DIABETES/NEUTROPENIA
From Topics and Advances in Internal Medicine, University of California, San Diego, School of Medicine
| KIDNEY ABNORMALITIES AND THE STAGES OF DIABETES —Roland C. Blantz, MD, Professor
and Head, Division of Nephrology-Hypertension, University of California, San Diego, School of Medicine
|
| Rising prevalence of diabetes: prevalence 3.1% in 1993; with expanded definition of diabetes, prevalence
≈7% today (≈20 million people); most growth in type 2 diabetes; increased longevity contributes to
growth in nephropathy; prevalence of 5-yr survival increased from 35% in 1966 to 75% in 1985; however,
most deaths attributable to increased cardiovascular- or infection-related causes before dialysis
stage
|
| Glycemic control: elevation in hemoglobin A1c (HbA1c ) correlates with abnormalities in kidney function
and increasing retinopathy, nephropathy, neuropathy, and microalbuminuria
|
| Hypertension: related to declining renal function in later stages of diabetes; rate of decline decreases
≈66% when hypertension controlled; World Health Organization found hypertension in—100% of patients
with renal failure; almost 90% of patients with proteinuria; 45% of younger (20-30 yr of age) type 1 diabetic
patients in early stages of disease (no proteinuria); almost 70% of older type 2 patients prior to developing
proteinuria
|
| Stages of diabetes: onset of disease—in type 1 diabetes, glomerular filtration rate (GFR) elevated (≤40%
higher than normal; mostly due to vasodilation and enlargement of kidneys) with normal renal function;
after diagnosis of type 2 diabetes—with good glycemic control, GFR decreases but remains above normal;
stage 2—reached in 5 to 12 yr; overt proteinuria present only during periods of poor glycemic control,
exercise, or certain diagnostic tests; renal function normal; stage 3—after 12 to 20 yr; persistent proteinuria;
stage 4—overt nephropathy; decline in renal function; average time to dialysis worldwide ≈22
to 23 yr; if patients remain below stage 3 >25 yr, “they may be home free”
|
| Questions under investigation: why does GFR increase (hyperfiltration) occur early in diabetes? would
changing this process reduce subsequent deterioration in kidney? why does kidney grow abnormally with
increase in filtration? what is diabetic kidney’s response to variation in salt intake and its relationship to
angiotensin? what is status of renin-angiotensin system in early diabetic kidney? why do angiotensin-converting
enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent progression?
|
| Focus of current research: renal abnormalities in early diabetes; elevated fractional reabsorption of salt
and water in proximal tubules; rapid increase in weight of kidney; GFR and kidney weight directly related
(agents that interrupt ability of kidney to grow also interrupt its ability to hyperfilter); cell growth
and division in proximal tubules related to hyperglycemia and insulin deficiency; leads to overexpression
of sodium-glucose transporters and decrease in sodium delivered to distal tubules where renin regulated
by feedback system, thus increasing GFR; pathogenic process could be interrupted by slowing
kidney growth and tubular reabsorption, eg, by normalizing glucose level; nitric oxide overproduced in
diabetic kidney, and blocking nitric oxide production reduces GFR
|
| Paradoxical response to salt: restricting salt in early diabetes leads to increases in GFR and growth of
kidney; response due to drop in renal vascular resistance (kidney vasodilates on low-salt diet); giving
ARB with low-salt diet further increases GFR, so process not mediated by angiotensin; increasing salt
intake has opposite effect (reabsorption in proximal tubule reduced, limiting GFR and kidney growth); in
early diabetes, proximal tubule ignores regulators that normally maintain reabsorption within constant
range
|
| Therapy with ACE inhibitors and ARBs: clinical trials involve patients at various stages of diabetes;
1993 study of ACE inhibitor captopril conducted in patients with stage 4 diabetes (overt nephropathy)
showed risk for renal failure reduced 48%; study of ARB losartan found similar results in stage 4 diabetes;
2001 study found ARB irbesartan prevented progression to overt proteinuria (stage 3 diabetes);
combination ACE inhibitor and ARB therapy further reduces angiotensin; renin-angiotensin blockade
reduces GFR and extends time to renal failure by 2 to 3 yr in stages 3 and 4; additional finding—
“nondippers” (no drop in nighttime blood pressure) are “hyperfiltering patients” and represent specific
phenotype with low levels of angiotensin; giving glucose (stimulus for renin) increases GFR; no benefit
from ACE inhibition
|
| Concluding comments: speaker unable to recommend when to begin ACE inhibitor or ARB therapy; appears
not much angiotensin produced in first 4 to 5 yr of diabetes; therapy beneficial if hypertension
present; reasons for glycemic control in early diabetes include preventing salt depletion (increases kidney
growth and GFR)
|
| DEALING WITH NEUTROPENIA —Edward D. Ball, MD, Professor of Medicine, and Chief, Division of
Bone Marrow Transplantation, University of California, San Diego, School of Medicine
|
| Neutrophils: most common white blood cell (WBC); do not divide; combat foreign invaders; distributed
throughout blood, marrow, tissues, inflamed tissue, and inflammatory secretions; WBCs come from common
hematopoietic precursor; maturation in bone marrow takes 10 days; half-life in blood 6 to 10 hr
|
| Definition of neutropenia: <1500 polymorphonuclear leukocytes (PML)/µL; pathogenesis—decreased
granulopoiesis (chemotherapy; drugs; bone marrow failure states); accelerated neutrophil destruction (autoimmune
abnormality); increased margination (pseudoneutropenia)
|
| Neutropenia and infection: number of patient-days with infection correlates with degree of neutropenia; infections
increase with time patient remains neutropenic (eg, by 12 wk, 100% of patients have neutrophil
counts <100 PML/µL); speaker institutes precautions at neutrophil counts <500 PML/µL (severe neutropenia)
|
| Causes of neutropenia: drug induced (predictable or idiosyncratic); irradiation; aplastic anemia; onset of
myelodysplastic syndrome; marrow invaded by fibrosis or tumor; autoimmune diseases; viral infection;
congenital neutropenia; cyclic neutropenia (rare); nutritional (vitamin B12 , folate, or copper deficiency,
eg, from gastric bypass); chemotherapy (most common); secondary to marrow infiltration
|
 | Drugs commonly causing neutropenia: consider drug as cause before referring patient to hematologist;
clozapine (can be severe); valproic acid; antithyroid drugs; enalapril; procainamide; antibiotics (trimethoprim-sulfamethoxazole
[Bactrim]; penicillins; cephalosporins)
|
| Primary prevention of infections: low-microbial diet (no fresh fruits or vegetables; fruits within peel allowed);
hand washing; avoidance of crowds; prophylactic antibiotics; cytokine growth factors (primarily
granulocyte colony-stimulating factor [G-CSF])
|
| Work-up of febrile neutropenic patient: blood cultures; urinalysis and culture; Gram’s stain of sputum;
chest x-ray; physical examination; inspect intravenous (IV) line sites
|
| Empiric therapy: monotherapy with ceftazidime or other cephalosporin; add vancomycin if gram-positive
organism likely (indwelling catheter; soft tissue signs of staphylococcal infection); if gram-negative
sepsis suspected, administer gentamicin
|
| Common bacterial infections: gram-positive cocci—coagulase-negative Staphylococcus most common; Enterococcus
; Streptococcus species; gram-negative bacilli—Escherichia coli; Pseudomonas species; Klebsiella;
covered well by ceftazidime
|
| Fungal infection: consider if fever persistent; ≈20% of budget at speaker’s hospital for antifungal therapy;
survival poor for mold infections; diagnosis—have high index of suspicion; chest x-ray for infiltrates;
computed tomography (CT) for diffuse nodular disease invisible on chest x-ray; difficult to grow mold
from sputum; bronchoscopy
|
| Fungal organisms and therapies: Aspergillus—common, Aspergillus fumigatus most common; (multiple
lesions with halo sign on CT); voriconazole or itraconazole for prophylaxis; zygomycosis
(mucormycosis)—affects immunocompromised patients and diabetics; pulmonary and sinus infections;
treat with liposomal amphotericin B; if disease progressive, try to get posaconazole (investigational); less
common but highly lethal fungi—Scedosporidium apiospermun less invasive and more manageable; Scedosporidium
prolificans can kill patient within 12 hr; others—yeast associated with central venous catheters
|
| Antifungal drugs: many products now available; not known how to sequence and combine drugs; lipid
forms of amphotericin less toxic and as effective as amphotericin B; azoles inhibit ergosterol synthesis
|
| Fluconazole: effective for Candida albicans and most Candida species, but not for Candida glabrata; no activity
against molds
|
| Itraconazole: somewhat more potent; activity against Aspergillus; tends to cause hepatitis (ie, elevates
transaminase and bilirubin; consequently, speaker now favors voriconazole)
|
| Voriconazole: very good activity against Aspergillus; active against Candida; obvious choice for antifungal
prophylaxis; not active against Mucor or Rhizopus; as effective as amphotericin B for invasive fungal
infections
|
| Questions about antifungal therapy: whether to combine antifungals; whether antifungal combinations
antagonistic, additive, or synergistic; does not seem to be antagonism; reasonable to combine voriconazole
or lipid amphotericin with caspofungin (different mechanism of action from voriconazole or amphotericin
B; no activity against Mucor)
|
| Mycafungin (Mycamine): echinocandin; effective against most Candida species; commonly used for prophylaxis;
no activity against Mucor; mycafungin and caspofungin relatively interchangeable
|
| Antifungal prophylaxis: not indicated for routine chemotherapy (duration of neutropenia not long enough
for fungal infections to become problem); indicated for stem cell transplant and acute leukemia patients
(similarly for aplastic anemia or other prolonged neutropenic states)
|
Educational Objectives
| The goal of this program is to educate the listener about kidney disease in relation to the stages of diabetes, and about
neutropenia. After hearing and assimilating this program, the clinician will be better able to:
|
| 1. Explain how the rising prevalence of diabetes contributes to the increase in kidney disease.
|
| 2. Institute control of blood glucose levels and hypertension to prevent progression of diabetes and consequent
decline in renal function.
|
| 3. Identify the stages of diabetes and the corresponding decline in renal function.
|
| 4. Diagnose neutropenia and identify the underlying cause.
|
| 5. Provide prophylaxis for bacterial and fungal infections commonly seen in neutropenic patients.
|
Discussed on This Program
Amphotericin B [Amphocin, Fungizone Intravenous]
Amphotericin B, lipid-based [Abelcet, AmBisome, Amphotec]
Ceftazidime [Ceptaz, Fortaz, Tazicef, Tazidime]
Cyanocobalamin (B12 ) [Big Shot B-12, Crystamine, Crysti 1000, Cyanoject, Cyomin, Nascobal, Rubesol-1000]
Enalapril maleate [Enalaprilat, Vasotec]
Fluconazole [Diflucan]
Folic acid (folacin; pteroylglutamic acid; folate) [Folvite]
Gentamicin sulfate (several trade names)
Itraconazole [Sporanox]
Mycafungin sodium [Mycamine]
Posaconazole [Posoril] (investigational)
Procainamide HCl [Procanbid, Pronestyl, Pronestyl-SR]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [several trade names]
Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Vancomycin [Vancocin, Vancoled]
Voriconazole [Vfend]
Suggested Reading
Blantz RC et al: Are the oxygen costs of kidney function highly regulated? Curr Opin Nephrol Hypertens 13:67,
2004; Blantz RC et al: Role of nitric oxide in inflammatory conditions. Nephron 90:373, 2002; Blantz RC et al:
The complex role of nitric oxide in the regulation of glomerular ultrafiltration. Kidney Int 61:782, 2002; Blantz RC:
Reflections on the past, transitions to the future: the American Society of Nephrology. J Am Soc Nephrol 14:1695,
2003; Dotis J et al: Effects of lipid formulations of amphotericin B on activity of human monocytes against Aspergillus
fumigatus. Antimicrob Agents Chemother 50:868, 2006; Eraly SA et al: Novel aspects of renal organic
anion transporters. Curr Opin Nephrol Hypertens 12:551, 2003; Ozer H et al: 2000 update of recommendations for
the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society
of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18:3558, 2000; Pannaraj PS et al: Advances in
antifungal therapy. Pediatr Infect Dis J 24:921, 2005; Peacock JE et al: Ciprofloxacin plus piperacillin compared
with tobramycin plus piperacillin as empirical therapy in febrile neutropenic patients. A randomized, double-blind
trial. Ann Intern Med 137:77, 2002; Segal BH et al: Current approaches to diagnosis and treatment of invasive aspergillosis.
Am J Respir Crit Care Med 173:707, 2006; Segal BH et al: Immunotherapy for fungal infections. Clin
Infect Dis 42:507, 2006; Smith TJ et al: 2006 update of recommendations for the use of white blood cell growth
factors: an evidence-based clinical practice guideline. J Clin Oncol 24:3187, 2006; Stevens DL et al: Practice
guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 41:1373, 2005; Thomson
SC et al: Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am J Physiol Renal
Physiol 286:F8, 2004; Vallon V et al: Glomerular hyperfiltration and the salt paradox in early [corrected] type
1 diabetes mellitus: a tubulo-centric view. J Am Soc Nephrol 14:530, 2003; Erratum in: J Am Soc Nephrol.Vallon V
et al: Salt-sensitivity of proximal reabsorption alters macula densa salt and explains the paradoxical effect of dietary
salt on glomerular filtration rate in diabetes mellitus. J Am Soc Nephrol 13:1865, 2002; Wade JC et al: NCCN: Fever
and neutropenia. Cancer Control 8:16, 2001; Wade JC et al: Vancomycin does not benefit persistently febrile
neutropenic people with cancer. Cancer Treat Rev 30:119, 2004; Weir MR et al: Blood pressure and cardiovascular
risks: implications of the presence or absence of a nocturnal dip in blood pressure. Curr Opin Nephrol Hypertens
12:57, 2003; Weir MR et al: The clinical utilization of albuminuria as a surrogate measure of cardiovascular disease
burden and risk for events: are we there yet? Curr Opin Nephrol Hypertens 14:39, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the faculty reported nothing to disclose.
Drs. Blantz and Ball were recorded at Topics and Advances in Internal Medicine in San Diego, CA, March 2-8, 2006,
and sponsored by the University of California, San Diego, School of Medicine. The Audio-Digest Foundation thanks
the speakers and the sponsor for their cooperation in the production of this program.
|
