PC.

Patients and methods

Prostate cancer (PC) and benign prostate tissue of 114 men who underwent radical prostatectomy were constructed to a tissue microarray. Immunohistochemical staining of FPPS was quantified by the Remmele/Stegner immunoreactivity-score. Patients’ clinical follow-up was assessed. IRS was correlated to pathological and clinical data. The impact of FPPS expression on clinical course was assessed univariate and multivariate.

Results

Mean IRS in PC and benign tissue was 5.7 (95% CI 5.0–6.5) and 2.6 (2.1–3.0, p < 0.0001). Mean IRS in PC tissue of patients with organ-confined and locally advanced disease (pT ≥ 3) was 5.09 (4.22–5.96) and 6.87 (5.57–8.17, p = 0.035). IRS of PC tissue significantly correlated with Gleason score (p = 0.03). Patients with PC tissue IRS >3 showed shorter recurrence-free survival compared to the remaining (p = 0.01). Increased FPPS expression is an independent risk factor for early biochemical recurrence (p = 0.032).

Conclusions

This is the first study on FPPS in PC specimens. The association of FPPS with established histopathological risk parameters and biochemical recurrence implicates a contribution of the mevalonate pathway to PC progression. Further functional analysis is required to explore the role of this pathway in PC and to investigate whether FPPS expression affects the response of PC cells to N-BPs.     

Cyclooxygenase-2 expression: Does it have a probable role in tumorigenesis mechanisms of renal cell carcinoma?

Objectives The purpose of this study was to evaluate the correlation between the levels of cyclooxygenase-2 (COX-2) expression with clinicopathologic features and determine the impact on prognosis in patients with renal cell carcinoma (RCC). Methods Expression of COX-2 was evaluated immunohistochemically in RCC tissues from 62 patients who underwent radical nephrectomy between 1996 and 2004. Percentage of COX-2 staining was scored as 0 (negative), 1 (1–24%), 2 (25–49%), 3 (50–74%), and 4 (75–100%). Immunohistochemical COX-2 staining score (ISS) was defined as summation of intensity and percentage of COX-2 staining. Results Twenty-seven patients (43.5%) with a median follow-up of 47.8 (25–115) months stained positively for COX-2. COX-2 expression was positive in 37.1%, 50%, and 66.7% of patients with stages 1, 2, and 3, respectively (P = 0.46). Correlation between ISS and pathological stage was statistically significant (P = 0.005). Multivariate regression analysis revealed no clinicopathologic parameter as independent predictors of progression. Kaplan–Meier analysis revealed statistically significant different survival rates in tumor stage, grade, and ISS. Conclusion Although COX-2 expression is not an independent predictor of progression in patients with RCC, patients with higher ISS values have significantly shorter progression-free survival rates. These results might be important to the clinician because positive COX-2 expression of a certain RCC might necessitate early adjuvant systemic therapy to delay the progression of RCC. For this reason, there is a need for innovative, prospective, and randomized studies in patients with positive COX-2 expression that will display the impact of systemic therapies in these patients.     

The role of the ubiquitin–proteasome system in kidney diseases

Proteins in mammalian cells are continually being degraded and synthesized. Protein degradation via the ubiquitin-proteasome system (UPS) is the major pathway for non-lysosomal proteolysis of intracellular proteins and plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, differentiation, apoptosis, sodium channel function, and modulation of inflammatory responses. The central element of this system is the covalent linkage of ubiquitins to targeted proteins, which are then recognized by the 26S proteasome composed of adenosine triphosphate-dependent, multi-catalytic proteases. Damaged or misfolded proteins, as well as regulatory proteins that control many critical cellular functions, are among the targets of this degradation process. Consequently, aberration of the system leads to dysregulation of cellular homeostasis and development of many diseases. Based on the findings, it is not surprising that abnormalities of the system are also associated with the pathogenesis of kidney diseases. In this review, I discuss (1) the basic mechanism of the UPS, and (2) the association between the pathogenesis of kidney diseases and the UPS. Diverse roles of the UPS are implicated in the development of kidney diseases, and further studies on this system may reveal new strategies for overcoming kidney diseases.     

Managing highly sensitized renal transplant candidates in the era of kidney paired donation and the new kidney allocation system: Is there still a role for desensitization?

Kidney paired donation (KPD) and the new kidney allocation system (KAS) in the United States have led to improved transplantation rates for highly sensitized candidates. We aimed to assess the potential need for other approaches to improve the transplantation rate of highly sensitized candidates such as desensitization. Using the UNOS STAR file, we analyzed transplant rates in a prevalent active waiting‐list cohort as of June 1, 2016, followed for 1 year. The overall transplantation rate was 18.9% (11 129/58769). However, only 9.7% (213/2204) of candidates with a calculated panel reactive antibody ≥99.9% received a transplant, and highly sensitized candidates were less likely to receive a living donor transplant. Among candidates with a CPRA ≥ 99.5% (ie. 100%), only 2.5% of transplants were from living donors (13 total, 7 from KPD). Nearly 4 years after KAS (6/30/2018), 1791 actively wait‐listed candidates had a CPRA of ≥99.9% and 34.6% (620/1791) of these had ≥5 years of waiting time. Thus, despite KPD and KAS, many sensitized candidates have not been transplanted even with prolonged waiting time. We conclude that candidates with a CPRA ≥ 99.9% and sensitized candidates with an incompatible living donor and prolonged waiting time may benefit from desensitization to improve their ability to receive a transplant.     

Cystic fibrosis transmembrane conductance regulator in the kidney: clues to its role?

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic adenosine monophosphate dependent, low-conductance chloride channel found on the apical plasma membrane of secretory epithelia. Surprisingly, since cystic fibrosis patients have no kidney phenotype, CFTR is highly expressed in the kidney, present from 12 weeks of gestation in the human metanephric kidney. As well as the mature, full-length, 165-kD wild-type protein (WT-CFTR) associated with renal tubule plasma membranes, intracellular, partially glycosylated forms are also seen in normal kidneys. In addition, a kidney-specific splice variant of CFTR translates a cytoplasmic truncated protein (TNR-CFTR), apparently associated with a specific small endosomal population, and is predominantly expressed in the renal medulla. WT-CFTR and TNR-CFTR show different patterns of developmental regulation, WT-CFTR being the major form expressed early in metanephric development when it is localized at the apical plasma membrane of developing collecting tubules. By contrast, TNR-CFTR expression increases with gestational age, reaching adult levels at 23 weeks. Evidence suggests that WT-CFTR plays a role in chloride secretion into the apical lumen of normal distal tubules. In autosomal dominant polycystic kidney disease, normally targeted CFTR at the apical plasma membrane in association with mislocalized Na-K-ATPase may result in abnormal fluid secretion into cysts. Similar colocalization of WT-CFTR and Na-K-ATPase at the apical plasma membranes is found in collecting tubules during development when it is speculated to play a role in the initiation of opening of the tubule lumen.