COVID-19 and Renal Diseases: An Update.

Michael R. Charlton, William J. Wall, Akinlolu O. Ojo, Pere Gines, Stephen Textor, Fuad S. Shihab, Paul Marotta, Marcelo Cantarovich, James D. Eason, Russell H. Wiesner, Michael A. Ramsay, Juan C. Garcia-Valdecasas, James M. Neuberger, Sandy Feng, Connie L. Davis, Thomas A. Gonwa, and the International Liver Transplantation Society Expert Panel Mayo Clinic, Rochester MN; Department of General Surgery, London Health Science Center, London, Ontario, Canada; Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; Liver Unit, Hospital Clinic, University of Barcelona School of Medicine, Barcelona, Spain; Department of Nephrology, University of Utah School of Medicine, Salt Lake City, UT; Medical School, University of Western Ontario, London, Ontario, Canada; Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada; Transplant Institute, University of Tennessee, Memphis, TN; Baylor University Medical Center, Dallas, TX; Hospital Clinic I Provincial, Barcelona, Spain; Queen Elizabeth Hospital, Birmingham, England; Department of Transplant Surgery, University of California San Francisco Medical Center, San Francisco, CA; Department of Medicine, University of Washington Medical Center, Seattle, WA; and Mayo Clinic, Jacksonville, FL

Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases.

Progression From Acute Kidney Injury to Chronic Kidney Disease: A Pediatric Perspective

Pretransplant Predictors and Posttransplant Sequels of Acute Kidney Injury after Allogeneic Stem Cell Transplantation

The increased success and availability of transplantation of solid organs other than kidneys has resulted in a large number of patients at risk for the usual medical complications of long-term immunosuppressive therapy. Acute and chronic renal failure play a critical role in the success of these

Theadministration of succinylcholine (SCh) in humans results in a mild and transient hyperkalemia. In normal individuals, the increase in serum potassium (K+) is approximately 0.5–1.0 mEq/L, occurs within 3–5 minutes after the IV administration of SCh, and lasts <10–15 minutes (1). This increase is probably caused by K+ release from cells as a result of depolarization at the neuromuscular junction. However, in certain conditions, such as trauma, burns, infection, and certain neuromuscular disorders (including spinal cord injury, upper motor lesions, and structural brain damage, peripheral nerve injury, peripheral neuropathy, Parkinson's disease, tetanus, and muscular dystrophy), there is an exaggerated increase in the serum K+ level that may manifest clinically in cardiac dysrhythmias and even cardiac arrest (1). In these conditions, it is believed that there is a proliferation of postsynaptic acetylcholine receptors beyond the neuromuscular junction (extrajunctional receptors) with the result that K+ flux is not restricted to the neuromuscular junction. This proliferation leads to an exaggerated increase in serum K+ levels on depolarization induced by SCh administration. Because K+ homeostasis is disturbed in patients with renal failure, the use of SCh in such patients has raised concerns of an exaggerated hyperkalemic response, with its resultant adverse cardiac effects. However, after several case reports (2–4), case series (5–6), and controlled studies (7–10), the consensus has been that use of SCh is safe in patients with renal failure, provided that there is no associated neuropathy or preoperative hyperkalemia, and that repeated SCh doses are avoided (5–10). Recently, in our institution, several patients with renal failure who were given SCh during surgery developed hyperkalemia in the postoperative period. These patients had normal preoperative serum K+ levels, but intraoperative levels were not measured. Although the cause of hyperkalemia in these patients was unclear, questions regarding the safety of SCh in patients with renal failure were raised. We thus decided to critically review the literature on the safety of SCh in renal failure patients undergoing surgery. In this report, we summarize the findings of this review and offer our conclusions. Studies of SCh and Renal Failure Roth and Wuthrich (2) first raised concerns about the risk of hyperkalemia and cardiac dysrhythmias after the use of SCh in patients with renal failure. They reported two patients with renal failure (a 74-yr-old woman and a 2-yr-old boy) who experienced cardiac arrest within minutes after the administration of SCh while undergoing emergency surgery. Both patients had elevated preoperative serum K+ levels (6.2 mEq/L and 6.5 mEq/L). However, post SCh administration K+ levels were not measured in the first case, so a hyperkalemic cause for the cardiac arrest could not be established. The K+ levels in the second (pediatric) case increased to 8.9 mEq/L. In patients with renal failure, Roth and Wuthrich (2) suggested that SCh should be absolutely contraindicated if preoperative serum K+ levels are elevated, and relatively contraindicated if they are normal. In a second case report, Powell (3) described a 44-yr-old woman with renal failure and a normal preoperative serum K+ level (4.1 mEq/L) who was given three doses of SCh within 25 minutes of anesthetic induction while undergoing elective bilateral nephrectomy. Within 6 minutes after the last SCh dose, the patient developed electrocardiographic (EKG) changes consistent with hyperkalemia and several short runs of ventricular tachycardia and had a serum K+ level of 6.9 mEq/L (3). Powell's (3) recommendations were even more stringent than Roth and Wuthrich's (2), suggesting that SCh should be absolutely contraindicated in all patients with renal failure, even when the preoperative K+ level is normal. In a third case report, Walton and Farman (4) reported on a patient with renal failure and uremic polyneuropathy who received two doses (50 mg and 25 mg) of SCh while undergoing bronchoscopy. The serum K+ level, which was 4.5 mEq/L at baseline, did not increase after the first dose, but did so markedly to 7.3 mEq/L within two minutes after the second dose. However, the patient did not exhibit any cardiac disturbances. The authors suggested that the combination of polyneuropathy and repeated doses of SCh may have triggered the hyperkalemia. Subsequently, four controlled studies (7–10) and two case series (5,6) that specifically measured serial serum K+ levels after SCh administration in patients with renal failure undergoing surgery did not show an increase in serum K+ more than that expected in individuals with normal renal function. In the first controlled study, Koide and Waud (7) measured serum K+ levels serially in 34 patients with chronic renal failure and in 22 with normal renal function. The mean levels of preoperative serum K+ in patients with and without renal failure who were pretreated with d-tubocurare were 3.8 ± 0.6 mEq/L and 4.1 ± 0.3 mEq/L, respectively. The levels were 4.4 ± 0.8 mEq/L and 4.2 ± 0.5 mEq/L, respectively, in those who were not pretreated with d-tubocurare. After a single of dose of SCh (1 mg/kg body weight), the mean maximal increase in K+ levels observed in both groups of patients was 0.5 mEq/L, with more variation in patients with renal failure. The authors did not observe any cardiac arrhythmias other than sinus tachycardia. They concluded that a single dose of SCh is safe in patients with renal failure who have preoperative serum K+ levels below 5.5 mEq/L. However, they cautioned its use in patients with high levels of preoperative serum K+, in whom even a small increase in the serum K+ may increase the risk of cardiac arrhythmias. In the second controlled study, Miller et al. (8) compared serial serum K+ concentrations after a single dose of SCh (1 mg/kg) in 10 patients with renal failure who were undergoing renal transplantation with 10 patients without renal failure undergoing intraabdominal surgery. Mean preoperative serum K+ levels in patients with and without renal failure were 5.0 ± 0.71 mEq/L (range 4.3 to 6.6 mEq/L; median 4.7 mEq/L) and 3.7 ± 0.42 mEq/L (range 2.8 to 4.1 mEq/L; median 3.85 mEq/L), respectively. They observed that the mean maximal increase in serum K+ in patients with renal failure was 0.24 ± 0.45 mEq/L (range −0.4 to + 0.6 mEq/L) which was not significantly different from the increase observed in patients with no renal disease, 0.18 ± 0.50 mEq/L (range −0.9 to + 0.7). The largest increase was 0.7 mEq/L, which was observed in a patient with no renal disease. The authors concluded that SCh at this dose was not contraindicated in patients with renal failure in the absence of uremic neuropathy. In the third controlled study, Day (9) studied serial serum K+ levels in 21 patients with chronic renal failure and 54 patients with normal renal function who received either SCh 100 mg IV or suxethonium (a depolarizing muscle relaxant similar in structure to SCh but with a shorter duration of action) 150 mg IV. After SCh administration, there was a similar increase from baseline (4.14 ± 0.47 control and 4.18 ± 0.61 mEq/L renal failure patients) in the mean serum K+ levels in both groups. However, statistically significant increases in the serum K+ levels from baseline were observed in the control group at 10 (4.37 ± 0.66 mEq/L) and 25 minutes (4.58 ± 0.72 mEq/L) and in the renal failure group at 2 (4.55 ± 0.49 mEq/L) and 10 minutes (4.60 ± 0.63 mEq/L) after SCh administration. No such increases were seen in patients with renal failure after suxethonium administration. One 24 yr-old patient with acute renal failure who received SCh developed cardiac arrest and was successfully resuscitated. His serum K+ level at the time of cardiac arrest was 4.3 mEq/L (baseline 4.5 mEq/L). Day postulated that this patient's severe metabolic disturbances, as evidenced by the preoperative plasma urea level (30 mmol/L), may have contributed to the arrest. No cardiac arrhythmias were observed in any of the other renal failure patients. In the fourth controlled study, Radnay et al. (10) evaluated serial serum K+ levels in 20 patients with chronic renal failure and 20 with normal renal function who received SCh (0.2 mg/kg) after the induction with neuroleptanesthesia (droperidol, fentanyl, nitrous oxide and oxygen) and pretreatment with hexafluorenium (0.3 mg/kg). Mean baseline serum K+ levels (3.90 ± 0.10 mEq/L in patients with normal renal function and 4.70 ± 0.12 mEq/L in those with chronic renal failure) decreased substantially after the induction with neuroleptanesthesia (3.59 ± 0.13 mEq/L, 4.17 ± 0.11 mEq/L, respectively) and even further after hexafluorenium administration (3.39 ± 0.10 mEq/L and 3.92 ± 0.11 mEq/L, respectively). Compared with the levels after hexafluorenium administration, the mean levels increased by 0.16 mEq/L in patients with normal renal function and 0.10 mEq/L in those with chronic renal failure after SCh administration. In neither group did the serum K+ levels exceed baseline levels. Based on these findings, the authors recommended a combination of neuroleptanesthesia and pretreatment with hexafluorenium preceding SCh administration as a suitable and "relatively risk-free" technique for muscle relaxation in patients with chronic renal failure. This technique, however, is not a feasible option; hexafluorenium, a nondepolarizing neuromuscular blocking drug with selective inhibition of plasma cholinesterase that was used mainly to prolong muscle relaxation and to minimize muscle fasciculations induced by SCh, has not been commercially available in this country for nearly two decades (11,12). In the first case series, Walton and Farman (5) measured serial serum K+ levels after a dose (1 mg/kg) of SCh in a random sample of 12 candidates for renal transplantation. Initial serum levels of K+ ranged from 2.7 to 7.3 mEq/L. In 11 of the patients, the variability in K+ level induced by SCh administration was <0.7 mEq/L; only 7 patients exhibited an elevation in their serum K+ levels. In the 12th patient, the K+ level increased by 1.2 mEq/L (from 3.3 mEq/L at baseline to 4.5 mEq/L, two minutes after the administration of SCh) but decreased to 3.5 mEq/L at 6 min. Interestingly, the two patients with high baseline K+ levels (6.5 mEq/L and 7.3 mEq/L) showed a maximal increase of 0.1 mEq/L and 0.7 mEq/L, respectively. The authors did not report any cardiac disturbances. In the second case series, Powell and Miller (6) studied the effects of repeated doses of SCh on the serum K+ levels of 11 patients undergoing renal transplantation. An initial dose of 1 mg/kg was followed by two more doses at 5-minute intervals. Serial serum K+ levels were measured at baseline, 2, 5, 7, and 10 minutes after each dose of SCh. The mean baseline serum K+ level was 4.7 ± 0.93 mEq/L. The largest increase in serum K+ with repeated SCh doses was 0.6 mEq/L. The mean net change was + 0.34 mEq/L with the mean increase and decrease being +0.5 mEq/L and −0.4 mEq/L, respectively. The largest serum K+ change was negative (-0.9 meq/L). The maximum increase in serum K+ in the patient with the highest baseline level (6.4 mEq/L) was 0.4 mEq/L and was seen 5 minutes after the second dose of SCh. In 15 of 22 (68%) of the repeated injections, the authors observed sinus bradycardia. The authors concluded that SCh administered repeatedly at this dose was not contraindicated in patients with renal failure. Effects of Repeated Doses of SCh on Serum K+ Levels In the case reports by Powell (3) and by Walton and Farman (4), an increase in serum K+ levels was seen only after repeated doses of SCh, suggesting that the cumulative effects of multiple doses may increase the risk of hyperkalemia. In addition, a patient who received a second dose of SCh in the study by Koide and Waud (7) had an additional increase in serum K+ of 1.0 mEq/L, in comparison to a 0.2 mEq/L increase after the first dose. Powell and Miller (6) specifically studied the effects of repeated doses of SCh on the serum K+ levels in patients with renal failure and did not find an excessive increase in serum K+ after repeated administration of SCh. Consistent with other reports (13,14), they found that 15 of 22 (68%) repeated injections in their study resulted in sinus bradycardia. List (14) reported bradyarrhythmias in 40% of 96 patients with heart disease after a second dose of SCh. Two of these patients developed asystole that responded to external cardiac massage. The mechanism for the bradycardia is postulated to be mediated via the effect of the parasympathetic nervous system on the heart or via a direct action on the myocardium (13) and not hyperkalemia per se. Pretreatment with glycopyrrolate or atropine protects against bradyarrhythmias induced by repeated administration of SCh (13,15–17). Prevention of SCh-Induced Hyperkalemia To minimize the hyperkalemia associated with SCh administration, investigators have tried pretreatment with various drugs, including nondepolarizing neuromuscular relaxants (7,10,18–23), flunitrazepam (24), diazepam (25,26), and magnesium sulfate (19) with mixed results. Only Koide and Waud (7) and Radnay et al. (10) specifically evaluated the role of pretreatment in patients with chronic renal failure. Koide and Waud (7) found that pretreatment with d-tubocurarine did not prevent an increase in serum K+ after SCh administration. In contrast, after the induction with neurolept anesthesia (droperidol, fentanyl, nitrous oxide and oxygen) and pretreatment with hexafluorenium, Radnay et al. (10) reported a SCh-induced increase in mean serum K+ levels of 0.16 mEq/L in patients with normal renal function and 0.10 mEq/L in those with chronic renal failure. In neither group did the serum K+ levels after SCh administration exceed baseline (i.e., preinduction) levels. As discussed earlier, this technique is not feasible in clinical practice because of the commercial unavailability of hexafluorenium. Effects of SCh on Serum K+ in Chronic Versus Acute Renal Failure In chronic renal failure, adaptive changes in the kidneys and the gut prevent significant hyperkalemia. Depending on whether K+ intake is normal or increased, the kidneys can maintain K+ equilibrium until a glomerular filtration rate of 5–10 mL/min or 10–40 mL/min, respectively. In chronic renal failure, fecal excretion of K+ is considerably enhanced. However, because the adaptive mechanisms in chronic renal failure are not present in patients with acute renal failure, they are at high risk of developing hyperkalemia (greater than 50% of cases) (27). The hyperkalemia is especially severe in the presence of oliguria and tissue destruction, with or without sepsis. K+ is distributed unevenly, with 98% in the intracellular and 2% in the extracellular fluid compartments. As a result, small changes in the extracellular K+ level cause significant hyperkalemia or hypokalemia, depending on the direction of the K+ shift. Since the membrane potential of cells is dependent upon the ratio of the intracellular to the extracellular K+ concentration [IK+/EK+], any acute increase in extracellular K+ will cause depolarization of the membrane, and resultant cardiac dysrhythmias. Thus, the actual level of serum K+ that causes toxicity may vary, with the rate of rise of K+ more important than the absolute level. Patients with chronic renal failure with chronic K+ elevations also have a higher intracellular K+, so that the ratio [IK+/EK+] is normal (27,28). Thus, the myocardium appears to have some tolerance to hyperkalemia in uremia, as evidenced by reports of cases of severe hyperkalemia without EKG changes (29). Because of the widespread availability of hemodialysis, a significantly elevated serum K+ level and its associated morbidity are infrequently encountered. Nevertheless, SCh-induced hyperkalemia in renal failure could result in adverse cardiac outcomes. The demonstrated absence of significant hyperkalemia and resultant adverse cardiac outcomes associated with SCh use in patients with chronic renal failure suggests otherwise. Discussion Since SCh was first introduced clinically in the early 1950s, it has been used extensively in situations requiring rapid tracheal intubation during the induction of anesthesia in an effort to avoid aspiration of gastric contents. Rapid induction is possible because of its rapid onset of action (one minute) and short duration of action (seven-eight minutes) when administered in doses of 1 mg/kg. However, because of the undesirable side effects of SCh, which include hyperkalemia, postoperative myalgia, and increased intraocular and intragastric pressure, some of the newer nondepolarizing neuromuscular relaxants, particularly rocuronium with an onset of action almost as rapid and without its side effects, have been recommended as alternatives (13,30). Interestingly, in an excellent review, Durant and Katz (13) in 1982 speculated that "is likely that suxamethonium will be of historical interest. This review may well be a requiem for suxamethonium." Nevertheless, the use of SCh continues, primarily because of the higher costs and longer duration of action of the newer anesthetics. Based on our review of the literature in English language medical journals, we conclude that there is sufficient evidence to support the current consensus that SCh can be safely administered to patients with renal failure. Of the nine studies (2–10) reviewed that specifically addressed the issue of SCh use and associated hyperkalemia in patients with renal failure, six (two case series and four controlled studies) did not find an excess risk of hyperkalemia or its adverse cardiac effects (5–10). Only three case reports (2–4) reported adverse cardiac effects after SCh use. In one (4), the authors attributed the hyperkalemia to a combination of uremic neuropathy and a repeated dose of SCh. The other two case reports (2,3) implicated SCh as the likely cause of the hyperkalemia and its ensuing cardiac consequences. In one report, SCh-induced hyperkalemia was not confirmed by serum K+ measurements or EKG evidence of hyperkalemia in one patient (2). In the other, there was a delayed appearance of EKG changes with the hyperkalemia persisting postoperatively for at least 24 hours (3). This finding led Miller et al. (8) to conclude that these effects could not be attributed to SCh-induced hyperkalemia. Alternative factors, such as the presence of acidosis, especially after hemorrhage or gut ischemia, have been reported to have a synergistic effect on SCh-induced hyperkalemia (31–34). Acidosis tends to drive K+ from the intracellular to the extracellular fluid compartment leading to hyperkalemia. In renal failure patients who have preoperative hyperkalemia, data on the safety of SCh are unclear. In four patients with preoperative hyperkalemia (5,6,8), there were no excessive increases in serum K+ after SCh administration. However, given the small number of patients in these studies and the known risks of cardiac dysrhythmias associated with hyperkalemia, prudence would dictate that it be avoided under these circumstances. Because even small increases in a hyperkalemic patient may increase the risk of triggering dangerous cardiac dysrhythmias, some authors recommend medical treatment of serum K+ levels above 6.0 mE/L preoperatively (35). The only study (6) that addressed the effect of repeated doses of SCh administration in patients with renal failure did not show an excessive increase in serum K+, but did show that 68% of the repeated injections resulted in sinus bradycardia—a finding consistent with the literature. Nevertheless, repeated doses of SCh in patients with renal failure are probably best avoided. If administration of repeated doses is contemplated, pretreatment with glycopyrrolate or atropine to protect against SCh-induced bradycardia should be strongly considered (13,15,16). Pretreatment with a nondepolarizing neuromuscular relaxant or diazepam to minimize SCh-induced hyperkalemia may also be considered in the clinical setting. In patients with renal failure who may also have associated conditions that increase the risk of an exaggerated hyperkalemic response, however (e.g., burns, trauma, tissue ischemia, infections, and neuromuscular disorders including neuropathies), SCh should be avoided. Conclusions Case reports (31,36–40) of SCh-induced hyperkalemia and cardiac arrests in various disease settings continue to appear in the literature. However, we did not find additional case reports and studies of SCh-induced hyperkalemia in patients with renal failure. This, and the clinical experience of investigators (5,8,41–43) who have safely used SCh in a large number of patients with renal failure corroborate the above conclusions that SCh, with the exceptions noted above, can be used safely in such patients.

Clinical practice guidelines for the provision of renal service in Hong Kong: Potential Kidney Transplant Recipient Wait-listing and Evaluation, Deceased Kidney Donor Evaluation, and Kidney Transplant Postoperative Care.

Sexual Function in Chronic Kidney Disease

Cardiovascular Disease Mortality in Kidney Transplant Recipients: No Light at the End of the Tunnel?

Case Scenario: Hemodynamic Management of Postoperative Acute Kidney Injury

Cardiovascular Disease in Children with Chronic Kidney Disease

Outcomes of Pediatric Kidney Transplantation in Recipients of a Previous Non-Renal Solid Organ Transplant.

Anemia After Renal Transplantation

Renal Physiology and Pathophysiology -- 1. Endothelin and endothelium-derived relaxing factor in the control of glomerular filtration and renal blood flow -- 2. Role of glomerular growth promoters in progression of renal disease -- 3. Reactive oxygen species and renal injury -- Glomerulonephritis -- 4. Changing views on the treatment of glomerulonephritis -- 5. Plasma exchange for renal disease -- 6. Albumin metabolism in the nephrotic syndrome. Implications for patient management -- Hypertension -- 7. Current recommendation for first line therapy of uncomplicated hypertension -- The Kidney and Diabetes -- 8. Risk factors for progression of renal insufficiency in diabetic nephropathy: therapeutic implications -- Chronic Renal Failure -- 9. Causes, consequences, and treatment of hyperlipidemia in patients with renal disease -- Dialysis -- 10. Acquired immunodeficiency syndrome (AIDS), Human immunodeficiency virus (HIV) infection, and dialysis -- 11. Continuous ambulatory peritoneal dialysis in diabetic end stage renal disease -- 12. Evaluation of central nervous system function in dialysis patients. A practical approach with implications for selection and modification of treatment modalities -- Renal Transplantation -- 13. Renal and pancreas transplantation in diabetic chronic uremic patients -- Diagnostic Methods in Nephrology -- 14. Accurate measurement of glomerular filtration rate.

There is evidence that HIV-associated nephropathy (HIVAN) can be prevented and its progression slowed by HAART. More than 20 antiretroviral drugs and drug combinations are available, and life expectancy of HIV-infected individuals is now measured in decades. However, it is likely that more indolent forms of HIVAN remain common in the HAART era, predisposing patients to nephrotoxicity from HAART and related therapies. Indeed, the prevalence of acute renal failure and chronic kidney disease appears to be increasing among HIV-infected patients in the United States [1,2], and kidney disease has emerged as an important predictor of mortality [2,3]. Adverse effects of antiviral treatments should be considered, including their long-term renal toxicity and their role in renal scarring after acute adverse events. In addition, the burden of comorbid chronic kidney disease is likely to increase with ageing of the HIV-infected cohort, continued growth of the epidemic among susceptible minorities and increasing prevalence of HAART-related metabolic abnormalities. In this population of patients, evaluation of renal disorders and prevention of evolution toward chronic renal failure are a crucial challenge. Epidemiology of HIV-associated nephropathy and HIV-related diseases Most epidemiological data on HIVAN generated in the pre-HAART era are based on the US Renal Data System (USRDS). Initial clinical studies indicated that 10% of HIV-1-infected patients appeared to develop renal disease, of which 90% showed clinical and/or pathological features consistent with HIVAN [4,5]. Past postmortem studies also yielded a prevalence of HIVAN ranging between 1% and 15%, depending on the population [6,7]. The prevalence and distribution of HIVAN was associated strongly with African-American ancestry [8,9] as indicated by an USRDS-based report of 3653 patients with end-stage renal disease (ESRD) secondary to HIVAN during 1992 to 1997 [10]. Since the introduction of HAART, national epidemiological data show a reduction of incidence of ESRD associated with HIV-associated renal disease in the United States [11,12] contrasting with the steady increase in HIV/AIDS in the general population [13]. From a mathematical model using available epidemiological data on HIV-infected patients in the USRDS database and the Centers for Disease Control and Prevention data for HIV-seropositive patients, Blower et al.[14] suggested that HAART decreases the incidence of ESRD in patients with HIVAN and the mortality from HIV, with an overall efficacy of 23%. This trend has been attributed, in part, to beneficial effects of HAART, which was commenced in 1996. Preliminary retrospective series or case reports support the efficacy of HAART in improving outcome in HIVAN [15–19]. In a retrospective cohort study, Szczech et al.[20] reported that treatment with protease inhibitors (and prednisone) was associated with a slower decline in renal function in patients with HIVAN or other HIV-1-related renal diseases. Cosgrove et al.[18] reported another retrospective series of 23 patients with HIV-1-related nephropathies, including patients with HIVAN. Patients with HIVAN were treated with HAART and none doubled their serum creatinine. In the non-HAART group, all patients showed a doubling of serum creatinine, two patients died and eight required dialysis. One study [21], retrospectively comparing two cohorts of 102 and 33 patients with biopsy-proven-HIVAN in the pre-HAART and in the HAART eras, respectively, also argues for improvement of renal survival by HAART. However, a recent postmortem-based survey reported that 12% of African-American patients dying of HIV-1 infection have histologically confirmed HIVAN [22]. Even if HAART decreases the incidence of HIVAN in African-Americans, the prevalence of HIVAN may not change because of the improvement in the survival of these patients. The onset of HIVAN could, therefore, just be delayed. Indeed, we have recently reported a patient with biopsy-proven HIVAN despite the lack of any past or present AIDS-defining condition and HAART-controlled HIV-1 infection for at least 2 years [23] Schwartz et al.[1] developed a mathematical model of the dynamics of HIV infection in the ESRD population in order to assess the impact of HAART on the progression of patients with AIDS to the development of ESRD and to predict the prevalence of HIV-related ESRD through to 2020. The authors concluded that, despite the potential benefit of HAART, the prevalence of HIV-related ESRD in the United States would be expected to rise in the future as a result of the expansion of the number with AIDS among black individuals. Nonetheless, while prospective controlled trials evaluating HAART on HIVAN or other HIV-1-related nephropathies are not ethically acceptable, consensus guidelines recommend consideration of HAART in HIV-infected patients with chronic renal insufficiency [24]. Changes in clinicopathological presentation HIV-associated nephropathy HIVAN is an unusual form of poorly responsive glomerular disease characterized by nephrotic syndrome, focal segmental glomerulosclerosis and a rapid fulminant progression to ESRD. Proteinuria occurs in up to 30% of HIV-infected patients, but not all of these patients have HIVAN [25–27]. The true prevalence of HIVAN is not known. The geographic distribution of HIVAN is not uniform, and it depends on specific risk factors for HIV disease, including race, gender and drug use. There is a striking predilection for HIVAN among African-Americans, as is also true for focal segmental glomerulosclerosis associated with intravenous drug use [4]. HIVAN is 7–10 times more common in men than in women, and 30–60% of people with HIVAN have a history of intravenous drug use [7]. In the pre-HAART era, patients with HIVAN typically presented with a nephrotic syndrome consisting of nephrotic-range proteinuria classically without oedema despite severe hypoalbuminaemia. Urinalysis reveals microhaematuria. Patients with HIVAN are typically not hypertensive, even in the face of renal insufficiency, and their kidneys are usually normal to large in size and highly echogenic by ultrasonography. The most common histological light microscopy finding is a collapsing form of focal segmental glomerulosclerosis. Tubulo-interstitial scarring, atrophy and marked dilatation of the tubules (microcystic dilatations) are usually present. Immunofluorescent microscopy is usually negative. Electron microscopy reveals wrinkling of the basement membranes, epithelial cell proliferation and focal foot process effacement. Tubulo-reticular structures in the glomerular endothelial cells consisting of ribonucleoprotein and membrane, the synthesis of which is stimulated by alpha-interferon, is highly predictive of HIVAN. Risk factors for progressive renal disease include CD4 cell count < 200 cells/μl, detectable plasma HIV RNA, hypertension, low plasma albumin and elevated serum creatinine [28]. In our experience during the HAART era, where most patients have well-controlled HIV, a nephropathy typically presents as stable or slowly progressive renal failure, hypertension, glomerular proteinuria, not necessarily of nephrotic range, and a preserved rather than increased kidney size. Pathologically, simple tuft ischaemia tends to replace florid (?) glomerular collapse while mild interstitial infiltration and cystic tubular dilatation are seen. Paradoxically, we noted more frequent atherosclerotic vascular changes even in younger affected patients. Until recently, the clinical course of HIVAN was one of inexorable progression to ESRD in 6–12 months, with limited treatment options. More options are now available to patients; these include antiretroviral therapy, steroid treatment and angiotensin-converting enzyme inhibitors. Evidence exists that antiretroviral therapy can reverse or improve the progression of HIVAN [15,16,19]; however despite the widespread use of HAART, no prospective studies have demonstrated benefit in slowing the progression of HIVAN. The survival benefit from antiretroviral therapy is indisputable. HAART may also prevent the development of HIVAN in at-risk groups. Lucas et al.[29] evaluated a cohort of 3976 at-risk patients in the Johns Hopkins HIV clinic database from 1989 to 2001. They identified 135 cases of HIVAN based on either clinical or pathological criteria. There was a 50% decline in HIVAN incidence in 1998–2001 compared with 1995–1997, and HAART was associated with a 60% reduction in risk for developing HIVAN. Patients with AIDS developed HIVAN at a rate of 12.5/1000 person-years, compared with 3.1/1000 person-years in patients without AIDS (relative risk, 4.1). However, it is notable that in over 1071 person-years of follow-up, no patient developed HIVAN when HAART was initiated prior to the onset of AIDS. The rationale for treating HIVAN with corticosteroids is that steroids are the mainstay of treatment for idiopathic focal segmental glomerulosclerosis [30]. The first report of steroid treatment in four patients with HIVAN found a significant reduction in serum creatinine after a course of corticosteroids lasting 2–4 weeks [31]. The initial case report study has now been extended to include 20 patients, and these results confirm that prednisone at a dose of 60 mg daily for 2–11 weeks leads to a significant reduction in serum creatinine and in 24-hour urinary protein excretion [30]. The encouraging short-term results must be balanced by the findings during the follow-up period. During a median follow-up of 44 weeks, 8 of 20 patients required maintenance dialysis, 11 of 20 died of HIV disease after completing prednisone treatment, and 6 of 20 developed serious infections while receiving prednisone. Only 7 of 20 patients were alive and free from ESRD after a median of 25 weeks following initiation of prednisone. A more recent retrospective study reported the course of HIVAN in 13 patients treated with prednisone and a further eight patients not treated with prednisone. Even after controlling for baseline creatinine, proteinuria, and CD4 cell count, among other variables, the prednisone group had an 80% reduction in risk of progressive azotaemia after 3 months [32]. Prednisone may work by reducing the amount of interstitial inflammation [33]. In 1995, The AIDS Clinical Trials Group (ACTG) designed a phase II randomized, double-blind, placebo-controlled multicentre trial to determine the efficacy of prednisone therapy in HIVAN, but this trial was cancelled because of poor patient recruitment. The angiotensin-converting enzyme inhibitors captopril and fosinopril have also been studied as possible therapy for HIVAN [34]. In one study in which 18 patients were enrolled, nine were treated with captopril, 6.5–25 mg three times daily, and nine controls did not receive captopril. All patients had biopsy-proven HIVAN, and renal survival was defined as the time from initiation of captopril treatment to initiation of dialysis (ESRD). The initial mean serum creatinine concentration was 34 mg/l (±7.0) in the captopril group and 37 mg/l (±0.5) in the controls. A small renal survival advantage of approximately 8 weeks (median 83 versus 30 days), was seen in the captopril group [35]. Two non-randomized studies have investigated the effect of fosinopril on the progression of HIVAN. Both studies showed a significantly lower risk of reaching ESRD in the fosinopril group compared with non-treated controls [35,36]. Despite the limitations of these studies, they suggest that therapy with an angiotensin-converting enzyme inhibitor initiated early may offer renal survival benefits in HIVAN. The ACTG is currently developing a clinical trial (protocol A5179) to compare treatment with an angiotensin receptor blocker (valsartan) plus HAART with HAART alone in patients with HIVAN. Indications for kidney biopsy The decision to obtain a renal biopsy sample is somewhat controversial in the general medical community. Even if a patient presents with the classic clinical features of HIVAN, clinical presentation is predictive of the biopsy diagnosis in only 50–60% of patients. Furthermore, non-invasive tests or clinical markers to identify the precise renal lesion do not exist. Renal biopsy should be offered to patients because a variety of renal lesions occur in HIV-infected patients, and the treatment implications and prognosis vary according to the biopsy results. We, therefore, believe that to distinguish HIVAN from other forms of renal disease, and to redefine HIVAN pathological findings in the HAART era, HIV-positive patients who have unexplained renal abnormalities (i.e., kidney failure and/or daily protein excretion greater than 1 g and/or microscopic haematuria) should have a renal biopsy. HAART-related kidney disorders Electrolyte and acid-base profiles It is noteworthy that the biological profile in HIV-infected patients has dramatically changed in the HAART era. Previous studies stated that hyponatraemia, hyperkalaemia or hypokalaemia and acidosis were the main biological abnormalities in HIV-positive patients [37,38]. A prospective cross-sectional descriptive study (1219 HIV-infected patients over 3 months) undertaken to assess the prevalence of fluid electrolyte and acid–base disturbances showed hyperuricaemia and hypophosphataemia to be the most prevalent abnormalities [39]. Hyperuricaemia was detected in 140 (41.3%) out of the 339 patients tested. Among hyperuricaemic patients, only 47% were treated with didanosine. Multivariate analysis showed that patients not taking non-nucleoside transcriptase inhibitors (NNRTI) had a 1.8-fold risk [95%confidenceinterval(CI),1.1–2.9] of hyperuricaemia. With protease inhibitor treatment and male gender, the risk of hyperuricaemia rose to 4.4 (95% CI, 2.1–9.6). A plasma phosphate level below the normal range was observed in 63 (17.2%) of the patients tested for plasma phosphate. Multivariate analysis showed that patients taking an NNRTI regimen had a 1.9-fold increase in risk of hypophosphataemia (95% CI, 1.1–3.3), male patients had a 2.6-fold increase in risk (95% CI, 1.1–6.3). Bicarbonate plasma level below the normal range was observed in 112 patients (13.6%) out of the 824 patients tested. Multivariate analysis showed that patients taking HAART had a 4.4-fold increase in risk having a low plasma bicarbonate level (95% CI, 2.2–8.9), women had a 2.4-fold increased risk (95% CI, 1.5–3.8) and patients with CD4 cell count < 200 cells/μl had a 1.8-fold increased risk (95% CI, 1.2–2.9). Only 13 patients (3.1%) out of the 419 patients tested exhibited low calcium levels (n = 13). Factors significantly associated with low plasma calcium concentrations were NNRTI regimen and CD4 cell count. An absolute CD4 count < 200 cells/μl was associated with an increased risk of hypocalcaemia when compared with a cont of > 200 cells/μl. Lactic acidosis Approximately 20–30% of patients who are treated with nucleoside reverse transcriptase inhibitors (NRTI) can be found to have asymptomatic hyperlactataemia; this typically develops after several months of therapy and may be transient [40–42]. Severe lactic acidosis is much rarer, occurring in 1.5–2.5% of patients, is usually preceded by fatigue, nausea, vomiting, anorexia, abdominal pain and other systemic symptoms, and is associated with a mortality rate of approximately 80%. Lipoatrophy, myopathy, peripheral neuropathy and pancreatitis are more often observed in patients with symptomatic hyperlactataemia rather than in patients who have frank lactic acidosis. Risk factors include NRTI use, longer duration of treatment, older age, female gender, pregnancy, hypertriglyceridaemia, obesity, concomitant hepatitis C infection, use of ribavirin, impaired kidney function and alcohol ingestion [41–44]. Acute renal failure Before the HAART era, mild acute renal failure, defined as a peak serum creatinine ≥ 20 mg/l, was been reported to occur in up to 20% of hospitalized HIV-infected patients [45]. This is in comparison with an incidence rate of 1% in hospitalized non-HIV-infected patients [46]. The two major acute renal complications in HIV disease that resulted in potentially reversible failure were acute tubular necrosis and HIVAN. Sepsis contributed to the development of severe acute tubular necrosis, defined as a peak creatinine ≥ 60 mg/l, in up to 75% of cases [47]. A study of kidney biopsy specimens in HIV-infected patients with severe acute renal failure not thought to be from prerenal causes or acute tubular necrosis reported the following distribution of renal lesions: 53% haemolytic uraemic syndrome; 40% acute tubular necrosis, either of ischaemic–toxic origin or rhabdomyolysis; 26% obstructive renal failure, extrinsic, drug induced or secondary to paraprotein precipitation; 23% HIVAN; 3% acute interstitial nephritis; and 6% various glomerulonephritides [48]. In a recent cohort study of ambulatory HIV-infected patients, acute renal failure occurred in nearly 10% of patients, with an incidence rate of 5.9 episodes/100 person-years [49] Antiretroviral agents have been shown to have a range of nephrotoxic effects, including crystal-induced obstruction, tubular toxicity, interstitial nephritis and electrolyte abnormalities. Drugs are responsible for one-third of all acute renal failure events. Although only responsible for a few events, antiretroviral drugs cause two-thirds of all obstructive acute renal failure. Indinavir, tenofovir, and nevirapine were the antiretroviral drugs associated with acute renal failure in this cohort [49–52]. Iatrogenic acute renal failure can be dose dependent, manifesting as acute tubular necrosis, acute glomerulopathy, vascular disease or interstitial immunoallergic reactions. Table 1 summarizes the nephrotoxicities induced by antiretroviral drugs [53–77]. According to the renal syndrome, the clinician will attempt to distinguish between possible causes from each of the four aetiopathogenic groups of nephropathies defined above. Depending on the situation, renal biopsy may be indicated. Table 2 proposes a diagnostic flowchart applicable for a HAART- treated patient with renal abnormalities.Table 1: Antiretroviral drug-induced renal abnormalities.Table 2: HIV-infected patients with renal abnormalities: a diagnosis proposition.Chronic renal failure Chronic renal abnormalities are frequently observed in HIV-infected individuals. Despite drug adjustment, some HIV-infected patients experience progressive renal disease. Usually, the diagnosis of renal toxicity of antiretroviral treatment is considered when patients experience acute renal abnormalities. However, the potential insidious long-term renal toxicity of antiviral treatment may be underappreciated in the pathogenesis of nephropathies of chronic progression in HIV infected patients. In prospective studies evaluating the safety and efficacy of the protease inhibitor indinavir, or some reverse transcriptase inhibitors, a of patients with acute renal failure did not their baseline renal function and data the of renal after acute renal related to antiretroviral the large range of kidney diseases that may occur in HIV-positive patients taking HAART, each case should be and the benefits and of drug The main for the clinician is to determine the of the nephropathy in order to specific in to symptomatic complications With the of HIV the complications associated with HIV infection have to include changes in HIV protease inhibitors and the to peripheral and impaired distribution elevated plasma and and elevated plasma have been reported in clinical trials and in changes in may be related to HIV disease or may be a of treatment with antiretroviral agents through in to long-term antiretroviral therapy the development of chronic kidney disease, through metabolic complications Indeed, black and have been associated with the development of Both protease inhibitors and NNRTI have been associated with and studies have shown plasma concentrations to be associated with increased mortality in in and/or older patients Evidence of hyperuricaemia in HIV-positive patients should to change in the of patients, as of The impact of and antiretroviral metabolic disorders on the of kidney or disease in patients with HIV therefore, an important Risk factors for nephrotoxicity renal adverse are not it is possible to identify patients who may be at increased risk factors for kidney disease, including older age, African-American comorbid and kidney disease, to be associated with renal failure in patients In addition, disease and hepatitis have been associated with increased risk for acute or chronic kidney disease in HIV-infected patients kidney function is one of the most of risk for acute or chronic kidney disease in patients The recently consensus guidelines for chronic kidney disease in all HIV-infected patients at the time of with frequent in the of kidney function or other evidence of kidney disease [24]. Initial should include and serum creatinine with of the glomerular rate by either the or of in Renal Disease has been in patients with HIV, are more than serum creatinine of patients with a glomerular rate < 60 will for dose of by the and should more frequent of kidney toxicity and The according to the glomerular rate and the of dose for each are in Table The of proteinuria by or also chronic kidney disease, and may identify patients at increased risk for nephrotoxicity [24]. In to chronic kidney disease, other factors as and concomitant of other nephrotoxic agents may also patients to the nephrotoxic effects of HAART or related HAART can also to Indeed, studies over the past 20 in patient have demonstrated a between in disease and et found a increase in the risk of developing elevated among patients receiving compared with receiving In addition, the results suggested that the increased risk associated with was at least in part, through an increase in Antiretroviral dose based on creatinine with HIV and hepatitis or C The effect of with hepatitis in and C on disease progression and survival among patients infected with HIV has an increasing this has from the effects of while this function and decreases the incidence of infections in HIV-infected patients, it also the of chronic disease to the overall and mortality of these individuals. use of alcohol is an in this Approximately of HIV-infected patients are Among intravenous drug with HIV, this rate is at least 50% and can be up to 90% in with and HIV is with of HIV-infected individuals having evidence of past or infection The prevalence of chronic of among HIV-infected individuals is Among intravenous drug 90% of HIV-infected individuals have evidence of to and 60% also have evidence of past infection with the of of renal disorders has not been reported in However, proteinuria and have been reported frequently in or patients without HIV proteinuria to and in infected patients; proteinuria to 30% and 30% in patients. has been in and patients and is characterized by and peripheral neuropathy The renal presentation of in patients may include renal insufficiency, proteinuria, and The course of renal disease is much more in the with some to ESRD in a of months However, while reports had shown between HIV and with et did not an between HIV infection and In patients not with HIV, the of nephropathy with and has also been and the reports of nephropathy in HIV-infected patients may be by the incidence of infection, and in this population The life expectancy of HIV-positive patients treated with HAART now that of the general The has to the and renal that can increase with more in patients hypertensive, 2 and risk factors to renal disorders from HIV infection and HAART. it more important to develop for treating these patients from the renal Renal to be in patients with HIV/AIDS and potentially reversible factors to be identified and the we suggest the antiretroviral drug use and kidney disease in HIV-infected patients. All patients at the time of HIV diagnosis should be for kidney disease with a for proteinuria and a of renal is no evidence of proteinuria at initial patients at risk for the development of renal disease (i.e., African-Americans, with CD4 cell < 200 cells/μl or plasma HIV > and with hypertension, or should Renal function should be on a to assess for changes over proteinuria, renal renal biopsy. Patients with glomerular rate 60 or with proteinuria > by or on should be to a for further evaluation and In HIV-infected patients with evidence of should be controlled to a level no than enzyme inhibitors or angiotensin receptor are the drugs of first for patients with proteinuria, and these drugs should also be considered in HIV-infected patients with renal disease. should be in patients receiving protease inhibitors. Patients with HIVAN should be treated with HAART at HAART should not be from patients because of the of their renal The antiretroviral regimen is a between the benefits of and the risk of adverse events, including The of renal insufficiency should the and dose of the antiretroviral of prednisone should be considered in patients with HIVAN if HAART alone not result in improvement of renal function or in patients with HIVAN renal failure is A that the of short-term the benefit of slowing the progression to ESRD and the should the decision reduction of for antiretroviral drugs that are the kidneys is With dose and renal insufficiency or ESRD is not an absolute to the use of any antiretroviral nucleoside should not be in patients with renal function for of the development of lactic acidosis. Drugs that are by dialysis should be after to of In HIV-positive renal are important between the inhibitors and protease inhibitors, and the NNRTI drug may increase levels of and tenofovir, their In the of protease inhibitors, a major reduction in the of inhibitors may be Although most antiretroviral agents are free of renal toxicity, renal can occur and may to be from progression of HIVAN or other HIV-related kidney kidney diseases by other infections or or kidney diseases to HIV infection and its and diseases have emerged as important complications in patients, infections as causes of among HIV-infected patients. patients with risk or a history of a consideration should be to or to protease antiretroviral with the use of NRTI or NRTI and and between disease and will diagnosis and treatment of chronic kidney and vascular diseases with the of progression to ESRD. The authors and for their The authors in the had to all the data in the study and had for the decision to to