Update on Acute Renal Failure Diagnosis and Treatment
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Update on Acute Renal Failure Diagnosis and Treatment
- 1. Update on Acute Renal Failure 2.0 Kenneth Chen, M.D.
- 2. Year 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 JASN 17:1135-1142, 2006
- 3. Incidence of Non-Dialysis ARF Kidney Int 2007
- 4. Incidence of Dialysis-Requiring ARF KI 2007
- 6. Year JASN 17:1143, 2006 1988 1990 1992 1994 1996 1998 2000 2002 Mortality (%) Inpatient Mortality - ARF
- 7. Inpatient Mortality From ARF JASN 17:1143, 2006
- 8. Inpatient Mortality From ARF-D JASN 17:1143, 2006
- 9. Increase in Total Cost of Hospitalization Increase in Serum Creatinine from Baseline JASN 2005;16:3365
- 17. “ Muddy” (Pigmented) Granular Casts
- 18. RBC Cast
- 19. Dysmorphic RBCs
- 27. AIN
- 31. % Incidence of CIN NEJM 2003;348(6):491 J Am Coll Cardiol 2006;48(4):692
- 32. CIN Arch Intern Med 2002;162:329
- 34. CIN Eur Heart J 2004;25:206
- 37. CIN Clin J Am Soc Nephrol 2008;3:10
- 41. CrCl = (140-age) x IBW/(Cr x 72) x 0.85 if female Cockcroft-Gault Equation
- 55. D’oh!
- 58. CIN Ann of Pharmacotherapy 2007;41:46
- 65. Increase in Serum Creatinine from Baseline JASN 2005;16:3365
Notes de l'éditeur
- The increased prevalence of ARF is present in all age categories and after adjusting for age, gender, and race and sepsis, ICU stay, or other organ failure (by logistic regression). In the previous study, the authors found more than a four fold increase in population-adjusted incidence of ARF and more than a 6 fold increase in ARF requiring dialysis between 1988-2002. The increased prevalence may be related to HIV and its related treatments, more frequent non renal organ transplants, more aggressive diagnostic and therapeutic interventions and increased prevalence of diabetics being treated with ACEI, ARBs which carry an increased risk for ARF especially during episodes of dehydration. Overall, 15% of patients with ARF required dialysis. Up to 40% of cases can be attributed to an iatrogenic cause which can be preventable (Arch Int Med 1991 151(9):1809)
- These studies may underestimate the true incidence of AKI by a factor of 4-6 fold
- ARF and dialysis are both significant contributors to mortality in the hospital and the incidence of ARF is rising yearly. And because the treatment of ARF is largely supportive we need to do our best to prevent ARF.
- This is data taken from a 20% sample of US hospitals that participate in the Healthcare Cost and Utilization project which includes teaching and nonteaching hospitals and is based on ICD-9 codes. Similar trends are noted even when adjusting for age, race, gender, and comorbidities. The inpatient mortality from ARF alone is significant. By comparison, the inpatient mortality for CHF is 4.7% for pneumonia 8 %. The good news is that the mortality has been falling over this period of time. The improvement in mortality may be attributed to “better” general and supportive care such as early goal-directed therapy resuscitation in sepsis and the maintainence of euglycemia with insulin drips in the ICU setting. There may also be a bias contributing to the decline in mortality from “code creep” where because of increasing awareness of ARF and importance of reimbursement, we are coding milder cases of ARF. ARF is predominantly a hospital-acquired disorder. The high mortality of patients is not entirely explained by comorbid conditions. Recent data suggests that ARF is in fact an independent contributor to morbidity and death. Again ARF should not be taken lightly and our focus should be on the prevention of ARF.
- The mortality from ARF remains high even after adjusting for comorbid conditions. The mortality from ARF Recent data also shows that ARF is an independent predictor of increased mortality. This slide shows the mortality from ARF adjusted for various comorbid conditions from 0-5+ comorbid conditions such as: sepsis, AMI, pneumonia, acute hepatic failure, pancreatitis, GI bleed, CKD. Comorbidity index
- Dialysis confers an additional increase in mortality. Data taken from 5% of Medicare beneficiaries based on ICD-9 codes. A third of patients who develop ARF requiring dialysis with just one comorbidity is 30%.
- RIFLE defines 3 grades of increasing severity of acute renal dysfunction (risk, injury, and failure; RIF) on the basis of graded changes in serum creatinine or urine output and two outcomes variables (loss and ESRD, L and E, respectively) based on the duration of loss of kidney function. AKIN (Acute Kidney Injury Network)
- The causes of renal failure are generally divided into Prerenal, renal or intrinsic, and postrenal or obstructive causes. Prerenal causes can include nephrotic syndrome (decreased effective circulating volume), CHF (cardiorenal syndrome), cirrhosis, pancreatitis, dehydration esp while taking drugs that can affect renal blood flow. In the ICU setting almost 70% of admissions are due to sepsis and/or circulatory failure so it is not surprising that most occurences of ARF in the ICU is going to be ATN or prerenal related. Most causes of renal failure can be divided into pre-renal, post-renal or intrinsic forms of renal failure.
- I find that in the hospital setting urinary electrolytes are not all that useful, but perhaps we may be underutilizing the FE urea which has been shown….. 92% of patients with prerenal azotemia had a FENa<1% and only 48% of patients with prerenal and diuretic therapy had a FENa<1%. While 89% of the latter group had a FEurea<35%. So a FE urea <35% is a more sensitive and specific indicator of prerenal azotemia than FENa, if diuretics have been administered (KI 2002;62:2223) FE urea in normal individuals is 50-65% and has a sensitivity of 90 and specificity of 96% in detecting prerenal azotemia.
- In normal individuals, under conditions conditions of hypoperfusion such as hypotension, CHF, RAS, volume contraction. When renal perfusion pressure falls, the afferent arteriole dilates to compensate, reducing the resistance to forward blood flow. Under the influence of angiotensin II, the efferent arteriole vasoconstricts to maintain the intracapillary glomerular pressure to sustain the GFR. This is called autoregulation. If you then give an ACE inhibitor or ARB blocking the effects of angiotension II the efferent arteriole is no longer able to vasoconstrict resulting in a fall in GFR. A common scenario where we see ARF is someone with class 4 CHF, on an ACE inhibitor and diuretics who fall ill and develop N/V/D or take NSAIDs In sepsis, cytokine mediated induction of nitric oxide synthesis that occurs in sepsis decreases SVR. So the hallmark of sepsis is generalized arterial vasodilatation. Early in sepsis renal vasocontriction mediated by endothelin and angiotensin II results in increased reabsorption of tubular sodium and water.
- Perhaps one of the most common factors contributing to a prerenal cause of renal failure is from medications affecting glomerular blood flow. ARF from vancomycin is underrecognized and we are seeing an increased number of cases of ARF from vancomycin with the increasing incidence of MRSA.
- Incidence of hydralazine associated ANCA vasculitis has a reported incidence of 2-21% , associated with higher doses >200 mg/day and slow acetylators
- The most frequent error I see with aminoglycosides is administration of it for UTI when the risk for ARF is increased and inappropriate dosing of it based on actual body weight rather than ideal body weight. Aminoglycosides should not be given to patients with CRF
- There are a few uncontrolled studes showing a benefit from steroids in terms of rapidity of improvement and final Scr level. The largest retrospective series to date of all cases of AIN at a tertiary care center of 2598 patients biopsied which showed no benefit from steroids but avg Scr was higher (7.0) and most cases were from NSAIDs which are less responsive to steroids. So if offending agent is stopped and there is no improvement in 3-7 days, then if biopsy confirmed, can it may be reasonable to consider a course of steroids. Eosinophiluria can be seen in pyelonephritis, cystitis, prostatitis, transplant rejection, GN, and atheroembolic disease.
- Sensitivity of eosinophilia in U/A is 40% sensitive and 72% specific with a positive predictive value of 38%.
- Cimetidine and bactrim will falsely elevate the serum creatinine by decreasing active secretion of creatinine.
- CIN is the 3 rd leading cause of ARF in the hospital but the overall incidence is low. The mechanism by which contrast agents produce nephrotoxicity is poorly understood but probably includes a reduction in renal perfusion resulting in regional hypoxia and hyperosmolar- and hypoxia-induced oxidative stress as well as direct tubular toxicity. In most cases, the Scr peaks between 2-5 days after contrast exposure and returns to normal within 14 days. Need for dialysis is 0.4% overall but 7% in the hospital.
- How contrast leads to CIN is poorly understood but probably includes a reduction in renal perfusion resulting in regional hypoxia and hyperosmolar- and hypoxia-induced oxidative stress as well as direct tubular toxicity.
- In a randomized, double-blind controlled trial (NEJM) of 129 patients undergoing coronary or aortofemoral angiography with DM and Cr 1.5-3.5 the incidence of CIN as defined by a rise in Cr >0.5 was 3 vs 26 %) (equal numbers of patients in each group received IV saline 500 ml before and 1L after). Weaknesses cited are more than twice as many proteinuric patients in the iohexol grp and more pts who had DM for longer duration 18yrs in the iohexol grp(vs 12 yrs) Keeping in mind the limitations of meta-analyses including differences in study populations and publication bias (where negative studies showing no difference is less likely to be published) a meta-analysis of 16 double-blind controlled trials comparing iodixanol vs low ismolar contrast showed an incidence of CIN (rise in Cr >0.5 within 3 days after contrast) among 2727 patients of 1.4 vs 3.5% overall, 2.8 vs 8.4% in 502 pts with CKD, and 3.5 vs 15.5% in 231 pts with CKD + DM. But most patients in the low osm grp were given ionic contrast. Most authorities fall short of recommending iodixanol over iohexol stating that conflicting results in the past suggest that there will continue to be conflicting evidence.
- The only proven method of preventing CIN based on several RCTs is IVF hydration. What was less clear was the optimal way to hydrate. This was first demonstrated with ½ NS given at 1 mg/kg/hr for 12 hrs before an angiogram and 12 hrs after. In a randomized controlled open label study, 1620 patients undergoing coronary angiography given low osmolar nonionic contrast were given NS vs D5 1/2NS at 1 mg/kg/hr starting at 8AM the day of the procedure and continued until 8 AM the next morning. Serum Cr checked the day before at 24 hrs and at 48 hrs. Contrast nephropathy defined as >0.5 mg/dl rise in serum cr within 24-48 hrs. This study proved the superiority of NS over ½ NS. Isotonic saline may be better than hypotonic fluids due to their enhanced ability to expand intravascular volume.
- The beneficial effects of NAC are reportedly due to the vasodilatory and antioxidant properties of NAC and its metabolite glutathione. There are over 30 randomized controlled trials and 12 meta-analyses on the use of N-acetylcysteine in the prevention of CIN yest we still have no definitive proof of its efficacy. There is a lot of weak evidence out there. And to muddy the waters further, one group has shown that NAC can interfere with the assay for Cr falsely lowering the Scr by 0.04. The reasons for this include the differences in patient populations, intervention protocols, hydration regimens making comparisons between studies difficult. Also negative studies are more likely to be published as an abstract only (publication bias) despite comparable study quality. The original study that looked at this was by Tepel. A randomized controlled trial of 83 pts with baseline Cr 2.4 undergoing CT scan with iopromide, a nonionic, low osmolality contrast. NAC 600 mg bid before and day of contrast with or without 0.45% saline at 1ml/kg/hr for 12 hrs before and after contrast. But limited by small numbers only one developed CIN in the NAC group and and 9 developed CIN in the saline grp. A few more numbers of CIN in the NAC group could have reduced the difference seen.
- Recent attention has focused on using higher doses of NAC to prevent CIN. NAC has a very low oral bioavailability with substantial inter patient variability (3-20%) and half-life of 5.6 hrs. The half-life of IV NAC is 6-40 min. Virtually no NAC is detected in the systemic circulation after IV or oral administration, suggesting that any benefit must be due to secondary effects such as glutathione synthesis. In a randomized controlled trial from Italy, 224 pts for elective coronary or peripheral angiography using iobitriolo (low osmol, nonionic contrast) with baseline Cr 1.6 received 600 mg bid vs 1200 mg po bid NAC with 0.45% NaCl at 1ml/kg/hr for 12 hr before and after contrast. Results 11% vs 3.5%
- Randomized, controlled trial 354 consecutive patients admitted to the CCU in Milan who received placebo (NS 1ml/kg/hr for 12 hrs after cath), 600 mg NAC IV bolus before cath and 600 mg po bid for 48 hrs after cath plus NS for 12 hrs after cath, and 1200 mg IV prior to cath and 1200 mg po bid for 48 hrs after cath plus NS for 12 hrs after cath. However some have questioned whether the results can be attributed to NAC since the baseline Cr was 1.0 where risk for contrast nephropathy is small and there were more patients in the placebo group who developed complications such as pulm edema requiring mechanical ventilation and cardiogenic shock. Although the complication rate between the two NAC groups were not different.
- Free radical formation is promoted by an acidic environment typical of tubular urine but is inhibited by the higher pH of normal extracellular fluid. So it may make sense to give NaHCO3 to alkalinize the urine to reduce free radical injury. But in the presence of ROS, bicarbonate actually enhances the generation of ROS such as peroxymonocarbonate (HCO4-). A randomized controlled trial of 119 patients with baseline serum Cr of 1.7 (NaCl group) and 1.9 (NaHCO3 grp), CIN defined as a 25% increase in Cr within 2 days after contrast, nonionic contrast iopamidol was used in patients undergoing interventional or diagnostic radiological procedures. NaHCO3 or NaCl was given at 3ml/kg 1hr before contrast and 1 ml/kg/hr for 6 hrs after contrast. For pts weighing more than 110 kg, 110 kg was the weight used. Due to ethical concerns of exposing the saline grp to a higher risk of nephropathy, the trial was terminated early. Problems – this is a small trial and only 1-2 more patients without nephropathy would have made the differences insignificant, the treatment group was not compared to the gold standard IVFs for 6-12 hrs before and after contrast, the trial was terminated early but there were no predefined stopping rules and the P value for the difference in event rates (P=0.02) was higher than is standard for stopping a trial early. Also the serum Cr in the NaHCO3 group fell by 0.07 (est GFR by MDRD rose by 8.5%) as opposed to a rise in 0.04 (fall in est GFR by 0.1%) in the NaCl group (P=0.02) raising the possibility that NaHCO3 may falsely lower the Scr due to better volume expansion. 13% of patients in each study arm were excluded because of lack of f/u tests or protocol violations after randomization and pts were excluded with known risk factors for CIN e.g. HTN, emergency catheterizations, recent previous contrast administrations. For pts who weren’t excluded from the study, cardiac caths consisted of 80% of the analyzed cases. Also the study showed a marginal statistical benefit in the bicarbonate grp and it was a a small trial that was terminated early after a small number of events, so the results should be viewed with skepticism.
- Real world population at the Mayo Clinic from 4/1/04-5/30/05, where most of the contrast exposure was from CT scans using low osmolar nonionic contrast. Regardless of how NaHCO3 was administered, the risk for CIN was greater. Bicarbonate in the presence of ROS enhances the generation of ROSFrom the Mayo Clinic, a retrospective cohort study of 7977 patients. The odds ratio for CIN was 3.1 (NaHCO3 alone), 1.16 (NAC alone), 1.07 (NaHCO3 + NAC), and 1.0 (no treatment), after adjusting for total volume of hydration (the day prior and day of contrast), Beta-blocker, diuretic, NSAIDS, ACEI/ARB, aspirin, age, gender, prior creatinine, contrast load, prior exposure to contrast, type of imaging study, heart failure, HTN, renal failure, multiple myeloma, and DM. The NaHCO3 alone grp were younger, had lower avg cr levels, and were less likely to have DM or HTN, had higher mean vol of precontrast hydration and fewer received ARB or diuretics.
- Controversy remains about what best to do for CIN. Clinical studies in nephrology have been poor unlike oncology trials where investigators look for a p value of less than 0.0000001, we’re happy if we see a p value of less than 0.05. We need more drug money. In general, any hydration is good. Forced diuresis with Lasix has also been shown to lead to a higher incidence of CIN with contrast studies. So if we’re going to give NAC there’s no harm and potential additional benefit to giving 1200 mg bid of NAC
- An approach to diagnosis consists of a careful review of their medication history. A clean U/A is most helpful as it is consistent with either a prerenal or postrenal cause of ARF. And if protein is present, it should be quantitated. Contrast can lead to a false positive protein on a dipstick. A normal U/A is most consistent with a pre- or post-renal cause of ARF. False positive results on protein dipstick can occur with gross hematuria, bacteria, alkaline urine pH>7.5, concentrated urine, semen, pus, vaginal secretions. Which is why quantitating the urine protein is important.
- Modification of Diet in Renal Disease. Formulas used to estimate GFR assume a steady-state cr level. If the Cr is rapidly rising or falling these eqns should not be used. Using ideal BW in the C-G eqn underestimates GFR by about 15% while using actual wt overestimates GFR by about 17% in the elderly.
- The FDA requires pharmaceutical companies to use the Cockcroft-Gault eqn to dose medications in renal failure. The MDRD formula has not been validated in diabetics and because of the characteristics of the MDRD study population, the MDRD formula is not accurate in patients at the extremes in age or body weight or near normal creatinine. With near normal creatinine levels, the MDRD formula underestimates the true GFR.
- Treatment for ATN is supportive with a focus on maintanence of fluid and electrolyte balance. The FDA requires that pharmaceutical companies dose medications according to CrCl estimated from the Cockcroft-Gault equation in ml/min, not normalized to 1.73 m2 BSA. Which assumes a steady state Cr. If the Cr is rising from 2 to 3 to 4 then you have to assume the GFR is less than 10. One common mistake is not adjusting medications as the creatinine is rising. The MDRD equation is more accurate and used as a more accurate estimation of GFR especially in patients between 18-70 and not at the extremes of body wt or age. Use ideal body weight risk overdosing a morbidly obese patient.
- If Lasix is given, it needs to be given at a higher dose in renal failure and nephrotic syndrome. Fleet’s should be avoided in all renal failure patients and in patient’s on an ACEI, ARB, diuretics or NSAIDs. Can cause phosphate nephropathy and nephrocalcinosis. Fosamax should be avoided with CrCl <35. Enoxaparin should be used once a day when GFR<30 ml/min. Enoxaparin has not been shown to increase risk of bleeding when used once a day for DVT prophylaxis. Effectiveness is unknown for treatment of DVT or MI. Contraindicated in ESRD.
- In uremic pericarditis, the EKG doesn’t usually show diffuse ST-T segment elevation due to lack of inflammatory cells penetrating the myocardium.
- Nephrogenic systemic fibrosis is a new condition that is being described in renal failure patients.
- Very astute observation, we want to be the superior physician and find ways to prevent kidney failure given the high mortality rate associated with ARF, increasing incidence of renal failure and limited treatment options once kidney failure has occurred.
- We need to stop this futile and costly war…..
- That’s not fair…He risked his life defending this country in Vietnam, and before that he fought the British in the revolutionary war, and if it weren’t for him taking on the dinosaurs……
- We need to have the audacity of hope that we can change. This is change we can believe in.
- Doesn’t Homer make you feel better about yourself?
- You don’t need a randomized controlled trial to tell you that a parachute will save lives.
- There have been at least two small studies comparing an oral hydration regimen to an IVF regimen showing no benefit to oral hydration however, a recent randomized controlled trial of 312 pts with baseline Cr of 2.3 or Cockcroft Gault GFR of 37 ml/min, comparing 1 g/10 kg/day (7000 mg Na/day which is 3x the Na we normally eat) for 2 days vs 0.9% NaCl at 2.5 ml/kg/hr for 6 hrs (3500 mg Na for a 70 kg which is the total sodium we eat in a day with a typical American diet) prior to contrast. NSAIDs and diuretics were held for 48 hrs prior to procedure.
- A retrospective study of 96 patients comparing NAC at least 600 mg before and 600 mg bid after contrast plus 0.9% NaCl at 1ml/kg/hr 12 hrs before and after contrast or NaHCO3 3 ml/kg/hr one hr before contrast and 1 ml/kg/hr for 6 hrs after contrast. The baseline Cr was about the same in each grp 1.7 (NaHCO3 grp) vs 1.8 (NaCl grp). There was no difference between groups which goes against the superiority of NaHCO3 vs NaCl but at least suggests that it is just as good and may be a reasonable alternative. Limited by selection bias and unanticipated differences between patients which could lead to the absence of a difference between treatment regimens.
- So in the next hour we’re going to review each and every cause of proteinuria shown here. Just kidding…
- Data taken from a 5% sample of US hospitalized Medicare beneficiaries for the years 1992-2001 based on ICD-9 codes.
- Don’t want to commit someone to long-term dialysis.
- The partial pressure of oxygen is lowest in the outer medullary region of the nephron where active sodium reabsorption occurs with high energy and oxygen requirements and make this area more susceptible to ischemia. Tubular backleak, obstruction and apoptosis occurs in ATN resulting in renal failure.
- Usually a K > 6.5 life-threatening. Peaked T waves, flattened P waves, shortened QT interval, widened QRS, then sine wave then V-fib. With widened QRS or flattened P waves, need to give calcium gluconate (calcium chloride is caustic and extravasation can cause tissue necrosis) to stabilize cardiac membranes and counteract the cardiac membrane effects of hyperkalemia. Then perform potassium lowering measures.
- ARF is often multifactorial. A large percentage of ARF occurs in patients in the ICU. Postoperative ARF occurs due to underlying comorbidity (DM, HTN, vascular dz, CHF) that leads to diminished baseline GFR and reduced renal reserve. CKD patients have reduced renal reserve
- Based on a consecutive sample of 19982 adults admitted to an urban academic medical center based on ICD-9 codes and after adjusting for age, gender, severity of illness (DRG weight), and ICD -9 categories of cardiovascular, respiratory, malignant, and infectious diseases.