**3. Diabetic ketoacidosis and renal failure**

Renal failure occurs with increased frequency in patients with diabetes. Fortunately, the co‐ incidence of type 1 diabetes with DKA and acute renal failure is uncommon. Volume over‐ load and hyperkalemia may complicate the condition. It has been reported that DKA in patients with acute renal failure may be sometimes associated with respiratory distress syn‐ drome [17].

#### **3.1. Diabetic ketoacidosis and acute renal failure**

Although acute renal failure (ARF) rarely develops in patients with diabetic ketoacidosis (DKA), these serious complications can be life threatening in critically ill patients [43]. The estimated mortality with combined DKA and ARF still reaches around 50%. ARF pre-renal failure may occur as a result of the severe fluid depletion associated with diabetic ketoacido‐ sis; underlying diabetic nephropathy as well as hypotension, sepsis, renal artery occlusion, serious urinary infections complicated by papillary necrosis and exposure to nephrotoxic agents. Of the latter, a certain antibiotics and radio-contrast agents, but also angiotensin con‐ verting enzyme inhibitors were mentioned. [51]. The increased incidence of cardiovascular disease may also lead to renal impairment.

The long-lasting ketoacidosis in combination with infused insulin can lead to severe hypo‐ phosphatemia. Patients with uncontrolled diabetes may already be predisposed to hypo‐ phosphatemia due to osmotic dieresis and often decreased muscle mass; however, the majority of the imbalance results from phosphate shift from extracellular to intracellular space[30]. In the presence of metabolic acidosis, proximal tubular reabsorption of phosphate is inhibited and their urinary excretion is initially increased, thereby critically reducing the overall level of the extracellular phosphate [10].

Hypophosphatemia, in turn, further contributes to the deepening of the metabolic acidosis. Acidosis cannot be compensated by renal production of ammonia, because later in the course of diabetic ketoacidosis, with a reduction in the total amount of phosphate in the body, a reduction in urinary excretion of phosphate ensues. Prolonged metabolic acidosis accompanied by hypophosphatemia may be the cause of transient rhabdomyolysis. Acidosis and rhabdomyolysis lead to renal injury. In addition, prolonged hypophosphataemia can lead to cardiomyopathy due to decreased concentration of intracellular adenosine - triphos‐ phate and 2.3diphosphoglycerate (DPG). [35]. It is, therefore important to detect changes in serum phosphate levels of order in early to prevent these complications.

Acute hypophosphatemia may be associated with respiratory problems, confusion, irritabili‐ ty, seizures, ataxia or coma, metabolic acidosis due to reduced phosphate reabsorption. However, even the severe symptoms may be hardly recognizable for they can mimic those of the underlying disease – e.g. DKA itself. Hipophosphatemia may be the cause of rhabdo‐ myolysis, which (though not often) can lead to occurrence of cardiomyopathy and acute re‐ nal failure.

Even after initiation of phosphate replacement, serum phosphate levels are often difficult to normalize, and a severe metabolic acidosis can last despite insulin-induced normalization of blood glucose.

In cases of severe acidosis, phosphate replacement is of paramount importance [31]. Howev‐ er, after initial-phase phosphate replacement, the re-institution of acid-base balance phos‐ phate re-shifts from intra- to extracellular space; this can lead to the hyperphosphataemia later in the course of treatment [13]. Therefore, serum phosphate levels should be monitored continuously. With the occurrence of acute renal failure, indications for haemodialysis in‐ clude oliguria, persistent metabolic acidosis resistant to standard therapy, fluid overload and hypertension. Early initiation of haemodialysis is not only effective against the direct consequences of acute renal failure - uremia and hypervolemia – but also contribute to rapid correction of metabolic acidosis and hypophosphatemia [28]. Indeed, the existing hypophos‐ phataemia is easily corrected once a normal acid-base balance is established by haemodialy‐ sis. Prompt institution of dialysis is important as the diabetic patient may tolerate uraemia less well. Uncontrolled ketosis may worsen hyperkaliemia and metabolic acidosis. Insulin requirements may be increased due to insulin resistance, or decreased due to impaired clearance of circulating insulin [38, 56].

The vast majority of patients require intermittent haemodialysis. Patients with cardiac dys‐ function or autonomic neuropathy tend to develop hypotension during treatment. Also, an‐ ticoagulation with heparin may increase the risk of hemorrhage from proliferative retinopathy, therefore prostacyclin may be a safer alternative [52]. Peritoneal dialysis may be complicated by peritonitis and chest infections. Also, haemodialysis allows greater fluid removal and remove restrictions for administration of drugs and nutrition [56].

#### **3.2. Diabetic ketoacidosis and chronic renal failure**

Treatment with bumetanide, an inhibitor of Na-K-2Cl co-transport, resulted in improve‐ ments in metabolic measures during untreated DKA and prevented cerebral metabolic ag‐

Renal failure occurs with increased frequency in patients with diabetes. Fortunately, the co‐ incidence of type 1 diabetes with DKA and acute renal failure is uncommon. Volume over‐ load and hyperkalemia may complicate the condition. It has been reported that DKA in patients with acute renal failure may be sometimes associated with respiratory distress syn‐

Although acute renal failure (ARF) rarely develops in patients with diabetic ketoacidosis (DKA), these serious complications can be life threatening in critically ill patients [43]. The estimated mortality with combined DKA and ARF still reaches around 50%. ARF pre-renal failure may occur as a result of the severe fluid depletion associated with diabetic ketoacido‐ sis; underlying diabetic nephropathy as well as hypotension, sepsis, renal artery occlusion, serious urinary infections complicated by papillary necrosis and exposure to nephrotoxic agents. Of the latter, a certain antibiotics and radio-contrast agents, but also angiotensin con‐ verting enzyme inhibitors were mentioned. [51]. The increased incidence of cardiovascular

The long-lasting ketoacidosis in combination with infused insulin can lead to severe hypo‐ phosphatemia. Patients with uncontrolled diabetes may already be predisposed to hypo‐ phosphatemia due to osmotic dieresis and often decreased muscle mass; however, the majority of the imbalance results from phosphate shift from extracellular to intracellular space[30]. In the presence of metabolic acidosis, proximal tubular reabsorption of phosphate is inhibited and their urinary excretion is initially increased, thereby critically reducing the

Hypophosphatemia, in turn, further contributes to the deepening of the metabolic acidosis. Acidosis cannot be compensated by renal production of ammonia, because later in the course of diabetic ketoacidosis, with a reduction in the total amount of phosphate in the body, a reduction in urinary excretion of phosphate ensues. Prolonged metabolic acidosis accompanied by hypophosphatemia may be the cause of transient rhabdomyolysis. Acidosis and rhabdomyolysis lead to renal injury. In addition, prolonged hypophosphataemia can lead to cardiomyopathy due to decreased concentration of intracellular adenosine - triphos‐ phate and 2.3diphosphoglycerate (DPG). [35]. It is, therefore important to detect changes in

Acute hypophosphatemia may be associated with respiratory problems, confusion, irritabili‐ ty, seizures, ataxia or coma, metabolic acidosis due to reduced phosphate reabsorption.

serum phosphate levels of order in early to prevent these complications.

gravation during initial DKA treatment.

drome [17].

322 Type 1 Diabetes

**3. Diabetic ketoacidosis and renal failure**

**3.1. Diabetic ketoacidosis and acute renal failure**

disease may also lead to renal impairment.

overall level of the extracellular phosphate [10].

Despite the strong prevalence of compromised immune status, constant state of protein mal‐ nutrition, frequent vascular accessing with a predisposition to significant infections, in‐ creased incidence of cardiovascular diseases, the occurrence of DKA in patients with chronic renal failure is quite rare. [41, 3]. Kidneys play a major role in insulin breakdown [38]; ad‐ vanced chronic renal failure is associated with both insulin resistance and decreased insulin degradation. The latter may lead to a marked decrease in insulin requirement. Therefore, many patients see an improvement in glycemic control when they progress to haemodialy‐ sis. Furthermore, in hyperglycemic dialysis-dependent patients volume contraction due to osmotic diuresis is not encountered. Since glycosuria and osmotic diuresis account for most of the fluid and electrolyte losses seen in DKA, anuric patients may be somewhat protected from dehydration. However they may still be prone to development of hyperkalemia and metabolic acidosis [37]. In persistent and long-lasting DKA, a substantial volume loss can still occur due to a prolonged decrease in oral intake or increased insensible water losses re‐ lated to tachypnea and fever.

acidosis corrected before potassium supplementation is initiated. All dialysis patients pre‐ senting with significant symptoms should undergo immediate cardiac monitoring. If there is clinical suspicion or electrocardiographic evidence of hyperkalemia, they should receive im‐

Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial

Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 325

In a study performed in USA in 2001 [1] the occurrence of diabetic ketoacidosis after renal transplantation was followed. A female sex, recipients of cadaver kidneys, patients age 33– 44 (vs. >55), more recent year of transplant, and patients receiving tacrolimus vs. cyclospor‐ ine had significantly higher risk of diabetic ketoacidosis. However, the rate of diabetic ke‐ toacidosis decreased more over time in tacrolimus users. Diabetic ketoacidosis was

In summary, acute renal failure rarely develops in patients with diabetic ketoacidosis, but it can be life-threatening. Insulin requirements may be increased due to insulin resistance, or

Patients with uncontrolled diabetes may already be predisposed to hypophosphatemia. In the presence of metabolic acidosis, proximal tubular reabsorption of phosphate is inhibited, and the overall level of the extracellular phosphate is further reduced. In cases of severe

Indications for haemodialysis in patients with acute renal failure and DKA include oliguria, persistent metabolic acidosis resistant to standard therapy, fluid overload and hypertension. Early initiation of haemodialysis is not only effective against uremia and hypervolemia but

The occurrence of DKA in patients with advanced chronic renal failure is quite rare. Chronic renal failure is associated both with insulin resistance and decreased insulin degradation. The latter may lead to a marked decrease in insulin requirement. In patients treated with peritoneal dialysis, glucose contained in peritoneal dialysate will tend to increase the need

In oliguric patients, fluid hydration in amounts usually administered in DKA treatment may precipitate severe pulmonary edema. Sodium and osmotic overload may be particularly problematic for anuric patients. Pulmonary dysfunction due to frequent pulmonary infec‐ tions can impair ventilatory compensation to metabolic acidosis. Bicarbonate administration is rarely of value in DKA. In this situation, significant metabolic acidosis will only be cor‐

Most DKA patients on both peritoneal and haemodialysis are hyperkalemic and the potassi‐

Diabetic ketoacidosis is serious metabolic complication in diabetic patients with acute myo‐ cardial infarction, stroke and renal insufficiency. Conversely, severe diabetic ketoacidosis is

also contribute to rapid correction of metabolic acidosis and hypophosphatemia.

mediate potassium lowering therapies, including emergent haemodialysis. [8].

independently associated with increased mortality.

for hypoglycemic therapy.

rectable by haemodialysis.

**4. Conclusion**

um replacement in DKA is usually not necessary.

decreased due to impaired clearance of circulating insulin.

acidosis, phosphate replacement is of paramount importance.

The uremic environment can affect methods used to assess glycemic control. Changes in di‐ etary intake and exercise (ie, reduced intake due to anorexia prior to starting dialysis) can also affect the response to administered insulin). Renal inability to reabsorb/regenerate bi‐ carbonate and excrete hydrogen ions may lead to metabolic acidosis even in the absence of DKA; in addition, patients often suffer from anorexia, nausea, vomiting, infections, and even acute coronary events predisposing them to catabolic pattern of metabolism. In pa‐ tients treated with peritoneal dialysis, glucose contained in peritoneal dialysate will tend to increase the need for hypoglycemic therapy.

Therefore, the treatment of oliguric patient certainly differs from the wide accepted DKA treatment guidelines. [8]. First of all, end-stage-renal-disease patients with DKA may be less likely volume depleted; in most cases the extracellular volume is expanded from its baseline secondary to hyperglycemia. The volume expansion may cause dyspnea, nausea, vomiting, seizures and coma [54]. In oliguric patient, fluid hydration in amounts usually administered in the DKA treatment may precipitate severe pulmonary edema. Therefore, the need for flu‐ id resuscitation in these patients must be justified clinically or by laboratory testing and po‐ tential volume resuscitation should be performed carefully, using central venous access for continuous monitoring. [2]. When volume overload is apparent, immediate haemodialysis is the therapy of choice.

Metabolic control can be difficult to achieve. Insulin is normally metabolized by kidneys and in chronic renal failure insulin degradation is much slower. Furthermore, insulin is not ex‐ creted either by haemodialysis or peritoneal dialysis. Hyperinsulinemia resulting from ag‐ gressive glucose – lowering therapies may easily lead to severe and prolonged hypoglycemia. One cannot readily predict insulin requirements in this setting and careful individualized therapy is essential.

As already emphasized, kidneys in end-stage renal disease are not able to contribute to the overall acid-base balance. Therefore, DKA in these patients may be both profound and pro‐ longed. In addition, pulmonary dysfunction related to volume overload and sometimes un‐ derlying pulmonary infections can impair respiratory compensation to metabolic acidosis. Bicarbonate administration is rarely of value in DKA [55] and the associated volume, so‐ dium and osmotic overload may be particularly problematic for anuric patients. In this sit‐ uation, significant metabolic acidosis will only be correctable by haemodialysis [53].

Total body concentration of potassium is unchanged, and patients with DKA and end stage renal failure frequently have a high serum potassium level. Lack of insulin causes transloca‐ tion of intracellular potassium to the extracellular compartment. Hyperglycemia causes hy‐ pertonicity of extracellular fluids, which also leads to shift of potassium from the cells to the extracellular compartment. The important potassium – lowering effect of osmotic diuresis is missing. DKA aggravates hyperkalemia in more than 50% of cases [48]. Even when testing reveals hypokalemia, total body potassium stores may be high, and these patients are un‐ able to excrete a potassium load. Consequently, hypokalemia must be documented and acidosis corrected before potassium supplementation is initiated. All dialysis patients pre‐ senting with significant symptoms should undergo immediate cardiac monitoring. If there is clinical suspicion or electrocardiographic evidence of hyperkalemia, they should receive im‐ mediate potassium lowering therapies, including emergent haemodialysis. [8].

In a study performed in USA in 2001 [1] the occurrence of diabetic ketoacidosis after renal transplantation was followed. A female sex, recipients of cadaver kidneys, patients age 33– 44 (vs. >55), more recent year of transplant, and patients receiving tacrolimus vs. cyclospor‐ ine had significantly higher risk of diabetic ketoacidosis. However, the rate of diabetic ke‐ toacidosis decreased more over time in tacrolimus users. Diabetic ketoacidosis was independently associated with increased mortality.

In summary, acute renal failure rarely develops in patients with diabetic ketoacidosis, but it can be life-threatening. Insulin requirements may be increased due to insulin resistance, or decreased due to impaired clearance of circulating insulin.

Patients with uncontrolled diabetes may already be predisposed to hypophosphatemia. In the presence of metabolic acidosis, proximal tubular reabsorption of phosphate is inhibited, and the overall level of the extracellular phosphate is further reduced. In cases of severe acidosis, phosphate replacement is of paramount importance.

Indications for haemodialysis in patients with acute renal failure and DKA include oliguria, persistent metabolic acidosis resistant to standard therapy, fluid overload and hypertension. Early initiation of haemodialysis is not only effective against uremia and hypervolemia but also contribute to rapid correction of metabolic acidosis and hypophosphatemia.

The occurrence of DKA in patients with advanced chronic renal failure is quite rare. Chronic renal failure is associated both with insulin resistance and decreased insulin degradation. The latter may lead to a marked decrease in insulin requirement. In patients treated with peritoneal dialysis, glucose contained in peritoneal dialysate will tend to increase the need for hypoglycemic therapy.

In oliguric patients, fluid hydration in amounts usually administered in DKA treatment may precipitate severe pulmonary edema. Sodium and osmotic overload may be particularly problematic for anuric patients. Pulmonary dysfunction due to frequent pulmonary infec‐ tions can impair ventilatory compensation to metabolic acidosis. Bicarbonate administration is rarely of value in DKA. In this situation, significant metabolic acidosis will only be cor‐ rectable by haemodialysis.

Most DKA patients on both peritoneal and haemodialysis are hyperkalemic and the potassi‐ um replacement in DKA is usually not necessary.
