Hyperglycaemic crisis secondary to emphysematous pyelonephritis

Abstract

A 49-year-old woman presented to the emergency department acutely unwell. Initial investigations revealed hyperglycaemia, ketosis and an acute kidney injury precipitated by urosepsis. She was found to have a new diagnosis of diabetes mellitus (type 2) with a glycated haemoglobin (HbA1c) of 156 mmol/mol. CT imaging of the abdomen and pelvis revealed unilateral emphysematous pyelonephritis (EPN), radiologically classified as stage 3 severity with gas extending beyond the renal collecting system. Escherichia coli was grown on blood and urine cultures. This was sensitive to second-generation cephalosporin cefuroxime. The patient was managed with fluid resuscitation, intravenous antibiotics and renal system decompression with urinary catheter insertion. She was commenced on an intravenous insulin infusion for hyperglycaemic crisis. This case illustrates a rare presentation of hyperglycaemic crisis precipitated by EPN in a patient without a previously known diagnosis of diabetes, successfully treated with medical management alone. Close clinical and radiological follow-up was arranged to monitor the need for future nephrectomy.

Background

Emphysematous pyelonephritis (EPN) is a rare necrotising infection of the parenchyma of the kidney. It is difficult to establish the overall incidence of EPN. One meta-analysis of published cases from 1980 to 2013 included 628 case reports in their review.² A total of 85%–95% of EPN patients have an underlying diagnosis of diabetes mellitus.^1–6 A number of cases of EPN presenting with hyperglycaemic crisis have been described.^7–13 Few cases have been described in those without a previously known diagnosis of diabetes.¹⁴

The gold-standard treatment for the management of EPN has been a subject of debate due to conflicting data and a lack of substantive evidence. Historically, early nephrectomy was regarded as being essential in management but there is currently a trend toward non-surgical treatment measures due to significantly improved patient outcomes.²

Case presentation

A 49-year-old woman was brought to the emergency department with a 72-hour history of vomiting and abdominal pain. The patient reported increased thirst over the previous number of days as well as nocturia twice per night for 2 weeks prior to admission.

She was not on any regular medication and there was no medical history of note. She was an ex-smoker with a 30 pack-year history. She had moderate alcohol intake of seven units per week. She was independent in activities of daily living. Her family history was significant for a brother who was diagnosed with type 2 diabetes mellitus in adulthood.

On examination, she was hypotensive with a systolic blood pressure of 90 mm Hg and febrile with temperature of 39.2°C. There was tenderness to palpation at the left renal angle. The patient had an elevated body mass index of 28 kg/m² and was noted to have ketotic breath. She was catheterised and a small volume of purulent urine was drained.

Investigations

Point-of-care investigations revealed significant hyperglycaemia with a glucose of 31.2 mmol/L and elevated serum ketones of 4.3 mmol/L. Venous blood gas showed a normal pH of 7.38 (7.35–7.45) with a bicarbonateof 24.3 mmol/L (24–28 mmol/L). The anion gap was elevated at 22 mmol/L.

Laboratory blood work demonstrated a leucocytosis of 10.9×10⁹/L, a neutrophilia of 10.3×10⁹/L and a thrombocytopaenia of 120×10⁹/L. The patient had an acute kidney injury (AKI) with a creatinine of 157 mmol/L (baseline creatinine of approximately 85 mmol/L). Sodium was 131 mmol/L potassium was 4.8 mmol/L and urea was 13.2 mmol/L. Inflammatory markers were significantly elevated with a C reactive protein of 655 mg/L and a lactate of 2.9 mmol/L. Serum osmolality was elevated at 293 mOsmol/Kg.

Urinalysis was strongly positive for glucose, ketones, protein, blood and leucocytes.

Both urine and blood cultures were colonised with a partially resistant gram-negative coliform; Escherichia coli. Glycated haemoglobin (HbA1c) was significantly elevated at 156 mmol/mol.

Differentials

As the patient was hypotensive and febrile, the clinical impression was that of septic shock with a likely urinary source. There was evidence of an acute hyperglycaemic crisis on the background of previously undiagnosed diabetes mellitus. The patient continued to experience persistent left sided flank pain and a non-contrast CT abdomen and pelvis was performed (see figures 1–3). This showed destructive changes in the left kidney with gas throughout the parenchyma and within the ureter, consistent with a diagnosis of EPN. The radiological severity was that of class 3 disease as per the Huang and Tseng classification system with evidence of gas extending beyond the renal collecting system into the retroperitoneum.¹ The urology team was consulted and reviewed the patient’s imaging. They advised that there was no evidence of a collection that was amenable to percutaneous drainage. The patient had an AKI, was thrombocytopaenic and in septic shock, all of which have been identified as poor prognostic indicators in EPN.¹⁵

Figure 1.

Non-contrast CT of the abdomen and pelvis in coronal view taken on presentation demonstrating extensive left kidney parenychmal destruction.

Figure 2.

Non-contrast CT of the abdomen and pelvis in axial view taken on presentation demonstrating extensive left kidney parenychmal destruction.

Figure 3.

Non-contrast CT of the abdomen and pelvis in saggital view taken on presentation demonstrating extensive left kidney parenychmal destruction.

In terms of metabolic disturbance, there was significant hyperglycaemia and ketosis. However, as the patient was not acidotic, the diagnostic criteria for diabetic ketoacidosis were not met. Similarly, serum osmolality was elevated but not high enough to be classified as a hyperosmolar hyperglycaemic state.¹⁶ The significantly elevated HbA1c supports a diagnosis of untreated diabetes mellitus. Initially, it was unclear as to whether this presentation was related to type 1 or type 2 diabetes mellitus. Islet cell antibodies and antibodies to glutamic acid decarboxylase (GAD) were later found to be negative which confirmed a diagnosis of type 2 diabetes.

The patient was found to be hypothyroid with an elevated thyroid-stimulating hormone (TSH) of 31.9mU/L (0.45–4.5mU/L) and a low free thyroxine of 4.1 pmol/L. (12–22 pmol/L). Antithyroid peroxidase antibodies were elevated at 229 IU/mL confirming a diagnosis of autoimmune hypothyroidism.

While diabetic antibodies were awaited, adrenal insufficiency remained in the differential as a possible underlying related autoimmune disorder. The patient was covered with a stress dose of intravenous hydrocortisone pending cortisol test results. A cortisol level taken before the initiation of intravenous hydrocortisone was later found to be appropriately elevated at 822 nmol/L and the hydrocortisone was stopped.

Treatment

As the patient was septic and hyperglycaemic with evidence of keto-acid production she was given intravenous fluid resuscitation and an intravenous insulin infusion. She was commenced on long acting subcutaneous insulin glargine (lantus) 10 units once daily. Serum potassium, glucose, pH and ketone level were monitored closely.

In terms of infection, the patient was initially treated for complicated urosepsis as per local antimicrobial guidelines with empiric intravenous coamoxiclav and creatinine clearance dose-adjusted gentamicin. A urinary catheter was inserted to aid in the decompression of the renal system.

Blood and urine cultures returned positive for gram negative coliform E. coli. Antibiotics were switched to a combination of second-generation cephalosporin cefuroxime and gentamicin based on the culture and sensitivity of the E. coli species. This was later narrowed to cefuroxime monotherapy.

The patient responded well to initial measures. AKI resolved within 48 hours of initiation of fluid resuscitation. When the hyperglycaemic crisis resolved, the insulin infusion was stopped and multiple daily injections of subcutaneous rapid acting insulin (novorapid) were commenced in addition to the long acting subcutaneous insulin glargine (lantus). An uptitrating dose of levothyroxine was commenced for management of newly diagnosed hypothyroidism. As per guidance from the microbiology department, the patient went on to completed a 3-week course of intravenous cefuroxime in hospital and was discharged home on a further 3-week course of oral ciprofloxacin.

Outcome/follow-up

Outpatient follow-up was arranged with both the endocrinology and urology teams.

In terms of EPN management, the patient had a follow-up CT abdomen and pelvis 8 weeks after her initial treatment. This showed improvement of the renal parenchymal destruction and fluid accumulation that had been seen during active infection (figure 4).

Figure 4.

Interval follow-up at 3 months following a prolonged course of antibiotics. CT imaging of the thorax, abdomen and pelvis with intravenous contrast in coronal view demonstrating interval improvement in left kidney parenchymal destruction.

The case was discussed at the urology/radiology multidisciplinary meeting. As there was no evidence of a collection amenable to drainage and the patient had responded to medical management, a non-surgical treatment approach was deemed to be suitable. The patient is being actively followed on a 6monthly basis and future consideration toward nephrectomy will be based on recurrence of infection.

A dimercaptosuccinic acid (DMSA) radionucleotide scan was performed to assess differential kidney function (figures 5 and 6). This showed 19% function in the left kidney and 81% in the right kidney. Fortunately, the patient’s acute kidney injury recovered fully following the treatment of sepsis as the contralateral kidney was not affected by the infection.

Figure 5.

Radionucleotide dimercaptosuccinic acid scan demonstrating differential kidney function of 19% function in the left kidney and 81% function in the right kidney. LT, Left; LPO, Left Posterior Oblique; RT, Right; RPO. Right Posterior Oblique.

Figure 6.

Radionucleotide dimercaptosuccinic acids can demonstrating differential kidney function taking into account kidney size

In terms of her new diagnosis of type 2 diabetes, the patient was optimised on long acting daily subcutaneous insulin glargine 40units. Her follow-up HbA1c at 6 months was greatly improved at 47 mmol/mol. There is scope to introduce oral hypoglycaemic agents alongside her insulin in the future if needed. She has been registered with diabetic retinopathy screening and attends the diabetic outpatient department every 6 months.

Thyroid function tests have normalised in response to levothyroxine 125 μg once daily. Most recent levels showed a free T4 of 18.2 pmol/L (12–22 pmol/L) and a TSH of 2.07mU/L (0.45–4.5mU/L)

Discussion

EPN is a rare necrotising infection of the renal parenchyma associated with gas producing organisms.^{1 5} In the past, EPN was associated with a high mortality rate, however more recent literature suggests an overall survival rate of 80%–90%.^{2 17–20} This improved survival rate is thought to be linked with improved medical management and earlier detection through widespread use of CT imaging. Factors linked to increased mortality include altered mental status, thrombocytopaenia, renal failure, severe hyponatraemia, severe hypoalbuminaemia, shock at presentation and polymicrobial infection^{17 19}

There is a strong female preponderance associated with EPN.⁶ Up to 95% of patients diagnosed with EPN have a history of diabetes mellitus.^1–6 HbA1c levels in these patients tend to be significantly elevated. Mixed acid fermentation of glucose by enterobacteriae is likely to be the major pathway for gaseous production of hydrogen and carbon dioxide.^{1 2} Factors such as chronically elevated blood glucose, impaired tissue perfusion and defective immune response are thought to contribute to the pathogenesis of EPN. A history of diabetes has not however, been shown to be associated with a higher mortality rate.¹⁵ It is unclear as to what factors, if any, predispose some persons with diabetes and not others to the development of EPN.

Several cases have been reported describing hyperglycaemic crisis associated with EPN.^7–14 In these cases, hyperglycaemic crisis was managed in conjunction with EPN. EPN management consisted of either medical management alone or a combination of medical management, percutaneous drainage and/or nephrectomy. Cases of EPN presenting with DKA without a previously known diagnosis of diabetes have been reported infrequently in the literature. One such case described a patient in DKA precipitated by EPN without a known history of diabetes but a history of schizophrenia on oral antipsychotic therapy. EPN in this case was treated with nephrectomy. The patient had a persistent postoperative infection treated with granulocyte colony-stimulating factor and antibiotics.¹⁴

Hyperglycaemic crisis refers to either diabetic ketoacidosis (DKA) or hyperglycaemic hyperosmolar state (HHS). Overall, DKA is a significantly more common presentation than HHS.^{16 21} Hyperglycaemic crisis results from a relative insulin deficiency in the presence of an increase in counter regulatory hormones (glucagon, catecholamines, cortisol and growth hormone). This state is often precipitated by sepsis.²² The patient described in our case most likely had a long-standing history of undiagnosed type 2 diabetes which predisposed her to the development of EPN with gas producing organisms. A hyperglycaemic crisis arose secondary to sepsis with an emergent DKA on admission.

One study enrolled 295 patients with hyperglycaemic crisis in the emergency department and compared clinical characteristics between patients with a history of diabetes and patients without a history of diabetes. 24.5% did not have a known diagnosis of diabetes and of these patients 88.9% had new type 2 diabetes while 11.1% had new type 1 diabetes. 93.8% of patients without a history of diabetes had a HbA1c >6.5% (48mmol/mol). This study concluded that patients without a previous diagnosis of diabetes were younger, predominately male and had less alterations in mental status and renal function compared with patients with a known history of diabetes.²³ These data are in contrast to a national UK survey of 281 patients which found 6.1% of DKA admissions to have no known history of diabetes.²⁴ Another retrospective study of 589 cases of hyperglycaemic crisis concluded that patients without a history of diabetes were younger and tended to have a more rural residence. This study found there to be an overall lower incidence of type 2 diabetes in those without a history of diabetes at 38.3% vs 53.7%.²⁵

In terms of EPN investigation, CT has been proven to be the imaging modality of choice. Huang and Tseng introduced a classification system that is widely used, to determine the radiological severity of EPN as follows: class (1): gas in the collecting system only, class (2): gas in the renal parenchyma without extension into the extrarenal space, class (3)A: extension of gas or abscess into perinephric space, class (3)B: extension of gas or abscess to pararenal space and class (4): bilateral or solitary kidney EPN.¹

The appropriate choice of antibiotic therapy is an essential element in both the surgical and non-surgical management of EPN. E. Coli is the most frequently isolated pathogen. Klebsiella pneumoniae and Proteus mirabilis are, respectively, the next most common pathogens isolated.^{1 3 6} Third-generation cephalosporins have been recommended as the initial empiric antibiotic with escalation to carbapenem in those that require haemodialysis or develop disseminated intravascular coagulation. This data is based on results from a single centre observational study of 51 patients in Taiwan. The authors of this study acknowledge that there are variations in pathogenic culture and sensitivity based on geographical location. This study advised the avoidance of gentamicin and fluoroquinolones as empiric treatment in EPN. However, the patient in our case was treated with intravenous second-generation cephalosporin cefuroxime, and creatinine clearance dose adjusted gentamicin. The microbiology department recommended these antibiotics as per sensitivities of the E. coli species grown. Similarly, on discharge, the patient completed a 3-week course of oral ciprofloxacin.

The standardised treatment of EPN is a controversial area. In 2007, a meta-analysis of 175 patients found conservative treatment alone to be a risk factor for fatal outcomes in patients with EPN.¹⁵ However, since then a number of individual case reports and case series have demonstrated favourable outcomes with a non-surgical approach.

A more recent meta-analysis of 628 cases of EPN showed an overall mortality rate of 18% and significantly higher survival rates in patients managed with either percutaneous drainage or medical management alone. This review found that both medical management alone and percutaneous drainage were associated with a significantly lower mortality rate than emergency nephrectomy and there was no significant difference between medical management alone versus percutaneous drainage. Medical management consisted of antibiotic therapy, hyperglycaemia control and intravenous fluids. The study also advocated open drainage of abscesses where required to avoid nephrectomy if possible.² There is an increasing body of evidence that supports medical management as first-line management with consideration toward percutaneous drainage, particularly in cases with urinary obstruction.3 4 17 19 Nephrectomy can be reserved as a salvage procedure in cases that do not respond despite adequate medical therapy.⁶

EPN can have detrimental effects on kidney function. One retrospective case series found that 8 of 13 patients with EPN had ongoing renal impairment at 6 months.⁵ In our patient, DMSA scan demonstrated a significant deterioration of the affected kidney function post-EPN. This patient regained overall renal function as disease was unilateral and the contralateral kidney is not functionally impaired. Case series have demonstrated that patients with bilateral EPN can be managed with aggressive broad-spectrum antibiotics with or without percutaneous drainage with good clinical outcomes. This approach potentially removes the need for long-term dialysis in this cohort.⁸

Further research is required to identify optimal management guidelines for patients diagnosed with EPN. The proportion of patients with medically managed EPN that suffer from relapsed infection and go on to require salvage nephrectomy remains unclear. Guidelines for the clinical and radiological follow-up of medically managed EPN is also yet to be established. The risks and benefits of radiation exposure in patients that are followed with interval CT imaging is a further consideration.

To conclude, this case illustrates the successful medical management of a case of EPN associated with hyperglycaemic crisis in a previously undiagnosed diabetic patient. Much of the literature published to date has focused on the surgical management of EPN, however, the medical management of this condition is becoming more important due to significantly lower associated mortality rates. The optimal medical management pathway has yet to be established. Further research is required to understand the epidemiology, goals of treatment and pathological mechanisms that underlie this complex condition.

Patient’s perspective.

I had been feeling really unwell for two or three days. I was exhausted, run down and tired. I had been feeling more thirsty than usual and nauseated for about 2 weeks. I went to my GP and when she saw how unwell I looked, she sent me to the emergency department. I had a temperature and my blood sugar was very high. I was scared at the time and I didn’t know what was happening, I started to think the worst. I was admitted to hospital and the doctors explained to me that I had a severe kidney infection and that I would need so stay in hospital for antibiotics. I was shocked when they told me that I had diabetes, I had no idea! The doctors explained to me that there was a chance I would have to get my kidney taken out because of the infection. I was frightened and overwhelmed at the idea of such a big surgery.

I was sick in hospital for weeks and I had to spend time in the cardiac care unit. I lost weight and strength, so much so, that I found it difficult to get out of bed. After a week or so of treatment I started to feel better. The diabetes nurse taught me about my diabetes and explained how to monitor blood sugars and inject insulin. My doctors decided not to take out my kidney for the time being which was a relief but I know that if this kidney gets infected again we will have to think about having surgery to remove it. I’ve been feeling very well since I left hospital eight months ago. Thankfully, I haven’t had any signs of another kidney infection. I’m hoping to stay well.

Learning points.

• Emphysematous pyelonephritis presenting with hyperglycaemic crisis in new diabetes mellitus can be successfully treated with medical management alone.

• Antibiotic therapy should be guided by blood and urine culture and sensitivities. Samples should be obtained and sent for analysis prior to the initiation of empiric antibiotics where possible. Specialist microbiology input should be sought.

• Successful medical management of hyperglycaemic crisis in emphysematous pyelonephritis relies on prompt recognition, initiation of fluid resuscitation, intravenous insulin, appropriate antibiotic therapy and input from the urology, endocrinology and microbiology teams.

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