The (pro)renin receptor: pathophysiological roles in cardiovascular and renal pathology

PURPOSE OF REVIEW: The pathophysiological role of the (pro)renin receptor is yet to be established. The present review summarizes the findings, suggesting that it may play pathological role in cardiac and renal fibrosis, and in hypertensive and diabetic nephropathy. RECENT FINDINGS: In-vitro and animal studies have shown that increased receptor expression could be linked to high blood pressure and to cardiac and glomerular fibrosis by activating mitogen-activated protein kinases and by upregulating gene expression of profibrotic molecules. Studies also suggest that the receptor is involved in diabetic nephropathy by activating receptor-bound prorenin, thereby increasing angiotensin II tissue generation. Moreover, in diabetic mice, a peptide able to block prorenin binding to the receptor was claimed to be more effective for renal protection than angiotensin-converting enzyme inhibitor. SUMMARY: The experimental data confirmed the pivotal role of the receptor in cell surface generation of angiotensin and suggested its potential role in tissue fibrosis via receptor activation and intracellular signaling. The data also questioned the ability of soon available renin inhibitors to inhibit the activity of receptor-bound renin and prorenin, and the benefit of a new class of drug--(pro)renin receptor blockers--to prevent tissue damage.     

The association between recipient alcohol dependency and long-term graft and recipient survival.

BACKGROUND: The causative role of alcohol consumption in renal disease is controversial, and its effect on renal graft and recipient survival has not been previously studied. METHODS: We analysed the association between pre-transplant [at the time of end-stage renal disease (ESRD) onset] alcohol dependency and renal graft and recipient survival. The United States Renal Data System (USRDS) records of kidney transplant recipients 18 years or older transplanted between 1 January 1995 and 31 December 2002 were examined. We used Kaplan-Meier analysis and Cox regression models adjusted for covariates to analyse the association between pre-transplant alcohol dependency and graft and recipient survival. RESULTS: In an entire study cohort of 60 523, we identified 425 patients with a history of alcohol dependency. Using Cox models, alcohol dependency was found to be associated with increased risk of death-censored graft failure [hazard ratio (HR) 1.38, P < 0.05] and increased risk of transplant recipient death (HR 1.56, P < 0.001). Subgroup analysis demonstrated an association of alcohol-dependency with recipient survival and death-censored graft survival in males (but not in females), and in both white and non-white racial subgroups. CONCLUSIONS: We concluded that alcohol dependency at the time of ESRD onset is a risk factor for renal graft failure and recipient death.     

Specific changes in plasma concentrations of matrix metalloproteinase-2 and -9, TIMP-1 and TGF-beta1 in patients with distinct types of primary glomerulonephritis.

BACKGROUND: Dysregulated renal expression of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMP) and TGF-beta1 contribute to the development of tubulo-interstitial fibrosis characteristic of progressive forms of primary glomerulonephritis (GN). There is little information on the circulating levels of these proteins in human GNs. Here, we assessed whether different histopathological GN types could be associated with distinct plasma patterns of MMPs and regulatory proteins. METHODS: Protein levels of MMP-2, MMP-9, TGF-beta1 and TIMP-1 were measured by ELISA in plasma from venous blood of 108 untreated patients with various types of primary GN defined by kidney biopsy, namely IgAN (n=63), membranous GN (MN, n=26), minimal change nephrotic syndrome (MCNS, n=12) and focal and segmental glomerular sclerosis (FSGS, n=7), and were compared with levels in 50 healthy subjects. Plasma samples were assayed for gelatinolytic activity (zymography). RESULTS: Zymography detected the proforms of MMP-2 and MMP-9. Compared with controls, IgAN patients exhibited a significant, parallel decrease in plasma levels of MMP-2, MMP-9 and TGF-beta1. In MN patients, decreased MMP-9 level contrasted with a high MMP-2 level and a normal TGF-beta1 level. In the MCNS/FSGS group, increased MMP-2 level contrasted with unchanged MMP-9 and decreased TGF-beta1 levels. Plasma concentration of TIMP-1 was elevated in all GN groups. There was no correlation between baseline MMP-2/MMP-9/TIMP-1/TGF-beta1 levels and the degree of renal dysfunction or with progression toward ESRD. CONCLUSIONS: Plasma concentrations of MMP-2, MMP-9 and TGF-beta1 significantly differed between the various histopathological types of primary GNs, thus suggesting the involvement of different underlying mechanisms in the regulation of glomerular and tubulointerstitial fibrosis in these renal diseases.     

Impact of endoluminal treatment on small abdominal aortic aneurysm: aneurysm sac regression and secondary interventions with 5 years of follow-up

Does early repair of small abdominal aortic aneurysms (AAAs) lead to faster aneurysm sac regression or less secondary intervention? Computed tomography scans and reconstructions from M2S of all patients undergoing endovascular AAA repair at our institution from 1996 to 2006 were retrospectively reviewed. A small aneurysm is defined as an aneurysm sac to renal diameter ratio of less than 2. There were 374 patients with endovascular AAA repair that had complete imaging studies. There were 75 patients (20%) with small AAAs; of those, 19 patients (25.3%) had endoleak compared with 108 patients (36.1%) with a large aneurysm ( P = .1). Over a mean follow-up time of 42 months (range, 1-109), 11 small AAAs (14.7%) had secondary interventions compared with 58 (19.4%) of the large AAAs (P = .41). Small AAAs at 5 years had a 2.5% volume sac regression but a 3.0% increase in diameter. Those with a large aneurysm had a slight increase in sac volume and diameter at 1 month (3.3%, 1.4%) and then steadily decreased to -13.4% and -8.8% at 5 years. Patients with Endologix (Endologix Inc., Irvine, Calif) devices have the most regression when compared with patients with AneuRx (Medtronic Inc., Minneapolis, Minn) and Talent (Medtronic Inc., Minneapolis, Minn) devices. Early endovascular intervention in small AAAs does not result in faster aneurysm sac regression or secondary intervention. Aneurysm sac regression is significantly affected by endoleak, aneurysm size, and device used.     

Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD

Post transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients is assumed to be the result of impaired Epstein-Barr Virus (EBV)-specific cellular immunity. We analyzed the absolute CD4 and CD8 T cell counts as well as the EBV-specific CD4 and CD8 T cell responses in relation to EBV load in SOT recipients with PTLD. A prospective, single center study was initiated and 10 immunosuppressed patients with diagnosis of PTLD were analyzed and compared to 3 patients without PTLD (2 SOT recipients with EBV-reactivation, 1 patient with Infectious Mononucleosis) and 6 healthy EBV positive controls. EBV-specific CD8 T cells were enumerated using HLA class I tetramers and the IFN-gamma cytokine secretion assay. EBNA1-specific CD4 T cells were analyzed after protein stimulation and EBV load was quantified by real-time PCR. Absolute CD8 T cell counts were highly variable in all 19 cases analyzed. In contrast, the absolute EBV-specific CD8 T cell count was found to be low in 7/9 patients with PTLD (<5/microl whole blood). These frequencies were similar to absolute EBV-specific CD8 T cell numbers observed in healthy EBV positive donors, but much lower compared to patients with EBV reactivation but no PTLD. Absolute CD4 T cell counts were significantly lower in PTLD patients (mean: 336/microl+/-161 vs. controls 1008/microl+/-424, p=0.0001), with EBNA1-specific CD4 T cell responses being also low, but highly variable. Moreover, low absolute CD4 T cell counts (<230/microl) were associated with an elevated EBV load (>1000 copies/microg DNA). We conclude that SOT recipients with PTLD have an inadequate functional EBV-specific T cell response. Our data suggest that the frequency and function of circulating EBV-specific CD8 T cells are dependent on absolute CD4 T cell counts. Further studies are needed to verify if a low absolute CD4 T cell count presents a risk factor for the development of PTLD in SOT recipients.     

Cardiac function during laparoscopic vs open gastric bypass

BACKGROUND: Hypercarbia and increased intraabdominal pressure during prolonged pneumoperitoneum can adversely affect cardiac function. This study compared the intraoperative hemodynamics of morbidly obese patients during laparoscopic and open gastric bypass (GBP). METHODS: Fifty-one patients with a body mass index (BMI) of 40-60 kg/m2 were randomly allocated to undergo laparoscopic (n = 25) or open (n = 26) GBP. Cardiac output (CO), mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP), central venous pressure (CVP), heart rate (HR), and mean arterial pressure (MAP) were recorded at baseline, intraoperatively at 30-min intervals, and in the recovery room. Systemic vascular resistance (SVR) and stroke volume (SV) were also calculated. RESULTS: The two groups were similar in terms of age, weight, and BMI. Operative time was longer in the laparoscopic than in the open group (p < 0.05). The HR and MAP increased significantly from baseline intraoperatively, but there was no significant difference between the two groups. In the laparoscopic group, CO was unchanged after insufflation, but it increased by 5.3% at 2.5 h compared to baseline and by 43% compared to baseline in the recovery room. In contrast, during open GBP, CO increased significantly by 25% after surgical incision and remained elevated throughout the operation. CO was higher during open GBP than during laparoscopic GBP at 0.5 h and at 1 h after surgical incision (p < 0.05). During laparoscopic GBP, CVP, MPAP, and SVR increased transiently and PAWP remained unchanged. During open GBP, CVP, MPAP, and PAWP decreased transiently and SVR remained unchanged. There was no significant difference in the amount of intraoperative fluid administered during laparoscopic (5.5 +/- 1.6 L) and open (5.6 +/- 1.7 L) GBP. CONCLUSION: Prolonged pneumoperitoneum during laparoscopic gastric bypass does not impair cardiac function and is well tolerated by morbidly obese patients.     

Usual interstitial pneumonia: histologic study of biopsy and explant specimens

The pathologic findings in biopsy and subsequent explant specimens from 20 patients with usual interstitial pneumonia (UIP) were reviewed to refine histologic criteria for diagnosis, to identify factors that may confound diagnosis, and to assess the relationship of UIP and nonspecific interstitial pneumonia (NSIP). One case of NSIP was also identified and included for comparison. Surgical biopsies from 15 of the 20 UIP cases were diagnosed as UIP, whereas 5 showed only nondiagnostic changes. An important new observation is that areas resembling nonspecific interstitial pneumonia (NSIP-like areas) are present in the majority of UIP cases in both biopsy and explant specimens, and they are extensive in some. Ten of the 15 UIP biopsies were considered straightforward, with typical patchy interstitial fibrosis, honeycomb change, and fibroblast foci. Five cases were considered difficult because of prominent NSIP-like areas in two, extensive honeycomb change in one, superimposed diffuse alveolar damage in one, and superimposed bronchiolitis obliterans-organizing pneumonia in one. The most helpful feature for diagnosing UIP in difficult cases was the presence of a distinct patchwork appearance to the characteristic uneven or variegated parenchymal involvement along with evidence of architectural derangement. No explant showing UIP was preceded by biopsy findings of NSIP, and the one NSIP case appeared similar at biopsy and explant. NSIP or NSIP-like areas and UIP may reflect different mechanisms of fibrosis related either to different severity of injury or to different injuries.     

Our experience with tissue expansion on a series of 50 cases in Vietnam

The authors reviewed their experience with tissue expansion from July of 1995 to December of 1999 at Hanoi Plastic Surgery Center. A total of 75 tissue expanders of various sizes were placed in 50 consecutive patients (16 men and 34 women) for the reconstruction of secondary defects (burn scars, skin graft scars, hypertrophic scars, keloids, capillary hemangioma, congenital nevi and micotia). The average age of patients was 21 years. The tissue expansion protocol was used in clinical as well as common principle. The main technical details are modified in this procedure by the authors: type of intralesional incision for expander insertion, closing of wound incision by three layers, evacuation of the liquid in the prosthesis pocket, injection with antibiotic solution and expanded flap capsulectomy. The complications rate was 10.6% (8 complications in 75 expanders). The most common complications consisted of infection, hematoma, exposure of valve, dehiscence of incision, necrosis of the distal expanded flap. The overall failure rate was 8%. Thus our modified surgical details allowed us to decrease the major complications and to achieve the best possible functional and aesthetic results.