Imaging patients with kidney disease in the era of NSF: can it be done safely?

Nephrogenic systemic fibrosis (NSF) was first recognized as a complication of gadolinium-based contrast (GBC) exposure in 2006 and confirmed subsequently by numerous investigators. Early information on the toxicity of free gadolinium (Gd3+) and the pharmacokinetics of this agent in patients with underlying kidney disease were likely unrecognized subtle clues to its potential for adverse effects in humans. Since the recognition of NSF as a complication of GBC exposure, our approach to imaging in patients with kidney disease has been altered. As these patients require various forms of imaging to diagnose associated conditions, we must utilize an evidence-based approach to imaging options. It is our responsibility to identify patients at high risk to suffer this complication and choose between non-GBC imaging modalities, radiocontrast-based imaging modalities, and GBC imaging modalities based on risk:benefit assessment. The benefits of rapid, accurate diagnosis must be weighed against risks associated with CT scan with radiocontrast (radiation exposure, allergic contrast reactions, acute kidney injury), GBC imaging (development of NSF), and missed diagnoses due to use of suboptimal imaging modalities in an effort to avoid radiocontrast and GBC agent exposure.

Experience with outpatient computed tomographic-guided renal biopsy.

Native kidney biopsy is still performed primarily with hospital inpatient observation period. Experience with outpatient Computed Tomographic (CT)-guided renal biopsy at Yale New Haven Medical Center was studied to assess efficacy and safety. A total of 146 outpatient native kidney biopsies were identified between 1995 and 2001. Records were reviewed for demographics, clinical, and laboratory data and details of the procedure. Time of admission to the outpatient unit, duration of procedure and post-biopsy observation period were recorded. Complications such as bleeding, infection, admission to the hospital, transfusion, or intervention for continued bleeding were noted. Mean age was 43.9 ± 14.9 years and mean serum creatinine was 1.8 ± 1.4 mg/dl. Renal size averaged 11.4 cm. Post-procedure observation time of 4 - 6 h appeared to be adequate. Diagnostic tissue was successfully sampled in 98.6% of cases. Procedure was well tolerated with no hemodynamically significant changes. Hematocrit and hemoglobin concentration changes averaged 3.6 ± 2.5% and 1.0 ± 0.9 mg/dl, respectively (p < 0.001). There were no instances of death or need for intervention. Transfusion was required in 1 patient while 6 patients had detectable bleeding and were hospitalized for observation. Outpatient CT-guided kidney biopsy provides adequate tissue and appears to be safe with very low complication rates.

Radiocontrast-induced nephropathy: an update.

Both diagnostic and therapeutic studies frequently utilize radiocontrast media to enhance images. As a result, use of these agents has increased markedly over the past decade with more than 10 million studies performed on a yearly basis in the United States. Development of acute kidney injury (AKI) is a common complication of radiocontrast exposure in patients who possess underlying risk factors. Impor-tantly, radiocontrast-induce nephropathy (RCIN) is associated with increased short- and long-term mortality. Thus, at risk patients should be identified prior to administration of radiocontrast to allow choice of other potential imaging options or employment of prophylactic interventions. Currently, use of isotonic intravenous fluids is the only proven beneficial preventive therapy. Use of low volumes of radiocontrast and avoidance of nephrotoxic medications are also accepted as nephroprotective. Mixed results exist on the utility of N-acetylcysteine (NAC) therapy and low versus iso-osmolar radiocontrast agents in preventing RCIN. While hemodialysis appears to have no beneficial role, a single center's experience with hemofiltration is associated with a reduction in RCIN and other clinical endpoints. Several therapies have no role in the prevention of RCIN and should be avoided. This review will provide an up to date examination of the current status of these issues as they relate to RCIN.

The role of extracorporeal blood purification therapies in the prevention of radiocontrast-induced nephropathy.

Radiocontrast-induced nephropathy (RCIN) is a common and potentially serious complication following diagnostic and therapeutic cardiology procedures using radiocontrast media. The first and most important step in reducing the likelihood of RCIN is to identify patients at risk, by medical history and measurement of serum creatinine concentration to allow calculation of estimated glomerular filtration rate (GFR). Extracorporeal blood purification effectively removes radiocontrast media from the circulation. Periprocedural extracorporeal blood purification (hemodialysis or continuous renal replacement therapy) does not reduce the incidence of RCIN compared with standard medical therapy, and cannot be recommended at this time. The potential benefit of continuous venovenous hemofiltration published by a single center should be confirmed with further studies before it can be recommended or disregarded, and higher doses of continuous renal replacement therapy may also merit further investigation.

Proton pump inhibitors and the kidney: critical review.

Proton pump inhibitors (PPIs) are widely prescribed to treat a number of gastrointestinal disorders due to excessive acid production. While effective and safe, adverse renal effects have been described. Most concerning is the ever increasing number of cases of acute interstitial nephritis (AIN) associated with PPI therapy. It appears to be a class effect as all PPIs have been documented to cause AIN. Several adverse drug event registries now note PPIs as the most common cause of drug-induced AIN. While most patients recover kidney function, many are left with some level of chronic kidney disease. Hyponatremia is an extremely rare complication and is thought to result from inappropriate ADH secretion. Interactions with calcineurin inhibitors may occur with certain PPIs when used in susceptible patients, particularly those with polymorphisms in the cytochrome P450-2C19 enzyme gene. This paper will critically review the effect of PPIs on the kidney.

Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase inhibitors.

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs), i.e. nonselective cyclooxygenase COX inhibitors have well-documented nephrotoxicity. Adverse renal effects occur because of inhibition of the synthesis of cyclooxygenase-derived prostaglandins which act to modulate pathologic processes that would normally impair various renal functions. The introduction of the selective COX-2 inhibitors raised hope that this class of drugs would reduce injury in both the gastrointestinal tract and the kidneys. Animal and human data, however, suggest that COX-2 synthesized prostaglandins are important in the modulation of renal physiology during adverse conditions. Hence, it appears that these drugs are equal in causing nephrotoxicity as the nonselective COX inhibitors.

Pharmacologic options available to treat symptomatic intradialytic hypotension.

Treatment of symptomatic intradialytic hypotension (IDH) is a difficult task for the practicing nephrologist. Minimizing patient factors that precipitate IDH as well as dialysis procedure-related components that lower blood pressure are the initial approaches to this problem. However, despite these maneuvers, hypotension often persists in a group of high-risk patients. Pharmacologic interventions are often used to reduce IDH. Unfortunately, many of the available therapies are marginally effective and/or poorly tolerated. A few therapies appear to be efficacious and well tolerated-carnitine, sertraline, and midodrine. This article reviews the various pharmacologic therapies used for IDH and makes recommendations for treatment of this difficult problem.

Indinavir nephropathy revisited: a pattern of insidious renal failure with identifiable risk factors.

Indinavir is a well-known cause of crystal-induced acute renal failure, dysuria and flank pain, and nephrolithiasis. Recently a more insidious tubulointerstitial lesion has been recognized as secondary to the drug. We report a case of a hepatitis C-positive patient on long-term indinavir therapy for human immunodeficiency virus (HIV) who developed a slowly progressive rise in serum creatinine. Renal biopsy revealed a diffuse interstitial infiltrate with numerous eosinophils and scarring. The tubules showed focal necrosis and dilation with elongated crystals present within their lumina. The elevated serum creatinine decreased to a new baseline over several months with the discontinuation of indinavir. We review the literature of renal syndromes associated with indinavir focusing on chronic progressive tubulointerstitial injury and speculate on risk factors and potential mechanisms of indinavir-induced renal injury.

COX-2 inhibitors and the kidney.

Prostaglandins produced by the COX-2 isoform of cyclooxygenase may be important for renal function--and perhaps even more so in diseases that render the kidney highly prostaglandin-dependent. COX-2 inhibitors may thus have much the same renal risks that a standard NSAID does. Several clinical trials have already focused on the new drugs' renal effects.

NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?

Selective cyclooxygenase-2 (COX-2) inhibitors have provided relief for patients suffering from chronic pain and other inflammatory conditions and have reduced adverse gastrointestinal effects. The documented reduction in gastric erosions, ulcerations, and perforations during the use of COX-2-selective inhibitors raises the question: would the kidney be similarly spared? Our understanding of these enzyme isoforms in the kidney is incomplete. However, kidney tissue seems to possess "constitutive" or homeostatic COX-2 enzyme, suggesting a role for prostaglandins produced by this isoform. In addition, studies evaluating the renal effects of the selective nonsteroidal anti-inflammatory drugs (NSAIDs) are inconclusive, and available data on the renal effects of COX-2-selective inhibitors are conflicting. Inadequate numbers, varied baseline patient characteristics, and different doses and lengths of drug treatment hampers comparison of the small number of clinical investigations available for review. Therefore, this article reviews the role of cyclooxygenase enzyme activity and associated prostaglandins in the kidney and the adverse renal effects of nonselective NSAIDs. We also touch on the COX-1/COX-2 selectivity of NSAIDs, the localization of COX enzymes in kidneys, and clinical studies examining the renal effects of selective COX-2 inhibitors.

Treatment of Severe Intradialytic Hypotension With the Addition of High Dialysate Calcium Concentration to Midodrine and/or Cool Dialysate.

Treatment of intradialytic hypotension (IDH) in the end-stage renal disease population has been a difficult task for nephrologists caring for these patients. The presence of multiple pathogenic factors contributes to hemodynamic instability and explains why therapies that modulate only a specific aspect of the problem are only partially effective. Cool dialysate (34.5 degrees C to 35.5 degrees C) and midodrine may provide hemodynamic stability through an increase in peripheral vascular resistance, whereas high dialysate calcium concentration (HDCa; 3.5 mEq/L) improves intradialytic blood pressure through preservation of cardiac output. Theoretically, the combination of these two types of therapies might further reduce the frequency and severity of hypotension during hemodialysis (HD). We undertook a study to evaluate the effect of HDCa added to midodrine and/or cool dialysate in the treatment of patients with severe IDH. Twenty-eight patients met the entry criteria, and 23 patients completed the prospective crossover study. Five patients dropped out of the study secondary to hypercalcemia. The addition of HDCa significantly improved post-HD mean arterial pressure (MAP; 95.6 +/- 12.7 versus 90.8 +/- 12.5 mm Hg; P = 0.002). The decreases in MAP from pre-HD to lowest intradialytic (16.3 +/- 8.2 versus 20.6 +/- 10.0 mm Hg; P = 0.009) and pre-HD to post-HD (2.0 +/- 8.5 versus 8.15 +/- 10.8 mm Hg; P = 0.002) were significantly reduced with HDCa compared with low dialysate calcium. However, there were no significant improvements in symptoms of or interventions for IDH. Thus, it appears that the addition of HDCa to midodrine and/or cool dialysate further improves blood pressure in patients with IDH. However, this therapy did not reduce symptoms or interventions required for IDH. In addition, hypercalcemia complicated this therapy in 22% of the patients.

Drug-induced hyperkalemia: old culprits and new offenders.

Prescribed medications, over-the-counter drugs, and nutritional supplements are used by many patients. Although most of these products are well tolerated, drug-induced hyperkalemia may develop in patients with underlying renal impairment or other abnormalities in potassium handling. Drug-induced hyperkalemia most often occurs from impaired renal potassium excretion. However, disturbed cellular uptake of a potassium load as well as excessive ingestion or infusion of potassium-containing substances may also occur. Physicians must be aware of medications that can precipitate hyperkalemia, how these drugs induce alterations in potassium homeostasis, and the patient characteristics that increase the risk of hyperkalemia.

ACE inhibitors do not induce recombinant human erythropoietin resistance in hemodialysis patients.

Angiotensin-converting enzyme (ACE) inhibitors may exacerbate anemia in patients with chronic renal failure, as well as in dialysis patients. To better answer this question, a prospective, crossover study was conducted to evaluate the effect of ACE inhibitors on recombinant human erythropoietin (rHuEPO) requirements in hemodialysis patients. Patients administered an ACE inhibitor when entering the study remained on this drug for the initial 4 months and were then switched to another antihypertensive agent for 4 more months. Patients not initially administered an ACE inhibitor were switched to lisinopril at 4 months. rHuEPO doses were adjusted using a sliding scale based on weekly laboratory hematocrit values. The inclusion criteria were met by 51 patients undergoing dialysis. Demographics were as follows: 61% were women, 64% were black, 46% had diabetes, average age was 53.2 +/- 13.3 years, and time on hemodialysis was 38.0 +/- 44.5 months. Thirty-three patients completed the study. Hematocrit averaged 32.7% +/- 1.9% while on ACE inhibitor therapy and 33.1% +/- 2.1% off ACE inhibitor therapy (P = 0.217). There was no difference in rHuEPO dose per treatment during each period (3,500 +/- 1,549 U on ACE inhibitor therapy versus 3,312 +/- 1,492 U off ACE inhibitor therapy; P = 0.300). No significant differences were found in degree of blood pressure control or various clinical and laboratory parameters that might be associated with rHuEPO resistance between the two periods. Similarly, no differences were found in hospitalization days, duration of infections, or transfusion requirements. These findings suggest that ACE inhibitors do not contribute to rHuEPO resistance in hemodialysis patients.

Acute renal failure in HIV-infected patients: a brief review of common causes.

Acute renal failure is a well-described renal syndrome observed in patients infected with the human immunodeficiency virus (HIV). Underlying glomerular disease and disturbances in renal tubular function predispose these patients to a number of hemodynamic and nephrotoxic insults. Prerenal azotemia from both "true" and "effective" depletion of intravascular volume is the most common cause of acute renal insufficiency in patients infected with HIV. Direct damage to the renal tubules from both nephrotoxic medications and prolonged ischemic processes occurs frequently in hospitalized patients. Injury to the tubulointerstitium of the kidney may also result from allergic reactions to medications prescribed to patients. Deposition of crystals in the tubular lumens, and rarely in the glomerular capillaries, will cause acute renal failure in the setting of tumor lysis syndrome or during therapy with medications associated with crystal nephropathy. Finally, obstruction of the urinary system will rarely cause postrenal azotemia in patients infected with HIV.

Are selective COX-2 inhibitors nephrotoxic?

Nonsteroidal anti-inflammatory drugs are well-known culprits in the development of acute renal insufficiency in high-risk patients. The recent release of the selective cyclooxygenase-2 enzyme inhibitors for the treatment of inflammatory diseases and pain syndromes has been associated with a clear-cut decrease in adverse gastrointestinal effects. However, the nephrotoxic potential of these agents in patients with prostaglandin-dependent states and chronic renal impairment is unknown. Many clinicians commonly wonder if these agents can be safely prescribed to such high-risk patients. We present two cases of acute renal failure complicating the course of therapy with celecoxib in patients with chronic renal insufficiency.

Trimethoprim-induced hyperkalaemia: clinical data, mechanism, prevention and management.

Cotrimoxazole (trimethoprim-sulfamethoxazole) is a combination antimicrobial that is frequently used to treat a wide variety of infections. Only recently has hyperkalaemia been recognised as a relatively common complication of therapy with trimethoprim. Hyperkalaemia has been demonstrated to occur with the administration of both high and standard dosages of trimethoprim. The recognition of this disorder of potassium homeostasis prompted the investigation and ultimate description of the mechanism by which trimethoprim causes hyperkalaemia. Trimethoprim was found to reduce renal potassium excretion through the competitive inhibition of epithelial sodium channels in the distal nephron, in a manner identical to the potassium-sparing diuretic amiloride. Increased risk for hyperkalaemia with trimethoprim treatment appears to be related to both higher dosages and underlying renal impairment. It is probable that other disturbances in potassium homeostasis, such as hyopoaldosteronism and treatment with medications that impair renal potassium excretion, are also risk factors for hyperkalaemia with trimethoprim therapy. Prevention of this adverse reaction depends upon recognition of patients at risk of developing hyperkalaemia as well as proper dosage selection of trimethoprim for the patient's prevailing glomerular filtration rate. Management of hyperkalaemia often mandates discontinuation of the drug, volume repletion with isotonic fluids, and other therapies specific to hyperkalaemia. In circumstances where continued treatment with trimethoprim is required, induction of high urinary flow rates with intravenous fluids and a loop diuretic, as well as alkalinisation of the urine, have been shown to block the antikaliuretic effect of trimethoprim on distal nephron cells.

Trimethoprim-sulfamethoxazole therapy in outpatients: is hyperkalemia a significant problem?

A prospective, randomized clinical study was undertaken to determine the effect of standard-dose trimethoprim-sulfamethoxazole combination treatment on serum potassium concentrations in outpatients treated in an ambulatory clinic. Ninety-seven patients were treated with oral antibiotics for a variety of infections. Fifty-one patients treated with trimethoprim-sulfamethoxazole (trimethoprim, 320 mg/day; sulfamethoxazole, 1,600 mg/day) constituted the treatment group, while 46 patients treated with other antibiotics served as controls. Serum potassium, sodium, and chloride concentrations, serum carbon dioxide content, blood urea nitrogen level, serum creatinine level, and serum glucose concentration were measured. The baseline serum potassium concentration in the treatment group was 4.30 +/- (SD) 0.36 mmol/l, and it increased significantly (p < 0.001) to 4.66 +/- 0.45 mmol/l on day 5 of therapy. Subgroup analysis of mean serum potassium concentration on day 5 of therapy failed to detect clinically relevant hyperkalemia. In patients with a serum creatinine level equal to or greater than 1.1 mg/dl (K+, 4.83 +/- 0.48 mmol/l), a nonsignificant difference (p = 0.3) in the potassium concentration was noted on day 5 as compared with patients with a serum creatinine level <1.1 mg/dl (K+, 4.63 +/- 0.44 mmol/l). Although diabetics had a higher serum potassium concentration (K+, 4.91 +/- 0.44 mmol/l) than nondiabetics (K+, 4.61 +/- 0.44 mmol/l), the difference was not statistically significant (p = 0.055). Patients aged >/=50 years (K+, 4.82 +/- 0.59 mmol/l) had a significantly different (p = 0.046) serum potassium concentration on day 5 than patients aged <50 years (K+, 4.55 +/- 0.28 mmol/l). In contrast, the baseline serum potassium concentration in the control group was 4.37 +/- 0.45 mmol/l, and it decreased (p = 0.1) to 4.22 +/- 0.4 mmol/l on 5 days of drug therapy. Trimethoprim-sulfamethoxazole therapy, when used to treat a variety of infections, leads to an increase in serum potassium concentration in most patients. After 5 days of therapy with this drug, the treatment group developed a statistically significant rise in the serum potassium concentration as compared with the control group. However, severe hyperkalemia (K+ >/=5.5 mmol/l) occurred in only 3 patients (6%) treated with trimethoprim-sulfamethoxazole. In addition, none of the subgroups of treated patients developed clinically important hyperkalemia. This suggests that outpatients, in contrast to acquired immunodeficiency syndrome patients and hospitalized patients with mild renal insufficiency, develop severe or life-threatening hyperkalemia less commonly when treated with this antimicrobial regimen. However, outpatients having risk factors which may predispose to the development of hyperkalemia should be carefully monitored when treated with trimethoprim-sulfamethoxazole.

Crystal-induced acute renal failure.

Several medications--notably acyclovir, sulfonamides, methotrexate, indinavir, and triamterene--are associated with the production of crystals that are insoluble in human urine. Intratubular precipitation of these crystals can lead to acute renal insufficiency. Many patients who require treatment with these medications have additional risk factors, such as true or effective intravascular volume depletion and underlying renal insufficiency, that increase the likelihood of drug-induced intrarenal crystal deposition. Acute renal failure in this setting may be preventable if it is anticipated by appropriate drug dosing, volume expansion with high urinary flow, and alkalinization of the urine when appropriate. Renal failure may be reversible if the drug is discontinued, and by volume repletion and alkalinization of the urine when appropriate. Management of established renal insufficiency includes volume repletion, dialytic support if necessary, adjustment of drug doses, and avoidance of further exposure to nephrotoxins.