Acute Renal Failure (ARF)
ARF is defined as a precipitous decline in renal function over a relatively short period (ranging from several hours to several weeks).
ARF is marked by a significant, rapid rise in serum creatinine (Scr) and urea nitrogen (BUN).
Oliguria (urine output <20 mL/hr)) often occurs in ARF, but non-oliguric ARF is not infrequent.
ARF which develops during hospitalization is associated with a high mortality rate (~35%). Cardiac complications, bleeding, and infections are the leading causes of death associated with ARF.
Conditions which precipitate ARF are usually classified as pre-renal, renal (intrinsic), or post-renal (Table 1).
A pre-renal condition is characterized by a marked reduction in renal blood flow (renal hypoperfusion, ¯RBF) which may be brought about by true ECF volume depletion (eg, severe diarrhea), hypotension (eg, congestive heart failure), or by a significant reduction in the effective circulating volume as in cirrhosis (see Table 1A).
Prerenal ARF is characterized by oliguria, a BUN/Scr ratio > 20 (except in pts with advanced liver disease), a normal or nearly normal urinalysis, a relatively concentrated urine (U_osm > 500 mOsm/L), and a low fractional Na excretion (<1% ) with U_Na< 25 mEq/L.
In most cases of prerenal disease, re-hydration or plasma expansion leads to a relatively rapid improvement in renal function (­urine flow and ¯ Scr).
The main intra-renal (tubular and vascular) mechanisms of ARF are summarized in Table 1B. Acute tubular necrosis (ATN) may be post-ischemic or toxic. In either case, ATN is characterized by necrosis of the epithelial cells especially those of the proximal tubule and the thick ascending loop of Henle. Also, the tubule lumen is often filled with cellular debris, or heme-pigment precipitate (in the case of hemolysis or rhabdomyolysis). In contrast to pre-renal disease, ATN is characterized by a normal BUN/Scr ratio (10-15), a low U_osm (£350 mOsm/L), a high fractional Na excretion (>2%), and a high U_Na (>40 mEq/L). Urine output may be reduced or normal.
Intensive pharmacologic intervention in the early stages of post-ischemic ATN may help minimize tubular damage if administered within 24 hrs of the initial ischemic insult. A combination of osmotic and loop diuretics (e.g., mannitol + furosemide) is believed to help wash out debris from the tubule lumen. The loop diuretic may help preserve cellular integrity in the loop of Henle by inhibiting active ion transport and reducing the cells energy (O₂) requirements. Hypertonic mannitol helps prevent post-ischemic cell swelling. Also, mannitol may act as a scavenger of reactive oxygen species (or oxygen radicals). Upon reperfusion, the production of these radicals rises dramatically and it is thought to be largely responsible for the post-ischemic injury.
A post-renal condition (Table 1C) refers to an obstruction at some point along the urinary tract which would partially or completely block urine flow.

• Prevention of ARF:
  • Preventive measures should be instituted before undertaking procedures or drug therapies which can cause ARF (e.g., surgery, contrast media, nephrotoxic drugs). Prevention is particularly important in high risk patients (Table 2).
  • The most important preventive measure is to ensure that the patient is well hydrated. Elevated urine flow may help dilute toxins and promote their elimination. Osmotic and loop diuretics are also used in certain cases. However, the value of diuretics in this area is not proven. Sodium loading prior to and during amphotericin therapy is believed to mitigate its nephrotoxic effect.
• Treatment of ARF:
  Once ARF is established, treatment consists of :
  • Supportive measures including adequate hydration, attention to improving renal perfusion and oxygenation, prevention of fluid overload, and avoidance of nephrotoxic drugs if possible.
  • Active pharmacologic intervention aimed primarily at converting oliguric to non-oliguric ARF. Non-oliguric patients are less likely to require hemodialysis and are easier to manage in terms of fluid and electrolyte balance, nutrition, and pharmacotherapy. The conversion may be accomplished with diuretics and dopamine (Table 3).

Table 2 Risk Factors For Acute Renal Failure
Post-operative ARF (~ 5 % of pts)	Pre-existing renal insufficiency, advanced age, male sex, heart disease, and hypertension.
Aminoglycoside-induced ARF (5 - 10 % of pts)	Advanced age, co-administration of other nephrotoxins, prolonged AG therapy, renal hypoperfusion, hypokalemia
Contrast Media-induced ARF (<0.02% of pts)	Ionic contrast agents, pre-existing renal insufficiency, co-administration of other nephrotoxins, advanced age, diabetes mellitus, hepatic disease.

1. Reduced Functional Reserve: When the GFR declines to 50 - 65 mL/min (about 50% of normal), the remaining nephrons are able, through complex physiologic adaptations, to maintain homeostasis (constancy of volume and composition of body fluids). Therefore, no symptoms or abnormal labaoratory values are observed.
2. Marked Renal Insufficiency: As the GFR falls to 25 - 40 mL/min, the functional reserve is essentially exhausted, and fluid and electrolyte balance becomes precarious, particularly in the face of additional challenges (infection, dehydration, nephrotoxins). Significant signs and symptoms may appear. In addition to elevated Scr and BUN, the patient may present with mild hypertension and slight anemia.
3. Renal Failure: As the GFR drops below 25 mL/min, the kidneys become unable to maintain normal fluid and electrolyte balance as a result of their failure to respond adequately to changes in salt and water intake. All or some of the symptoms of CRF may become evident. Most patients can lose over 80% of GFR before developing overt clinical signs of renal failure (hypertension, CHF, edema, hyperkalemia, hypocalcemia, and anemia).
4. End-Stage Renal Disease (ESRD): This is the most advanced stage of CRF in which virtually all renal function is lost (GFR < 10 mL/min). Water and electrolytes are no longer in balance (input > output), body fluids composition is markedly abnormal, and cellular function is grossly compromised (see below). At this point, dialysis and/or kidney transplant becomes necessary.

Table 5 Common Causes of Chronic Renal Failure (CRF)

1. Glomerular and Vascular Diseases (77% of all cases ) Glomerulonephritis (14%). Diabetes (diabetic glomerulosclerosis / nephropathy) (34%). Hypertension (glomerulosclerosis) (29%).

2. Tubular and Interstitial Diseases Chronic interstitial nephritis (eg, phenacetin abuse nephropathy). Chronic pyelonephritis (usually due to vesico-ureteral reflux). Intratubular obstruction as in myeloma kidney, hypercalcemia, hyperuricemia (tumor lysis), poorly soluble drugs (acyclovir, methotrexate, sulfonamides, etc. Polycystic kidney disease (PKD) (3.4%) Severe, irreversible ATN (e.g., due exposure to heavy metals)

At the basis of these disorders is the body's partial or complete inability to:
1. excrete excess water and electrolytes.
2. excrete organic waste products including fixed acid (H⁺), urate, urea, creatinine, and other "uremic toxins".
3. produce sufficient amounts of the hormones calcitriol and erythropoietin.

Sodium:
As the number of functioning nephrons declines, the kidneys become unable to maintain Na balance in the face of the usual fluctuations in salt intake. If salt intake exceeds the excretory capacity of the remaining nephron, ECFV expansion, edema, and hypertension will result. Therefore, Na intake restriction is often necessary. It should be noted that with advancing CRF and the inability of the kidney to dilute the urine and excrete excess water, the serum Na⁺ level may be lower than normal (hyponatremia) despite a significant degree of Na⁺ retention.

Potassium:
Normally, the kidneys excrete the equivalent of 90-95% of the K⁺ intake. Patients with renal failure retain excess K+ and develop hyperkalemia (>5 mEq/L). Because hyperkalemia can lead to life-threatening cardiac complications, it is often an indication for dialysis.

Acid-Base Balance
In an average healthy individual, the non-volatile (fixed) acid production in the course of normal cell metabolism is ~ 1 mEq/kg/day. Normally, about two thirds of this amount is excrete in the form ammonium (NH₄⁺) and one third in the form of titratable acids such as H₂PO₄-. In CRF, the ability of each of the viable nephrons to excrete fixed acid in the form of NH4⁺ may be increased by as much as four fold. This adaptation is sufficient to maintain acid-base balance during the earlier stages of the disease. However, as the number of functioning nephrons dwindles, H+ accumulates in the body, resulting in metabolic acidosis, reflected in a markedly decreased arterial HCO3- level. Excess H⁺ are partly buffered by bone alkali, a process that promotes bone demineralization and may contribute to the development of bone disease. Patients with CRF often receive alkali therapy in the form of NaHCO3 (650 mg tid - 1950 mg tid). It should be noted that oral alkalization is blunted by the co-administration of drugs that inhibit gastric HCl secretion (e.g., the proton-pump inhibitors like omeprazole).

Calcium and Phosphate Metabolism:

---

Figure 1

Figure 2

---

Figure1 and Figure 2 above summarize the normal daily turnover of calcium and phosphate in an healthy subject. Figure 3 and Figure 4 show the formation and the physiological actions of calcitriol respectively. Chronic renal failure (CRF) can have a profound effect on bone metabolism, and is often associated with a complex bone disease known as renal osteodystrophy (see Figure 5 ). The alterations in bone metabolism in CRF stem primarily from reduced calcitriol production and the resultant hypocalcemia, which is further complicated by hyperphosphatemia.

Figure 3

The combination of hypocalcemia and hypocacitriolemia promote the release of parathyroid hormone (PTH), leading to secondary hyperparathyroidism and the development of osteitis fibrosa cystica. The low levels of calcitriol interfere with normal bone remodelling, resulting in osteomalacia, which can be treated with either exogenous calcitriol (025 µg PO qday or IV with each dialysis) or paricalcitol (Zemplar).

Figure 4

Figure 5	Paricalcitol (Zemplar®) is a relatively new product (FDA approved in 4/98) that is indicated specifically for the prevention and treatment of secondary hyperparathyroidism. It is a synthetic analogue of 1,25-dihydroxycholicalciferol (calcitriol) that suppresses PTH release with little or no effect on calcium and phosphate metabolism. Therefore, the use of paricalcitol minimizes the side effects of hypercalcemia and hyperphosphatemia associated with calcitriol.
Paricalcitol is administered intravenously three times per week (at any time during the dialysis session). The usual dose ranges from 0.04 to 0.1 µg/kg, while the maximum dose is 0.24 µg/kg ]. The three most common adverse effects with paricalcitol were nausea, vomiting, and edema, which are common in hemodialysis patients in general. Paricalcitol is contraindicated in patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to the product. The ingestion of aluminum-containing antacids such as Al(OH)2 or Amphogel (used as phosphate binders) may lead to aluminum intoxication, which leads to a type of osteomalacia that does not respond to calcitriol or paricalcitol.	Figure 6

---

Hematologic Consequences of CRF
Patients with CRF suffer from erythropoietin deficiency which results in normochromic, normocytic anemia. Before the advent of exogenous erythropoietin therapy, there was an inverse relationship between serum creatinine and blood hematocrit in patients with CRF. To maintain the hematocrit ³ 36%, patients are now treated with epoetin alpha (Epogen), which is usually given subcutaneously (SQ) at a dose of 50 - 100 units/kg 1 - 3 times/week.. Despite its low bioavailability (25%), SQ epoetin is preferable to the intravvenous route because it provides a more sustained (t_½ = 22 hrs) stimulation of erythroid precursors and a better hematocrit response. During epoetin treatment, a special attention must paid to the patient's iron stores. Iron deficiency is the most common cause of "resistance to epoetin therapy". Trasferrin saturation should be maintained ³20% to sustain the increased rate of erythropoiesis. If the iron stores are adequate, oral iron supplementatin with ferrous salts may be sufficient to maintain iron stores. However, often intravenous suppementatin is necessary. This is accomplished by the administration of intravenous iron dextran or non-dextran-containing iron preparations such as sodium ferric gluconate complex (Ferrlecit). In order to replenish the iron stores via the intravenous route, the total body deficit must first be estimated based on the patient's body weight and hemoglobin concentration. Here is an equation that I use for a rough estimation:

Where: Hb = Hemoglobin concentration (g/dL); DHb = 15 - actual Hb
Thus for a 70-kg patient with a Hb of 9 g/dL, I would estimate a dose of 1508 mg or approximately 1.5 grams. In the case of iron dextran, the entire dose may be diluted in one liter of normal saline and infused over an 8-hr period. In the case of Ferrlecit, the dose should be given in installments of 125 mg each over a period of weeks. Each dose of Ferrlecit is diluted in 100 mL of normal saline and infused over one hour. In both cases it is a good idea to give a test dose (25 mg) first to see if the patient is allergic to the preparation. The iron dextran test dose is diluted in 50 mL of normal saline and infused over 20 minutes. The Ferrlecit test dose is diluted in 50 mL normal saline and infused over one hour. The patient is observed carefully during the infusion and for at least 2 hrs after the infusion for signs of a hypersensitivity reaction including anaphylaxis. Such reactions are infrequent and usually mild and manageable with diphenhydramine and hydrocortisone.
Oral iron is available as ferrous sulfate, gluconate, or fumarate. The usual dose is equivalent to 65 mg of elemental iron three times daily. It should be taken on empty stomach and should be separated by at least 2 hrs form antacids, phosphate binders and other drugs that tends to raise stomach pH (a low pH helps maintain the iron in the ferrous state which promotes absorption).

Summary of the Pharmacotherapeutic Management of Chronic Renal Failure

Hyperphosphatemia: Phosphate binders:  CaCO3; Ca-acetate; Mg (OH)2; Al(OH)3. For patients who must avoid Al, Ca, and Mg, there is sevelamer ( Renagel), which decreases the incidence of hypercalcemic episodes in hemodialysis patients relative to patients on calcium acetate treatment. Each Renagel® capsule contains 403 mg of sevelamer. The recommended starting dose is 2 to 4 capsules with each meal depending on the severity of hyperphosphatemia.

Secondary Hyperthyroidism & Renal Osteodystrophy: Calcitriol [e.g., 0.25 µg qday] Paricilcitol (Zemplar) [0.04 - 0.1 µg/kg IV 3 times / week]

Metabolic Acidosis: Moderately low protein diet + Alkali (NaHCO3, vegetables)

Anemia: Make sure the patient has an adequate iron level with a transferrin saturation ³ 20%. Oral iron supplementation may be sufficient. However, if necessary use iron dextran or other intravenous iron forms (e.g., Ferrlecit] Vitamin supplements (particularly B12 and folate) Epoetin [starting dose 50 - 100 units/kg SQ 3 times/wk]

Hyperlipidemia: Hypertriglyceridemia: niacin, clofibrate, atorvastatin etc. Hypercholesterolemia (an HMG-CoA-RI like atorvastatin) To learn more about dyslipidemias click here Also, here is a summary table of Lipid-Lowering Drugs

Hypertension: Target Blood Pressure: <130/85; Prevent fluid overload, but protect RBF and avoid hyperkalemia Diuretics: avoid K-sparing (specially triamterene); ACE inhibitors: fosinopril is best for renal pts (no dose adjustment required) ß-blockers: labetolol may be the best choice; it does not reduce RBF and does not require renal dose adjustment)

Three basic renal processes determine the rate of drug excretion in the urine - glomerular filtration, active secretion by the tubule cells, and passive reabsorption. The contribution of filtration to drug elimination is a function of the glomerular filtration rate (GFR), the plasma concentration of the unbound (filterable) drug, and the extent of passive reabsorption of the drug following its filtration. Glomerular filtration does not contribute significantly to the elimination of drugs that are highly protein bound such as the non-steroidal antiinflammatory drugs (NSAIDs), many penicillins, and most diuretics. The same is also true for drugs that have a large molecular size (e.g., certain dextrans), particularly those bearing negative charges (e.g., heparin) because they are unable to cross the glomerular filtration barrier freely.

Active secretion results in the net transfer of the drug from the peritubular capillaries into the tubule lumen. It is a much more efficient mechanism of drug elimination than glomerular filtration particularly for drugs that are highly protein bound.. Approximately 80% of the renal plasma flow (RPF) is exposed to the secretory sites, whereas only about 20% of the RPF is filtered. There are two independent secretory systems, both of which are located in the proximal tubule. The organic anion transport system is responsible for secreting acidic substances such as aspirin, penicillin, and furosemide (Table 8A). The second system specializes in the secretion of basic (cationic) compounds such as ephedrine, epinephrine, cimetidine, and morphine (Table 8B).

The renal clearance of a particular drug depends on how it is handled by the kidney. A drug that is freely filtered, but neither secreted nor reabsorbed (e.g., gallamine, vitamin B₁₂, inulin, iothalamate, etc.) is cleared at a rate that is equivalent to GFR. A freely filterable, nonpolar (lipophilic) drug will be mostly reabsorbed, and its clearance will be equal to the urine flow rate. The clearance of a drug that is completely removed (by active secretion) during a single pass through the kidney will equal the RPF; familiar examples include penicillin, p-aminohippurate (PAH), and iodopyracet (Diodrast).

1. A substantial fraction (> 40%) of the rug dose is excreted by the kidney either unchanged or as an active (or toxic) metabolites.
   
2. The drug or its active metabolite has a narrow therapeutic window such that drug accumulation cannot be tolerated.
   
3. The kidney is a major site for the inactivation of the drug. This applies mainly to peptides like insulin, glucagon, PTH, and imipenem.
   
4. There is a significant drop in the binding of the drug to plasma proteins. For instance, a decrease in the protein binding from 99 to 95% results in a fourfold rise in the unbound, active drug concentration.

1. Extension of the dosing interval.
   
2. Reduction of the maintenance dose.
   
3. Administration of a loading dose.
   
4. Monitoring serum drug levels.
   

Clinical Evaluation of Renal Function
In the vast majority of clinical situations, the GFR is an accurate measure of overall renal function, particularly the ability of the kidney to excrete metabolic waste products (eg, urate, urea, creatinine, etc), drugs, and drug metabolites. In a healthy, young adult male the GFR is about 125 mL/min (70-75 mL.min^-1.m^-2 BSA). This rate is maintained until about the age of 45 yrs, after which it declines by about 1 mL/min/yr. The normal GFR of the adult female is approximately 85-90% of the male's.
In clinical practice, an approximate value of the GFR may be obtained either by direct determination or indirect estimation of the endogenous creatinine clearance (CLcr). Creatinine is derived from the metabolism of muscle creatine. The production rate of creatinine is dependent on muscle mass and the metabolic rate of the individual. In the steady state creatinine production and excretion are equal. Since creatinine is excreted primarily through glomerular filtration, its plasma or serum level (Scr) is determined by the GFR according to the relationship:

It is clear from this relationship that as the GFR declines the Scr rises and vice versa.
To determine the CLcr directly, urine is collected over a known time interval (usually 8, 12, or 24 hrs), its volume is measured, and the urine flow rate (V, mL/min) is calculated. Urine and plasma creatinine concentrations (Ucr and Scr) are measured, and the clearance is then calculated as follows:

Because this process is time consuming, clinicians are often content with an indirect estimate of CLcr obtained using one of several empirical equations such as Cockroft's:

The "normal range" of Scr is 0.6 - 1.2 mg/dL, but the Scr value should be interpreted in the context of the patient's conditions. Consider, for example, two patients having the same Scr of 1.0 mg/dL; patient A is a 60 yrs old male weighing 85 kg, and patient B is an 85 yrs old female weighing 60 kg. Using the above equation, the estimated CLcr values are 94 and 39 mL/min respectively. Thus, one must not rely solely on the fact that the Scr is within "the normal range". Elderly, frail, malnourished, or cirrhotic patients may show "normal" Scr levels despite markedly reduced GFR. Elderly patients with significantly reduced muscle mass (e.g., atrophy due to a neurological disorder) may have extremely low Scr despite having poor renal function. Using the Cockroft equation in these patients leads to a gross over-estimate of GFR. Better estimates of GFR in these patients can be obtained using the Sanaka equations, which make use of the patient's serum albumin level :

Starting from a baseline of < 2.7 mg/dL, an increase in Scr by ³ 0.1 mg/dL per day for ³ 3 days strongly suggests a developing acute renal failure (ARF). The latter afflicts 2-3% of patients during their hospital stay. This demonstrates the need for close monitoring the Scr values of critically ill patients.
For patients with chronic renal disease, a plot of 1/Scr vs time is a useful tool to follow long-term changes in renal function.