text:
Jürgen E. Scherberich 1
Reinhard Fünfstück 2
Kurt G. Naber 3
1 München Klinik Harlaching; Teaching Hospital of LMU Munich and KfN Munich; Germany
2 Internal medicine, Sophien-und Hufeland-Klinikum Weimar/Gesundheitszentrum Weimar, Jena, Germany
3 Technical University of Munich, Straubing, Germany
Epidemiological studies show an increasing number of patients worldwide suffering from chronic kidney diseases (CKD), which are associated with a risk for progression to end-stage kidney disease (ESKD). CKD patients stage 2–5, patients with regular chronic dialysis treatment (hemo- or peritoneal dialysis), and patients suffering from kidney allograft dysfunction are at high risk to develop infections, e.g. urinary tract infections (UTI) and/or sepsis (urosepsis). These groups show metabolic disturbance, chronic inflammation, and impaired immunocompetence. Escherichia coli is still the most common pathogen in UTI. A wide variety of other pathogens may be involved in UTI. Urological interventions, catheterization, as well as repeated courses of antibiotics contribute to an increased challenge of antimicrobial resistance. The diagnosis of UTI in CKD is based on standard clinical and laboratory criteria. Pyuria (≥10 leucocytes/µl) is more often observed in patients with oligoanuria and low bacterial colony counts. The treatment strategies for this population are based on the same principles as in patients with normal renal function. However, drugs cleared by the kidney or by dialysis membranes need dose adjustment. Antimicrobials with potential systemic toxicity and nephrotoxicity should be administered with caution.
Chronic kidney disease (CKD) is a very common problem especially in elderly patients. Approximately 11% of the US adult population (20 million people from 1988 to 1994) are suffering from CKD at various stages. The CKD stages are defined in Table 1. The prevalence of early CKD stages (CKD stages 1 to 4; 10.8%) is more than 100 times higher than the prevalence of kidney failure (CKD stage 5; 0.1%) [1]. The prevalence of ESKD in Germany is listed in Table 2 [2].
Table 1: Staging system for chronic kidney disease, K/DOQI, KDIGO [1]
GFR/ml per minute per 1.73 m2
Kidney damage with normal or increased GFR
Mild decrease in GFR
Moderate decrease in GFR
Severe decrease in GFR
End-stage kidney disease (ESKD)
<15,
or dialysis (=stage Vd)
Table 2: Incidence rates of various kidney diseases with potential progression to end stage kidney disease; results of the German Dialysis Registry for the years 2000 and 2004 [2]
Incidence rate (%)
Year 20001
Diabetes mellitus type 2 and type 1
Renal vascular diseases (arterial hypertension vascular calcification, others)
Glomerular nephropathies
Tubulointerstitial nephritis3
Polycystic kidneys (adult type autosomal dominant)
Kidney disease caused by systemic diseases (vasculitis, pararheumatic diseases)
Hereditary disease
Unknown causes
Unclassified renal disease
1Based on 5641 patients, 2based on 6390 patients, 3includes pyelonephritis
The typical sign of kidney injury is loss of renal function, as indicated by a reduced estimated glomerular filtration rate (eGFR). CKD is defined as a clinical condition where eGFR persists abnormally (≤60 ml/min/1.73 m2) for more than 3 months, often combined with proteinuria. Beside morphological alterations and tissue remodelling within the kidney (interstitial fibrosis, microvascular rarification and calcification, nephron loss), various other serious alterations are involved in these processes, e.g. alterations of calcium-phosphate and vitamin-D metabolism (hyperparathyreoidism, vascular calcification), electrolyte and water imbalance (impaired volume shift, hyperkalemia), metabolic acidosis, microinflammation, dysregulation and instability of blood pressure (arterial hypertension and hypotension) or endothelial dysfunction, increased risk of cardiovascular events, mediasclerosis, stroke, maldigestion, sarkopenia, frailty, and immunodysfunction.
Clinical, biochemical, and immunological risk factors that contribute to UTI in chronic renal failure:
Congenital abnormalities of kidney and urinary tract (CAKUT)
Other malformations
Urological (urogenital) surgery & instrumenting and devices
Frequent admission to hospital, e.g. ICU
Presence of indwelling catheters
Nephrostoma
Impaired glucose tolerance, Diabetes mellitus
Chronic prostatitis; recto-ano-genital syndrome
Nephrolithiasis, renal tubular acidosis, nephrocalcinosis
Urolithiasis (ureter, bladder, calculi)
Autosomal dominant polycystic kidney disease (ADPKD)
Diverticulae of the bladder, urethra
Inborn metabolic syndromes (cystinosis, oxalosis, cystinuria)
Medullary cystic kidney disease
Reflux (pelvirenal, ureter, vesicoureteral)
Female pelvic floor dysfunction
Neurological disorders, bladder incontinence, fecal incontinence
Senile brain syndrome; low fluid intake, malnutrition
Comorbidities: lymphoma, myloma, cancer, etc.
Urethral stenoses; endoluminal valves
Cancer of the urothel
Interstitial nephritis
Phagocytosis capacity, recruitment of immunocompetent cells
Hypoproteinaemia, anaemia, uremia
Innate immunity (monocytes, lymphocytes, dendritic cells)
Immunoglobulin subclass deficiency
Blood group B, AB, and non-secretor of blood group component
Complement activity, -activation (aquired, genetic alterations)
Mutations of UMOD gene (low to very low biosynthesis of Uromodulin)
RANTES polymorphism (deficiency)
Immunosuppressive and cytotoxic drugs
Drugs/toxins altering the urothelial mucosal barrier
Disturbed microbioma of the intestine and the urinary tract
Parenteral iron supplementation (peaking levels), iron overload
Sodium-glucose-cotransporter-2 inhibitors (SGLT2 inhibitors)
Only little data exist on how many of these patients are suffering from urinary tract infections (UTI). The incidence of infections associated with CKD is less than 1 per 5,000 people per year [3], [4], [5]. Nevertheless, frequent UTI episodes increase the risk of developing ESKD [5]. In infants and young children, the incidence is higher than in adults, but still moderate at about 1% [6]. Clinical risk factors and comorbidities other than UTI as mentioned above are suspected to be of more relevance for developing ESKD. In CKD patients, a variety of predisposing factors responsible for developing UTI includes gender, age, genetic disposition, diabetes mellitus, obstructive nephropathy, arteriolosclerosis (microvascular calcification, ischaemic nephropathy), nephrolithiasis, cast-nephropathy, immunodeficiency syndromes, and immunosuppressive therapy [3], [7].
2 Material and methods
A literature search was performed in various data bases, e.g. Medline, the Cochrane Database, as well as Embase; and publications of Karger, Elsevier, Klywer, Springer, Thieme, Urban & Fischer, and Dustri were studied. The following keywords were used: urinary tract infection/UTI, renal insufficiency, kidney insufficiency, end-stage renal disease/end-stage kidney disease, diseases of the kidneys, dialysis (hemo-/peritonealdialysis), microbiome, microorganisms of the urinary tract, obstruction, antibiotic treatment, prophylaxis in recurrent UTI, evaluation of renal function, and bacteriuria. Only publications with published abstracts were evaluated.
3 Risks of UTI and comorbidities
Apart from the impaired immune defence associated with CKD, the risk for developing UTI also depends on the underlying kidney disease. High-risk groups are patients suffering from diabetic nephropathy, nephrotic syndrome, and hypoproteinaemia, patients with analgesic nephropathy, autosomal dominant polycystic kidney disease, Randall plaques (suburothelial interstitial Ca/P nanoparticles), and renal stone formers. Among them, one may also find those with congenital errors of the metabolism: cystinosis, oxalosis, chloride channel mutations, Fabry's disease, Dent's disease, Bartter syndromes (e.g. Bartter type V), renal tubular acidosis, idiopathic hypercalciuria, hypocitraturia, familiar hypomagnesiaemia, nephrolithiasis, genetic defects of the calcium-sensing receptor, etc. Obstructive nephropathy associated with an increased risk for UTI may arise from papillary necrosis and/or exfoliation of tissue debris into the tubular lumen, most commonly in ischaemia as well as diabetic and analgesic nephropathy. A variety of primary kidney diseases (e.g. minimal change glomerulonephritis (GN), membranous GN, focal sclerosing glomerulopathy) are treated with immunosuppressive agents. Early diagnosis of UTI may be missed easily in those patients with no or only minor clinical symptoms. In a similar manner, CKD patients suffering from systemic vasculitis, autoimmune disease, and renal allograft dysfunction should be closely monitored for UTI. Typical signs of an infection are often completely missing in these cases.
In patients with mild and moderate CKD (stages of CKD see Table 1), and with an anatomically normal urinary tract, lower UTI (cystitis) can be classified as 'uncomplicated'. However, any severe infection – such as an acute episode of pyelonephritis or an uroseptic syndrome, UTI in patients with ESKD undergoing dialysis, with urinary tract abnormalities, polycystic kidney disease, urolithiasis, or unstable metabolism (diabetes mellitus) – should be classified as 'complicated'. Under these conditions, preexisting chronic renal failure may progress rapidly ('acute to chronic').
4 Pathogenetical aspects
4.1 Uropathogens
There are only few studies that evaluate the uropathogens involved in patients with UTI and renal insufficiency, or in patients undergoing dialysis. Escherichia coli strains still remain the most common infecting organism. In addition, a wide variety of other bacteriae, such as Proteus mirabilis, Pseudomonas aeruginosa, Enterobacter spp., Staphylococci, and Enterococci were detected to cause UTI in these patients [8], [9], [10], [11].
Nosocomial exposure, (semi-)invasive urological interventions, and catheterizations in combination with repeated courses of antimicrobial therapy increase the risk of overgrowth of organisms with augmented antimicrobial resistance. Due to various comorbidities, CKD patients and hemodialysis (HD) patients are at high risk of being admitted to a hospital and to an intensive care unit (ICU) more frequently than non-CKD patients. Because of the immunocompromised status in CKD, problems arise from vascular access complications, chronic blood loss, frequent treatments regarding the extracorporeal circuit, alterations of the intestinal microbiome, etc. All these factors contribute to higher rates of hospitalization. Focusing on patients admitted to the ICU, the incidence of contracting a severe nosocomial infection and of being colonized with multidrug-resistant (MDR) microbes is usually increased. MDR pathogens most frequently include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Acinetobacter spp., Klebsiella spp., Morganella morganii, and E. coli, often resistant also to carbapenemes. Unfortunately, there are no detailed studies characterizing the properties of virulence factors in uropathogens. In selected febrile patients, also rare uropathogens, e.g. Leptospira bacteria, should be excluded [12]. Leptospirosis, as a kidney-prone infection, may involve patients in both acute and chronic infections (acute renal failure, chronic tubulointerstitial nephritis, interstitial fibrosis). The problem of CKD and UTI in CKD patients is also a problem of people living in low-income regions where the incidence of diseases is higher compared to those living in wealthy nations.
Recent research indicates that the urinary tract (UT) is hosting specific and complex bacterial communities, the so-called 'urinary microbiome', regularly present in healthy persons. It is speculated that it might have implications for maintaining urinary health [13]. This suggests that UTI also result from an 'imbalance' in the UT microbiome. Future studies will demonstrate whether or not the urinary microbiome reveals protective or pathogenic properties, and if antibiotic therapy impacts its microbial pattern [14], [15]. The specific role of the microbiome in patients with CKD also needs to be better evaluated and considered [16], [17], [18].
Infections caused by hantaviruses, especially UTI, are rare, but the diseases can be severe. The infection is also described as 'nephropathia epidemica'. Hantaviruses are RNA viruses; after infection, the incubation time is in general 3 weeks, in rarer cases 5 to 60 days [19], [20]. The central phenomena behind the pathogenesis are increased vascular permeability and acute thrombocytopenia. The pathogenesis is likely to be a complex multifactorial process that includes contributions from immune responses, platelet dysfunction, and the deregulation of endothelial cell barrier functions. A genetic predisposition related to HLA type also seems to be important for the severity of the disease [21].The disease is characterized by elevated temperature, shivering fits, and oliguria, as well as functional and morphological kidney alterations. Sometimes, proteinuria and hematuria without bacteriuria are observed. Pathological findings correlate with acute interstitial nephritis combined with deteriorations of tubular structures. As there is no effective treatment or vaccine approved for use in the USA and Europe, public awareness and precautionary measures are the only ways to minimize the risk of hantavirus disease [19], [21].
4.2 Nanobacteria
Another unsolved issue is the urinary presence of ultra-small bacteria, so-called 'nanobacteria'. These are about 200 nm in diameter, exhibit densly packed spirals and few ribosomes; some show hairlike appendages of the cell surface. Hjelle et al. [22] found nanobacteria or their antigens in polycystic kidney disease. Some cyst fluids were also positive for LPS antigens from E. coli, Bacteroides fragilis and/or Chlamydia, and Bartonella henselae.
4.3 Host defence in CKD and ESKD
Numerous data demonstrate that the immunological profile of patients with CKD or ESKD is more or less compromised with regard to their humoral and cellular adaptive and innate immunity [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34].
CKD and HD patients show elevated endotoxin serum levels and a chronic microinflammatory status, mainly due to an increased translocation of bacteria and microbial material from the intestine. In addition, endotoxins from the dialysate fluid may enter the blood compartment and contribute to chronic inflammation and a risk for infectious diseases [32], [35], [36].
Even under immunosuppression, patients with a renal transplant disclose an increase of proinflammatory blood monocytes [33]. In patients who received a renal allograft, the amount of UTI episodes showed an imbalance of all IgG subclasses, where particularly lower serum levels of the IgG4 subclass were predictive [30]. CKD patients reveal a variety of cellular defects, which explains the increased risk for infections [7], [11]. Fibroblast growth factor 23 (FGF23) is elevated in CKD; it disturbs the immune defence by inhibiting chemokine-activated leucocytes to adhere through integrins to endothelia, and blocks the transendothelial migration of neutrophil leucocytes [37]. Elderly CKD patients (eGFR 15–44 ml/min/1.73 qm) show high hospitalization rates due to urogenital infections (+180% compared to non-CKD patients) and urosepsis, complications which are associated with an extremely high (100-fold) mortality in HD patients [38], [39], [40], [41], [42], [43], [44], [45].
The importance of toll-like receptors (TLR) (pattern recognition receptors) and the role of defensins in the pathogenesis of UTI, especially TLR2 and TLR4, and alterations in the expression of TLR in CKD patients were repeatedly confirmed [32], [46], [47]. The chronic inflammatory status of CKD parallels a decrease in the cellular expression of human leukocyte antigen – DR isotype (HLA-DR), TLR2 as well as TLR4, and impairs immune defence. In addition, the activity of the hexose-monophosphate shunt pathway, responsible for maintaining an effective phagocytosis by leukocytes, is disturbed [7], [48]. Phagocytes not only kill and eliminate bacteria, they also produce cytokines and activate other components of the immune system, among them lymphocyte and monocyte proinflammatory CD14+ and CD16++ monocyte subpopulations. Alteration of granulocyte function, impaired migration, chemotaxis, degranulation, and blockade of glucose uptake potentially promote adhesion and colonisation of host target cells, usually followed by invasion after passing the mucosal barrier of the urogenital tract [11]. It is unknown to what extent there may be a shift of virulence of uropathogens in CKD patients, and how these potential alterations are influenced by an imbalance of endogenous defensins [27], [49], [50], [51]. A small subgroup of CKD and HD patients may present congenital abnormalities of the kidney and urinary tract (CAKUT), known to trigger and promote UTI [52].
In selected cases, we identified patients with cancer of the urothel (involving either the bladder, ureter, or pyelon), where symptoms of recurrent episodes of UTI preceeded the final diagnosis of the tumor. Cancer of the urothel is more often detected in CKD and HD patients, especially in those with so-called analgesic nephropathy. Differential diagnosis may include (abacterial) interstitial nephritis, IgG4-related interstitial nephritis, and autosomal tubulointerstitial kidney disease due to mutations of the UMOD gene [53], [54].
Immunological factors contributing to UTI are summarized in Table 3.
Table 3: Immunological factors contributing to UTI in chronic renal failure, following kidney transplantation and in chronic dialysis patients
Disturbances in patients with CKD and ESKD
Cellular immunity
Reduced phagocytosis capacity and chemotactic response
Increased reactive oxygen radicals (ROC), apoptosis +
Decrease in L-selectin (adhesion molecule)
Monocytes
Cell expansion, dysregulation, preactivation (CD16+)
Decreased pleiotropic membrane LPS-receptor CD14
Reduced phagocytic capacity, disturbed TLR expression
Increased proinflammatory subset CD14+CD16++
Increased release of cytokines
Depletion
Lymphopenia; altered synthesis of IgG subclasses, impaired humoral immunity, increased sCD23 (B-cell dysregulation)
Reduced CD4/CD8 ratio; depletion of memory T cells
Impaired activity
Cell-cell cooperation
Impaired CD86-CD28 cross talk (monocytes-T helper cells)
Impaired monocyte HLA-DR expression
Decreased opsonin receptors (CD11b, CR1, RFcy)
Humoral immunity
IgG, IgM, IgA
Usually lower serum levels of IgM, partially of IgG (mostly in uremic children)
IgG subclass deficiency
IgG1, IgG2, IgG4 (IgG4 in transplant patients with UTI)
Secretory immunglobulins (sIgA, sIgM)
Disturbed synthesis and decreased release into urine
Complement soluble (immune) mediators
Low serum levels of C3 in HD patients, especially in malnutrition
Defensins
α-defensins, β-defensins, histatins, cathelicidin LL57 (CAP18 protein),
urinary ribonuclease 7
Uromodulin (THG)
Impaired synthesis by epithelia of the thick ascending limb of Henle
Low urinary and serum levels due to CKD/ESKD
UMOD gene mutations
4.4 Uromodulin (Tamm-Horsfall-Uromucoid) in CKD patients
Uromodulin, a 85–95 kDa glycoprotein, exclusively synthesized by cells of the thick ascending limb of Henle's loop, is the major urinary inhibitor of renal stone formation and acts as a potent antimicrobial kidney-specific defensin [55], [56]. Distinct epitopes of uromodulin filaments act as multivalent ligands for bacterial type-1 pili, associate with uropathogens, mediate microbial aggregation, prevent epithelial adherence, and facilitate bacterial clearance [57]. Uromodulin is not only secreted into urine (approx. 70–100 mg/day) by apical shedding from the luminal plasma-membrane, but is also transferred (as a very stable antigen) into the blood compartment by a contraluminal, basolateral cellular pathway [34]. It is very important to notice that the uromodulin concentration in urine as well as in serum decreases progressively with the stage of CKD [34], [58].
Even at very early stages of CKD, the biosynthesis of uromodulin is significantly altered, and the capacity to neutralize bacterial components is impaired. Study participants with higher uromodulin urine levels (>39 µg/ml) had lower risk for UTI compared to those in the lowest quartile (<17 µg/ml), supporting the common view of a major protective role of uromodulin against uropathogens [59]. Since patients with ESKD and those under long-lasting renal replacement therapy disclose no or only borderline low serum and – in case of residual urine output – very low urine uromodulin, these patients are at higher risk for UTI and urosepsis due to the lack of the defensin. Inheridate progressive kidney diseases, which are related to mutations of the UMOD gene, reveal low to very low uromodulin concentrations even before the decline in eGFR, progressive renal papillary calcification, and urolithiasis, and are at risk to develop UTI and ESKD. Furthermore, low uromodulin levels are associated with a worse metabolic profile, higher prevalence of diabetes mellitus, arterial hypertension, heart failure, and overall mortality [60]. In addition, low serum uromodulin is associated with higher concentrations of various biomarkers of inflammation in the blood such as hsCRP, TNFα, IL18, sICAM-1, MPO, where men had higher IL6 levels compared to women [61].
Selected natural factors which are important for defence and are involved in overcoming UTI are summarized in Table 4.
Table 4: Selected natural (intrinsic) defensins involved to overcome UTI
Cathelicitin (LL37)
Neutrophils, proximal tubule, renal pelvis, ureter
α-defensins (HNP 1-3)
Neutrophils, promyelocytes, azurophil granula
Human α-defensin 5
Neutrophils, uroepithelia, increased urine levels in UTI
Human β-defensin 1, 2
Epithelia of Henle's loop, distal tubule, collecting duct
Ribonuclease 6, 7
Collecting duct, uroepithelia (ureter)
Hepcidin (LEAP1)
Liver, excreted into urine
Uromodulin
Thick ascending limb of Henle's loop, (low urine and serum levels in CKD, ESKD, UMOD gene mutations)
Distal tubule
Lipocalin
5 Diagnostic procedures
The diagnosis of UTI is mainly based on a typical symptomatology and few robust routine laboratory methods: presence of urinary viable bacteria and increased leucocytes (pyuria), or surrogate parameters such as leucocyte esterase and positive nitrite reaction. For patients with CKD, an overview of markers and recommendations for routine and advanced diagnosis of UTI are summarized in Table 5.
Table 5: Recommendations for routine and advanced diagnostics of UTI in patients with CKD
General diagnostics: anamnesis (history), family history, clinical symptoms
General physical examination
Routine diagnostics
Blood/plasma/serum
Red and white blood count: erythrocytes, leukocytes, thrombocytes
Complete differential blood count: creatinine, eGFR, (eGFR-EPI)
(Urea), uric acid
Electrolytes: sodium, potassium, calcium, phosphate
Total protein, serum electrophoresis
Acid-base-balance, pH
Glucose (HbA1c)
Cystatin C
IgG subclasses
Complement C3, C4
β1-defensins
Inflammatory CD14+ CD16+ monocytes
Toll-like receptors (TLR): TLR2, TLR4
Monocyte HLA DR expression
Monocyte chemoattractant protein-1 (MCP1)
Clean catch urine specimen
Suprapubic aspiration (in cases of inconsistent findings)
Dipstick: pH, glucose, leukocytes, erythrocytes, nitrite, total protein, albumin
Microscopy: erythrocytes, leucocytes, casts, tubular cells, bacteria, fungi
Pattern of proteinuria (quant. nephelometry, turbidimetry)
α-1 microglobulin
IgG/g (creatinine)
Kidney-related enzymuria, e.g. β-NAG, APM, GGT, NGAL, DAP-IV etc.
Secretory IgA, IgM (sIgA, sIgM)
Proteomics, metabolomics
TNF-α gene polymorphism
Decoy cells (polyoma v.)
Urine culture
Colony forming units (CFU)/ml
Bacterial species (uropathogens)
Antimicrobial susceptibility, e.g. MALDI-TOF-MS
Blood culture (in case of sepsis)
Urological examinations
Uroflowmetry, residual urine
Physical & chemical analysis of urolithiasis
Urodynamics
Ultrasound (including contrast enhanced ultrasound)
X-ray abdomen w/o CM
C-reactive protein (CRP)
Magnet resonance imaging
The criteria for diagnosing UTI in patients with renal insufficiency are similar to those used in patients with normal renal function. Some clinical characteristics should be addressed. However, in febrile patients, where renal involvement cannot be excluded (pyelitis, pyelonephritis), blood and urine analysis as well as microbiological cultures should be performed first.
In patients with ESKD treated by HD and suspicious for an UTI (elevated CRP), blood cultures can easily be saved from extracorporeal circuit lines with the highest sensitivity and specificity compared to cultures taken by venepuncture [49]. However, in this high-risk group, despite elevated CRP, leucocytosis may not be prominent. It is a diagnostic pitfall that leucocytes of HD patients may just reach upper normal levels of healthy controls or are borderline elevated only.
Some clinical symptoms of UTI may interfere with symptoms associated with kidney-related diseases, e.g. fatigue, muscle/back/joint pain, fever, erythema, loss of appetite, and weight gain. In addition, in patients with cystitis or pyelonephritis, uncharacteristic symptoms of UTI can be misinterpreted as complications of a uremic neuropathy. Furthermore, dysuria, alguria, pollakisuria, nycturia, low-grade proteinuria, and hematuria may also be present in abacterial interstitial cystitis, which might be misinterpreted as UTI, but contradicts antibiotic treatment [53].
Pyuria is defined by a white blood cell count of more than 10 cells/µl and is also of diagnostic power in UTI in CKD and HD patients. However, 31 to 53% of dialysis patients present pyuria, but do not suffer from UTI [62], [63] (evidence: level 3). The urinary leucocyte count is broadly inversely related to the urine volume [62], [63], [64] (evidence: level 2a). This may be due to increased concentrations of a constant number of leucocytes secreted from the urothelial surfaces and the kidney itself. Low urine volume in oligoanuric patients, not uncommon in ESKD and usually present in patients on maintenance hemodialysis, effects a disturbed and abnormal 'concentration' of leucocytes and cell debris.
The increasing prevalence of multiresistant bacteria necessitates a rapid identification of uropathogens including their pattern of antibiotic resistance, e.g. MALDI-TOF-MS identification from blood culture fluid [65].
Diluted urine in polyuric patients with CKD may reduce the bacterial counts and reveal a negative nitrite reaction on the dipstick test, thus presenting misleading data. In patients with symptoms suggestive of UTI, one should not rely on dipstick testing if urinary culture is recommended. Although 'significant' bacteriuria is usually defined as colony forming units (cfu) of ≥105/ml, lower-count bacteriuria (<105 cfu/ml) may also be pathologically relevant, particularly in cases where a single microbe is cultured and leucocytes (granulocytes, lymphocytes) are present in high numbers.
A minor part of CKD patients with transient 'significant' bacteriuria may not suffer from 'true' invasive UTI, whereas others exhibiting lower bacterial counts with pyuria, fever, elevated C-reactive protein, leucocytosis may represent 'active' tissue-invasive bacterial interstitial nephritis [64]. Therefore, to determine the clinical significance of specific levels of bacteriuria in patients with decreased renal function and in patients undergoing dialysis treatment, there should not be an exclusive focus on fixed numbers, but clinical aspects should be considered primarily.
The risk that pathogens cross the mucosal urothelial barrier depends on the host defence mechanisms, which may be altered in patients with renal failure [11].
Apart from bacterial uropathogens, interstitial nephritis may involve nephrotropic viruses mimicking pyelonephritis, but lacking positive urine cultures and mass pyuria. Kidney pathohistology typically reveals granulomatous interstitial nephritis including epithelial necrosis of tubuli, associated with intranuclear inclusions, interstitial inflammation, giant cells, and epithelioid macrophages. Human herpes virus 6 (HHV6) involves tubular epithelial cells of the distal nephron and lymphocytic interstitial infiltrations. Interstitial nephritis due to polyoma virus infection shows positive SV-40 large-T antigen staining of nuclei of infected tubular cells, tubular atrophy, and urinary excretion of so-called 'decoy cells'. In addition, infections with adenovirus (e.g. type 11) are usually accompanied by hemorrhagic cystitis. In all cases, elevated urinary α-1-microglobulin (>15 mg/g creatinine) indicates decreased epithelial reuptake of the biomarker due to tubular epithelial injury.
Patients with inflammatory (autoimmune) kidney diseases (chronic immunosuppression), diabetes mellitus, patients after urological procedures, and patients with indwelling urinary catheter are prone to develop funguria (candiduria), characteristically after inappropriate antibiotic therapy. Asymptomatic funguria may trigger or be caused by serious and potentially life-threatening candiaemia. In cases with 'sterile' pyuria, often associated with microhematuria, and 'negative' urine cultures, dysuria, fever of unknown origin, abdominal pain, and (micro)calcifications of the kidneys also involving the ureters, urogenital tuberculosis should be ruled out. In the potential risk group of migrants, micro/macrohematuria, dysuria, alguria, fever, and abdominal pain appear suspicious for urogenital schistosomiasis (prevalence in Nigeria 26–40%). Praziquantel is the drug of choice; and clinical reports address that in CKD stage 1–5, no dose adaptation is necessary. Furthermore, migrants also have a significant risk of carrying multidrug-resistant organisms (MDRO), including multidrug-resistant Gram-negative organisms (MDRGN) and methicillin-resistant Staphylococcus aureus (MRSA) [66].
Intravenous urography has mainly been superceded by high resolution ultrasound, ultrathin section (spiral) computed tomography (CT), and magnetic resonance imaging (MRI). High-end ultrasound investigation including contrast media is recommended as a first-line diagnostic tool in CKD and HD patients. If modern X-ray contrast media (CM) (nonionic monomers & dimers) are necessary, a study has shown that the incidence of acute kidney injury, dialysis, and death does not differ between the CM group and the control group [67]. On the contrary, conventional i.v. contrast media are relatively contraindicated in patients with progressive decline in kidney function (eGFR), or should be administered under extreme care and supervision [68].
6 Treatment options
Effective treatment of UTI requires a high antimicrobial concentration in urine. This is usually achieved as many antimicrobials are excreted predominantly by glomerular as well as by tubular secretion [69]. Dosing of drugs needs to be adapted to eGFR and plasma halflives of antibiotics, which are usually prolonged in CKD.
6.1 Treatment strategies and dosage adjustment
The treatment strategies of UTI in renal insufficiency are mainly based on the same principals as for patients with normal renal function [70], [71]. UTI should respond rapidly, without recurrence, and no rise of resistant pathogens. Acute and chronic kidney diseases affect glomerular blood flow and filtration, tubular secretion and reabsorption, bioactivation and metabolism of antibiotics. Drug absorption, bioavailability, protein binding, distribution volume, and nonrenal clearance (metabolism) can be altered in CKD especially in hemo- and peritoneal dialysis [72], [73]. Apart from recommendations how dosing of antibiotics should be adapted in CKD and HD patients [74], drug dosing errors increase the risk of side effects and poor outcome [75], [76].
A majority of patients with early CKD show normal or increased urine volumes (KDIGO stage-1 and CKD2). Oliguria is characteristic in patients treated over years by dialysis, where the residual urine volume declines progressively until (oligo-)anuria. In this context, however, oliguria is combined with reduced ability to concentrate urine, which is also seen in polyuric acute renal failure (stage 3,4,5/K/DOQI staging system). Patients on dialysis even with residual urine output will not reach effective concentrations of antibiotics [55]. There are rare reports that in anuric patients, i.v. treatments with antibiotics (cephalosporins, aminoglycosides, carbopenems) of recurrent UTI were successful [77].
The dosage of those drugs that are preferentially cleared by the kidney needs to be adjusted according to the eGFR [74], [78] (Table 6). The calculation of renal function is only valid in a stable situation and with a constant level of endogenous serum filtration marker. Drug dosing calculated on the basis of GFR is replaced by the CKD-EPI eGFR equation (CKD-EPI = chronic kidney diseases epidemiology collaboration).
Table 6: Antimicrobial agents for treatment of UTI: Dosing requirements in patients with chronic renal failure [71], [72]
Dosage adjustment in percentage of usual dosage (based on GFR ml/min/1.73 m2)
*[78], [98], [99]
400 mg i.v.
500 to 750 mg orally every 12 hours
Levofloxacin
250 to 750 mg every 24 hours
500 to 750 mg initial dose, then 250 to 750 mg every 24 hours
500 mg init. dose, then 250 to 500 every 48 hours
Gatifloxacin
400 mg every 24 hours
400 mg initially,
then 200 mg daily
400 mg initially, then 200 mg
250 to 500 every 8 hours
Ampicillin/
Sulbactam
1 to 2 g ampicillin and 0.5 to 1 g Sulbactam every 6 to 8 hours
100% (GFR>30)
(GFR 15 to 29)
Every 24 hours (GFR 5 to 14)
250 to 500 mg every 8 hours
50 to 100%
Cefamandole
0.5 to 1 g every 4 to 8 hours
Every 6 to 8 hours
Every 8 to 12 hours
Cefazolin
0.25 to 2 g every 6 hours
50% every 24 to
Cefotaxime
1 to 2 g every 6 to 12 hours
Every 24 hours or 50%
Trimethoprim
Every 12 hours (GFR>30%);
(GFR 10 to 30%)
Fosfomycin Trometamol [98]
3 g single oral dose
3 g single
Fosfomycin IV [99]
Given its absence of renal and systemic toxicity, the daily dosage of fosfomycin could remain unchanged regardless of the degree of insufficiency.
*Restricted use [82], [83], [84]
Various antimicrobial agents are cleared by the kidney either by glomerular filtration and/or tubular secretion. In CKD, this group of antibiotics requires vigorous dosing adjustment. Nomograms and electronic calculators, easily available on the Internet, are helpful for dose adjustments of antibiotics in patients with CKD and on regular chronic dialysis treatment [74]. An initial loading dose and maintenance dosing are recommended in most routinely used antibiotics [78], [79]. Dialysis therapy requires special attention with regard to dosing and which agents are cleared by the dialysis membrane (Table 7).
Table 7: Dialysance of antimicrobial agents in patients undergoing haemodialysis treatment [79], [74]
Partially cleared
Not cleared
Aminoglycoside
Cotrimoxazole
Methicillin
Teicoplanin
Membrane clearance of drugs depends on the techniques of extracorporal treatment (hemodialysis, hemofiltration, hemodiafiltration) and the intrinsic characteristics of the dialyzer (membrane as high cut off, low cut off membrane, their hydraulic permeability, biocompatibility profile). In a similar manner, treatment modalities in patients on peritoneal dialysis (continuous technique, tidal dialysis, nocturnal peritoneal dialysis) also influence drug levels. Furthermore, the cell viability of the peritoneal membrane governs uptake (i.p. administration of antibiotics) and clearance of i.v. antibiotics, and severely alters in cases with encapsulated peritoneal sclerosis associated with high membrane transport.
6.2 Choice of antibiotics
The antibiotic for treatment should be chosen according to the severity of symptoms, the susceptibility of the causative microorganisms, the level of CKD, and whether or not additional comorbid factors have to be taken into account. Substances with nephrotoxic potential, e.g. aminoglycosides, should be used with great caution. Antibiotics without cumulative effects, and a wide therapeutic range index, should be preferred. Broad-spectrum cephalosporins and fluoroquinolones may be effective and are the drugs of choice in this setting [80], [81], but the potential short- and long-term side effects of chinolones should be noted [82], [83], [84]. Nitrofurantoin and TMP-SMZ should be avoided in renal failure since these drugs are not sufficiently excreted into the urine and toxic serum concentration may lead to severe peripheral neuropathy [11]. Patients with CKD are also susceptible to the nephrotoxic effects of certain drug combinations, e.g. cephalosporins in addition with furosemide or ethacrynic acid [85]. In patients with impaired renal function, polymyxin/colistin should be administered with great caution because of its high potential risk of nephrotoxicity. Both polymyxins – colistin, administered as its inefficient prodrug colistimethate, and polymyxin B, administered as the active form – are cytotoxic to renal tubular cells and are prone to cause nephrotoxicity in vivo because of the renal handling mechanisms that facilitate accumulation of these compounds in these cells [86]. The available data, however, strongly suggest significantly higher rates of acute kidney injury (AKI) in patients treated with colistimethate (CMS) compared to patients treated with polymyxin B. This finding may be due to differences in pharmacokinetics and renal handling mechanisms of colistimethate and formed colistin versus polymyxin B, and consequently the relative amount of polymyxin material delivered to tubular cells. A lower risk of AKI with polymyxin B is one of several potential advantages over CMS. The relative safety and efficacy of the two agents however require closer examination in well-designed clinical studies [86]. If, however, colistin is needed because the pathogens to be treated are resistant to other possible antibiotics, underdosing patients also needs to be avoided [87]. Since a recent publication suggested that current recommendations on the use of colistin in patients with reduced renal function are likely to be inadequate, the dosing guidelines of both the European and American regulatory agencies have recently been updated [88]. In the patients requiring intermittent hemodialysis (HD), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., a total of 4.5 MIU for HD days) [89].
Other antibiotics cause (secondary) elevation of serum creatinine by mechanisms other than direct nephrotoxicity, e.g. trimethoprim inhibits tubular secretion of creatinine [90]. Oxytetracycline has an antianabolic effect in renal failure and should be avoided; doxycycline may be used, e.g. in patients suffering from urethritis. Observations suggest an antianabolic effect caused by oxytetracycline therapy [91]. Other antimicrobials (carbapenems, cephalosporins) are not contradicted in patients with CKD stages 2–5 and in dialysis patients, although dosage adjustments adapted to the level of renal impairment and drug clearance ('dialysance') are mandatory [63], [74].
6.3 Asymptomatic bacteriuria
Asymptomatic bacteriuria, ranging from 27% to 44%, has frequently been reported in CKD patients and HD patients [38], [43], [92], [93]. In patients with progressive renal disease receiving immunosuppressive agents, asymptomatic bacteriuria should probably be treated [94], pp. 898 and 1392; [95], pp. 831-2. Few retrospective studies report on increased rates of renal transplant pyelonephritis and acute rejection episodes in patients with asymptomatic bacteriuria. In CKD and HD patients (with residual urine volume excretion) and diabetes mellitus, where asymptomatic bacteriuria is accompanied by peripheral neuropathy, leucocytosis, and elevated CRP, antibiotic treatment of bacteriuria according to resistogram is recommended. However, stable patients with asymptomatic bacteriuria should not receive antibiotics.
6.4 Duration of antimicrobial therapy
There are no valid published data from randomized trials determining the optimal duration of treatment of UTI in patients with CKD and in dialysis patients. It is customary to treat even uncomplicated cystitis for at least 7 days and to continue for 21 days or more, depending on clinical severity [11], [70]. However, the response to even longer courses of antibiotics in higher dosage may only be transitory. Even if the urinary concentration of the antibiotic is adequate, the underlying infection may not be eradicated, thus leading to a relapse after the end of antimicrobial treatment.
Recurrent UTI presumably occur due to bacterial regrowth from colonies of non-planktonic bacteria residing in a protected biofilm environment. Persistent microbial niches may develop and colonize deeply within damaged renal parenchymal or urothelial tissue. Furthermore, antibiotic therapy may select highly resistant intracellular, ecologically stable bacterial communities living temporarily as commensals, so-called 'small colony variants' (SCV).
Ultimately, the available option is surgical excision of diseased tissues. Nephrectomy is only very occasionally performed in patients with incurable relapsing destructive pyelonephritis and signs of rapidly progressive CKD. Here, the majority of patients shows resistance to any further antimicrobial treatment, and suffers from a malignant form of nephrolithiasis, heavily scarred kidneys, abscess formation, severe congenital obstruction, as well as severe recurrent UTI in polycystic kidney disease.
Importantly, recent studies have confirmed again that any infection irrespective of severity is an independent risk factor for increased adverse events in the CKD population [96].
There is no sufficient evidence that UTI (e.g. cystitis in patients with mild or moderate CKD without urinary tract abnormalities) or asymptomatic bacteriuria generally worsens kidney function (eGFR). Leukocyturia and inflammation markers are important signs of UTI. Recurrent episodes of UTI increase the risk of ESKD in CKD patients. Any severe infection, such as acute episodes of pyelonephritis, recurrent UTI, urosepsis, or any UTI in symptomatic patients with ESKD and on dialysis with comorbidities should be adequately treated with antibiotics according to the recommendations of 'antimicrobial stewardship' in order to lower the rates of bacterial resistance. Unfortunately, no prospective clinical trials are available to assess the optimal management of UTI in patients with CKD stage 4–5 and in dialysis populations, respectively.
AKI: acute kidney injury
CAKUT: congenital abnormalities of the kidney and urinary tract
CKD: chronic kidney disease
CKD-EPI: chronic kidney diseases epidemiology collaboration
CM: contrast medium
CMS: colistimethate
CT: computed tomography
eGFR: estimated glomerular filtration rate
eGFR-EPI: estimated glomerular filtration rate – epidemiology collaboration
ESKD: end-stage kidney disease
FGF23: fibroblast growth factor 23
GN: glomerulopathy, glomerulonephritis
HD: hemodialysis
HHV6: human herpes virus 6
HLA-DR: human leukocyte antigen – DR isotype
ICU: intensive care unit
IgG: immune globulin G
KDIGO: Kidney Disease: Improving Global Outcomes (organization)
MDR: multidrug-resistant microbes
MRSA: methicillin-resistant Staphylococcus aureus
MRI: magnetic resonance imaging
PCR: protein chain reaction
PPI-Inhibitor: proton secretion inhibitor
SCV: small colony variants
SLE: systemic lupus erythematosus
TLR: toll-like receptor
UT: urinary tract
UTI: urinary tract infection
VRE: vancomycin-resistant enterococci
This chapter was first published in GMS Infectious Diseases [97].
JS declares that he has no competing interests.
RF reports consulting fees within the last two years (2019, 2020) from Novartis Pharma GmbH and Boehringer.
KN reports personal consulting fees within the last two years (2019, 2020) from Adamed, Biomerieux, Bionorica, Eumedica, Hermes, Immunotek, Janssen, Klosterfrau, Medice, OM Pharma.
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© Scherberich JE et al.


Do you know that Singapore proposed to Finland 3 years ago? - The Hieno!
Yeahh– there had been a wedding proposal in 2013, but Finland hasn't replied yet!
*frowns* Suspicious Singaporeans. Back in 2013, I'd always wondered why the Singaporean PR guys made this video. Definitely the idea of "Finland" didn't drop from the sky, and back in 2013 Singaporeans weren't very into Northern Lights yet.
So how on earth did the SG PR guys get knowledge of "Finland"?
It's only recently at the Finnish embassy that we discovered that a Finnish gentleman (his name is Antti) worked in the same office as the two Singaporean guys. And 2013 was when the 6.9 million population for white paper was announced by our SG ministers. I could totally imagine the conversation the Singaporean PR folks had with Antti which inspired this video. LOL.
You know, last year was SG50, Singapore's 50th year of independence. Next year would be FI100, Finland's 100th year of independence.
As someone who had been involved in SG50, and know many, many other passionate Singaporeans who were heavily involved, I can't help but reflect on the process of nation-building for both countries.
Singapore's nation-building initiatives have largely been top-down, whereas Finland's nation-building initiatives so far have been bottom-up. This has led for some to comment that Singapore's national identity is more constructed than real.
Yet, if we were to think closely about it, all national identities are but constructs. There are many, many things people in this construct "Singapore" can learn from people in this construct "Finland", and vice versa.
But could it also be that, because of concerted efforts to "construct" this national identity, we receive something real and tangible as well?
Both countries didn't get to where they are today, by chance. The past generations fought for the land, built the infrastructure for this generation, next generation, and the next next generations. And given the Brussels terrorist attacks yesterday, let's not take safety in Singapore and Finland for granted.
On a sidenote, I wonder if we can ever push for a Finland x Singapore fashion runway locally, during Finland's 100 year anniversary celebrations! 😀 That would be an initiative that would excite the masses and the black collar in both countries. Maybe such a runway can be organised…! ^^ This would be the best way to charm and win the heart of the FI/SG masses–And kick-start future FI-ASEAN events!!
And to end off before I go to zzzzz (hehe, today is my partial rest day), I can't help but emphasise the need for Finns and Singaporeans to represent their countries well on a global stage.
Insist/persist on putting your countries on the map. I think this is vital for young countries, in particular.
As for me, my homes are both Finland and Singapore.
Why more Finns should learn business and why more Singaporeans should learn vision. From each other.
As Finland's credit rating was lowered last week to AA+ I think Finland should say yes now to Singapore's marriage proposal. I like your idea of kicking of the FI-Asean events next year in Singapore. This is what I have already briefly discussed with Anna Ratala/Finnish Business Council in Singapore. And it would be great if Finland got at least engaged with Singapore in 2017 as this would create free media and buzz! I hope WW is actively involved in these plans and execution.


text:
Missouri Archaeological Society
Articles of Incorporation and Bylaws
The Missouri Archaeological Society's Articles of Incorporation and Bylaws as they stand as of January 2008.
1. The name of the corporation is: Missouri Archaeological Society, Inc.
2. The period of duration of the corporation is: perpetual.
3. The address of its initial Registered Office in the State of Missouri is: 1815 University Avenue in the city of Columbia, County of Boone, and the name of its initial Registered Agent at said address is Jesse E. Wrench.
4. The first Board of Directors shall be seven in number, their names and addresses being as follows:
Jesse E. Wrench, 1815 University, Columbia, Missouri;
Henry W. Hamilton, 787 East Eastwood, Marshall, Missouri;
J. Allen Eichenberger, Hannibal National Bank, Hannibal, Missouri; Leonard W. Blake, 5014 Westminister Place, St. Louis, Missouri;
Walter M. Davis, 1265 North Grant, Springfield, Missouri;
Carl H. Chapman, 129 Edgewood, Columbia, Missouri;
O. D. Evans, 320 Market St., St. Louis, Missouri
[The above four articles have not been amended since initial incorporation; articles 3 and 4 cannot be amended.]
[The following articles 5 through 7 are complete revisions, and articles 8 through 11 are additions approved by the Missouri Archaeological Society at its annual meeting, 9 April 1983.]
5. The corporation is organized, and shall exist exclusively for the following scientific, educational, and charitable purposes:
(a) To unite, in pursuit of the Society's purposes, those interested in the archaeology and in the early peoples of Missouri;
(b) To promote a scientific approach to archaeology;
(c) To promote and foster cooperation among professional archaeologists, amateur archaeologists and others interested in archaeology;
(d) To promote the scientific study, investigation, and reinterpretation of (1) prehistoric and historic remains and sites in Missouri in order to develop a better understanding of the cultures and lifeways of the early peoples of the area, and (2) the associations and relationships of these early peoples with each other and with those of other areas;
(e) To provide for the dissemination, through publications and other means, of knowledge and research in archaeology and related disciplines;
(f) To provide for the recording, preservation, and display of remains and sites of early peoples of the area covered by the present state of Missouri, and for the scientific and educational use of such information and material;
(g) To promote a constructive and supportive public attitude toward these remains and sites and toward the scientific approach to archaeology;
(h) To do all things and perform all acts as may be necessary or convenient in order to carry out such purposes and to have such powers as are provided by Section 355.090, Missouri Revised Statutes 1953, and all amendments thereto, but shall not carry on any activities not permitted to be carried on (1) by a corporation exempt under federal income tax under Sec. 501 (c) (3) of the Internal Revenue Code of 1954 (or the corresponding provision of any future United States Revenue Law) or (2) by a corporation, contributions to which are deductible under Sec. 170 (c) (2) of the Internal Revenue Code of 1954 (or the corresponding provision of any future United State Internal Revenue Law);
(i) To make contributions, upon decision of the Board of Directors, to organizations that qualify as exempt organizations under Section 501 (c) (3) of the Internal Revenue Code of 1954 (or the corresponding provision of any future United States Revenue Law).
(j) To recognize that artifact surface collecting and reporting has potential importance when performed in a manner consistent with the purposes and policies of the Society, specific guidelines, and Archaeological Survey of Missouri site recording procedures.
6. The control and management of the corporation shall be vested in a Board of Directors which shall consist of such number of persons, not less than 3, as may be provided for in the Bylaws of the corporation.
7. The corporation shall have members, and either one or more classes of members, the designation of which class or classes and the qualification and rights of the members of each class shall be set forth in the Bylaws of the corporation. An institutional class shall not be entitled to vote at any meeting of members of the corporation. Institutional class is defined as any association, business or non-profit corporation, partnership, trust, or syndicate.
8. Officers of the corporation shall consist of a president, one or more vice presidents, a secretary, a treasurer and such other offices as may be authorized by the Bylaws of the corporation, each of whom shall be elected or appointed for such term, not exceeding 3 years, as may be prescribed in the Bylaws of the corporation. If the Bylaws so provide, any 2 or more offices may be held by the same person, except the offices of president and secretary shall not be held by the same person.
9. No part of the net earnings of the corporation shall inure to the benefit of, or be distributed to, its members, trustees, officers, or other private persons, except that the corporation shall be authorized and empowered to pay reasonable compensation for services rendered and to make payments and distributions in furtherance of the purposes set forth in Article 5 above.
10. No substantial part of the activities of the corporation shall be the carrying on of propaganda or otherwise attempting to influence legislation, and the corporation shall not participate in or intervene in (including the publishing or distribution of statements) any political campaign on behalf of any candidate for public office.
11. In the event of dissolution of the corporation, the Board of Directors shall, after paying or making provision for the payment of all of the liabilities of the corporation, dispose of all of the assets of the corporation exclusively for the purposes of the corporation in such manner, or to such organizations organized and operated exclusively for charitable, educational, or scientific purposes, as shall at the time qualify as an exempt organization or organizations under Sec. 501 (c) (3) of the Internal Revenue Code 1954 (or the corresponding provision of any future Unites States Internal Revenue Law), as the Board of Directors may determine. Any such assets not so disposed of shall be disposed of by the Circuit Court of Boone County, Missouri, exclusively for such purposes or to such organization or organizations, which are organized and operated exclusively for such purposes, as said Court shall determine.
ARTICLE I—Name, Registered Office, and Registered Agent
1. The name of the corporation is Missouri Archaeological Society, Inc., a not-for-profit corporation authorized under Chapter 355, Missouri Revised Statutes 1953 and amendments thereto.
2. The corporation's registered office is 901 S. National Ave., Missouri State University, Springfield, Missouri 65897, and the name of its registered agent at said address is Neal H. Lopinot.
3. The registered office and registered agent may be changed from time to time by resolution of the Board of Directors.
ARTICLE II—Powers
1. The corporation shall have all the rights and powers set forth in Section 355.090 Missouri Revised Statutes 1953, and all amendments thereto and such other rights and powers set forth in Chapter 355, Missouri Revised Statutes 1953 and all amendments thereto, which are not inconsistent with the corporation's Articles of Incorporation and Bylaws.
ARTICLE III—Amendment of Articles of Incorporation
1. Amendments to the Articles of Incorporation shall be made by members of the corporation entitled to vote, in the following manner:
(a) The Board of Directors shall first adopt a resolution setting forth the proposed amendment and directing that it be submitted to a vote at any annual or special meeting of members entitled to vote thereon. Written notice setting forth the proposed amendment or a summary of changes to be effected thereby, shall be given to each member entitled to vote at such a meeting within the time and in the manner provided in these Bylaws for the giving of notice of meetings to members. Voting thereon may be either in person or by proxy, and same shall be deemed adopted upon receiving at least two-thirds of the votes entitled to be cast by members present in person or by proxy at such meeting, or
(b) Amendments may alternatively be made at anytime if the Board of Directors shall first adopt a resolution setting forth the proposed amendment and directing that it be submitted in writing to each member entitled to vote thereon. The proposed amendment shall be adopted upon obtaining the consent in writing of two-thirds of all members entitled to vote with respect thereto.
2. Any number of amendments may be submitted and voted upon at any one meeting, or alternatively consented to in one writing.
ARTICLE IV—Amendment of Bylaws
1. Amendments to the Bylaws shall be made by members of the corporation entitled to vote in the following manner:
(a) The Board of Directors shall first adopt a resolution setting forth the proposed amendment and directing that it be submitted to a vote at any annual or special meeting of the members entitled to vote thereon. Written notice setting forth the proposed amendment or a summary of changes to be effected thereby, shall be given to each member entitled to vote at such a meeting within the time and in the manner provided in these Bylaws for the giving of notice of meetings to members. Voting thereon may be either in person or by proxy, and same shall be deemed adopted upon receiving a simple majority of the votes entitled to be cast by members present in person or by proxy at such meeting,
or
(b) Amendments may alternatively be made at anytime if the Board of Directors shall first adopt a resolution setting forth the proposed amendment and directing that it be submitted in writing to each member entitled to vote thereon. The proposed amendment shall be adopted upon obtaining the consent in writing of a simple majority of all members voting with respect thereto.
2. Any number of amendments may be submitted and voted upon at any one meeting, are alternatively consented to in one writing.
3. Amendments changing the address of the registered office of the corporation and the name of the registered agent at such address, may be made from time to time by resolution of the Board of Directors, without any action on the part of the membership.
ARTICLE V—Membership
1. Membership in the corporation is open to any person or institution on payment of the membership fee set out herein for the class of membership desired by the applicant, or may be conferred without fee to "honorary members" by the Board of Directors.
2. Annual membership fees are as follows:
Student $15.00
Active $30.00
Household $35.00
Institutional $40.00
Supporting $50.00
Patron $90.00
Life $850.00
All members shall receive all regular corporate publications during the membership year and such special publications as may be authorized by the Board of Directors with one exception: student members are entitled to receive quarterly publications.
3. All members, with the exception of institutional and honorary members, shall have the right to vote on all matters properly before the membership, and each such voting member is entitled to vote on each separate matter or proposal.
4. No member of the corporation shall be individually or personally liable for the debts, liabilities, or obligations of the corporation.
5. No member of the corporation shall use the name of the Missouri Archaeological Society or any chapter name of the Missouri Archaeological Society in order to promote buying, selling, or trading of artifacts.
6. Any membership can be revoked and terminated by the Board of Directors for good cause, in the opinion of the Board. Any member against whom revocation proceedings are pending is entitled to reasonable notice and an opportunity to be heard.
ARTICLE VI—Meetings of Members
1. The corporation shall hold an annual meeting each year on such date and at such place and time as the Board of Directors may annually determine. Written notice of the annual meeting shall be mailed to each member not less than 15 nor more than 40 days prior to the date of each annual meeting. Such notice shall be mailed and shall be deemed effective upon deposit of same in the United States mail addressed to each member whose name and address appears on the corporate records.
2. Special meetings of the membership may be called at any time by the president or the Board of Directors. Written notice of any special meeting shall include the specific purposes of such special meeting and shall be given in accordance with the procedure herein above set forth for giving notice of an annual meeting.
3. Not less than 25 members holding voting memberships shall constitute a quorum to transact business at any annual or special meeting of the membership of the corporation and a majority vote of any quorum is required to carry any issue before the membership, unless otherwise specifically required in these Bylaws or the Articles of Incorporation.
ARTICLE VII—Proxy Voting
1. In lieu of voting in person at any membership meeting, a member may vote by written proxy signed by himself and dated authorizing another member to cast his vote. He may designate the manner in which his authorized proxy shall cast his vote or he may grant complete discretion to his proxy. The member or members authorized to vote the proxy must be present in person at the meeting in order for the vote to be counted. No proxy shall be valid after 3 months from date of execution. Proxies may be revoked in writing signed by the member at any time prior to the call of the meeting to order and shall be revoked by personal attendance of the member. Attendance and voting by proxy is herein deemed equivalent to attendance and voting in person.
ARTICLE VIII—Board of Directors
1. The control and management of the corporation shall be vested in the Board of Directors.
2. The Board of Directors shall consist of the 13 principal officers of the corporation, namely, the president, eight vice presidents, the secretary, the treasurer, the chair of the Board of Trustees, and the chair of the Committee on the Preservation of Sites. All but the vice presidents shall be elected or appointed annually for a one-year term and until his successor is duly elected, or appointed, and qualifies. Each of the eight vice presidents shall be elected to serve three-year terms, with either two or three vice presidents being elected or re-elected each year, depending on how many terms expire at that time. There is no limit on the number of terms a board member can serve.
3. At each annual meeting the voting membership of the corporation shall elect the president, vice presidents as defined in (2) above, secretary, and treasurer, each of whom shall, by virtue of his office, be one of his office, be one of the members of the Board of Directors.
4. At the first meeting of said elected members of the Board of Directors held following the annual meeting of the membership of the corporation, the elected Board of Directors shall appoint a chair of the Board of Trustees from the membership of the Board of Trustees and shall also appoint a Chairman of the Committee on Preservation of Sites, each of whom shall, by virtue of his office, be members of the Board of Directors.
5. If during his term the position of any officer/member of the Board of Directors except a vice president becomes vacant from any cause, the remaining members of the Board of Directors may appoint a successor to fill the unexpired term of such officer/member until his successor is elected or appointed, and qualifies. In the case of a vice president, the appointee will serve until the next annual meeting. At that time, the voting membership shall elect a person to serve any remaining portion of that particular term.
6. All members of the Board of Directors, elected or appointed, shall hold a voting membership in the corporation.
7. No members of the Board of Directors shall be individually or personally liable for the debts, liabilities, or obligations of the corporation.
8. The Board of Directors shall hold such meetings, regular or special, as it may determine necessary or required. Special meetings may be called by the president or by a majority of the Board of Directors. Regular meetings may be established by resolutions of the Board from time to time adopted. At least one meeting shall be held annually, at the same place and following the election of the Board of Directors at the annual meetings of the membership of the corporation.
9. The time and place of any regular meeting established by the resolution of the Board of Directors shall be noted by each member without further notice; notice of the time and place of any special meeting shall be given each member personally, by mail or by telephone at least two days before the meeting; notice of the annual meeting shall be deemed given when the required notice to all the members of the corporation of the annual meeting is given. Notice of the purposes of any annual or regular meeting of the Board of Directors shall not be required, but notice, oral or written, of the general purposes of a special meeting shall be given to each member of the Board at the time of giving notice of the meeting.
10. By resolution of the Board of Directors from time to time adopted, other offices may be created to serve at the pleasure of the Board of Directors.
11. The Board of Directors may appoint a president pro-tem from among the members of the Board of Directors. The president pro-tem shall serve at the pleasure of the board of Directors and shall preside at all meetings of the Board of Directors in the absence of the president.
12. A majority of the members of the Board of Directors shall constitute a quorum to do business at any meeting of the Board of Directors, and a majority vote of those present shall be required to carry an issue, unless otherwise specifically provided in these Bylaws. Each member of the Board of Directors is entitled to one vote on all matters properly before the Board of Directors. At a non-quorum board meeting, at the discretion of the president, issues before the Board can be voted on by using mail ballots.
ARTICLE IX—Officers
1. All officers of the corporation, elected or appointed, shall hold voting memberships in the corporation and each shall hold office until his successor is duly elected, or appointed, and qualifies.
2. Any two or more offices may be held by the same person, except the offices of president and secretary shall not be held by the same person.
3. Elected officers of the corporations shall consist of a president, eight vice presidents, a secretary, and a treasurer, all of whom shall be elected annually by the membership for a one-year term at the annual meeting of the membership of the corporation, and each of whom by virtue of his office shall be one of the members of the Board of Directors.
4. Other officers of the corporation shall be: (a) The chair of the Board of Trustees, who shall be appointed by the elected members of the Board of Directors from the elected members of the Board of Trustees, in the manner, at the time, and for the term specified by these Bylaws, and (b) The chair of the Committee on the Preservations of Sites, who shall be appointed by the elected members of the Board of Directors from the Committee on the Preservation of Sites, in the manner, at the time, and for the term specified in these Bylaws.
5. The president with the approval of the Board of Directors may appoint a president(s) emeritus of the corporation. Each person so appointed shall hold the honorarium at the pleasure of the Board of Directors. President(s) emeritus shall be ex-officio member(s) of the Board of Directors without voting privileges, unless the honoree is also a corporate officer/member of the Board of Directors and thereby entitled to vote.
6. No officer of the corporation shall be individually or personally liable for the debts, liabilities, or obligations of the corporation.
7. The president shall be the principal officer of the corporation and the presiding officer of all meetings of the Board of Directors, unless in his absence the president pro-tem presides. He shall be elected by the membership at the annual meeting of member in the manner, at the time, and for the term specified in these Bylaws. The president by virtue of his office shall be a voting member of the Board of Directors.
8. The eight vice presidents shall be successive to the president and equal in authority among themselves. Each vice president shall be elected by the membership at the annual meeting of members of the corporation in the manner, at the time, and for the term specified in these Bylaws. Each vice president by virtue of his office shall be a voting member of the Board of Directors.
9. The secretary of the corporation shall keep minutes of all meetings of the membership and the Board of Directors. The secretary shall be an archaeologist at Missouri State University, Springfield, and the secretary's office shall be the principal office of the corporation. The secretary shall be elected by the membership at the annual meeting of the corporation, in the manner, at the time, and for the term specified in these Bylaws. The secretary by virtue of his office shall be a voting member of the Board of Directors.
10. An assistant secretary may be appointed by resolution of the Board of Directors and shall serve at the pleasure of the Board of Directors. His duties shall be those assigned to him by the Board of Directors from time to time.
11. The treasurer of the corporation shall be in charge of the moneys of the corporation and shall receive all moneys due the corporation. He shall disburse such corporate funds as directed from time to time by resolution of the Board of Directors. He shall make bond for the discharge of his duties in such amount as the Board of Directors may require by resolution from time to time adopted, the expense of which shall be borne by the corporation. He shall be elected by the membership at the annual meeting of the corporation, in the manner, at the time, and for the term specified by these Bylaws. The treasurer by virtue of his office shall be a voting member of the Board of Directors.
12. An assistant treasurer may be appointed by resolution of the Board of Directors who shall serve at the pleasure of the Board of Directors. An assistant treasurer before entering onto any duties shall be bonded in the same manner and for the same amount as the treasurer. His duties shall be those assigned to him by the Board of Directors.
13. The chair of the Committee on the Preservation of Sites shall be an officer of the corporation appointed annually from among the members of that Committee by the members of the Board of Directors in the manner, at the time, and for the term specified in these Bylaws. The chair of the Committee on the Preservation of Sites, shall, by virtue of his office, be a voting member of the Board of Directors.
14. The chair of the Board of Trustees shall be an officer of the corporation appointed annually by the Board of Directors from the membership of the Board of Trustees, in the manner, at the time, and for the term specified in these Bylaws. The chair of the Board of Trustees shall be an officer of the corporation appointed annually by the Board of Directors from the membership of the Board of Trustees, in the manner, at the time, and for the time specified in these Bylaws. The chair of the Board of Trustees, by virtue of his office, shall be a voting member of the Board of Directors.
ARTICLE X—Board of Trustees
1. A Board of Trustees consisting of not more than 75 members of the corporation shall be elected by the membership of the corporation. Not more than 25 shall thereafter be elected at each annual meeting of the membership, for a three-year term.
2. The Board of Trustees shall uphold and further the aims and purposes of the corporation and shall keep the corporation informed of local discoveries and threats to archaeological sites and remains, serve as field ambassadors of the corporation, encourage participation in its activities, and promote financial support of its programs.
3. Vacancies in the membership of said Board of Trustees may be filled by the Board of Directors for the unexpired term.
4. A trustee may apply to the Board of Directors for emeritus status after serving a minimum of three (3) terms of three years each. Trustee emeritus status shall not carry voting privileges at Board of Trustee meetings. Trustees emeriti shall be recognized on published rosters of the Board of Trustees.
ARTICLE XI—Committee on the Preservation of Sites
1. There is hereby created a Committee on the Preservation of Sites, which Committee shall assist in the location of archaeological sites worthy of preservation and shall undertake and solicit such aid as is possible in accomplishing such tasks.
2. The Committee shall consist of not more than 33 persons appointed by the Board of Directors from the membership of the corporation, all of whom shall serve at the pleasure of the Board of Directors.
ARTICLE XII—Committee Appointment
1. The president with the approval of the Board of Directors may appoint such other committees as the Board of Directors may from time to time authorize by resolution.
2. Such committees shall serve at the pleasure of the Board of Directors and shall be assigned such duties as the Board may designate.
ARTICLE XIII—Chapters
1. Five or more members of the corporation living in geographic proximity may organize a chapter of the corporation for the purpose of furthering the interests and objectives of the corporation, subject however to the approval of the Board of Directors. Other organizations having kindred interests, but whose members are not affiliated with this corporation, may also organize a chapter, subject however to the approval of the Board of Directors.
2. No chapter shall use the name of the MAS or any chapter name of the MAS in order to promote buying, selling, or trading of artifacts.
3. Any chapter approved may be revoked and affiliation terminated by the Board of Directors for good cause in the opinion of the Board. The chapter against which revocation proceedings are pending is entitled to reasonable notice and an opportunity to be heard.
ARTICLE XIV—Publications
1. The Board of Directors shall authorize all publications of the corporation.
2. Regular publications of the corporation shall consist of an annual bulletin titled The Missouri Archaeologist and a periodical newsletter.
3. Special publications may be made from time to time as the Board of Directors may determine and as funds and materials permit.
4. The Board of Directors shall designate editors of publications.
ARTICLE XV—Removals for Cause
1. Any officer, any member of the Board of Directors, or any member of the Board of Trustees or the Committee on the Preservation of Sites may be removed for good cause by a two-thirds vote of the membership entitled to vote at any special meeting of the corporation membership called for such purpose.
2. The person against whom such removal proceedings are pending is entitled to reasonable notice and an opportunity to be heard.
MAS Organization
Textbooks, Publications, and Apparel
Collecting and Identifying Artifacts
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redpajama_set_name: RedPajamaCommonCrawl