Nifedipine improves recovery function of kidneys preserved in a high- sodium, low-potassium cold-storage solution: study with the isolated perfused rat kidney technique

BACKGROUND: Extracellular types (high-Na) of cold-storage solution (CSS) have been shown to be more effective in preserving kidneys than intracellular CSS (high-K). On the other hand, calcium entry blockers (CEB) have been demonstrated to improve graft function when administered after and/or prior to transplantation. The ischaemia reperfusion syndrome involves, in part, an alteration in intracellular calcium metabolism that induces an increase in renal vascular resistances (RVR) and other cellular dysfunction, and high-K CSS per se are vasoconstrictive. Since CEB act via a modification in intracellular calcium metabolism on vascular smooth muscle, glomerular, and tubular cells, we evaluated the actual benefit on CEB on kidneys preserved in Belzer's CSS (K-UW) and a high-Na version of Belzer's CSS (Na-UW). METHOD: The isolated perfused rat kidney (IPK) was used, first as a vascular bed to test the effects of CSS on RVR, and the influence of nifedipine. Second, the recovery function of the IPK was assessed by GFR and tubular Na reabsorption, after 24 h preservation in K-UW and Na- UW, with or without nifedipine. Results were compared with a control group in which renal function was measured without prior cold-storage. RESULTS: K-UW but not Na-UW induced an increase in RVR when flushed into the kidney. This vasoconstriction is prevented by nifedipine. K-UW CSS was more deleterious to renal function than Na-UW. Addition of nifedipine to the flush, the CSS for 24 h, and to the normothermic reperfusate further improved recovery function of the IPK cold stored in Na-UW but not in K-UW, without any modification of RVR. CONCLUSION: Nifedipine may be of potential effect in attenuating ischaemic injury by a mechanism which does not involve its vasodilatory properties.      

Effect of IGL-1, a new preservation solution, on kidney grafts (a pre-clinical study)

Ischemia-reperfusion injury conditions short-term and long-term graft function. The effects of the inversion of K⁺ and Na⁺ concentrations and substitution with polyethylene glycol for hydroxyethyl starch in University of Wisconsin (K-UW) solution were evaluated in isolated perfused rat kidneys and in autotransplanted pig kidneys. In the rat model kidneys were cold-stored for 24 h in K-UW or Na-UW or Na-PEG UW solutions (IGL-1 solution). Fractional sodium reabsorption and glomerular filtration rate was better in kidneys preserved in Na-UW and IGL-1 solution than those preserved in K-UW solution. In the pig model the left kidney was harvested and preserved in K-UW or IGL-1 solution for 24 h and then transplanted. In the autotransplanted pig model, kidneys preserved in IGL-1 solution showed a better function and a significant reduction of MHC class II expression, cellular apoptosis and interstitial fibrosis. In conclusion, kidneys preserved in IGL-1 solution tolerated ischemia/reperfusion injury better than those preserved in K-UW solution.     

High-Na + low-K + UW cold storage solution reduces reperfusion injuries of the rat liver graft

The isolated perfused rat liver model was used to assess graft viability after 24 h of cold preservation. Two solutions were compared for liver preservation: Belzer's original UW solution (high-K ⁺ UW) and a solution containing the same components but with inverted concentrations of sodium and potassium (high-Na ⁺ UW). During the 120 min of normothermic reperfusion, livers preserved in the high-Na ⁺ UW solution released lower levels of creatine kinase-BB isoenzyme, transaminases (ALT and AST), and potassium than those preserved in the high-K ⁺ UW solution. Bile flow and biliary excretion of indocyanine green increased when livers were preserved in the high-Na ⁺ UW solution. We found no statistical differences for oxygen consumption and tissue ATP concentration. The results of this study support the concept that a high-Na ⁺ UW solution is a more effective means of preserving rat livers, at least after 24 h of cold-storage and 120 min of reperfusion in the isolated perfused model, than the original high-K ⁺ UW solution. Liver preservation in the high-Na ⁺ UW solution reduces damage to sinusoidal endothelial and hepatocellular cells. The use of an extracellular-like Belzer cold storage solution eliminates potassium-related problems in cold preservation and subsequent normothermic reperfusion while keeping all the qualities of the original UW solution. Received: 26 August 1997 Received after revision: 12 November 1997 Accepted: 28 November 1997     

新型器官保存液低温保存猪肾效果的研究

目的研究新型器官保存液Lifor液对猪肾脏的低温保存效果。方法 24只白色杂种猪,随机均分为Lifor液保存组和威斯康星大学保存液（UW液）组各12只,建立离体肾脏非循环灌注模型,供肾取出后分别以0~4℃的Lifor液和UW液灌注并低温保存,再根据保存时间随机分成2个亚组,分别为保存24h、48h组,然后行猪自体肾移植。比较两组肾脏低温保存结束后其病理学及肾皮质三磷腺苷（ATP）含量的改变,并观察自体肾移植后肾功能恢复情况。结果供肾离体保存24h、48h后,Lifor液组与UW液组的肾组织病理学改变基本一致,肾皮质ATP含量比较差异无统计学意义（P〉0.05）。移植后两组血清肌酐水平比较差异亦无统计学意义（P〉0.05）。结论 Lifor液低温保存肾脏的效果与UW液相当,且成本低廉,因此更具有临床应用前景。     

Renal sodium handling in experimental diabetes: role of NO

Recent studies have suggested that diabetes is a state of increasedrenal nitric oxide (NO) activity as assessed by urinary excretionof nitrites and nitrates (NO_x), and that NO synthase inhibitorsreverse the increased glomerular filtration rate (GFR) observedin experimental diabetes. In addition to being a potent vasodilatorin the renal vasculature, NO also plays a role in modulationof renal sodium excretion. To explore the role of NO in diabetes-associatedalterations in renal excretory function, renal haemodynamicand sodium handling parameters were evaluated in conscious control(C) and streptozotocin diabetic rats (D) and correlated to therenal activity of NO, as assessed by urinary excretion of itsmetabolites NO_x. To further explore this issue, the changesin renal haemodynamics and sodium handling were also assessedafter NO synthase inhibition with a non-pressor dose of L-nitro-arginine-methyl-ester(L-NAME) and after administration of the NO donor, glyceryltrinitrate (GTN). Systolic blood pressure was not differentbetween C and D rats. D rats exhibited marked hyperglycaemia(P<0.001), and increases in GFR (P<0.001), renal plasmaflow, filtration fraction, urinary sodium excretion (U_NaV, P<0.001),filtered load of sodium (FL_Na, P<0.01), and a decrease infractional reabsorption of sodium (FR_Na, P<0.0001). In contrast,total reabsorption of sodium (TR_Na) was increased in D ratscompared to C rats (P<0.0001). The urinary excretion of NOwas markedly increased in D rats (P<0.01). Regression analysesperformed in D rats revealed a close relationship between U_NaVand GFR and a weaker correlation with urinary NO_x. AlthoughFR_Na correlated only with urinary excretion of NO_x, there wasa strong relationship between TR_Na and GFR. In contrast to Drats, control rats demonstrated only a relationship betweenTR_Na and GFR and no other correlations were found, in D rats,NO inhibition with L-NAME (1 mg/kg body weight) resulted ina marked decrease in GFR and urinary NO_x associated with decreasesin FL_Na and TR_Na but did not influence FR_Na. In contrast, inC rats the post-L-NAME decrease in NO_x was not associated withsignificant changes in GFR and renal sodium handling. GTN-treatedC rats exhibited a renal vasodilatory response and an increasein natriuresis and urinary NO_x whereas no renal changes wereobserved in D rats during GTN administration. The present dataindicate that changes in renal sodium handling before and afterNO modulation in experimental diabetes are related to changesin GFR rather than to the renal activity of NO. Therefore, incontrast to the effects on renal haemodynamics, NO does notplay an important role in the altered renal sodium handlingobserved in experimental diabetes.     

Successful 72-hour cold storage of dog kidneys with UW solution

Effects of three cold-storage solutions on kidney function in dogs were examined with the isolated perfused (IPK) kidney model and the autotransplant model. EuroCollins' (EC) solution, phosphate-buffered sucrose solution, and a new solution developed at the University of Wisconsin (UW) were studied. Kidneys were cold-stored for 48 hr or 72 hr. With the IPK model, cold storage for 48 hr or 72 hr in each of the three solutions caused creatinine clearance to decrease by 80%-90%. More protein was excreted by kidneys stored for 48 hr in PBS solution than by kidneys stored in EC or UW solution; protein excretion after 72 hr of storage was similar for kidneys stored in EC or UW solution. Sodium reabsorption decreased after 48 hr or 72 hr of storage, but was higher in kidneys stored in UW solution (83% and 56%, respectively) than in EC solution (52% and 22%, respectively). With the autotransplant model, 40% of the kidneys were viable after 48-hr storage in PBS solution, but 80% viable when stored in EC solution and 100% were viable when stored in UW solution. All kidneys were viable when stored for 72 hr in UW solution; none were viable when stored for 72 hr in EC solution. These results suggest that UW solution effectively preserves kidneys for 72 hr. We previously reported successful 72-hr pancreas preservation. Recently UW solution was able to preserve canine livers for 30 hr. Thus, this single solution appears to be effective for preserving all intraabdominal organs and may simplify cold storage of organs for transplantation.     

Deferoxamine Reduces Cold-Ischemic Renal Injury in a Syngeneic Kidney Transplant Model

In cell-culture models, addition of deferoxamine (DFO) to University of Wisconsin Solution (UW solution) reduces cold-storage injury. The efficacy of DFO was therefore tested in a kidney transplantation model employing inbred Wistar Furth rats. Donor left kidneys, cold stored for 18 h in UW solution with or without 0.125 mM or 0.625 mM DFO were transplanted to the recipients' left renal fosse. Deferoxamine dose-dependently and significantly increased glomerular filtration rate (GFR) and renal blood flow (RBF), and suppressed renal F2-isoprostanes (vasoactive lipid peroxidation products) and apoptotic and necrotic injury 3 days post-transplantation. In a second set of similar experiments, the remaining native kidneys of the recipient rats were removed on day 7 of transplantation. Transplanted kidneys' function assessed by serum creatinine was 75% higher in the cold-stored transplanted kidneys treated with DFO compared with untreated kidneys. Moreover, the DFO treatment was attended by a significant reduction in apoptotic and necrotic tubular injury. Thus, our consistent findings from two sets of studies in a transplant model suggest that a simple strategy of including DFO in the cold-storage solution reduces cold ischemia-associated renal transplant damage and improves renal function. Our findings have potentially important ramifications for cold preservation of kidneys, and possibly other organs, in clinical transplantation.     

Comparison of University of Wisconsin and University of Pittsburgh solutions for heart transplantation

The effectiveness of University of Wisconsin (UW) and University of Pittsburgh (UP) solutions for the preservation of rat hearts was compared. Lewis rat hearts were preserved with UW (group A, n=45) or UP (group B, n=45) solution for 0 or 24 h and then transplanted heterotopically into the recipients' abdomen. Ten recipients in each group were observed to obtain 1-week graft survival rates. Tissue water content and tissue content of adenine nucleotides were measured 2 h after transplantation in six grafts from each group. Six hearts preserved for 0 h and seven hearts preserved for 24 h were taken from each group 24 h after grafting for histopathology. The 1-week graft survival rates of groups A24 and B24 were 60% and 10%, respectively. In the 24-h preserved grafts, adenosine triphosphate (ATP) and energy charge [(ATP+adenosine diphosphate/2)/(ATP+adenosine diphosphate+adenosine monophosphate)] of groups A and B were 0.972±0.165 and 0.200±0.123 mg/g wet tissue (P<0.05) and 74.4% and 61.1% (P<0.05), respectively. The tissue water content of group A24 was 71.7%, whereas that of group B24 was 74.1% (P<0.05). Histopathology revealed more severe muscle edema and necrosis and infiltration of polymorphonuclear cells in group B24 than in group A24. We conclude that UW solution is more appropriate for rat heart preservation than UP solution.     

Baculovirus as delivery system for gene transfer during hypothermic organ preservation

Concerns over the safety of conventional viral vectors have limited the translation of gene transfer from an exciting experimental procedure to a successful clinical therapy in transplantation. Baculoviruses are insect viruses, but have the ability to enter mammalian cells and deliver potential therapeutic molecules with no evidence of viral replication. This study provides evidence of the ability of recombinant baculovirus to enter mammalian kidneys and livers during cold preservation. Six kidneys and six liver lobules retrieved from large pigs were perfused with University of Wisconsin (UW) solution containing a baculovirus tagged with green fluorescent protein and preserved for 8 h. In addition, six kidneys were perfused with UW containing a baculovirus expressing red fluorescent protein and preserved for 24 h. Green fluorescent virus particles were detected within transduced kidneys and livers after 8 h standard cold storage and red fluorescent protein mRNA was detected in kidneys after 24 h of cold preservation. There were no significant differences in tissue architecture, cell morphology or ATP content between experimental organs and their controls. Ex vivo transduction of organs with recombinant baculovirus during conventional cold preservation was demonstrated with no evidence of additional injury or reduction in cell viability.     

Propionyl-L-carnitine prevents renal function deterioration due to ischemia/reperfusion

BACKGROUND: Ischemia-reperfusion injury after organ transplantation is a major cause of delayed graft function. Prevention of post-transplant ischemia acute renal failure is still elusive. METHODS: The present study was designed to examine whether propionyl-l-carnitine, an acyl derivative of carnitine involved in fatty acid oxidation pathway and adenosine 5'-triphosphate (ATP) generation of mitochondria, prevented renal function deterioration and structural injury induced by ischemia-reperfusion in an ex vivo rat model of isolated perfused kidney (IPK) preparation and in vivo in a model of syngeneic kidney transplantation. RESULTS: In the model of ischemia (20 or 40 min)/reperfusion (90 or 70 min) in IPK, untreated kidneys showed a marked reduction of glomerular filtration rate (GFR) and renal perfusate flow (RPF) as compared to baseline, when perfusion was established by restoring effective perfusion pressure to 100 mm Hg. Exposure of kidneys to propionyl-l-carnitine before establishing the ischemia insult to tissue, largely prevented renal function impairment. Pre-exposure of ischemic kidneys to propionyl-l-carnitine largely reduced the percent of lactate dehydrogenase (LDH), a cell injury marker, released into the perfusate after reperfusion as compared to untreated ischemic kidneys. Histologic findings showed very mild post-ischemic lesions in kidneys exposed to propionyl-l-carnitine as compared to untreated ischemic kidneys. Immunohistochemical detection of 4-hydroxynonenal protein adduct, a major product of lipid peroxidation, was very low in kidney infused with propionyl-l-carnitine and exposed to ischemia/reperfusion as compared to untreated ischemic kidneys. ATP levels were not affected by propionyl-l-carnitine treatment. Renal function of kidneys exposed for four hours to cold Belzer UW solution added with propionyl-l-carnitine and transplanted to binephrectomized recipients was largely preserved as compared to untreated ischemic grafts. Propionyl-l-carnitine almost completely prevented polymorphonuclear cell graft infiltration and reduced tubular injury at 16 hours post-transplant. CONCLUSIONS: These data indicate that propionyl-l-carnitine is of value in preventing decline of renal function that occurs during ischemia-reperfusion. The beneficial effect of propionyl-l-carnitine possibly relates to lowering lipid peroxidation and free radical generation that eventually results in the preservation of tubular cell structure. The efficacy of propionyl-l-carnitine to modulate ischemia-reperfusion injury in these models opens new perspectives for preventing post-transplant delayed graft function.     

Iron chelators do not reduce cold-induced cell injury in the isolated perfused rat kidney model.

BACKGROUND: In vitro, cold-induced injury is an important contributor to renal tubular cell damage. It is mediated by iron-dependent formation of reactive oxygen species and can be prevented by iron chelation. We studied whether iron chelators can prevent cold-induced damage in the isolated perfused rat kidney (IPK) model both after cold perfusion (CP) and after cold storage (CS). We hypothesized that in the CP model iron-dependent cold-induced injury is more pronounced, since oxygen is constantly provided. METHODS: The IPK was either flushed with University of Wisconsin (UW) solution and stored for 4, 18 or 24 h at 4 degrees C or perfused during 4 h at 4 degrees C with UW for machine perfusion. The iron chelators 2,2'-dipyridyl or desferal, or the negative control 4,4'-dipyridyl were added during the cold perfusion. Kidney function was measured during 2 h reperfusion at 37.5 degrees C and compared to a control group (without cold preservation). RESULTS: Compared to control perfusion, kidney function was decreased in all experimental protocols. glomerular filtration rate and FR(H2O) were significantly decreased, while FE(gluc) and FE(Na) were higher after 4 h CS and CP. After 4 h CP, also renal vascular resistance was increased. Addition of 2,2'-dipyridyl did not improve kidney function after either CS or CP. Prolonged periods of CS worsened kidney function. The addition of 2,2'-dipyridyl or desferal did not improve kidney function after longer periods of CS. CONCLUSIONS: Addition of an iron chelator to the preservation solution UW did not improve kidney function after both CS and CP. Iron chelation is not able to prevent cold-induced damage in the isolated perfused rat kidney.     

Light-chain-induced renal tubular acidosis: effect of sodium bicarbonate on sodium-proton exchange

We measured sodium-proton (Na⁺/H⁺) exchange in lymphocytes andplatelets of a 46-year-old woman with the adult Fanconi syndromebefore, during, and after treatment with NaHCO₃. Kappa lightchains in her urine and unique but rarely observed crystallinestructures confirmed the presence of light-chain nephropathy.Her glomerular filtration rate was only moderately impairedat 72 ml/min. NaHCO₃ at 1, 3, and 5 mmol/kg/day for 5 days increasedher serum HCO₃ and pH from 17 to 21 mmol/l and 7.28 to 7.39respectively. Plasma renin and aldosterone values were decreasedby NaHCO₃. Na⁺/H⁺ exchange (H_i/min) was measured with the fluorescentmarker BCECF after acidification of lymphocytes and plateletswith sodium propionate at five (10–50mM) doses. Na⁺/H⁺exchange was accelerated in this patient compared to normalcontrols. NaHCO₃ treatment significantly decreased Na⁺/H⁺ exchangein lymphocytes, but not in platelets. These findings suggestthat Na⁺/H⁺ exchange can be influenced by NaHCO₃ ingestion atdoses that only modestly affect systemic pH. Since Na⁺/H⁺ exchangeis involved in stimulus response coupling, cell growth regulation,cell differentiation, and perhaps the progression of nephrosclerosis,these observations may have clinical relevance.     

Continuous perfusion of donor hearts with oxygenated blood cardioplegia improves graft function

Donor hearts cannot be preserved beyond 6 h using cold storage (CS). Improving preservation methods may permit prolonged storage of donor heart. We compared graft function in large animal model after prolonged preservation (8 h) using continuous perfusion (CP) and CS method. Twenty‐four miniature pigs were used as donors and recipients. Donor hearts were either stored in University of Wisconsin solution (UW solution) for 8 h at 0–4 °C (CS group, n = 6) or were continuously perfused with oxygenated blood cardioplegia at 26 °C for 8 h (CP group, n = 6). After preservation, hearts were transplanted into recipients and reperfused for 3 h. Left ventricular (LV) function, cardiac output (CO), malondialdehyde (MDA) and adenosine triphosphate (ATP) levels, and water content were measured. Although water content of CP hearts was higher than that of CS, LV contractility and diastolic function of CP hearts were superior to those of CS. In addition, CP hearts performed better than CS hearts on CO in working heart state. ATP was better preserved and MDA levels were lower in CP hearts compared with those of CS (P < 0.0001). Donor hearts can be preserved longer using continuous perfusion with oxygenated blood cardioplegia and this method prevents time‐dependent ischemic injury.     

Evaluation of a preservation solution containing fructose-1,6-diphosphate and mannitol using the isolated perfused rat kidney. Comparison with Euro-Collins and University of Wisconsin solutions

The renal preservation ability of a flushing solution (F-M)with fructose-1,6-diphosphate (1 g/dl) and mannitol (2 g/dl)during cold ischaemia was studied with the isolated perfusedrat kidney model and compared with the Euro-Collins (EC) andUniversity of Wisconsin (UW) solutions. Kidneys were storedin hypothermia for 4 and 18 h after initial flushing with thesolution being tested, and then reperfused at 37°C in anisolated perfusion circuit for 90 min with a Krebs-Henseleitsolution containing 4.5% albumin. Forty-four kidneys were studied and divided in a control groupand six study groups according to the cold ischaemia time andflushing solution used. Renal functional parameters of plasmaflow rate (PFR), renal vascular resistance (RVR), urine flowrate (UFR) glomerular filtration rate (GFR), fractional (FRNa)and net (TNa) sodium reabsortion were assessed during reperfusion.Conventional histology and malon-dialdehyde tissue levels (MDA)were also evaluated. Our results show that PFR, RVR, and UFR were similar in allstudy groups. After 4 and 18 h of cold ischaemia, GFR, FRNaand TNa were better, and conventional histology worse in F-Mthan in EC flushed kidneys. After 4 and 18 h of cold ischaemia,GFR, FRNa and TNa, in fact, were not different between F-M andUW flushed kidneys. After 4 h of cold ischaemia, conventionalhistology was similar in F-M and UW flushed kidneys. Nevertheless,after 18 h of cold ischaemia, UW flushed kidneys showed worsehistological parameters than F-M flushed kidneys. After 4 hof cold ischaemia, MDA was similar in kidneys flushed with thethree solutions. After 18 h of cold ischaemia MDA was higherin EC than in F-M or UW flushed kidneys. In summary, our newly developed cold storage solution showspromising results in renal preservation and its ability to preserveis at least as good as UW solution assessed in the isolatedperfused rat kidney.     

Protective Roles of Polyethylene Glycol and Trimetazidine against Cold Ischemia and Reperfusion Injuries of Pig Kidney Graft

Ischemia‐reperfusion injury (IRI) represents an allo‐independent risk factor which favors chronic allograft nephropathy (CAN). Here we analyzed the influence of preservation solutions on the function of autotransplanted pig kidneys over 1–16 weeks after surgery. Kidneys were cold‐flushed and cold‐stored for 24 or 48 h either in University of Wisconsin (UW), modified‐UW Hôpital Edouard Herriot, polyethylene glycol 20 kDa (PEG)‐supplemented preservation solutions with low K⁺ (ECPEG) or high K⁺ (ICPEG) content. Animals autotransplanted with kidneys cold‐stored for 24 h in ECPEG exhibited the greatest levels of creatinine clearance (C_cr: 161 ± 12 mL/min, n = 10) and the lowest levels of proteinuria (0.5 ± 0.03 mg/mL) 16 weeks after surgery as compared with pigs autotransplanted with kidneys cold‐stored in the other solutions tested (C_cr ranging from 80 and 140 mL/min). Similar differences, but with lower C_cr levels, were achieved after a prolonged period of cold‐storage(48 h). ECPEG better preserved the kidneys from monocytes/macrophages and CD4⁺ T cells infiltrations, VCAM‐1 and MHC class II overexpressions and occurrence of renal interstitial fibrosis (2%) as compared with the other preservation solutions (5%–20%). Adding the anti‐ischemic drug trimetazidine (TMZ) to the preservation solutions, particularly ECPEG, further improved the quality of the week‐16 post‐transplanted kidneys (C_cr: 182 ± 12 mL/min, n = 10). These findings demonstrated that adding PEG to extracellular‐like (with low K⁺ content) preservation solutions in combination with TMZ significantly improved the long‐term outcome of kidney grafts in this model of autotransplanted pig kidney.     

Kidney preservation with the UW and Euro-Collins solutions. A preliminary report of a clinical comparison

This is a preliminary report of a European Multicenter Trial of the efficacy and safety of the UW solution in kidney preservation. The results obtained with the UW solution are compared with those obtained with Euro-Collins solution in a prospectively randomized study. To date 257 patients have been evaluated, with 128 receiving kidneys preserved in UW solutions and 129 receiving kidneys preserved in Euro-Collins solutions. Demographic characteristics of donors and recipients were identical in both groups. Median (and range) preservation times were similar (24 hr in EC and 24 hr in UW). Maximum preservation time in each group was about 48 hr. The results show that the UW solution is a safe preservation solution for kidneys, with postoperative renal functions, at least, equivalent to those seen in patients transplanted with kidneys preserved in EC solution. In this preliminary analysis of 257 kidneys, use of the UW solution resulted in a more rapid reduction in postoperative serum creatinine, higher creatinine clearance rate, and less postoperative dialysis (21% vs. 31%) when compared with kidneys preserved in EC solution. This study indicates that the UW solution is an effective preservation medium for clinical kidney transplantation. It supports the use of UW solution as a general flushout and cold storage solution for all intraabdominal organs used for transplantation.     

Influence of Vasoactive Substances on Early Toxic Acute Renal Failure in the Dog

The influence of different vasoactive substances on the evolutionof HgCl₂-induced acute renal failure (ARF) was evaluated inthe dog. HgCl₂ alone caused a progressive fall in both glomerularfiltration (GFR) and renal blood flow (RBF) during the first3 h of the mercury administration ( after 3 h:–44% and–39%) and provoked a concomitant stimulation of the renin-angiotensin(RAS) and thromboxane systems. The administration of the thromboxaneinhibitor dazoxiben (2 mg/kg i.v. every 2 h) adequately inhibitedthe activation of the thromboxane system after HgCl₂, but couldnot prevent the fall in GFR and RBF. The continuous intrarenaladministration of the Ca²⁺ entry blocker verapamil (0.005 mg/kgper min) into the left kidney resulted in the prevention ofthe postmercurial fall in GFR and RBF at the perfusion site.This beneficial effect was immediately lost when the verapamiladministration was stopped. Finally, the administration of theconverting enzyme inhibitor captopril (300 µg/kg every2 h) resulted in an effective inhibition of the renin-angiotensinsystem. the prevention of the postmercurial fall in RBF, andthe partial attenuation of the fall in GFR. This beneficialeffect was immediately lost after the intravenous administrationof indomethacin (2 mg/kg). These results indicate that the fall in GFR after HgCl² canbe prevented by vasoactive agents such as captopril and verapamiland point at least in part to a pathophysiological role of therenin-angiotensin system or of an alteration in the equilibriumbetween renin-angiotensin and prostaglandins. The thromboxanesystem is seemingly of no major importance.     

Evaluation of preservation solutions by ESR-spectroscopy: superior effects of University of Wisconsin over Histidine-Tryptophan-Ketoglutarate in reducing renal reactive oxygen species

Despite the causative role of oxidative stress in renal ischemia-reperfusion (I-R) injury effects of preservation solutions on reactive oxygen species (ROS) release have not been sufficiently evaluated. We compared the effects of most common solutions in kidney transplantation, University of Wisconsin (UW) and Histidine-Tryptophan-Ketoglutarate (HTK). ROS formation in isolated perfused rat kidney was detected by electron spin resonance spectroscopy using spin label 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine. Donor kidneys from Lewis rats were pretreated with saline (controls), in therapeutic groups, kidneys underwent 18 h of cold storage (CS) preserved by HTK or UW solution. Experimental protocol included a stabilization period followed by additional I-R. Kidneys preserved by HTK produced highest ROS values in the control period after CS, whereas levels in UW and control group did not vary significantly. A peak release induced by additional I-R was also significantly highest in HTK kidneys, and UW did not differ from controls. During reperfusion, levels in HTK exceeded control and UW values. Renal vascular resistance, caspase-3-activity, and tissue hydration were enhanced in HTK compared with UW group, whereas ATP concentration was less reduced in UW-preserved tissue. These data show the greater antioxidative potential of UW solution, which also attenuated organ impairment after CS in the early reperfusion period.     

Renal function on and off lithium in patients treated with lithium for 15 years or more. A controlled, prospective lithium-withdrawal study

BACKGROUND.: Controversy remains over the magnitude and reversibility ofreduced renal function in long-term lithium patients. METHOD.: Thirteen patients with 18 years (range 15–24) on lithiumdiscontinued the treatment, and were re-examined twice after5 and 9 weeks (4–16) off lithium. They were compared toa non-lithium psychiatric control group, matched for age andsex. RESULTS.: Glomerular filtration rate (GFR) tended to improve from 69 (39–96)to 74 (39–94) ml/min/1.73 m² BSA, P=0.057, which was notsignificantly different from 78 (61–106 ml/min per 1.73m² BSA in the controls. Reduced GFR was found in only two ofthe lithium patients off lithium, and in none of the controls.Maximal urinary concentrating capacity did not improve at all.It was 637 (130–875) mOsm/kg H₂O in the lithium patients,which was lower than 856 (705–1.035) mOsm/kg H₂O (P<0.01)in the controls. Two of the lithium patients had isosthenuria. CONCLUSIONS.: Lithium patients often have an irreversible, clinically importantreduction of Umax, sometimes progressing to nephrogenic diabetesinsipidus, while GFR is well preserved in most patients.