1. Description of the problem
What every clinician needs to know
Acute kidney injury (AKI) is a common disorder, with a population incidence of about 2,000 per million population (pmp). Patients with chronic kidney disease (CKD), as evidenced by a low eGFR or presence of proteinuria, are at higher risk for developing AKI, a condition known as acute on chronic renal failure (ACRF). CKD is a strong risk factor for cardiovascular events, and patients with CKD are at particular mortality risk if they develop ACRF.
The clinical features of ACRF are similar to those in patients with de novo AKI. Not all patients will develop these clinical features/complications, but the common one are listed below:
Hypocalcemia/hyperphosphatemia (as a consequence of secondary hyperparathyroidism)
Uremia (elevated BUN, platelet dysfunction, changes in mental status, pericarditis)
Key management points
If the underlying cause of the acute component of ACRF can be ascertained, it should be treated promptly.
Hemodynamics and blood pressure should be optimized.
Manage the sequelae of ACRF (hyperkalemia, uremia and volume overload can be life-threatening).
If the sequelae of ACRF cannot be managed medically, prompt consideration of renal replacement therapy should be done.
2. Emergency Management
Acidemia: Patients with ACRF can be profoundly acidemic (pH less than 7.1). In patients without severe volume overload, acidemia can be treated with intravenous sodium bicarbonate. In patients in whom sodium bicarbonate or similar base cannot be given, renal replacement therapy is indicated. If patients are in respiratory distress as a consequence of their ACRF, mechanical ventilation should be considered.
Hyperkalemia (See chapter)
Volume overload: Patients with ACRF can become volume overloaded as a consequence of their renal failure. Hypertension and pulmonary edema are manifestations of severe volume overload. The most dangerous form of volume overload is pulmonary edema. Medical therapies aimed at decreasing venous return can be employed as temporary measures. Such therapies include nitroglycerin (oral, topical, or parenteral), nesiritide and low-dose morphine sulfate. Diuretic therapy can also be used to augment urine output.
Patients with renal failure often need high doses of loop diuretics (e.g. furosemide), often in conjunction with thiazide-type diuretics (e.g. metolazone) in order to achieve meaningful diuresis. Care should be taken to avoid sustained high-dose loop diuretics in order to avoid ototoxicity. If patients are hypertensive, afterload reduction may help.
Hypocalcemia (see chapter)
Hyponatremia (see chapter)
Uremia: The three most severe forms of uremia are encephalopathy, bleeding diathesis, and pericarditis. Each of these clinical entities can be life-threatening, and they represent an indication for urgent/emergent renal replacement therapy.
Assess all medications that are being prescribed to the patient and verify that the doses are appropriate for the current level of renal function. This should be done with the knowledge that the serum creatinine is often dynamic and equations such are Cockcroft-Gault and MDRD are inappropriate in the acute setting.
All nephrotoxic therapies should be stopped if possible.
Consider stopping all medications that block angiotensin II (ACE inhibitors and angiotensinII blockers).
The diagnostic considerations for AKI are the same whether it is acute on chronic or de novo AKI. However, patients with underlying CKD often progress more rapidly to renal failure when they suffer an episode of AKI compared to patients with normal renal function. When patients present with renal impairment, the acuity of the renal failure is often unknown (e.g. upon arrival to the emergency department).
Differentiating pure CKD from ACRF is important because patients with ACRF often recover some degree of renal function if treated appropriately. Because patients with ACRF are at high risk for progression to renal failure that requires renal replacement therapy, forestalling this progression with appropriate intervention is critical.
Therefore, if the baseline renal function is unknown, various investigations can be used to determine if underlying renal disease is present. Kidney size, as ascertained by CT or ultrasound, is often helpful. Patients with abnormal kidney size (particularly if small) typically have some form of underlying kidney disease. In addition, increased echogenicity as assessed by US is often suggestive of underlying CKD.
Laboratory investigations can sometimes be useful in helping differentiate CKD from ACRF. Patients with CKD are often anemic and often suffer from secondary hyperparathyroidism. This often results in a low serum total calcium, an elevated serum phosphorus and a low hematocrit. However, because patients with AKI can also develop these biochemical abnormalities, laboratory parameters in isolation may not be able to differentiate CKD from ACRF.
In addition, urinary assessment can help distinguish CKD from ACRF. The urine assessment in patients with CKD often shows abnormalities related to the underlying cause of CKD. Common abnormalities in CKD are proteinuria, broad casts and isosthenuria. In ACRF, evidence of the cause of AKI is often present (acute tubular necrosis [ATN] – granular casts; acute interstitial nephritis [AIN] – pyuria, urinary eosinophils).
AKI is a syndrome with multiple potential causes, and similarly ACRF has multiple potential causes. The current way to ensure the correct diagnosis is to document loss of renal function by elevation of serum creatinine and/or oliguria.
Non-AKI causes of rising creatinine can be due to certain medications, particularly in patients with CKD. Drugs that block the secretion of creatinine that cause a rise in serum creatinine not due to decreased GFR include cimetidine, trimethoprim, cefoxitin and flucytosine.
AKI that is primarily manifested as oliguria requires assessment of obstructive causes.
AKI that is primarily manifested as a small elevation of serum creatinine should be assessed to make sure that medications affecting creatinine secretion are not the cause of the creatinine elevation.
4. Specific Treatment
The treatment of AKI and consequently ACRF is predicated on treating the underlying cause.
There are no validated specific therapies for the treatment of ACRF.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
The hallmark of recovery of ACRF would be at least partial improvement in serum creatinine and/or urine output. Long-term prognosis of patients suffering from ACRF is variable. Some patients are able to return to baseline function, whereas others can rapidly progress to advanced stages of CKD.
Patients who suffer from ACRF are high risk for progression to advanced CKD and ESRD. Consensus recommendations for the follow-up and care of these patients are not currently available. However, given the risk of progression to advanced forms of CKD, avoidance of nephrotoxic exposures and blood pressure control are likely to be particularly important for these patients.
Frequent follow-up visits with nephrology consultation as needed should be conducted in these patients, particularly those with a low eGFR at baseline and those with proteinuria.
The pathophysiology of ACRF is congruent with the pathophysiology of AKI. However, within each stratum of pathologic mechanism of injury of AKI special considerations exist for those patients with pre-existing CKD.
Decreased renal perfusion pressure
Patients with a decreased perfusion pressure will often suffer from a drop-off in GFR. Patients with CKD often have impaired autoregulation and do not have the same compensatory mechanisms to help offset a decrease in renal perfusion.
Common causes of CKD that blunt the autoregulatory response are diabetes mellitus and hypertension. The diminishment of autoregulatory mechanisms makes patients with CKD more susceptible to hemodynamic variability and potential ischemia. In addition, patients with CKD are often treated with angiotensin II blockade (ACE inhibitors and angiotensin II blockers).
These medications have been shown to decrease the rate of CKD progression, but the presence of these medications may in fact increase susceptibility to ACRF. During episodes of decreased renal perfusion pressure, angiotensin II activation is critical in maintaining intra-glomerular pressure and GFR. The presence of these medications may not be beneficial during low-flow states.
Intrinsic renal disease
There are multiple causes of ATN, and they are commonly categorized nephrotoxic or ischemic. Sepsis and similar inflammatory syndromes may represent a unique form of AKI but are often grouped in the category of ATN. Patients with CKD are more vulnerable to all forms of tubular injury.
Aside from the hemodynamic considerations discussed previously, CKD patients usually have a decreased number of functioning nephrons. As a consequence, the renal reserve that allows for dynamic increases in GFR in response to an increased physiologic load in healthy patients is minimal in patients with CKD. Therefore, small degrees of injury result in increased workload for remaining nephrons and generally result in drop in GFR.
Endothelial injury can be an important feature of ATN, and since patients with CKD often have underlying vascular disease, susceptibility to ACRF is likely enhanced. Inflammation can cause direct proximal tubular epithelial cell injury via iNOS. Interactions between fibroblasts and NO vascular reactivity are impaired in CKD, thus likely rendering CKD patients more susceptible to the causes of AKI.
The best estimates of the incidence of AKI and ACRF combined range from 500 to 2,000 pmp, depending on the definition. A study conducted in Scotland using the consensus RIFLE criteria placed the incidence at 2,147 pmp. In the the U.S. and Western Europe, the effect on an aging population with an increased number of comorbidities is an increase in the incidence of AKI.
The incidence of ACRF is lower as a population metric and is estimated between 300 and 600 pmp. The risk of ACRF is inversely proportional to the baseline renal function. Patients with the lowest eGFR are at the highest risk for developing ACRF. This observation is logical given that patients with CKD have diminished renal reserve. In addition, patients with proteinuria are at increased risk for the development of AKI. Because the presence of proteinuria is considered an early form of CKD, ACRF encompasses this group of patients.
Patients who suffer an episode of ACRF are at risk for progression of CKD, development of ESRD and death. Patients who experience the most severe form of ACRF (RIFLE F, requiring RRT) have an inpatient mortality of 34-54%. Of those patients who survive the hospitalization, between 27% and 77% go on to develop ESRD, with patients who have the lowest baseline eGFR at highest risk.
Inpatient mortality for patients with ACRF appears to be less than for de novo AKI. It has been hypothesized that this occurs because a lesser degree of insult is required to cause ACRF as compared to de novo AKI. Nonetheless, the aggregate effect of ACRF for the composite endpoint of ESRD/death is significant.
Because patients with ACRF tend to have multiple comorbidities, it is difficult to assess the attributable mortality of ACRF as compared to the other factors that led to ACRF. However, the available population studies suggest that the prognosis for ACRF is poor. In one study, only 35% of patients regained renal function back to baseline.
The prognosis of ACRF is dependent on five main factors: baseline renal function, proteinuria, severity of AKI, advanced age and comorbidities. Male gender and African descent are also risk factors for ACRF. High levels of proteinuria have a significant impact on the outcomes of ACRF.
Patients have a step-wise increase in risk of ESRD/death for each 10-ml/min loss of baseline eGFR. However, if the patient has significant baseline proteinuria, this risk is increased four- to five-fold. Therefore, patients who suffer ACRF with high levels of baseline proteinuria are at particular risk for poor outcomes.
Special considerations for nursing and allied health professionals.
What's the evidence?
Ali, T, Khan, I, Simpson, W. “Incidence and outcomes in acute kidney injury: a comprehensive population-based study”. J Am Soc Nephrol. vol. 18. 2007. pp. 1292-8..
Glynne, PA, Picot, J, Evans, TJ. “Coexpressed nitric oxide synthase and apical beta(1) integrins influence tubule cell adhesion after cytokine-induced injury”. J Am Soc Nephrol. vol. 12. 2001. pp. 2370-83.
Grams, ME, Astor, BC, Bash, LD, Matsushita, K, Wang, Y. “Albuminuria and estimated glomerular filtration rate independently associate with acute kidney injury”. J Am Soc Nephrol. vol. 21. 2010. pp. 1757-64..
James, MT, Hemmelgarn, BR, Wiebe, N. “Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study”. Lancet. vol. 376. 2010. pp. 2096-103..
Hsu, CY, Chertow, GM, McCulloch, CE, Fan, D, Ordonez, JD. “Nonrecovery of kidney function and death after acute on chronic renal failure”. Clin J Am Soc Nephrol. vol. 4. 2009. pp. 891-8..
Liano, G, Pascual, J. “Acute renal failure. Madrid Acute Renal Failure Study Group”. Lancet. vol. 347. 1996. pp. 479
Mehta, RL, Pascual, MT, Soroko, S. “Spectrum of acute renal failure in the intensive care unit: the PICARD experience”. Kidney Int. vol. 66. 2004. pp. 1613-21..
Sutton, TA, Fisher, CJ, Molitoris, BA. “Microvascular endothelial injury and dysfunction during ischemic acute renal failure”. Kidney Int. vol. 62. 2002. pp. 1539-49.
Yilmaz, MI, Sonmez, A, Saglam, M. “FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease”. Kidney Int. vol. 78. 2010. pp. 679-85..
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- 1. Description of the problem
- 2. Emergency Management
- 3. Diagnosis
- 4. Specific Treatment
- 5. Disease monitoring, follow-up and disposition
- Special considerations for nursing and allied health professionals.
- What's the evidence?