Prevention of acute renal failure after kidney transplantation

Summary The incidence of acute renal failure (ARF) after renal transplantation has always been about 50%. The most important factors for the development of ARF are the hemodynamic condition of the donor, the mode of preservation of the kidney, and the hemodynamic parameters of the recipient. Optimal hydration of the donor and the minimalization of the length of warm ischemia time decreased the incidence of ARF. Further improvement in the incidence of ARF could be achieved either by adding calcium antagonists to the preservation fluid or by using a new preservation fluid (Belzer solution). With moderate hydration of the recipient and the administration of mannitol just before clamp release, we also accomplished a decrease in ARF; however, neither moderate hydration nor mannitol alone could achieve this. By application of these methods, it is now possible after renal transplantation to achieve an incidence of ARF of <20%.     

Mutual supplementation in treatment of renal failure by blood purification and kidney transplantation

More than 100,000 uremic patients have been maintained by various blood purification modalities in Japan. However, their quality of life is far from satisfaction not only in terms of physical problems related to the complications specific to long-term dialysis treatment, but also the restriction in social activities by spending much time for hospital dialysis. A graft functioning rate in kidney transplantation has been remarkably improving after introduction of Cyclosporine A as an immunosuppressant and is presently approximately 90% one year after transplantation. As long as the transplanted kidneys function, further extensive social activities and highly-graded quality of life is warranted compared to artificial kidney treatment. On the other hand, patients in end-stage renal diseases and with rejected transplants are expected to undergo safe kidney transplantations as being maintained by dialysis therapy. Furthermore, recent development in blood purification technology has made the specific kidney transplantations successful in recipients with the preformed antibody (-ies) and the incompatible ABO blood type antibody (-ies). Nowadays, relation between blood purification and kidney transplantation is not competitive, but mutually supplementary as a matter of realism.     

Erythropoietin deficiency in acute renal failure

Erythropoietin (Epo) was sequentially measured by radioimmunoassay in 11 patients with acute renal failure (ARF) of varied aetiology. Epo rapidly decreased to a level inappropriately low for the haemoglobin, the reduced Epo value persisting throughout the oliguric phase and for up to 2 weeks after the restoration of apparently normal renal function. Epo values found in ARF were: at referral 18.2 +/- 9.5, mid-oliguria 14.4 +/- 6.8, diuresis 15.6 +/- 5.8, and recovery 25.1 +/- 15.8 mU/ml. Results are compared with 34 patients with end-stage chronic renal failure, 42 with non-renal anaemia, and 96 normal subjects. Epo deficiency alone is an inadequate explanation of the rapid reduction in haemoglobin at the onset of ARF, but would appear to be an important factor in the maintenance of anaemia in prolonged ARF and accounts for the slow increase in haemoglobin following recovery.     

Enterosorption in experimental acute kidney failure

The paper provides the results of 32 experiments on 22 mongrel male dogs with a view to measuring creatinine levels in the lumen of various intestinal segments before and after bilateral nephrectomy and evaluating the effects the enterosorbent brand SKN administered into isolated portions of the intestinal tube on alteration of intraluminal concentrations of creatinine, serum creatinine, and "middle-sized" molecules. Four parts of the intestine were identified: (1) proximal; (2) middle and (3) distal portions of the small intestine, and (4) the large intestine up to the anal sphincter. Two days following bilateral nephrectomy, creatinine levels were increased in the proximal, middle, distal portions of the small bowel and in the large bowel by 18, 11, 5, and 1.4 times, respectively, as compared to the baseline creatinine concentration in the intestinal parts mentioned. The administration of the enterosorbent into the different intestinal parts revealed that with its 6-hour exposure, the most potent effect (lower concentrations of creatinine and "middle-sized" molecules in serum) was observed in the proximal portions of the small bowel. This phenomenon is likely to be attributable to greater vascularization and the maximal creatinine and "middle-sized" molecule concentration in these intestinal portions. With this, it was shown that the higher baseline concentrations of serum creatinine and "middle-sized" molecules were, the more actively they absorbed on the charcoal enterosorbent brand SKN in the intestine.     

L-arginine supplementation accelerates renal fibrosis and shortens life span in experimental lupus nephritis

BACKGROUND: Inducible, high-output nitric oxide (NO) production has been identified as a central mediator of cell injury in immune-mediated renal disease. In acute anti-thy-1 glomerulonephritis prefeeding with the NO precursor L-arginine increases mesangial cell injury and the subsequent fibrosis. The present study tested the hypothesis that L-arginine supplementation may also be detrimental in chronic, NO-mediated murine lupus nephritis. METHODS: Groups (N = 18) of female MRL/lpr mice with lupus nephritis were fed the following diets: (1) normal protein (22% casein); (2) normal protein and 1.0% L-arginine in the drinking water; (3) low protein (6% casein); (4) low protein + 0.4%l-arginine; and (5) low protein + 1.0% L-arginine. After 40 days mouse survival, albuminuria, matrix accumulation, inflammatory cell infiltration, immunoglobulin G (IgG) deposition, expression of transforming growth factor-beta 1 (TGF-beta 1), fibronectin and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein, anti-DNA antibody titer, inducible nitric oxide synthase (iNOS) mRNA expression, blood amino acid levels, blood urea nitrogen (BUN) concentrations and blood and urinary NOx (nitrite + nitrate) levels were assessed. RESULTS: L-Arginine supplementation increased mortality significantly (P < 0.02). The death rate increased from 0% in the lowest to 50% in the highest L-arginine intake group (normal protein + 1.0% L-arginine). L-Arginine administration increased albuminuria, renal matrix accumulation, TGF-beta 1, fibronectin, PAI-1, blood L-arginine, L-citrulline, BUN and blood and urine NOx levels, while protein restriction reduced these parameters. Renal cell infiltration and iNOS mRNA expression were decreased in the low protein group only. Anti-ds DNA-IgG and renal IgG deposition were comparable in all groups CONCLUSIONS: Increasing L-arginine intake increases the severity of renal fibrosis and the likelihood of death in MRL/lpr mice. The results appear to be at least in part mediated through enhanced cytotoxic NO generation via iNOS. The data suggest that L-arginine restriction should be considered in human immune-mediated renal diseases.     

L-arginine reduces tubular cell injury in acute post-ischaemic renal failure.

BACKGROUND: The pathophysiology of renal ischaemia, resulting in tubular cell injury and leading to acute renal failure (ARF), remains unclear. An ever-increasing number of investigations focus on a possible role of nitric oxide (NO) in regulating circulation during ARF. In this context, we investigated the influence of chronic stimulation or inhibition of NO synthesis, or both, on haemodynamic parameters, histology and plasma renin activity (PRA) after ischaemia-reperfusion injury of rat kidneys. METHODS: Experiments were performed on adult, male Wistar rats. Before induction of ARF, a group of animals was treated with a NO synthesis inhibitor (L-NAME) and another group was treated with a precursor of NO synthesis (L-arginine). The animals received those substances for 4 weeks. Control groups received the same amount of tap water for 4 or 8 weeks and were divided into groups with ARF (4 weeks--ARF group and 8 weeks ARF group) and a sham-operated group. Another group of rats was treated first with L-NAME and then with L-arginine in their drinking water, for 4 weeks for each of these two substances. All parameters were evaluated 24 h after the induction of ischaemic ARF or the sham operation. RESULTS: Our results show that such long-term stimulation of NO release by L-arginine improved renal haemodynamics in the ischaemic form of ARF. Renal blood flow (RBF) increased by 96% in the L-arginine-treated rats with ARF compared with the group with ARF alone. Inhibition of NO synthesis worsens renal haemodynamics after ARF. However, this aggravation can be reversed by L-arginine. The rate of water reabsorption was reduced in all groups with ARF, but this reduction was least in the group treated with L-arginine. The rate of Na+ reabsorption was reduced in all groups 24 h after renal ischaemia, but a significant decrease was observed after the inhibition of NO synthesis. Histological examination of the kidney specimens showed that morphological changes were least in the rats treated with L-arginine, when compared with all other groups with ARF. Nevertheless, the lesions were most prominent in the L-NAME+ARF group. In this group, the areas of corticomedullar necrosis were more widespread in comparison with other groups, especially the L-arginine group where only swelling of the proximal tubular cells was observed. Treatment with L-NAME was not accompanied by any significant alteration in the plasma concentration of angiotensin I (ANG I), while in the group treated with L-arginine ANG I had a tendency to decrease. CONCLUSIONS: Acute post-ischaemic renal failure may be alleviated by administering the NO substrate (L-arginine). NO acts cytoprotectively on tubular epithelial cells in ischaemia--reperfusion injury of rat kidney. Evidence of this comes from both histopathological findings and increased tubular water and sodium reabsorption. However, inhibition of NO synthesis (provoked by L-NAME) worsens renal haemodynamics and aggravates morphological changes after ARF. These aggravations can, however, be reversed by L-arginine.     

Foscarnet-induced crystalline glomerulonephritis with nephrotic syndrome and acute renal failure after kidney transplantation.

Foscarnet nephrotoxicity has been reported to be associated with acute tubulointerstitial nephritis. Crystals in glomerular capillary lumens have also been observed in patients with acquired immunodeficiency syndrome who were treated with foscarnet for cytomegalovirus disease. We describe a kidney transplant recipient who developed a nephrotic syndrome with microscopic hematuria and nonoliguric acute renal failure within 15 days after starting foscarnet therapy for cytomegalovirus infection. A kidney biopsy specimen showed the presence of crystals in all glomeruli and in proximal tubules. Fourier transform infrared microscopy analysis demonstrated that crystals were made from several forms of foscarnet salts: mixed calcium and sodium salts, and unchanged trisodium foscarnet salts. Renal function and proteinuria spontaneously improved, and a second transplant biopsy performed 8 months after the first one revealed fibrotic organization of half of the glomeruli and of interstitial tissue, and crystal vanishing. We were thus able to provide proof of the possible precipitation of foscarnet in a transplanted kidney.     

Blood viscosity in experimental acute renal failure

We measured blood viscosity in rats 24 h after induction of acute renal failure by glycerol or HgCl2 injections. The blood viscosity values of rats with acute renal failure were significantly higher than those of controls at any shear rates. The mean values of plasma fibrinogen in animals with glycerol - (302.5 +/- 35.2 mg/100 ml) or HgCl2 - (342.1 +/- 15.9 mg/100 ml) induced acute renal failure were significantly elevated compared to control levels (169.6 +/- 16.7 mg/100 ml). We believe that the increased blood viscosity in acute renal failure was primarily due to high concentration of plasma fibrinogen. The elevated blood viscosity may affect capillary microvascular circulation of glomerular capillary beds.     

Effect of essential amino acid supplementation in acute renal failure

The effect of intravenous (i.v.) essential amino acids (EAA) in the treatment of acute renal failure was evaluated in 50 patients. Thirty patients (Group A) received daily 13.4 g of i.v. EAA solution [Nephramine^® (Don Baxter, McGraw) 250 ml/d]+dopamine i.v. 2 μg/kg/min+20% hypertonic glucose solution 500 ml/d as dompared with twenty patients (Group B) who received dopamine i. v. 2 μg/kg/min+20% hypertonic glucose solution 500 ml/d. In Group A patients showed lower daily increase in blood urea nitrogen (BUN) (p<0.05), higher serum total protein and albumin levels on the 15th day of the posttherapy period (p<0.001), lower complication rate (p<0.005), lower mortality rate (p<0.005) and a reverse relation between serum total protein concentration, duration of oliguria and age (p<0.01, r²=0.26; p<0.001, r²=0.32). These data suggest that treatment of such patients with i.v. EAA solutions significantly improves survival.     

L-arginine supplementation improves function and reduces inflammation in renal allografts

Recovery from ischemia/reperfusion and immune-mediated injury in the renal transplant is associated with reduced renal hemodynamics and increased leukocyte infiltration. In diverse models of renal failure, L-arginine supplementation improved hemodynamics and reduced inflammation. However in a proinflammatory environment, L-arginine can worsen renal injury. This study investigated the therapeutic potential of L-arginine supplementation in allogeneic renal transplantation: Brown Norway rat kidneys were transplanted into Lewis rat recipients, with one native kidney remaining. Recipients received low-dose cyclosporin A (2.5 mg/kg per d subcutaneously) to obtain moderate vascular and interstitial rejection, with or without 1% L-arginine in drinking water for 7 d posttransplantation. Transplantation increased renal vasoconstriction (from 16.9 +/- 1.33 to 35.1 +/- 8.6 units; P: < 0.01), thereby reducing GFR (from 0.96 +/- 0.09 to 0.48 +/- 0.10 ml/min; P: < 0.05). Treatment with L-arginine restored renal graft function to levels found in normal donors (renal vascular resistance, 15.7 +/- 1.69 units; GFR, 0.80 +/- 0.06 ml/min). L-arginine significantly reduced vascular occlusion because of less inflammation, endothelial disruption, and thrombosis. L-arginine also decreased tubulitis, interstitial injury, and macrophage infiltration. These protective effects suggest that L-arginine might be useful as additive therapy to conventional immune suppression.     

Effects of pentoxifylline in experimental acute renal failure

The beneficial effects of post-insult administration of pentoxifylline, a novel hemorheologic agent experimentally studied in various ischemic diseases, were evaluated in two models of acute renal failure (ARF): direct nephrotoxicity (mercuric chloride 4 mg/kg via femoral vein) and hemoglobinuria (glycerol 10 ml/kg i.m.). Glomerular filtration rate (GFR) was estimated at baseline and following drug administration by creatinine clearances; tubular function was assessed by renal fractional and absolute electrolyte excretions. The incidence of mortality was decreased with a single dose of pentoxifylline 45 mg/kg (21.4%) compared to control rats (71.4%) 48 hours following induction of ARF with mercuric chloride. Although GFR and renal electrolyte excretion were significantly greater in rats given pentoxifylline compared to saline, the magnitude of difference was minimal. A return to baseline GFR was observed in the glycerol group administered a single i.p. dose of pentoxifylline 45 mg/kg (100.8 +/- 54.8%) compared to saline controls (45.6 +/- 22.7%; P less than 0.05). No differences in renal electrolyte excretion or mortality were observed in this model. Taken together, these data suggest that pentoxifylline, administered shortly after the initiation of ARF, exerts an ameliorative effect on the course and mortality of experimental ARF. The mechanism of amelioration most likely involves the stimulation of renal vasodilator prostaglandins as well as prevention of vascular congestion.     

急性肝功能衰竭患者肝移植术后急性肾功能衰竭的病因分析及综合治疗

目的 分析急性肝功能衰竭(acute liver failure,ALF)患者肝移植术后肾功能衰竭的原因,评价以持续肾脏替代治疗(continuous renal replacement therapy,CRRT)为基础的综合疗法的疗效.方法 回顾性分析2001年1月至2006年6月在我院施行的412例肝移植资料,根据UNOS肝功能分级标准筛选出54例ALF患者(UNOS1和2A),其中17例移植术后出现急性肾功能衰竭(acute renal failure,ARF).在CRRT治疗基础上,进行抗排斥、抗感染、营养支持等治疗,并对患者围手术期情况、术后并发症、死亡原因及随访结果进行了分析.结果 CRRT治疗过程中无并发症发生.无ARF组围手术期死亡率为5.4%,术后并发症发生率为35.1%,1、3年生存率分别为89.2%和81.1%.ARF组围手术期死亡率为58.8%,术后并发症发生率为100%,1、3年生存率分别为41.2%和41.2%.结论 肝移植效果主要取决于肝外器官功能和术前肝功能状态.ALF患者围手术期死亡率较高,其中术前血肌酐高术后出现ARF率高,死亡率更高.以CRRT为基础的综合疗法能有效治疗ARF患者.     

Ischemic acute renal failure in the rat: effects of L-arginine and superoxide dismutase on renal function

BACKGROUND: Regulation of renal hemodynamics -- especially intraglomerular hemodynamics -- is closely related to the L-arginine (L-Arg)/nitric oxide (NO) pathway, both under basal conditions and in acute renal failure (ARF). Also, superoxide anions -- which may react with NO -- play a role in ischemic ARF. L-Arg not only has beneficial effects on glomerular filtration rate (GFR) but also reduces O2(-) production and prevents NO synthase isoform I up-regulation. Thus, it is of interest to elucidate whether the potential beneficial effects of L-Arg in reperfusion can be augmented by additional treatment with superoxide dismutase (SOD). METHODS: ARF was induced by renal artery clamping for 40 minutes. Animals were treated with either L-Arg, SOD, a combination of both, or saline. GFR, renal plasma flow (RPF), filtration fraction (FF) and blood pressure were recorded at baseline, after induction of ARF, during drug infusion and thereafter. RESULTS: Renal artery clamping induces a severe drop of GFR, RPF and FF, which all are improved by L-Arg and SOD. Increasing GFR is mainly due to better renal perfusion. FF fell after reperfusion and increased with L-Arg and SOD, indicating improvement of disturbed intrarenal hemodynamics. Combined administration of L-Arg and SOD showed similar effects in comparison with each substance alone, but did not induce additional effects on GFR and RPF. CONCLUSIONS: L-Arg and SOD exert beneficial effects in ischemic ARF. Probably, improvements in reducing NO availability and in enhancing O2(-) formation are both playing a mediating role. The underlying mechanisms regulating the interplay between NO availability and O2(-) formation need to be elucidated in further studies using -- aside from other means -- selective NOS inhibitors, intervention in different experimental phases and treatment for a longer period.     

Captopril-induced acute renal failure in a kidney transplant recipient

A living related kidney transplant recipient with normal renal function and severe hypertension secondary to renal artery stenosis, was treated with captopril and developed reversible renal failure requiring temporary hemodialysis. This complication of captopril, an angiotensin converting enzyme inhibitor, has been reported previously in hypertensive patients with renal artery stenosis with and without a kidney transplant. It is recommended that this drug be used with caution in this setting.     

Successful simultaneous liver‐kidney transplantation for renal failure associated with hereditary complement C3 deficiency

Hereditary complement C3 deficiency is associated with recurrent bacterial infections and proliferative glomerulonephritis. We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis, and end‐stage renal failure. Following isolated kidney transplantation he would remain C3 deficient with a similar, or increased, risk of infections and glomerulonephritis. As C3 is predominantly synthesized in the liver, with a small proportion of C3 monocyte derived and kidney derived, he proceeded to simultaneous liver‐kidney transplantation. The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow‐up. Simultaneous liver‐kidney transplant is a viable option to be considered in this rare setting.     

Simultaneous heart and kidney transplantation for combined cardiac and renal failure

Simultaneous heart and kidney transplantation (SHKT) is feasible for combined cardiac and renal failure. Herein we reviewed our 10-year experience in SHKT. Six patients underwent SHKT from June 1995 to December 2004. Their ages ranged from 13 to 63 years old with a mean of 45.5 +/- 15.8 years. They were all men except one girl, who was the youngest (aged 13) who suffered from dilated cardiomyopathy with congestive heart failure and chronic renal failure due to systemic lupus erythematosus. Because of aggravating heart failure, she changed from hemodialysis to peritoneal dialysis. Because of intractable heart failure, she underwent SHKT from a 24-year-old female donor. All received hemodialysis before SHKT. The indications for heart transplantation included dilated cardiomyopathy (n = 3), ischemic cardiomyopathy (n = 1), cardiac allograft vasculopathy (n = 1), and cardiac allograft failure (n = 1). The immunosuppressive protocol and rejection surveillance were these employed for heart transplantation. No operative mortality was noted in this study. The 1-year and 5-year survival rates were the same, 83%. The 10-year survival rate was 55%. No cardiac or renal allograft rejection was noted. No renal allograft loss was noted. There were two late mortalities: the one, who underwent redo heart transplantation for coronary artery vasculopathy died of cardiac allograft failure 1 year after SHKT. The other patient died of massive ischemic necrosis of the intestine at 6 years after SHKT. Our experience showed that SHKT had good short- and long-term results without increasing immunosuppressive doses. End-stage failure of either the heart or the kidney did not preclude heart plus kidney transplantation.