RENAL FAILURE


See also Estimating Renal Function for details on estimating GFR etc.

I. Decreased GFR indicated by elevated serum creatinine (more reliable) or urea

  1. Can indicate global decrease in nephron function or decrease in # of functioning nephrons

II. Reduced single-nephron GFR (i.e. global decrease)

  1. "Prerenal azotemia"--due to renal hypoperfusion but normal renal function
  1. Causes include
  1. Decreased extracellular fluid volume (hemorrhage, 3rd-spacing)
  2. Hypotension
  3. Renal artery stenosis
  4. Renal vein obstruction
  1. Results in decreased single-nephron GFR and increased tubular reabsorption of Na and H20
  2. Urine will be low volume and concentrated because of ADH
  3. FENa (see below) will us. be < 1.0
  4. Serum BUN/Cr ratio will be high (>10) because urea is reabsorbed and creatinine is not
  1. Other causes of high BUN/Cr:
  1. Tetracyclines
  2. Glucocorticoids
  3. Blood in GI tract
  4. High protein turnover due to trauma, burns, or rhabdomyolysis
  1. n.b. Diuretics inhibit tubular Na and can mask the oliguria and high urinary Na of prerenal azotemia
  1. "Postrenal"--due to obstruction in urinary tract (stone, clot, tissue, pus, tumor, prostatic disease)
  2. With dysfunction of renal tubules
  1. Get decreased single-nephron GFR, decreased tubular reabsorptive function, azotemia
  2. Causes
    1. Toxic nephropathies
    2. Tubular nephropathies
      1. Crystals (uric acid, oxalic acid, sulfonamids, methotrexate)
      2. Protein deposition, e.g. Ig's
    3. Interstitial nephropathies
      1. Hypercalcemia
      2. Hypokalemia
      3. Pyelonephritis
      4. Certain drugs (antimicrobials, NSAIDs, certain diuretics and anticonvulsants, allopurinol, azathioprine)
      5. Gout
    4. Acute tubular necrosis (ATN)
      1. Also known as "renal angina"
      2. Most common cause of acute renal failure
      3. Response of kidney to damage to tubular epithelium
      4. Causes include renal ischemia, toxins (aminoglycosides, nephropathy from radiologic contrast material, heavy metals), and pigments, e.g. myoglobin and hemoglobin
      5. 2 phases: oluguric/anuric (7-14d) and diuretic; higher morbidity and mortality if have sig. oliguria
      6. Dx-distinguished from prerenal azotemia by FENa (U/P Na divided by U/P creatinine x 100; us > 1.0 in ATN and < 1.0 in prerenal azotemia)
      7. Tx-Lasix (Ref: J. Am. Soc. Nephr., 1990; articles by Epstein)
      8. May also be treatable with atrial natriuretic peptide, which increases GFR (reduced need for dialysis in pts with ATN and oliguria but not ATN without oliguria in one study, NEJM 336:828, 1997-JW)
      9. Fenoldopam mesylate (a dopamine agonist, decreases systemic vascular resistance and increase renal blood flow) for ATN
        1. In a study in 155 ICU patients with early ATN and mean arterial pressure > 70mm Hg randomized to fenoldopam drop x 72h vs. placebo, the 3wk incidence of (death or dialysis) and mortality were not sig. diff. in the two groups, though the incidence of the former was sig. lower in pts without diabetes (25% vs. 44% with placebo) (Am. J. Kid. Dis. 46:26, 2005-JW)
  1. Get azotemia and oliguria, but
  1. Urinary Na us. > 20 mMol/l
  2. BUN/Cr ratio is normal
  3. Urine osmolarity is not so much (<350)

III. Reduced number of functioning nephrons

  1. With increased single-nephron GFR (SNGFR)
  1. Normal reaction to loss of functioning renal parenchyma
  2. Causes
    1. Surgical loss
    2. Post-infective scarring
    3. Polycystic Kidney disease
    4. Chronic tubulointerstitial disease (see above)
  3. Remnant nephrons get larger
  4. With extreme loss of nephrons, tubules can't reabsorb all the Na, and GFR falls below normal
  5. Patient must maintian increased Na intake to compensate for losses (and H20 too, because it follows the Na)
  1. With normal single-nephron GFR
  1. Occurs in glomerular disease: reactive increase in SNGFR is absent
  1. Glomerulonephritis
  2. Diabetic glomerulosclerosis
  1. Urinary Na is decreased
  2. Patients are highly susceptible to prerenal azotemia
  1. With decreased single-nephron GFR
  1. More literally, relative, acutely decreased SNGFR in patients with decreased # of functioning nephrons due to chronic renal disease
  2. At baseline, have decreased nephron #, increased SNGFR compared with a normal kidney, and borderline or normal GFR
  3. With acutely lowered SNGFR, e.g. from dehydration, the SNGFR goes down-it may still remain above that of a normal kidney, but nevertheless, the GFR falls to below a normal rate and azotemia results.
  4. Urine Na is low
  5. Urine/Plasma creatinine <10, Urine/plasma urea <3
  6. Urine osmolarity < plasma osmolarity
  7. Modest increase in serum BUN/Cr, but <20

IV. Diagnosing intrinsic acute renal failure by microscopic examination of urinary sediment--see under "Urinary Casts"

V. Oliguria/anuria

  1. Oliguria = urinary output insufficient to sustain life (e.g. <400ml/d in average adult)
  2. Anuria: us. caused by obstruction; also by total renal arterial or venous occlusion; renal causes are rare, but include cortical necrosis, fulminant glomerulonephritis
  3. Must differentiate acute vs. chonic problem with serum BUN/Cr, urine Na, urea, creatining, osmolarity

VI. Predicting progression of chronic renal failure

  1. In 177 pts with nondiabetic renal disease and proteinuria, spot urine protein-creatinine ratio was found to correlate well with 24h urinary protein excretion; in addition, protein-creatinine ratios was better than 24h urine protein excretion at predicting progression to ESRD in the ensuing 12mos (< 5% with ratio < 1.7; 12.5% with ratio 1.7-2.7; 21.2% with ratio > 2.7; BMJ 316:504, 1998--JW)

VII. ACE Inhibitors (see "Diabetic Nephropathy" for discussion specific to diabetics)

  1. To prevent progression of Chronic Renal Failure
  1. 583 pts with CRF (serum Cr 1.5-4.0) from various causes (glomerulopathy, interstitial nephritis, nephrosclerosis, polycystic kidney disease) randomized to benazepril 10mg QD vs. placebo. Over median 3y f/u, 10% benazepril pts vs. 20% on placebo reached end point of doubling of baseline serum Cr or dialysis. Especially effective for glomerulopathy; ineffective for PCKD. Effect was independent of effect on BP. More deaths with benazepril (8 vs. 1 with placebo); unclear why! (NEJM 334:939, 1996-JW)
  2. 186 nondiabetic pts with 1-3g/24 proteinuria and CrCl 20-27ml/min randomized to ramipril vs. non-ACEI antihypertensives; Ramipril group had less ESRD (9% vs. 21%) and less progression to severe proteinuria (15% vs. 31%) than non-ACEI group; summary didn't specify duration of study or whether pts had HTN (Lancet 354:359, 1999--JW)
  3. In a meta-analysis of 11 RCT’s (comparing ACEIs vs. other meds) in pts with nondiabetic kidney disease (> 84% of which had HTN; mean baseline urine protein excretion 0.7-2.3g/24h), over mean 2.2y f/u, ACE’s ass’d with RR 0.67 (sig.) of (doubling of baseline serum Cr or initiation of dialysis) after adjustment for achieved BP and protein excretion. (“AIPRD Study”--Ann. Intern. Med. 139:244, 2003)  
  4. In a study in 224 nondiabetic pts with advanced renal failure (serum Cr 3.1-5.0) and persistent proteinuria (> 300mg/d) randomized to benazepril 10mg BID vs. placebo, over mean 3.4y f/u, incidence of (doubling of serum Cr, need for dialysis or renal transplantation, or death) was sig. lower in benazepril pts (41% vs. 60%); no sig. diff. in BP reductions between the two groups (NEJM 354:131, 2006--JW)
  5. In hypertensive African-American patients
    1. 1094 African-Americans with HTN (mean baseline BP 150/96) and hypertensive renal disease (GFR 20-65 mL/min per 1.73m2 no other identified causes of renal insufficiency) randomized to target mean arterial pressure 102-107 vs. < 92, and also to initial tx with one of the following, in a 3 x 2 factorial design; open-label agents (furosemide, doxazosin, clonidine, hydralazine, and minoxidil) added to as needed to achieve BP goals:
      1. Metoprolol 50-200mg/d
      2. Ramipril 2.5-10mg/d
      3. Amlodipine 5-10mg/d

      At 3y, amlodipine arm was terminated b/c of higher rates of end-stage renal disease & death. At 4y f/u mean GFR slope and incidence of a composite clinical outcome ((GFR reduction by 50% or more or > 24mL/min/1.73m2), ESRD, or death) were not sig. diff. in the two BP-goal groups.  Amlodipine pts had sig. lower SBP than those in the other 2 groups.  GFR slope was not sig. diff. in the different drug groups, but incidence of the composite outcome was sig. lower in the rampiril group compared with the metoprolol and amlodipine groups (RR 0.78 and 0.62, respectively); no diff. between amlodipine and metoprolol groups in the composite outcome.  No sig. diff. between the two BP-goal groups or any of the drug groups in 4y incidence of all-cause mortality, CV mortality, or first CV events ("AASK" Study, JAMA 288:2421, 2002).

  6. In combination with Angiotensin Receptor Blockers ("ARB's")--263 pts 18-70yo w/nondiabetic renal disease & baseline serum Cr 1.5-4.5mg/dL randomized to trandolapril 3mg QD, losartan 100mg QD, or both; over median 2.9y f/u, incidence of (doubling of serum Cr or end-stage renal disease) was 11% in combo-therapy group and 23% in both single-therapy groups (sig.).  No diffs. between groups in BP lowering ("COOPERATE" trial, Lancet 361:117, 2003--JW)
  1. To prevent Renal Failure in patients with proteinuria
    1. Ramipril sig. slowed disease progression in nondiabetic pts with > 3g/d proteinuria ("REIN" trial, Lancet 349:1857, 1997--UW Pharm letter)

VIII. Treatment of renal failure

  1. Lead chelation therapy
    1. In 32 pts with CRI (serum Cr 1.5-4.0; stable x 6mos) and mildly increased serum lead (150-600ug/72h urine collection after EDTA mobilization), weekly tx wih IV EDTA x 2mos ass'd with slower increases in serum Cr (at 2 & 12mos) than no those pts randomized to no chelation therapy (Ann. Int. Med. 130:7, 1999--JW)
    2. In a randomized trial of 202 pts with nondiabetic chronic renal failure (serum Cr at baseline 1.5-3.9 mg/dL) and "high-normal body leaed burdens" by EDTA-mobilization testing, IV EDTA vs. placebo was, over 2y f/u, ass'd with sig. better changes in mean GFR (NEJM 348:277, 2003--JW)
  2. "Renal-dose Dopamine"--Click HERE for information
  3. Diuretics
    1. Often used in acute renal failure, especially when oliguria is present
    2. In a cohort study of 552 patients with acute renal failure, after adjustment for confounding variables, diuretic use as ass'd with sig. higher in-hospital mortality (RR 1.7) (JAMA 288:2599, 2002--JW)
    3. In a study in 338 pts with acute renal failure randomized to furosemide 25mg/kg/d (IV over 6h, max 2g/d) vs. placebo x 1mo or until renal function improved, there was no sig. diff. in overall mortality, time in renal replacement therapy, or time to achieve serum Cr M 2.3mg/dL (Am. J. Kid. DIse. 44:402, 2004--JW)
    4. In a meta-analysis of 9 randomized studies involving 849 pts with or at risk for acute renal failure, furosemide vs. placebo was not associated with any sig. dif. in mortality, risk for dialysis, or incidence of persistent oliguria (BMJ 333:420, 2006--JW)
  4. Treatment of Anemia associated with chronic renal failure-See Erythropoietic Growth Factors