The protective effect of Clostridium novyi type B alpha-toxoid against challenge with spores in guinea pigs

Acute renal failure continues to be a difficult clinical problem despite developments in dialysis and critical care. Diagnosis of the etiology frequently determines treatment. Urinalysis remains an essential diagnostic tool in the approach to acute renal failure, particularly with the current emphasis on cost-containment and evidence-based medicine. This review focuses on some of the characteristic features in the urinalysis found in different forms of acute renal failure, current developments into the molecular basis for these urinary abnormalities, and new markers on the horizon.     

Perioperative renal dysfunction and cardiovascular anesthesia: concerns and controversies

In patients with renal disease undergoing cardiovascular surgery, perioperative management continues to be a challenge. Traditional answers have turned into new questions with the introduction of new agents and the redesign of old techniques. For ARF prevention, early recognition of pending deleterious compensatory changes is critical. Theoretically, therapeutic intervention designed to prevent ischemic renal failure should be designed to preserve the balance between RBF and oxygen delivery on one hand and oxygen demand on the other. Maintenance of adequate cardiac output distribution to the kidney is determined by the relative ratio of renal artery vascular resistance to systemic vascular resistance. Indeed, it should not be surprising to learn that norepinephrine (despite its vasoconstricting effect) has been reported to have no deleterious renal effects in patients with low systemic vascular resistance. Until recently, strategies for the treatment of ARF have been directed to supportive care with dialysis (to allow tubular regeneration). Various therapeutic maneuvers have been introduced in an attempt to accelerate the recovery of glomerular filtration, including dialysis, nutritional regimens, and new pharmacologic agents. A recent small prospective trial of low-dose dopamine in the prophylaxis of ARF in patients undergoing abdominal aortic aneurysm repair showed no benefit in those patients receiving dopamine. Conversely, the effects of intravenous atrial natriuretic peptide in the treatment of patients with ARF appear to offer benefit in patients with oliguria. Among 121 patients with oliguric renal failure, 63% of those who received a 24-hour infusion of atrial natriuretic peptide required dialysis within 2 weeks compared with 87% who did not. Whether this effect will be borne out in the future remains to be determined. The administration of epidermal growth factor after induction of ischemic ARF in rats has been shown to enhance tubular regeneration and accelerate recovery of kidney function. Human growth factor administration has been shown to increase GFR 130% greater than baseline in patients with chronic renal failure, but no data for clinical ARF have been reported. In addition, there have been significant improvements in dialysis technology in the treatment of ARF. Modern dialysis uses bicarbonate as a buffer as opposed to acetate, which reduces cardiovascular instability, and has more precise regulation of volume removal. Dialysate profiles and temperatures improve hemodynamics and reduce intradialytic hypotension. Techniques of hemodialysis without anticoagulation have reduced bleeding complications. Finally, dialysis membranes activate neutrophils and complement less with the biocompatible membranes used today that reduce recovery time and dialysis treatment. Evidence indicates that activation of complement and neutrophils by older dialysis membranes caused a greater incidence of hypotension, adding to ischemic renal injury. It remains to be determined whether early and frequent dialysis with biocompatible membranes, as well as other therapeutic interventions, will increase the survival of patients with perioperative ARF.     

Acute renal failure: controversies, clinical trials, and future directions

Acute renal failure (ARF) is an important clinical syndrome. Despite the frequent occurrence of ARF, nephrologists have not made major therapeutic inroads in the treatment or prevention of ARF. This article will speculate as to why it has been so difficult to gain a substantial foothold in the ongoing battle against ARF. First, some of the major controversies regarding the pathogenesis of ARF will be considered. Scientific debates regarding the mechanisms of ARF have greatly enriched the scientific literature, but may have slowed the development of clinically applicable therapies. Controversies regarding the treatment of ARF will then be discussed. Next, the fate of several recent clinical trials in ARF will be examined. Finally, the future directions that research in ARF may pursue will be contemplated.     

Hippocratic medicine and nephrology

The history of nephrology is a part of culture in general and should be treated not as a hobby or an isolated specialty of medical science, but as closely connected with medical education and everyday clinical practice. In the age of the apotheosis of renal biotechnology, medicine more than ever needs to combine Hippocratic messages with renal technologic achievements, in order both to restore quality of life in patients with renal disease and to bring harmony and balance to individuals impaired in body and soul. Indeed, Hippocratic medicine lies at the root of the development of clinical nephrology. Hippocratic writings have not lost their nephrologic interest, despite the enormous recent advances in renal technology. Today's practising nephrologist can still learn not only from Hippocratic clinical observations, but also from the prognostic thoughts, the ethical principles, the philosophic concepts and the humane messages of the 'father of clinical nephrology'.     

Acute failure of the transplanted kidney--pathophysiology, diagnosis and prevention

Acute failure of the transplanted kidney is a major problem in the early posttransplant phase and is recognized as a major cause of graft loss. Early renal transplant dysfunction is mainly due to ischemic damage (acute tubular necrosis), rejection, infection, and cyclosporin A toxicity. Less common causes include bleeding, ureteral obstruction, urinary leak, venous thrombosis, and stenosis or occlusion of the renal transplant artery. Recent advances in both invasive (renal biopsy) and non-invasive (imaging and biochemical) techniques have improved specificity and sensitivity of the diagnosis of the acute renal failure. Several procedures which aim to prevent the kidney transplant failure have recently been introduced. Although they were shown to reduce the incidence of early allograft failure, their influence on the long-term graft survival remains to be proven.     

Metabolic encephalopathy as a complication of renal failure: mechanisms and mediators

Among patients with end-stage renal disease, nervous system dysfunction remains a major cause of disability. Patients with chronic renal failure who have not yet received dialysis may develop symptoms ranging from mild sensorial clouding to delirium and coma. Dialysis itself is associated with at least three distinct disorders of the CNS: dialysis disequilibrium syndrome; dialysis dementia; and progressive intellectual dysfunction. Peripheral neuropathy is also a major cause of disability in uremic subjects. It is believed that aluminum contributes to the pathogenesis of dialysis dementia. Biochemically, brain calcium is elevated in patients with renal failure, probably because of actions of parathyroid hormone on the brain. The diagnosis of dialysis disequilibrium syndrome, intellectual dysfunction, dialysis dementia, and uremic neuropathy can be made by the characteristic clinical pictures of these syndromes and the exclusion of other causes of nervous system dysfunction.     

The acute abdomen. An overview and algorithms

The diagnosis and management of the patient with an acute abdomen remains one of the most difficult challenges for the surgeon. A thorough understanding of the anatomy and physiology of the abdomen are essential to properly generate a differential diagnosis and to formulate a treatment plan. While recent advances in technology can be extremely helpful in certain situations, they cannot replace a physician's clinical judgment based upon a good history and physical examination. This article provides a general overview of the evaluation of the patient with an acute abdomen. It will also suggest algorithms to consider in the diagnosis and treatment of these patients.     

Focal segmental glomerulosclerosis

Over the last 2 decades, we have learnt that focal segmental glomerulosclerosis (FSGS) is a ubiquitous phenomenon underlying the progressive deterioration of many different types of renal diseases in both pediatric and adult populations. FSGS may also be the primary renal lesion, whether in new disease entities such as glycogen storage disease and human immunodeficiency virus infection, or in idiopathic FSGS. Although the mechanism which triggers the development of primary FSGS still remains unknown, laboratory and clinical studies have identified several key pathophysiological events leading to end-stage renal disease. While therapeutic modalities have not changed remarkably, a recent study, although uncontrolled, demonstrated an impressive efficacy of intravenous steroid pulse therapy in inducing remission. Nevertheless, it remains largely unknown whether such a forced remission decreases the overall risk of developing chronic renal failure. Studies have revealed an important pathophysiological role of angiotensin and the therapeutic efficacy of angiotensin converting enzyme inhibitors in progressive loss of renal function in diseases where glomerulosclerosis is secondary; however, it remains to be verified whether these results hold true in primary FSGS. As a result of the improvement in allograft survival rate, the benefit of renal transplant outweighs the risk of recurrence of FSGS, hence transplantation continues to be a vital therapy for FSGS patients who have reached renal failure. Thus, FSGS is not one disease, but rather a range of lesions seen in many settings. The type of lesions and the patient's unique genetic factors contribute to prognosis, and also may dictate choice of optimum therapy.     

Morbidity and mortality on maintenance haemodialysis

Despite the many technical advances in medical care and dialysis delivery, mortality and morbidity remain high in end-stage renal disease (ESRD) patients. A number of factors seem to contribute. Cardiovascular diseases are the leading cause of death: volume overload, anaemia, hypertension, arteriovenous fistula, uraemia-related myocardial cell injury all contribute to the development of ischaemic heart disease and congestive heart failure. The underlying disease is determinant for prognosis, with diabetics displaying an excess cardiovascular mortality. Elderly are also more likely to experience intercurrent medical conditions, vascular disease and diabetes, thus increasing the risk of death. Protein-energy malnutrition and wasting also contribute to the higher mortality in renal replacement therapy. Although nowadays high-risk patients are dialysed too, the rate of acceptance of ESRD patients still varies widely in different countries, possibly because of hidden selection criteria. The patients in the registries with a higher acceptance rate are more likely to be affected by co-morbid conditions and greater disease severity; the assessment of these co-morbid conditions is extremely important when comparing outcomes in different haemodialysis populations. Dialysis adequacy, obtained by means of longer duration of the treatment, is also of paramount importance; it allows minimizing the clinical effects of ultrafiltration and ensure that correct dry weight is reached. This means decreasing the incidence of intradialytic hypotensive episodes, but also improving blood pressure control, a strong predictor of survival. Family and social support, together with adequate medical care, greatly affect the quality of life of patients and can improve compliance to dialysis, diet and drugs and therefore survival.     

Brain stem death and organ donation

Rhabdomyolysis was diagnosed in two dogs with babesiosis. The first animal presented with muscle pain and caramel-coloured urine, and had markedly elevated serum myoglobin and muscle enzymes. Acute renal failure complicated the clinical picture. The second dog exhibited muscle pain and tremors, together with neurological signs and pulmonary oedema, and died soon after admission. Muscle necrosis and haemorrhage were found at necropsy. In human malaria, a disease clinically similar to canine babesiosis, rhabdomyolysis is unusual, but clinically silent muscle damage appears to be common. Likewise, biochemical evidence of muscle damage is readily found in experimental bovine babesiosis. Muscle enzymes were mildly elevated in three dogs with severe babesiosis and pigmenturia but there was no obvious muscle damage, indicating that this might also apply to canine babesiosis. The pathogenesis of infection-associated rhabdomyolysis and acute renal failure remains unclear, but inflammatory cytokines and nitric oxide could play an important role.     

Serious renal disease in Egypt

We studied serious renal disease in Egypt by registering all 155 patients coming to the nephrology service at the University of Cairo during a period of 62 days in 1993. The patients presented with severe uremic symptoms. Admission creatinine and urea levels were high, 804 mumol/l and 64 mmol/l. Fifteen percent of the patients died; 115 underwent dialysis. Sixty patients presented with chronic renal failure; 53 with acute renal failure, but 24 of these were later found to have end-stage renal failure. Of 29 patients with true acute renal failure, 11 (38%) had pre-renal failure and 7 (24%) post-renal failure. Twenty-one patients were followed up after transplantation and chronic dialysis, another 17 had nephrotic syndrome, 3 hypertension, and one had asymptomatic urinary abnormalities. The most common specific etiology for chronic end-stage renal failure was diabetes mellitus type II in the older patients; second most common was Schistosoma in the younger ones. Most diabetic patients came from the city. All but one Schistosoma patient came from rural Egypt. In the 22 patients who underwent renal biopsy the most common diagnosis was mesangio capillary glomerulonephritis. The prevalence of acute renal failure, particularly iatrogenic-toxic, is increasing.     

Acute renal failure due to severe Landry-Guillain-Barré syndrome

BACKGROUND: Blood urea nitrogen (BUN) >60 mg/dl has been reported to occur commonly in patient's with severe Landry-Guillain-Barré syndrome. AIMS: To find out the cause for this high BUN we compared the renal function tests of 30 consecutive cases with severe Landry-Guillain-Barré syndrome to those of 30 controls. RESULTS: Acute renal failure occurred in seven patients with Landry-Guillain-Barré syndrome and none of the control group. Acute renal failure was found more in cases with Landry-Guillain-Barré syndrome compared to controls (P=0.0049). Six out of seven cases with Landry-Guillain-Barré syndrome and acute renal failure had dysautonomia and became oliguric while being in a hypotensive state. Of 30 patients with Landry-Guillain-Barré syndrome seven cases died. From eight patients with dysautonomia six cases who had acute renal failure died. The mortality rate was higher in cases with dysautonomia and acute renal failure (P = 0.0001 and 0.00001, respectively). Interestingly no glomerular disease was found. CONCLUSION: In conclusion acute renal failure can occur commonly in cases with severe Landry-Guillain-Barré syndrome particularly in those with dysautonomia, causing high mortality.     

HIV infection and the kidney

HIV-infected patients may present with a variety of patterns of renal involvement. Acute renal failure is common and most often a result of sepsis, hypotension, and nephrotoxic agents. It is potentially avoidable, and support through the period of renal failure may lead to resolution of the renal dysfunction. HIV-associated nephropathy is a unique pattern of sclerosing glomerulopathy that ranges in prevalence from 1 to 10% of the HIV-infected population in different geographic locales. This complication of HIV infection will likely present a growing challenge to the medical community as HIV infection continues to spread worldwide. Deciphering the pathogenetic mechanisms of this most rapidly progressive form of focal segmental sclerosis is not only clinically relevant, but will hopefully provide valuable insights into the mediation of the more common idiopathic form of the disease. The potential for improved renal survival of patients with HIV-associated nephropathy has become more realistic with the development and use of antiretroviral agents, as well as studies on the role of immunosuppression and ACE inhibition in this population. An awareness of other glomerular lesion and tubulointerstitial lesions has broadened our understanding of populations with renal disease who have been infected by HIV. Moreover, as prolonged survival of HIV-infected individuals is being achieved with modern antiviral therapy, the percentage of patients surviving with nephropathy will likely grow in coming years. Awareness of the growth of this population and those requiring short- and long-term hemodialysis and peritoneal dialysis will allow appropriate planning for ESRD in the HIV-infected population.     

A prospective study of ward referrals for renal disease at a Jamaican and a United Kingdom hospital

Seventy ward referrals for renal disease were prospectively studied at each of two tertiary hospitals: University Hospital of the West Indies (UHWI), Kingston, Jamaica and Nottingham City Hospital (NCH), England. At UHWI, the referral population was significantly younger, 89% being less than 60 years of age compared to 40% at NCH (p < 0.05). The leading cause of acute renal failure (ARF) at UHWI was systemic lupus erythematosus (SLE) followed by acute tubular necrosis (ATN). The leading causes of ARF at NCH were ATN and obstructive uropathy. Primary renal disease and diabetes mellitus were the major causes of end-stage renal disease (ESRD) at both centres, followed by SLE and hypertension at UHWI and renovascular disease and chronic pyelonephritis at NCH. Nephrotic syndrome occurred more frequently at UHWI than at NCH but the numbers were small (p < 0.05). Mortality rates were similar among patients with ARF and nephrotic syndrome at both centres, but were higher for patients with chronic renal failure (CRF) at UHWI than at NCH (p < 0.05). Continuous ambulatory peritoneal dialysis (CAPD) was a frequent mode of renal replacement therapy at NCH (76% v 19% on haemodialysis). At UHWI, CAPD was not available and 45% of patients with ESRD were not offered maintenance dialysis because of inadequate facilities. The major difference in management and outcome between the two centres occurred in cases with CRF, suggesting that survival in patients with CRF in Jamaica could be improved if this therapeutic modality was available.     

Biocompatible dialysis membranes and acute renal failure: a study in post-operative acute tubular necrosis in cadaveric renal transplant recipients

Previous experimental and human data suggests a detrimental effect on the course of acute renal failure related to exposure of blood to artificial dialysis membranes of poor biocompatibility. We performed a 2.5-year prospective randomized trial to compare the clinical course of acute renal failure (post-operative ischemic acute tubular necrosis, ATN) in patients receiving a cadaveric renal transplant requiring supportive hemodialysis in the immediate post-transplant setting. Patients were randomized to either a cuprophane or polymethylmethacrylate (PMMA) conventional hollow fiber dialyzer. All patients received a standard immunosuppressive regimen which included induction therapy with either horse anti-thymocyte gamma globulin (ATGAM) or the murine anti-CD3 monoclonal antibody (OKT3). Of 53 patients randomized, 17 were excluded (2 for intervening biopsy-proven rejection prior to recovery from ATN, 10 for primary graft nonfunction and 5 for other reasons), leaving 36 evaluable cases of uncomplicated ATN, 18 in each group. There was no difference by age, race, gender, cause of ESRD, immunosuppressive regimen, cold or warm ischemia time, use of pre-transplant dialysis, percent oliguria or the incidence of intra-dialytic hypotension between the 2 groups. There was no difference in the mean time to recovery from ATN posttransplant (8.9 days in the cuprophane group vs 9.5 days in the PMMA group, p = NS) or in the average number of hemodialysis treatments required (3.6 in both groups, p = NS). There was also no difference in long term allograft outcome in terms of the nadir serum creatinine, the number of episodes of subsequent acute rejection or in the development of chronic rejection. An intent-to-treat analysis of all 53 originally randomized patients similarly yielded no significant differences. A subsequent, non-randomized study using a membrane of intermediate biocompatibility (Hemophan) also showed no difference in recovery time from ATN. Bioincompatible membranes do not seem to have a significant clinical impact on the course of recovery of this form of acute renal failure. The striking benefits of biocompatibility in the course of ARF seen in other human trials may relate more to the non-renal systemic toxic effects of bioincompatibility.     

Prevention of renal osteodystrophy in peritoneal dialysis

BACKGROUND: Renal osteodystrophy (ROD) is still one of the major long-term complications in end-stage renal disease leading to considerable morbidity. Despite some progress in understanding the pathogenesis of secondary hyperparathyroidism (sHPT) during recent years, prevention and treatment of ROD is still suboptimal, requiring surgical parathyroidectomy in 6 to 10% of all patients on dialysis after 10 years. In addition, the spectrum of bone lesions has changed, with non-aluminum-related adynamic bone disease (ABD) found in up to 43% of peritoneal dialysis (PD) patients. METHODS: Current recommendations concerning prevention of ROD in PD based on the literature and personal recent data were reviewed. The focus is on (i) the importance of early prophylactic intervention to prevent parathyroid gland hyperplasia, (ii) the pathogenesis of ABD, and (iii) the role of metabolic acidosis in ROD. RESULTS: There is ample evidence that sHPT starts early during the course of renal failure and results from both hypersecretion of PTH by parathyroid cells and glandular hyperplasia. As shown by experimental and clinical studies, established parathyroid cell hyperplasia is hardly reversible by pharmacological means, and therefore prevention of parathyroid cell proliferation needs to start early. Recent data from randomized trials document the efficacy and safety of low dose active vitamin D (0.125 to 0.25 microgram/day) and/or an oral calcium substitute to prevent progression of sHPT in patients with mild to moderate renal failure. Since little is known about the pathogenesis, natural course and clinical impact of ABD in PD, specific therapeutic concepts have not yet been generated. Diabetes and advanced age are established risk factors, whereas the role of calcium and vitamin D overtreatment or the type of dialysis (PD vs. HD) are still controversial. Currently no evidence for different functional behavior of the parathyroids in ABD and sHPT has been found. The role of circulating or local factors such as cytokines, growth factors or the presence of advanced glycation end-product (AGE)-modified matrix proteins for the pathogenesis of either type of ROD deserves further investigation. Avoiding oversuppression of parathyroid gland and the use of low calcium dialysate may help prevent ABD. There is growing evidence that a correction of metabolic acidosis will influence ROD by both direct effects on the bone and on parathyroid cell function. New dialysate composition for CAPD with a high HCO3 concentration will allow normalization of acid-based metabolism in PD patients. Their effects on ROD under long term conditions remain to be determined. CONCLUSION: Therapeutic efforts should aim to prevent the development of parathyroid gland hyperplasia and sHPT early during the course of renal failure, and should include the use of low dose vitamin D therapy and oral calcium substitution as well as correction of metabolic acidosis. Concerning ABD, more information is needed regarding the causes and consequences of this type of bone lesion to develop a more specific therapy.     

Acute urinary tract obstruction. Imaging update

Although urinary tract obstruction is an age old problem with IVU the time-honored imaging technique of choice, recent advances in renal ultrasonography and abdominal and pelvic CT scanning have advanced these alternative modalities to the forefront. No rigid algorithm for renal obstruction is recommended, because the utilization of these techniques is in a state of flux. The use of one modality over another as a first-line imaging technique likely will depend on the equipment availability and expertise of a given institution. The choice also may be guided by each institution's cost of each type of examination. Although a role for the IVU remains in the evaluation of acute renal obstruction, ultrasonography and CT scan have emerged as alternative primary screening tools. Undoubtedly, the future will bring further changes in our assessment of renal obstruction. The cost effectiveness and definitiveness of evaluation likely will become more important driving factors than they have been in the past. The radiologist and urologist together must assess available imaging techniques, their effectiveness, and the institution's expertise to develop a cost-effective and efficient system for assessment of renal obstruction.     

Acute renal failure. Community hospital experience with hemodialysis as intensive care adjunct

A 3-year experience with 50 acute renal failure patients managed by hemodialysis in a 417-bed community hospital is reviewed. The 58% survival rate was better than that reported in other recent series. Possible reasons for our favorable mortality experience include: (1) Hemodialysis was performed within the ICU facility by the ICU staff. Continuity of total care was thereby maintained and hemodialysis problems, such as maintenance of circulating volume, were managed in the context of continued assessment of the patient's cardiopulmonary status. (2) In contrast to previous reports, the presence of sepsis did not influence recovery rates from acute renal failure. Early administration of specific antibiotics, mainly gentamicin, rapid drainage of abdominal abscesses, and early and frequent dialysis were all utilized in spetic patients and may have contributed to their high recovery rate. (3) The use of agressive dialysis may also have lessened other uremic complications, notably gastrointestinal bleeding. Our dialysis organization and procedures are described.     

Nephrotoxicities of nonsteroidal anti-inflammatory drugs

While the relative incidence of serious nephrotoxicities in the population consuming nonsteroidal anti-inflammatory drugs (NSAIDs) is very low, the frequency of adverse events in patients at risk has considerably increased due to the rising popularity of the use of the drugs in recent years. Under normal conditions, NSAIDs have relatively little effect on the kidney because of low renal production of prostaglandins. However, in the presence of renal hypoperfusion in which local synthesis of vasodilator prostaglandins is increased to protect the glomerular hemodynamics and to maintain appropriate renal tubular transport of fluid and electrolytes, inhibition of prostaglandin synthesis by NSAIDs can lead to vasoconstrictive acute renal failure as well as fluid and electrolyte disorders such as sodium retention and resistance to diuretics, hyponatremia and hyperkalemia. Conditions that increase the risk for NSAID-induced nephrotoxicities include volume depletion from diuretics and other causes, edematous states such as congestive heart failure and cirrhosis of the liver, old age and underlying renal disease, especially in the presence of renal functional impairment. In addition, renal parenchymal diseases may develop in susceptible patients taking NSAIDs. These include acute tubulointerstitial nephritis, frequently associated with nephrotic syndrome, and chronic progressive renal disease, with or without renal papillary necrosis. Rare cases of vasculitis and glomerulonephritis have also been reported. Finally, NSAIDs may aggravate hypertension by interacting with antihypertensive drugs, especially with diuretics and beta-blockers. Withdrawal of NSAIDs in patients at risk can frequently reverse or improve the nephrotoxicities. It is recommended that physicians be aware of the clinical settings that increase the risk for NSAID-induced nephrotoxicities and take preventive or therapeutic measures accordingly.