Review

Transcription

Review

1
2
Review
12, Parliament Road, Middlesbrough,
TS1 4LF United Kingdom
Vuk Vrhovac Institute, University Clinic for Diabetes
Endocrinology and Metabolic Diseases,
Dugi dol 4a, HR-10000 Zagreb, Croatia
KIDNEY INFECTIONS IN DIABETES MELLITUS
Mahadeva Santhakumar Balachandar1, Pajica Pavkoviæ2, @eljko Metelko2
INTRODUCTION
It is widely held that urinary tract infection (UTI) is
more common in subjects with diabetes mellitus.
Although there are relatively few recently published
data, there is evidence suggesting that bacteriuria is
more common in females but not in males with
diabetes. Certain renal tract infections, including
emphysematous
pyelonephritis
and
cystitis,
perinephric abscess, and candidiasis, show close
association with diabetes mellitus. These, together
with renal papillary necrosis, form the basis of UTI (1).
Urinary tract is the most important and most common
site of infection in diabetic patients. Diabetic patients
have been found to have 5-fold frequency of acute
pyelonephritis at autopsy than nondiabetics (2).
The incidence of bacteriuria in diabetic men with
good control of blood sugar is reported to be similar as
in nondiabetic men, however, in pregnant diabetic
women it is 2-4 times as common as in control groups
(3,4).
Most urinary tract infections in diabetic patients are
relatively asymptomatic. The presence of diabetes
predisposes to much more severe infections, especially
in patients with poor diabetic control, acute
ketoacidosis, or diabetic complications such as
nephropathy, vasculopathy and neuropathy. This
asymptomatic infection can lead to severe kidney
damage and cause renal failure (5).
Diabetologia Croatica 31-2, 2002
In Wheat’s review of the issue of infections and
diabetes from 1980, 72% of 22 patients with
emphysematous pyelonephritis, 80% of 19 patients
with emphysematous cystitis, 57% of 250 patients with
papillary necrosis, 36% of patients with prenephrotic
abscess, and 10% of 130 patients with metastatic
infection had diabetes (6).
Bacteriuria is very common among diabetic patients
because if unrecognizable and inadequately treated, it
can lead to low grade foci of inflammation that can
ultimately result in serious renal damage (7).
Therefore, investigation of bacteriuria in diabetic
patients by screening for urinary tract infection is very
important to enable it to be properly treated to prevent
the development of renal complications of diabetes and
eventually severe renal damage and failure (8).
CLASSIFICATION OF URINARY TRACT
INFECTIONS ACCORDING TO TYPE OF
INFECTION (9-11)
Symptomatic UTI
Asymptomatic UTI
•
•
•
•
•
acute
recurrent
chronic
complicated
uncomplicated
85
M. S. Balachandar, P. Pavkoviæ, @. Metelko / KIDNEY INFECTIONS IN DIABETES MELLITUS
Localization of UTI
Factors predisposing to reinfection
A. Infections of upper urinary tract (12,13)
• acute pyelonephritis
• chronic pyelonephritis
B. Infections of lower urinary tract (12,13)
• cystitis
• urethritis
1. incomplete voidance of urinary bladder
Diabetes can increase proneness to various
infections
•
Figure 1. Classification of uncomplicated and complicated UTI (9,12,13)
Renal imaging
No associated
disease
Cause of symptoms
No kidney damage
Abnormal
Normal or abnormal with
associated disease
*Diabetes mellitus
*Sickle-cell disease/trait
*Analgesic abuse
*NSAID abuse
*Stones
*Obstruction
*Vesico-ureteric reflux
reflux
*Vesicourethral
'Complicated'
FACTORS INFLUENCING RESISTANCE
TO URINARY TRACT INFECTION (14-16)
1) hyperglycemia
2) ketoacidosis
3) neutrophil function
4) immune response
5) influence of endocrine systems
6) vascular insufficiency
7) neuropathy
FACTORS CAUSING COMPLICATIONS IN
DIABETIC PATIENTS WITH UTI (17,18)
Factors predisposing to renal impairments
1.
2.
3.
4.
calculus
obstruction
vesico-ureteric reflux
papillary necrosis
Factors predisposing to recurrent infections
1.
2.
3.
4.
5.
6.
86
•
Impaired monocyte
function
Immune disorders (decrease in the levels of complement
/C4 / and T-helper lymphocytes) (20)
Infections can cause poor diabetes regulation
(21)
Risk of kidney damage and septicemia
'Uncomplicated'
Impaired chemotaxis, phagocytosis,
adhesion, intercellular
destruction of microorganisms
•
Normal
Impaired neutrophil
function (15-17)
calculus
scars/spongy medulla
prostatitis
foreign bodies in the urinary tract
urinary tract fistula (vesicoenteral)
congenital anomalies
• increased secretion of counterinsular hormones
(glucagon, cortisol, growth hormone and catecholamines)
• insulin secretion inhibition (sympathicus)
• insulin resistance of peripheral tissues (increased
cytokine secretion) (22)
PATHOPHYSIOLOGY OF URINARY
TRACT INFECTION
Infection pathways (23)
- ascending
- hematogenic
Infection factors (23,24)
- number of microorganisms
- virulence of microorganisms
Defense mechanisms of the host (23,24)
- length of the urethra
- vesicourethral valvula
- increased liquid intake and frequent urination
- complete voidance of urinary bladder
Abnormalities of urinary tract (19,23,24)
- obstruction
- vesico-ureteric reflux
- foreign bodies
- incoplete voidance of urinary bladder
The etiology of urinary tract infection includes
transfer of organisms from remote foci in the body, from
adjacent sources via bloodstream or lymph channels, or
through urinary orifices; urinary tract obstruction by
stone or other urinary bladder abnormality due to
autonomic neuropathy or after catheterization of the
urethra; residual urine in the urinary bladder is a
medium favoring the growth of organisms (23,24).
Acute urinary tract infection is more common in
diabetic women due to the short urethra readily
accessible to organisms from the vagina and rectum
(23,24).
Bladder has been confirmed to possess an inherent
resistance factor, which is necessary for the
maintenance of uninfected state. The frequency of
bladder emptying helps reduce the bacterial factor in
the bladder and is thought to be essential.
Pyelonephritits usually develops secondarily to lower
urinary tract infection, as shown in Table 1 (25). The
most common agents of UTI in diabetic patients are:
- bacteria
- viruses
- fungi
- tuberculosis
Table 1.
Bacterial infections
Fungal infections
Viral infections
Cystitis
Invasive candidiasis *
Cystitis *
Emphysematous
cystitis *
Renal actinomycosis
Pyelonephritis
Pyelonephritis
Vulvovaginal
candidiasis *
Emphysematous
pyelonephritis*
Papillary necrosis
Perinephritic abscess
* close association with diabetes mellitus
Bacteria
Many different microorganisms can infect urinary
tract in diabetic patients, but the most common agents
of bacteria are gram-negative bacilli; Escherichia coli
causes approximately 90% of acute UTI in diabetic
patients without urologic abnormality or calculi. The
other bacilli involved, i.e. Protease, Klebsiella,
Enterobacter, Serratia and Pseudomonas, account for a
lower proportion of uncomplicated infections (26,27).
These organisms are of increasing importance in
recurrent infection of UTI in diabetic patients,
especially after urologic manipulation such as the
placement of catheters for urine retention due to
autonomic neuropathy and urinary bladder
vasculopathy (25,28,29).
The Protease species by virtue of urea production and
Klebsiella species through production of extracellular
slime and polysaccharides predispose to stone
formation (23,29).
Gram-positive cocci play a less important role in UTI
in diabetic patients. Enterococci and Staphylococcus
aureus can cause bacteremic infection of the kidneys
and consequential renal damage. A saprophytic
novobiocin resistant coagulase negative staphlycoccus
has been recognized as an important cause of acute
symptomatic UTI in a young diabetic female (30).
Chlamydia trachomatis appears to be an important
etiologic agent (23).
Viruses
Viruses can cause pyelonephritits in animals and may
increase the susceptibility of the kidneys to infection
with coliform bacteria (23). In humans, viruses are
most commonly found in urine samples without
evidence of acute UTI in diabetic patients, although
some adenoviruses have been implicated as a cause of
cystitis (31).
Fungi
Fungal infection of UTI in diabetic patients is
important but clinically insignificant. Diabetic patients
with urinary tract Torulopsis globrata infection account
for 20%-90% of all infections with this Candida species.
Torulopsis globrata can cause cystitis, pyelonephritis,
renal or perirenal abscess, fungus ball, and a picture of
gram-negative sepsis (33,34). The presence of candida
at a rate of >10000 colonies/m2 urine indicates
candidal infection, but diabetic patients with
indwelling catheters may have higher counts with no
significant evidence of infection by candida, which may
lead to chronic infection with severe renal damage
(29).
Tuberculosis
Tuberculosis is a serious comorbidity in diabetics, in
whom it is more extensive and 3-16 times more
common than in nondiabetics (24). The association of
UTI and tuberculosis is very common in diabetic
patients due to the impaired body defense
87
mechanisms. Not all diabetic patients with microscopic
hematuria should be automatically regarded as
glomerulonephritis as a diabetic complication before
renal tuberculosis has been excluded (23,35).
It may still be advisable to recommend periodic
tuberculin test in diabetic patients. Those who have
never been tested should receive underdose medical
supervision, prophylactic treatment with isoniazid
pyridoxine for a year due to the greater severity of
tuberculosis in diabetic patients (24).
BACTERIURIA
Bacteriuria is the presence of bacteria in the urine.
The concept of significant bacteriuria was introduced
to distinguish between the bacteria that are actually
multiplying in the urine from the contaminants in
collecting vessels, periurethral tissues and urethra, and
gross fecal or vaginal contamination (36). The criterion
for significant bacteriuria is the presence of 100,000
colonies/ml urine or more, and is an excellent
operational definition. When the clean void method is
used for sample collection, it is based on the finding of
contaminants at a number ranging from 1000 to
100,000 colonies/ml urine. The organisms found in
urinary tract infection grow well in urine and may reach
from more than 100,000 colonies/ml to 10 million
colonies/ml, however, with proper instructions,
cleaning and refrigeration of urine samples, and with
prompt processing of the culture it is usually not
difficult to obtain reliable results and make an accurate
diagnosis of UTI in diabetic patients with
asymptomatic infection (37).
The examination and screening procedure for
bacteria generally require 2 or 3 consecutive positive
specimens, indicating that the patient has a persistent
significant bacteriuria. A bacterial count lower than
100,000 colonies/ml urine may occur in patients with
bacteriuria, but when the clean void method is used
these counts become valid when shown to be
persistent and when the same species of bacteria are
present. The bacterial count becomes higher when the
urine is allowed to incubate for long time, so the first
morning specimen is preferred but not essential. Low
or borderline counts may be due to diabetes in properly
hydrated patients.
Aseptic methods of urine collection from renal pelvis
or urethra, or by bladder puncture in specific situations
permit the diagnosis of significant bacteriuria in
diabetic patients regardless of the organism count
(38,39).
88
Differentiation between the upper and lower urinary
tract infection is performed by studying the antibodies
coating the bacteria in urine specimens. Urine
specimens are tested for the presence of antibody
coated bacteria by direct immunofluorescence with the
use of fluorescein-conjugated horse antiserum to
human globulin (40).
Gram-positive bacteria are antibody coated to a lesser
extent than gram-negative urinary pathogens, because
of the less frequent renal parenchymal invasion or
lower immunogenicity. The bacteria infecting the
kidneys are only coated by antibody and this infection
does not occur in the lower urinary tract segment (41).
Causes of bacterial persistence (42)
- infected renal calculi
- chronic bacterial prostatitis
- unilateral infected reflux nephropathy
- medullary sponge kidneys
- infected necrotic papillae
- infected urachal cysts
- vesicovaginal fistulae
- vescointestinal fistulae
- ectopic ureter draining dysplastic renal segment
- foreign body
Several controlled studies have examined the
prevalence of bacteriuria in diabetic compared with
nondiabetic subjects (43,44). Bacteriuria predisposes
to cystitis and upper UTI (8). Of 12 studies, 75%
reported a higher (2- to 4-fold) prevalence of
bacteriuria in diabetic subjects. Nearly all these studies
chose cases among diabetic subjects attending
outpatient clinics. Since clinic attendance is probably
related to the underlying disease severity, it is possible
that these studies included diabetic subjects with a
more severe disease and comorbid conditions, who
were therefore at a higher risk of bacteriuria.
One study that sampled diabetic and control
nondiabetic subjects from a defined community still
found a higher prevalence of bacteriuria associated with
diabetes (5). Thus, these data support the concept of
the higher prevalence of bacteriuria in diabetic
subjects. There are no data on the incidence of
bacteriuria associated with diabetes, as presented in
Table 2.
Studies on the association between diabetes and
bacteriuria 1989 – 1991
Table 2.
Outcome
Outcome
Description of subjects
prevalence (%)
Definition
Diabetic
Adjustment
Nondiabetic
Diabetic Nondiabetic Factors
Asymptomatic Outpatients;
Outpatients;
F:18.0
F:6.0
Bacteriuria
F:54, M:37
F:337, M:102
M:5.0
M:4.0
Bacteriuria
Outpatients;
Casualty dept; F:19.8
F:18.7
Similar age and
F:91, M:59
F:91, M:59
M:1.7
sex distribution
M:3.3
None
Several uncontrolled case series demonstrate a low
prevalence of bacteriuria in children with IDDM. In
two studies, the prevalence of bacteriuria was 1.6%2.0% among 266 girls aged 6-15 years attending a
diabetes summer camp (45), and 1% in 304 girls and 0
in 337 boys attending regular follow-up appointments
at a diabetic clinic (46). Although these female rates
may exceed those of nondiabetic children, the data
suggest that bacteriuria is quite uncommon in girls and
boys with IDDM.
Longer duration of diabetes but not of glucose control
is associated with higher bacteriuria prevalence. A
statistically significantly longer diabetes duration was
recorded in diabetic subjects with than in those
without bacteriuria (47).
The prevalence of bacteriuria increased 1.9-fold for
every 10 years of diabetes duration (5). However, there
was no association between longterm glucose control as
reflected by the glycosylated hemoglobin level, and the
prevalence of bacteriuria (5,47).
and, with two exceptions (34,35), is two- to threefold
that in nondiabetic females. As for males, only Bahl et
al. (1970) (53) recorded a difference.
From a restrospective hospital-based survey of
infection, MacFarlane et al. (1986) (54) have concluded
that diabetes mellitus increases the risk of bacteremia.
Escherichia coli was the most common pathogen and the
principal source was urinary tract. In a similar
prospective study in diabetic individuals, Leibovici et
al. (1991) (55) confirmed the importance of urinary
tract as a source for bacteremia. In this study, Klebsiella
spp. were more frequent isolates in diabetic (25%)
than in nondiabetic individuals (12%) when urinary
tract was the source of infection. In an uncontrolled
study, Forland et al. (1977) (40) investigated the
localization of infection in the renal tract of diabetic
subjects and found 19% of women and 2% of men to
have UTI. Using antibody-coated bacteria, 43% of a
selected group of 42 patients had evidence of renal
parenchymal diseases, which rose to nearly 80% over a
week period in the absence of treatment. Out of the
total of 333 patients, 22 had recurrent infections
following treatment, i.e. 14 cases of reinfection
(recurrence with a different organism or serotype) and
8 cases of recurrent infection with the same organism
or serotype.
Table 3. Summary of available studies on urinary tract
infection in diabetic subjects
Study
Diabetic
Nondiabetic
Total Bacteriuric Total
(%)
Bacteriuric
(%)
Women
CLINICAL PICTURE OF KIDNEY
INFECTIONS IN DIABETES
Urinary tract infection
Autopsy studies suggest that urinary tract infection is
more common in diabetes mellitus (48,49). Such
studies, which primarily examined upper renal tract
disease are, by virtue of case selection, open to bias. In
one study, 6.8% of diabetic subjects had pyelonephritis,
as compared to 1.6% of normal subjects (48). Even this
difference may be an overstimate as some other
conditions, e.g., ischemia, renal papillary necrosis, and
reflux nephropathy, may mimic pyelonephritis (50).
Controlled clinical studies suggest that bacteriuria is
more common in diabetic females but not in males.
Table 3, adapted from Wheat (6), summarizes these
studies. The proportion of females with diabetes and
bacteriuria is consistent in these studies (9%-20%)
Kass HE (1957) /43/
54
337
6
20
91
19
19
114
8
11
100
3
81
18
81
4
44
16
27
15
341
9
100
5
2
O’Sullivan DJ, Fitzgerald
MG, Meynell MJ et al.
(1961) /51/
91
Vjelsgaard (1966a) /61/
128
Bahl AL, Chugh RN,
Sharma KB (1970) /53/
97
Ooci BS, Chen B, Yu M.
(1974) /66/
Williams DN, King H,
Harris DM (1975) /52/
Schmitt JK, Fawcett CJ,
Gullickson G (1986) /47/
18
Men
O’Sullivan et al. (1961)
59
3
59
Vjelsgaard (1966a)
141
1
146
2
Bahl et al. (1970)
97
11
100
3
Ooi et al. (1974)
67
8
67
3
Harkonen et al. (1977)
37
5
102
4
Schmitt et al. (1986)
411
1
100
0
89
Prior instrumentation may increase the risk of
bacteriuria in diabetic and nondiabetic patients (56),
this paper suggesting doubling of the risk. All UTI may
be asymptomatic (45), however, a significant proportion of these may lead to a more severe infection
(6).
antibiotics is recommended for pyelonephritis (64). A
cephalosporin, given i.v. for 48 hours, is suitable. Where
relapse occurs, a six-week treatment is advocated (65).
The factors that predispose diabetic individuals to
infection are ill-understood. Many factors may combine
to increase the frequency of infection, including
autonomic neuropathy leading to delayed bladder
emptying (57), diabetic nephropathy, and impaired
host defense mechanisms (58). The prevalence of UTI
in diabetic nephropathy is reported to be 13% (59).
Sawers et al. (60) found bacteriuria to be more common
in diabetic women with autonomic neuropathy, but
surprisingly they found no evidence for increased
residual urine volume after micturition. The duration
of diabetes (61) and the presence of complications (47)
have been related to increased bacteriuria in diabetes.
Asymptomatic bacteriuria is common in diabetic
women, particularly in the older age group, with
Escherichia coli being the most common isolate.
Untreated infections may lead to renal parenchymal
infection which may impair renal function (66).
Accordingly, all UTIs should be treated regardless of
symptoms. In case of recurrent UTI, imaging of the
renal tract should be done to exclude underlying
pathology (e.g., renal papillary necrosis); it may
indicate the need of prolonged antibiotic therapy.
Treatment for at least 6 weeks may be required.
In alloxan-induced diabetic rats, Obana et al. (62)
found greater adherence of Serratia marcescens to
bladder epithelial cells than in control animals.
Contrary to what one might expect, poor glycemic
control does not contribute to the frequency of UTI.
Schmitt et al. (47) found no relationship between
HbA1c and bacteriuria in 752 NIDDM patients. In
another study, the mean HbA1c was 11.5% in
bacteriuric and 11.4% in non-bacteriuric diabetic
women (58).
Pathogens
Escherichia coli is the most common organism isolated.
Schmitt et al. (47) found it to account for 75% of
isolates from female diabetics. There is no significant
difference in bacterial isolates between diabetic and
control subjects, although bacterial counts are generally
higher in the former (6). Group B streptococcus is said
to be more common in diabetic subjects with
pyelonephritis (59).
Therapy
Positive urine cultures (i.e. >10 organisms/ml) should
be treated in diabetic individuals even if
asymptomatic. The choice of antibiotic should reflect
the sensitivity of the organism, and treatment does not
differ between diabetic and nondiabetic individuals,
although some authors prefer longer duration of
treatment in diabetic patients (63). A 14-day course of
90
Conclusion
INFECTIVE TUBULOINTERSTITIAL
NEPHRITIS
This poorly recognized cause of infection and
occasionally of acute renal failure in unobstructed
kidneys was initially documented in two series by
Richet and Mayaud (1978) in 30 cases (67), and by
Baker et al. (1979) in five cases (68). The larger series
included histologic evidence for an acute infection with
microabscesses. The condition was reviewed by Cattell
(1992) (69). From the published series it appears that
diabetes is a risk factor for acute renal failure in this
group (69,70), along with analgesic abuse, nonsteroidal drug use, sickle-cell disease (or trait), and
possibly alcoholism.
ACUTE RENAL FAILURE
Although definite data are lacking, there is an
impression that diabetic patients may be more likely
than nondiabetics to suffer renal failure as a result of
UTI and subsequent pyelonephritis and septicemia.
Apart from infective tubulointerstitial nephritis
described above, this may result from the failure of
autoregulation of renal blood flow with falls in blood
pressure in patients with even moderate degrees of
diabetic nephropathy (71).
RENAL TRACT CANDIDIASIS
Diabetes appears to be more common in individuals
with fungal UTI. It is present in up to 90% of patients
with Candida glabrata (formerly Torulopsis glabrata)
(72,73). Candida albicans was cultured from the urine of
35% of patients with diabetes mellitus as compared to
only 9% of controls without glycosuria (74). Candida
gives rise to a wide variety of infections of the renal
tract. Although many are asymptomatic, they may lead
to cystitis, pyelonephritis, renal abscesses, and fungal
ball formation (72,75).
It has been concluded that a significant proportion of
candidal infection in the urinary tract remains to be
fully established (76). A value of >10000 organisms/ml
is currently taken to reflect infection (77,78). Infection
may originate from the genital region, gastrointestional
tract, or by hematogenous spread.
There is no agreement as to whether all infections in
diabetic patients should be treated. Indeed, control of
blood sugar may be all that is required to clear the
urine. Symptomatic individuals and those with
candiduria accompanied by pyuria should receive
antifungal therapy. Patients with indwelling catheters
that cannot be removed may be treated with
intermittent instillations of amphotericin B. Where oral
therapy is adequate, flucytosine is advocated (79).
Alternatively, fluconazole may be used (80). Most
lower UTIs clear within two to three weeks (76). Renal
candidiasis often requries a more aggressive approach,
including irrigation of the renal pelvis with antifungal
drugs, oral or parenteral therapy, and sometimes
surgical intervention. Amphotericin B alone or in
combination with flucytosine is the treatment of choice
(81).
PERINEPHRIC ABSCESS
This type of abscess generally develops in renal
parenchyma, spreading therefrom to the surrounding
fascia. Diabetes is present in 30%-40% of cases (82-84).
Bilateral abscesses are rare, occurring in only 2% in one
series (83). A single case of association with type 1
diabetes mellitus has been described (85). The
infection may arise from an ascending UTI or by
hematogenous spread. The onset is frequently
insidious with symptoms often present for more than
five days. These include flank discomfort, nausea,
vomiting, dysuria, and occasionally hematuria. Two
thirds of patients have flank tenderness or a mass (86).
Laboratory investigations may show an elevated white
cell count or erythrocyte sedimentation rate (ESR) but
are not helpful in diagnosis. If the abscess, blood and
urine cultures are examined, then more than 90% show
positive culture (84).
Intravenous urogram (IVU) is often abnormal, but
ultrasound (US) or computed tomography (CT) scan
offer the best hope for a positive diagnosis. Sometimes
a delayed and repeat scanning is necessary before the
abscess becomes apparent. US or CT scan-guided
aspiration of the abscess may then follow. As in other
renal tract diseases, gram-negative organisms are most
commonly isolated. Anaerobes and gram-positive cocci,
including Staphylococcus aureus, are also frequently
found.
Treatment includes intravenous antibiotics and
control of hyperglycemia if present. Surgery includes
percutaneous drainage of the abscess, or nephrectomy.
Relief of obstruction caused by renal calculi may be
required. The mortality associated with this condition
is now less than 20% (59). Early diagnosis with the
increasing use of isotope scans and direct imaging
techniques should help reduce this figure further, but
increased awareness of the diagnosis by a nonspecialist
is required.
RENAL PAPILLARY NECROSIS
The pathogenesis of this condition is poorly
understood. Infarction of the renal papilla is most likely
involved, with infection probably as a contributory
factor. Autopsy studies indicate that renal papillary
necrosis (RPN) is more common in diabetic subjects
(48,87). Of 859 diabetic patients autopsied in the first
series, 29 (3.4%) and 16 of 307 (5.2%) in the second
study showed papillary or pyramidal necrosis. The
prevalence in cases of pyelonephritis was much higher,
reaching 25% (87,88). The prevalence of RPN in
nondiabetic subjects was 0.07% in these two studies.
The prevalence of RPN based on autopsy studies may
be an underestimate. A prospective study of 76 IDDM
individuals showed a prevalence of 23.7% (89). Given
that the upper limit of creatinine in the individuals in
this study was 200 µmol/l, even this may be an
underestimate.
The relationship between RPN and diabetes can be
traced back to Turner (1888) (90). However, Froboese
(1937) (91) and Gunther (1937) (92) are to be given
credit for having firmly established the link with
diabetes mellitus. In their combined series of 20
subjects, 17 (85%) had diabetes mellitus. Drawing
extensively on the German literature, Mandel (1952)
(93) identified a total of 160 cases of RPN prior to
1950. Of these, 96 (60%) were diabetic. More recent
estimates suggest that the proportion may be nearer to
30%, with obstructive uropathy accounting for the
remainder.
91
Clinical presentation
The presentation of RPN may be acute or chronic. The
former may be fulminant with flank pain, fever and
septicemia. It is generally unilateral. Papillae may
slough, leading to renal colic. The affected kidney may
be enlarged (94). The chronic indolent form is more
commonly observed. Here changes are often bilateral.
Unilateral papillary necrosis suggests the presence of
renal artery stenosis or atrophy associated with
previous ureteric obstruction. The changes in the
kidney may be patchy with the papillae exhibiting
differing degrees of necrosis.
RPN is most usually seen in the 6th and 7th decades of
life (93), women being more often affected than men
(3:1) (95). Microscopic hematuria is a common finding,
occurring in 44% of diabetic subjects with RPN (89). A
previous history of UTI was found in 68% of cases (89).
Renal insufficiency develops in 15% (96). The
diagnosis should be suspected in a subject with UTI
who responds poorly to antibiotics, or develops
unexplained renal failure (95).
Diagnosis and treatment
The diagnosis of RPN depends on the demonstration
of papillary/caliceal abnormalities without focal loss of
renal tissue (94). Intravenous urography (IVU) is the
most sensitive investigation for RPN but it is not
frequently used today because of the adverse effect of
contrast media on renal function in diabetic subjects.
Contrast studies were observed to contribute to
worsening of renal function in 50% of diabetic subjects
with pre-existing renal impairment (97). However, a
more recent assessment in IDDM individuals with
creatinine values below 200 µmol/l using newer
nonionic contrast agents (Isopaque and Omnipaque)
did not demonstrate any adverse effect (89).
Clinically apparent RPN is now relatively rare (98).
The reasons for this are unclear, but early identification
and treatment of UTI, together with a reduced
frequency of IVU examinations may contribute to both
real and apperant decline. Improved metabolic control
cannot be discounted.
Treatment includes aggressive antibiotic therapy when
infection is demonstrated. Relief of obstruction may
also be required. The prognosis for this condition is not
well defined. Patients may have well-preserved renal
function despite extensive papillary damage (99). In
others, progression to renal failure may be inexorable,
92
although this may be due to the underlying
parenchymal disease (e.g., diabetic glomerulosclerosis)
rather than renal papillary necrosis.
EMPHYSEMATOUS RENAL TRACT
DISEASE
Introduction
The presence of gas in the renal tract is relatively
uncommon but shows strong association with diabetes
mellitus. Pneumaturia was first described as early as
1671 (cited in Taussig, 1907) (100), but this and
subsequent observations often failed to specify the
origin of gas, which may arise in three ways:
1) prior instrumentation,
2) vesicocolic or vesicovaginal fistula, and
3) spontaneous gas formation in the bladder.
Raciborski (1860) (101) is credited for the first
description of spontaneous gas formation. An earlier
much quoted case described by Brierre de Bosmont
(cited in Kelly and MacCallum, 1898) (102) is open to
doubt.
The link with diabetes mellitus was recognized early
by Guiard (1883) (103) who described four cases of
pneumaturia in association with glycosuria. The first
substantive literature review by Kelly and MacCallum
(1898) (102) reports on 9 of 16 cases of pneumaturia to
have glycosuria. The validity of some of these cases is
questioned by Turman and Rutherford (1971) and
Zabbo et al. (1985) (104,105).
The classification of emphysematous renal tract
disease (ERTD) presents a problem. That of Turman
and Rutherford (1971) (104) is most logical and
comprehensive (Table 3). However, some of these
(e.g., emphysematous ureteritis) may not exist as
distinct entities, whilst two or more, such as
emphysematous pyelonephritis and perirenal gas may
occur in combination. It is proposed to concentrate on
the three conditions most commonly seen, i.e.
emphysematous pyelonephritis with perirenal gas,
emphysematous pyelitis, and emphysematous cystitis.
All early descriptions of pneumaturia where a fistula
was excluded probably referred to emphysematous
cystitis, as emphysematous pyelonephritis rarely gives
rise to this symptom.
The pathogenesis of ERTD is incompletely
understood. Early theories (106) that the gas, usually
CO, although N, H, O and CH (methane) are also
present, is a product of glucose fermantation, still hold
today (107,108). Obstruction, and perhaps diabetic
microangiopathy, may facilitate the development of
infection. Why occasional cases are seen in nondiabetic
individuals is not known. Impaired vascular supply may
be important. Schainuck et al. (1968) (109) have
proposed that necrotic tissue may act as a substrate for
gas-forming organisms. Subramanyam et al. (1980)
(110) have described a case of emphysematous
pyelonephritis following traumatic renal infarction and
tissue necrosis.
Table 4. Classification of emphysematous renal tract
disease
Collecting system
Outside of
renal tract
Tissue
Kidney
–
Emphysematous
pyelonephritis
Perirenal gas
Pelvis
Intrapelvis gas
Emphysematous
pyelitis
–
Ureter
Intraureteral gas
Emphysematous
ureteritis
Periurethral gas
Bladder
Intracystic gas
Emphysematous
cystitis
Pericystic gas
Emphysematous pyelonephritis
It is defined as the presence of gas in renal
parenchyma and is often associated with perirenal gas.
It is a severe life-threatening necrotizing infection with
a mortality in excess of 60%. No substantive series of
this condition exists, although there are some literature
reviews (111-113).
Clinical features
Ninety percent of cases of emphysematous
pyelonephritis are associated with diabetes mellitus
(113), although no breakdown of the type of diabetes is
given. The mean age reported is 54 (range 19-81) years,
and women are affected twice as often as men. In
contrast to earlier findings that the left kidney was
more commoly affected (112,114), a more recent
survey (113) found no difference. Bilateral
involvement in association with diabetes has been
described in rare cases (105,115,116), and in several
cases in transplanted patients (117-119).
The clinical presentation is often suggestive of severe
acute pyelonephritis, but it may also have an indolent
course over several months. In 43 cases the average
duration of symptoms was 21 days, ranging from less
than a day to eight months (112). Nausea, vomiting
(40%) and abdominal pain (55%) are common
symptoms. Fever is seen in 80% (113). A palpable mass
is rare as in crepitus, although abdominal tenderness is
common. Pneumaturia is not found unless there is
coincidental emphysematous cystitis.
Laboratory investigations
Neutrophil leukocytosis is observed in the majority of
cases. Pyuria is found in 96% (113). Pre-existing renal
function was abnormal in 82% of 36 subjects (112).
Microbiologic investigation shows Escherichia coli to be
the most common causative organism. In one series,
68% of cases were due to this organism and 9% due to
Klebsiella (120). Multiple organisms were found in 14%.
Other organisms are rare and many are reported as
single cases. Candida albicans (105), Candida tropicalis
(121), cryptococcus (116), and anaerobic streptococcus
(43) have been recorded. Clostridium spp. has not been
described (112). Pathologic examination of the tissue
will often reveal an acute inflammation of the
interstitium with multiple micro- and macroabscesses.
Diagnosis
Renal tract emphysema is a radiologic diagnosis as the
symptoms and signs are a little different from other
renal infections. The diagnosis should be suspected in
any diabetic patient with nausea, vomiting and
abdominal pain, particularly where antibiotic therapy
fails to improve an ’acute pyelonephritis’ in three to
four days. Plain abdominal x-ray or IVU will reveal gas
in 50%-80% of cases (112,113). Contrast studies should
be used judiciously in diabetic subjects with impaired
renal function. Langston and Pfister (1970) (122)
describe radiologic features of emphysematous
pyelonephritis and highlight three patterns. An initial
mottling with gas in the renal parenchyma is followed
by the development of a crescent of gas surrounding
the parenchyma. Finally, extravasation of gas occurs
through Gerota’s fascia into the retroperitoneal space.
Such x-ray features are, however, seen in relatively few
cases. A simplified classification is suggested by
Michaeli et al. (112):
stage 1: gas in the renal parenchyma or perirenal tissue
stage 2: gas in the kidney and surrounding tissues
stage 3: extension of gas through Gerota’s fascia
Where there is some doubt, or where delineation is
important, the patient should have a CT scan.
93
Therapy and prognosis
The prognosis for emphysematous pyelonephritis
depends on the mode of therapy and the extent of
infection. The highest mortality, 80%, is seen in
individuals where the infection extends into the
perirenal space and who receive medical treatment
alone (123,124). Mortality rates of 60% are recorded
when infection is confined to the renal parenchyma and
is treated with antibiotics plus local drainage. A
combination of fluid replacement, intravenous
antibiotics and nephrectomy may reduce the mortality
rate to 20%. Comparison of these data should allow for
improved diagnostic techniques and resuscitation, but
it is evident that there has been little change in
mortality.
Emphysematous pyelitis
In this condition, gas is limited to the collecting
system. Evanoff et al. (113) found the condition to be
more common in women (3:1), with an overall mean
age of 51 (range less than one to 79) years. In contrast
to emphysematous pyelonephritis, only 59% of subjects
had diabetes, presumably due to a higher proportion of
patients with obstruction in this group (64% vs. 37%).
For reasons that are not clear the left kidney was
affected more commonly than the right one (53% vs.
36%), and bilateral gas was rarely observed (125).
The total number of cases is not documented. The
symptoms are similar to those in emphysematous
pyelonephritis. Escherichia coli is again the most
common organism. Radiology reveals gas in the
collecting system. US or IVU may demonstrate an
obstruction. Gas occurs rarely in the bladder in
association with emphysematous pyelitis (124).
Histopathologic studies in this condition show acute
inflammation with submucosal hemorrhage of the renal
pelvis and ureter. Renal parenchyma may show an acute
interstitial reaction (127).
Treatment for this condition includes antibiotic
therapy with relief of obstruction where necessary. The
reported mortality is 18% (113).
emphysematosa (52 cases). Bailey, who considered
them to be the same entity, added another 19 cases to
the literature. Diabetes mellitus was recorded in 29/46
and 13/19 cases, or in total 51% of the combined series.
Why the proportion of diabetes should be so low in the
second group is not clear. Women were more common
(2:1) in Bailey’s series. Mean age was 54 (range 25-83)
years. The mean duration of diabetes was 14 (0-35)
years.
Escherichia coli is the most common infecting
organism. Enterobacter is also relatively common, and
there are occasional reports of Proteus species,
Staphylococcus aureus, Streptococcus species, and yeasts
(128). Gross hematuria is a common finding. Eleven of
19 cases had gas in the lumen and in the bladder wall,
two in the wall, and six in the lumen alone.
Autopsy studies in two patients showed acute and
chronic submucosal inflammation with vesicles and
ulcerated areas in the mucosa. X-rays of the bladder are
characteristic with a narrow radiolucent line of gas
bubbles outlining the bladder wall that may resemble
cobblestones (94). IVU or US may demonstrate an
obstruction (e.g., prostatic hypertrophy).
In contrast to the conditions discussed above, the
prognosis for emphysematous cystitis is good and no
death as a direct consequence of the infection was seen
in Bailey’s series.
Conclusion
ERTD, although uncommon, may be associated with
a high mortality. Many cases are associated with
diabetes mellitus. A high index of suspicion,
appropriate radiologic assessment, and early surgical
intervention offer the best hope for cure in
emphysematous pyelonephritis. Emphysematous
pyelitis and cystitis are more benign and are treated
with antibiotics alone or a combination of antibiotic
and relief.
Emphysematous cystitis
METHODS TO DETECT KIDNEY
INFECTIONS IN DIABETES
The early descriptions of pneumaturia in the absence
of fistulous communication or instrumentation must
have referred to this condition. Prior to the review of
Bailey (128), gas production was arbitrarily described as
primary pneumaturia (46 cases) or cystitis
Dip slide culture technique
Filter paper method (122,130)
Pipette method (122,130)
Cup method (122,130)
Pad culture method (122,130)
94
Alternative methods for detecting urinary
leukocytes and bacteria
There are a number of rapid techniques for detecting
urinary leukocytes and bacteria. Most are highly
specific but not particularly sensitive. For these
reasons, the tests are recommended primarily for
screening purposes in settings where the anticipated
prevalence of infection is low and falsely positive
results are undesirable (129).
* leukocyte esterase test
* nitrite test (Greiss test)
* automated systems for detection of bacteria
Bacteriologic criteria for diagnosis of UTI (8)
• 108/ml from two consecutive midstream urine
(MSU) specimens
• 108/ml from one MSU uncentrifuged specimen,
leukocyte count 10/mm
• 108/ml from one MSU specimen with symptoms of
cystitis or acute pyelonephritis
• 107/ml from one MSU specimen and any number
from suprapubic aspiration
• pure growth of the same bacteria unserotyped
Table 5. Radiologic guide to urinary tract infection
Patient group
IVP - Intravenous
pyelography
Micturition
cystogram
Children 4 years
After one infection
After one infection
Recurrent infection
Children 4 years
Recurrent infection
Renal scar or ureter
on IVU
Women with
bacteriuria
Recurrence soon after
short courses of Abs
IVU suggestive of
urinary obstruction
Women with
cystitis
Onset in middle age
or unassociated with
severe cystitis; rarely
helpful in young adult
Rarely helpful
Women with
acute
pyelonephritis
After one infection
Rarely helpful
Men diabetic
After 1-2 episodes of
infection whether
overt or symptomatic
IVU of shows
abnormality
Elderly men and
women
Consider early of
symptoms of
recurrent onset
Rarely helpful
High risk
patients
High obstruction
urolithiasis, persistent
pyuria
Rarely helpful
Symptomatic women (131):
>102 coliform organisms/ml urine plus pyuria
or
>105 of any pathogenic organism/ml urine
or
any growth of a pathogenic organism from urine
obtained by suprapupic aspiration
above the minimal inhibitory concentration of the
pathogen (133). There are some agents that do not
achieve an adequate serum level to destroy gramnegative bacteria, so these agents must not be included
in the treatment of UTI. Therefore, urine culture and
sensitivity should be done in each patient (133,138).
Symptomatic men (131):
>103 pathogenic organisms/ml urine
Diabetes control during UTI
Asymptomatic patients (132,142):
>105 pathogenic organisms/ml urine in two consecutive samples
MANAGEMENT OF RENAL INFECTIONS
IN DIABETIC PATIENTS
The goals of treatment for urinary tract infections in
diabetic patients are to relieve acute symptoms and to
treat or prevent sepsis, and ultimately to prevent or
retard the progression of renal parenchymal damage
(35). The general principle of antibiosis is to deliver an
adequate concentration of an effective antimicrobial
agent to the site of infection. It depends upon whether
the pathogen is sensitive or the agent can penetrate or
be delivered to the site of infection at a concentration
¾ Outpatients (134,135):
• frequent glycemic control (at 4-hour intervals)
• higher insulin dose for correction of
hyperglycemia
• sufficient liquid intake
• consultation with a diabetologist/nephrologist
• urgent hospitalization in case of: vomiting
development of hyper- or hypoglycemia
¾ Inpatients (134,135):
• frequent glycemic control (at 2-hour intervals)
• higher insulin dose for correction of
hyperglycemia
- intravenous rapid acting insulin when
required
• starting insulin therapy in patients on oral
therapy
95
• sufficient liquid intake
- intravenous liquid intake when
required
¾ There are many important principles for the
management of UTI infection in diabetic
patients:
• quantitative urine cultures should be obtained
to identify the organism before starting the
treatment (136)
• antimicrobial sensitivity testing should be used
to control infection and significant bacteriuria
in diabetic patients (41,137)
• good treatment for factors predisposing to
infection such as neurogenic bladder,
ketoacidosis, indwelling catheter, or any
obstruction (28)
• good control of blood sugar level and careful
treatment of ketoacidosis leads to control of
UTI by switching the patient to regular doses
of plain insulin 3 or 4 times daily if he was on
diabetic diet or oral hypoglycemic agents (28)
• regular insulin dose must be increased by 20%
of total daily requirement as an average initial
dose for supplementary use when there is
glycosuria (138)
• relief of clinical symptoms does not indicate
bacteriologic cure and follow up cultures after
therapy should be obtained (138)
• bacteriuria must be diagnosed and treated
completely to prevent renal damage (139)
• lower UTI responds well to low doses and
short duration therapy; reinfection indicates
lower UTI (139)
• upper UTI needs high doses and longer
treatment; relapse indicates upper UTI (139)
• community acquired infections, especially
initial infection, are nearly always due to
antibiotic resistant strains
There are no antimicrobial agents that are
contraindicated for diabetic patients, however, the
above principles should be followed to improve
antimicrobial therapy in these patients. We must know
the types of infection that frequently occur in diabetic
patients and the strains causing them. Also, the
knowledge of microbial sensitivity will improve the
usefulness of antibiotics in diabetic patients and
reduce the rate of complications (134).
Frequently, diabetics who are most prone to
developing infection have some impairment of renal
function. Renal dysfunction is the most important host
factor for the choice of non-nephrotoxic drugs and
antimicrobials (131). If nephrotoxic drugs are to be
96
used in an emergency, they should be switched to a
drug that is not nephrotoxic as soon as culture results
are available or immediately upon improvement of the
patient’s condition. Follow up testing of renal function
should be repeated during the treatment period. If
renal function becomes worse, the drugs such as
aminoglycosides and cephalosporins should be
discontinued and a combination of nephrotoxic drugs
and non-nephrotoxic drugs such as penicillin and
gentamycin should be introduced (131,138).
Uncomplicated infection by obstruction or many
previous episodes will generally respond to oral therapy
with sulfonamides, cotrimoxazole (trimethoprim +
sulfamethoxazole, ampicillin, nalidixic acid, cephalexin
or nitrofurantoin). Cotrimoxazole and nitrofuration can
be used in recurrent cases. Pseudomonas infections
respond well to carbencillin. A 10-day duration of
treatment for UTI in diabetic patients is enough,
sometimes short courses of high doses of parenteral
therapy such as ampicillin or gentamycin or their
combination or cephlosporin may be required in case of
therapeutic failure or poor patient condition (133,140).
Bacteria should disappear within 24-48 hours even if
pyuria is present.
Highly recurrent infections: They may be managed
by either very close follow up and treatment of each
episode, or by prophylaxis with nitrofurantoin or
cotrimoxazole or nalidixic acid and mandelate salt or
hippuric acid given as a single bed time dose. Some
agents like nitrofurantion and mandelamine,
tetracycline, melthicillin, cloxacillin and hippuric acid
require acid urine to achieve good effect of pH below
5.5, which can be achieved by high protein diet,
ammonium chloride, ascorbic acid, or methionine given
at a dose of 10 g/day (13,140,141).
Table 6. Drug dosage in renal insufficiency
Drug
Dose (mg)
Nitrofurantoin
50
Trimethoprim
100
Norfloxacin
200
Ciprofloxacin
125
Cephalexin
125
(useful if renal insufficiency)
From: Rubin et al., 1992 (142)
If infected urine is alkaline and the organisms may be
Proteus, cotrimoxazole or ampicillin can be tried, as
Proteus is usually resistant to nitrofurantion and
tetracycline. Some other agents require alkaline urine
to achieve good effect and can be made alkaline by
sodium bicarbonate or sodium or potassium citrate,
lactate or acetate. These agents are sulfonamides,
cotrimoxazole, gentamycin, aminoglycosides and
cephalosporins (133,134,138). Other agents are active
in neutral urine, e.g., ampicillin, calistin and
chloramphenicol (133).
Relapse: As relapse is caused by the same species
and specific strain of microorganism as before
treatment, it is more common with drugs that are
effective in urine but not in tissues, e.g., with
nitrofurantoin and low dose of sulfonamides relapse
implies infection of the upper UTI (143). The
treatment should include the use of drugs capable to
achieve high tissue levels, e.g., ampicillin and
gentamycin (13).
Reinfection: Reinfection means that pathogens have
appeared during or after treatment due to organisms
outside the urinary tract, thus indicating lower UTI,
and is treated by continuous prophylactic use of
mandelate salt or hippuric acid at doses of 3-6 g to keep
the urine sterile (143).
¾ Antimicrobials most widely used in UTI:
Ampicillin (133,142,144,145)
Cotrimoxazole (138,141,142,146)
Nitrofurantoin (141,142,147)
Methicillin, amoxicillin, and others (141,142,148)
Cephalosporins (141,142,149)
Gentamicin and tobramicin (141,142,148,149)
Tetracyclines (141,142,149)
Amikacin (141,142,148,149)
Carbencillin (141,142)
Methenamine mandelate and hippuric acid
(141,142,149)
PREVENTION OF UTI AND KIDNEY
INFECTION
Good diabetic control is very essential for the control
and prevention of urinary tract infection because high
hyperglycemia and ketoacidosis may occur, which will
lead to reduction in the host mechanisms of defense
against infection. This in turn will entail recurrent UTI
and bacteriuria (28,151,152).
During infection, a number of humoral substances are
released, which may complicate the treatment of
diabetic patients (153). During infection, there is a
decreased caloric intake, which leads to hypoglycemia
that stimulates pituitary adrenal axis and sympathetic
nervous system to release glucagon and catecholamines. These in turn stimulate hepatic and muscle
glycogenolysis and release glucose to the circulation,
thus leading to hyperglycemia and glycosuria (13,154).
Also, these hormones cause direct inhibition of
pancreatic insulin and increase peripheral insulin
resistance (155).
Hypoglycemia also stimulates adrenal cortex to
release glucocorticoids, which then stimulate
glycosuria. Insulin therapy becomes inadequate and
blood glucose too high, along with excess levels of free
fatty acids in the circulation, so the patient may
develop ketoacidosis and even coma (156). The patient
becomes more susceptible to infection, so good blood
sugar control improves host mechanisms of defense
against infection (151). Any diabetic patient requiring
an indwelling catheter may get bacteria and infection,
so the following advice should be adopted:
1. Careful preselection of criteria for catheterization
(157).
2. Use of aseptic close drainage or antimicrobial
bladder rinse during prolonged catheterization;
the catheter should be removed as soon as it is no
longer needed (157).
3. Intermittent self-catheterization may be of great
benefit in patients with neurogenic bladders.
Each diabetic patient should be taught how to
use dip slide method to monitor his urine for
bacteria frequently as well as to test urine for
sugar acetone (42,157).
After proper use and incubation, the urine should be
clear from bacteria. The presence of black dots
indicates bacteria and the patient should visit the clinic
for proper urine culture and appropriate treatment
(157).
COUNSELING AND EDUCATION
An important role is identified for the diabetes
specialist nurse in instructing diabetic patients and in
briefing the community and practice nurses charged
with their care about the following:
- renal complications
- construction of a data set
- health economic analysis
- research program
RECOMMENDATIONS (25,158)
1. All patients who have had IDDM for more than 1
year and who are above the age of 12 years, and
all patients with NIDDM from the time of
diagnosis should be screened for albuminuria at
least once a year. The monitoring of patients
97
with persistently elevated albumin excretion
rates should be performed as often as clinically
required, along with estimates of glycemic
control, blood pressure, serum lipids and serum
creatinine, and check up for retinopathy,
neuropathy, and coronary and cerebrovascular
disease.
2. Persistent microalbuminuria should be treated by
improved
blood
glucose
control
and
antihypertensive therapy when indicated.
3. Counseling and education of diabetic patients
and briefing of primary health care personnel
should be provided throughout all stages of
diabetic kidney disease.
4. Methods of analysis and population studies
should be reviewed and updated, and the need of
largescale clinical trials should not be overlooked.
THERAPEUTIC GOALS
These must be appropriate to the individual patient
or population. Educational programs have been shown
to reduce the frequency of acute metabolic
complications such as ketoacidosis and hypoglycemia,
thus also reducing hospital admissions (159). Diabetes
education has had some impressive results in reducing
the frequency of certain diabetic complications such as
kidney
infections,
nephropathy,
retinopathy,
neuropathy, foot ulcers, and amputations (160).
CONCLUSIONS (160,161)
Despite great advances in recent decades, diabetic
kidney infections and urinary tract infections remain
quite poorly treated and disabling diseases in many
patients. There is a great need of proper tools for
timely detection of kidney infections in diabetics. This
is because of our inability to extrapolate the results of
basic and clinical research into treatment regimens that
are appropriate and acceptable to the individual
patient. The main challenge for the immediate future
will be to disseminate the message of effective
diabetes programs from the relatively few centers
where these have been implemented at present to as
many patients as possible (162).
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