Military nephrology: a review of cases 1985-2011.

OBJECTIVE: Evidence of the prevalence of renal pathology in military populations is rare, probably as a result of a traditionally cautious military medical attitude that limits applicants with evidence of renal disease joining the Armed Forces and the continued service of military personnel who develop this later. The aim of this paper is to provide the first comprehensive review of renal diseases in a British military population. METHODS: An archive of out-patient consultations, discharge summaries and renal biopsies between 1985 and 2011 was reviewed. Cases were classified according to diagnosis providing a frequency distribution over this 26-year period. Serum creatinine concentration and demographic data permitted retrospective calculation of estimated glomerular filtration rate (eGFR) at presentation and follow-up. Calculation of an annualised rate of deterioration of eGFR (ml/min/1.73 m2/y) was undertaken when there were at least four follow-up values. In those cases where there was a statistically significant negative correlation with time, the probability of deterioration of renal function according to diagnosis was calculated. Where numbers of patients with a given diagnosis were sufficient for statistical purposes, correlations were also attempted between initial eGFR and both initial mean arterial pressure (MAP) and initial proteinuria. RESULTS: The most frequent condition was IgA nephropathy, present in 115/346 (33%) of cases. Follow-up data permitted analysis of change in eGFR in 50 of these and 11 (22%) deteriorated. In this condition, there were statistically significant negative correlations between initial eGFR and MAP (r = -0.35, p = 0.0008) and proteinuria (r = -0.4, p = 0.0006). Other conditions showing deterioration despite therapeutic interventions included adult polycystic kidney disease (15/2 2 = 68%) and membranous nephropathy (4/ 7 = 57%). Altogether, 8/13 (61%) conditions included cases where eGFR deteriorated and this was present in 40/161 (25%) individual cases. CONCLUSIONS: Cases of renal disease are discovered de novo in serving military personnel and, despite interventions to maintain renal function, a significant proportion deteriorate supporting the traditionally restrictive policy concerning applicants with evidence of renal disease.

Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease.

OBJECTIVE: C-reactive protein (CRP) concentrations are predictive of cardiovascular disease, and levels are heritable, in part. We identified novel polymorphisms in the CRP gene and assessed their influence on CRP level. METHODS AND RESULTS: CRP was measured in 250 male army recruits before and after strenuous exercise and perioperatively in 193 coronary artery bypass graft (CABG) patients. Two novel polymorphisms were identified in the CRP gene, -717G>A in the promoter and +1444C>T in the 3'UTR. Among army recruits, CRP was higher in +1444TT homozygotes than +1444 C-allele carriers at baseline (1.04+/-0.38 versus 0.55+/-0.06, P=0.014) and at all time points after exercise (2.35+/-0.68 versus 1.07+/-0.12, 2.11+/-0.53 versus 0.88+/-0.09, and 1.77+/-0.44 versus 0.71+/-0.09, P=0.034, P=0.007, and P=0.013, at 2, 48, and 96 hours after exercise, respectively). In the CABG patients, mean CRP (mg/L) rose from 1.97+/-0.36 at baseline to 167.2+/-5.0 72 hours postoperatively. Genotype did not influence CRP at baseline; however, peak post-CABG CRP levels were higher in +1444TT homozygotes compared with +1444C-allele carriers (198+/-17 versus 164+/-5, P=0.03). CONCLUSIONS: The CRP gene +1444C>T variant influences basal and stimulated CRP level. These findings have implications both for the prediction and pathogenesis of coronary heart disease.

The effect of fibrinogen genotype on fibrinogen levels after strenuous physical exercise.

We have examined the effect of two beta-fibrinogen gene promoter polymorphisms (-455G>A and -854G>A) on the fibrinogen response to severe exercise in a group of male army recruits undergoing basic training. Fibrinogen was measured pre-training and again serially after severe 48 h final military exercise (FME). Out of 884 subjects, 762 completed training of whom 250 were selected for post-FME study. Fibrinogen levels (g/l) were significantly elevated over baseline levels 2, 48 and 96 h after FME, representing increases of 15.7%, 3.4% and 7.6% (p <0.005; p = 0.05 and p <0.005 respectively), with higher levels in -455A allele carriers than genotype -455GG: 3.17+/-0.05 vs. 2.94+/-0.05 (p <0.001), 2.86+/-0.05 vs. 2.60+/-0.05 (p <0.0005) and 2.98+/-0.06 vs. 2.69+/-0.06 (p <0.0005) at 2, 48 and 96 h respectively. There was no effect of the -854G>A polymorphism on fibrinogen, even after taking into account beta-fibrinogen -455 genotype. Thus the fibrinogen -455G>A polymorphism influences fibrinogen levels following exercise. The effect of genotype might be clinically relevant at times of hyperfibrinogenaemia such as following an acute inflammatory response.

Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with losartan.

BACKGROUND: Local cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophic responses. The absence (deletion [D]) of a 287-bp marker in the ACE gene is associated with greater myocardial ACE levels and exercise-related LV growth than is its presence (insertion [I]), an effect potentially mediated through either increased activity of the cellular growth factor angiotensin II on the angiotensin type 1 (AT(1)) receptor or increased degradation of growth-inhibiting kinins. We sought to confirm ACE genotype-associated exertional LV growth and to clarify the role of the AT(1) receptor in this association. METHODS AND RESULTS: One hundred forty-one British Army recruits homozygous for the ACE gene (79 DD and 62 II) were randomized to receive losartan (25 mg/d, a subhypotensive dose inhibiting tissue AT(1) receptors) or placebo throughout a 10-week physical training program. LV mass, determined by cardiac magnetic resonance, increased with training (8.4 g, P:<0.0001 overall; 12.1 versus 4.8 g for DD versus II genotype in the placebo limb, P:=0.022). LV growth was similar in the losartan arm: 11.0 versus 3.7 g for DD versus II genotypes (P:=0.034). When indexed to lean body mass, LV growth in the II subjects was abolished, whereas it remained in the DD subjects (-0.022 versus 0.131 g/kg, respectively; P:=0.0009). CONCLUSIONS: ACE genotype dependence of exercise-induced LV hypertrophy is confirmed. Additionally, LV growth in DD (unlike II) subjects is in excess of the increase in lean body mass. These effects are not influenced by AT(1) receptor antagonism with the use of losartan (25 mg/d). The 2.4-fold greater LV growth in DD men may be due to the effects of angiotensin II on other receptors (eg, angiotensin type 4) or lower degradation of growth-inhibitory kinins.

Malaria remains a military medical problem.

OBJECTIVE: To bring military medical problems concerning malaria to the attention of the Defence Medical Services. METHOD: Seven military medical problems related to malaria are illustrated by cases referred for secondary assessment over the past five years. Each is discussed in relation to published data. RESULTS: The cases of failure of various kinds of chemoprophylaxis, diagnosis and treatment of malaria may represent just a fraction of the magnitude of the overall problem but in the absence of reliable published military medical statistics concerning malaria cases, the situation is unclear. CONCLUSION: Present experience suggests there are a number of persisting problems affecting the military population in relation to malaria. Only publication of reliable statistics will define their magnitude. Interim remedies are proposed whose cost-effectiveness remains to be established.

Adverse reactions to anthrax immunisation in a military field hospital.

OBJECTIVE: To determine the outcome of anthrax immunisation. METHODS: Adverse reactions (occurrence, nature, severity and incapacity) and immune responses to a voluntary programme of anthrax immunisation at 0, 3, 6, and 24 weeks were monitored by questionnaire and voluntary blood sampling in 129 members, including 24 immunised 7 years previously (immunes), of a military field hospital alerted for possible deployment. RESULTS: Follow-up was complete in 85%. Ninety-eight (76%) received the first anthrax immunisation. Uptake was greater (p = 0.015) in immunes. Initial prevalence of adverse reaction was 63%. Subsequent uptake and adverse reaction dwindled significantly (p < 0.001). Only 28 (22%) were immunised at 24 weeks. Proportions reporting adverse reactions following the initial immunisation were greater in immunes (p = 0.046) and officers (p = 0.02). There was no significant (p = 0.36) correlation between uptake of immunisation and prevalence of adverse reaction. Antecedent adverse reaction did not reduce the proportion of participants accepting immunisation subsequently. The nature of adverse reactions (47% local, 24% systemic and 27% both) and severity were the same throughout. Forty-five percent of adverse reactions caused incapacity. Seventy-four percent of these had pain in the injected arm (+/- systemic symptoms) which prevented lifting or driving for 48 hours in 63%. Immune responses were greater in immunes. CONCLUSIONS: It was concluded that anthrax immunisation results in a higher than expected prevalence of adverse reaction with initial incapacity of military significance affecting 18%. Greater immune responses may increase adverse reaction but this does not affect acceptance of anthrax immunisation. Poor completion rates necessitate development of a new anthrax immunisation strategy.

Side effects of mefloquine prophylaxis for malaria: an independent randomized controlled trial.

A prospective randomized double-'blind' trial was undertaken during a military exercise in East Africa to determine whether there was a significant difference in the incidence of side effects experienced by soldiers taking mefloquine 250 mg weekly compared with those taking chloroquine 300 mg weekly and proguanil 200 mg daily as chemoprophylaxis for malaria. Subject to their informed voluntary consent, male soldiers who were not aviators were included in the study. Identical questionnaires were completed voluntarily at the end of 2 and 8 weeks. Symptoms were classified by nature into-'all', 'neuropsychological', 'enteric' and 'other', and by severity into 'severe' and 'very severe'. The proportions of respondents experiencing side effects were compared to seek statistically significant differences between the chemoprophylactic groups. Questionnaire 1 was completed after 2 weeks by 183 of 317 subjects (58%) randomly assigned mefloquine and by 176 of 307 subjects (57%) randomly assigned chloroquine-proguanil. The incidence of putative side effects was not significantly different between the groups (71/183 vs. 70/176), odds ratio 0.96 (95% confidence interval [CI] 0.63 to 1.47). Questionnaire 2 was completed after 8 weeks by 145 of 317 subjects (46%) randomly assigned mefloquine and by 142 of 307 subjects (46%) randomly assigned chloroquine-proguanil. The incidence of putative side effects was still not significantly different between the groups (95/145 vs. 103/142), odds ratio 0.72 (95% CI 0.43 to 1.19). None of the subjects developed a serious neuropsychological reaction. Among respondents, 12.8% and 38% admitted lack of full compliance at 2 and 8 weeks, respectively. Exclusion of these subjects during a secondary analysis did not affect the results. None of the subjects developed malaria in the 12 months following return to the UK. Subject to the limitations of a response rate that was smaller than desired and the fact that the study was conducted in fit male military personnel, these results support evidence which indicates that mefloquine is no more toxic than chloroquine-proguanil.

Methods of estimating cardiac output in the field.

Simultaneous estimation of cardiac output (CO) by thoracic electrical bioimpedance (TEB) and thermodilution (TD) confirmed the results of a previous study which showed good agreement between these methods in selected, principally non-septic, patients. Poor agreement was found between simultaneous TEB and oesophageal Doppler monitoring (ODM) estimates of baseline and acute changes in CO. Taken with the results of previous studies, this implies that although isolated ODM estimates of CO, which tend to underestimate, are less reliable, ODM is the preferred method to monitor acute changes in CO. For many reasons, not least the speed with which a large number of seriously injured soldiers could be assessed, ODM is probably the better method if a non-invasive estimate of CO is required in field hospitals.

Mesalazine-associated interstitial nephritis.

BACKGROUND: When used for oral treatment of inflammatory bowel disease, Asacol (a coated form of mesalazine = 5-aminosalicylic acid) can cause interstitial nephritis. The spectrum of severity, frequency of occurrence and the best renal function test to detect this complication are not known. The value of immunosuppression in addition to drug withdrawal is similarly undetermined. METHODS: Four cases of interstitial nephritis which occurred in association with oral Asacol treatment are presented and a further 12 cases who received similar treatment are reviewed. Clinical trials published previously were scrutinized to assess the frequency of impaired renal function. RESULTS: The available evidence suggests that renal impairment of any severity may occur in up to 1 in 100 patients, but that clinically significant interstitial nephritis occurs in less than 1 in 500 patients. This is most reliably detected by an elevated serum creatinine concentration. If the diagnosis of nephrotoxicity is delayed until 18 months after commencement of medication, restoration of renal function, which is seen on withdrawal of medication alone up to 10 months, does not occur and there is no evidence to date to indicate that addition of immunosuppression confers any significant advantage at this later stage. CONCLUSIONS: It is suggested that serum creatinine concentration should be measured each month for the first 3 months of treatment, 3-monthly for the remainder of the first year and annually thereafter. The use of concurrent immunosuppressive therapy may necessitate extension to the period of intensive monitoring. Any elevation of serum creatinine which cannot be related to a relapse of inflammatory bowel disease should prompt immediate withdrawal of Asacol and related medications and substitution of alternative therapy. Neither the lack of urinary abnormalities on routine testing nor the absence of clinical or laboratory features of drug allergy can be relied upon to rule out interstitial nephritis during oral therapy with these drugs.

Leptospirosis--a cause for concern?

A severe case of Weil's disease is presented. The particular relevance of this condition to the Armed Forces and Service physicians is discussed, together with methods of diagnosis.

Patterns of response to intravenous enoximone.

The cases of four male patients with severe cardiac failure due to ischaemic heart disease are presented. They were selected on the basis of their wide variation in response to the intravenous administration of enoximone, an haemodynamic stimulant licensed recently. They serve to emphasize the need for close haemodynamic and electrocardiographic monitoring in a unit with appropriate facilities for remedial action if adverse responses occur when this drug is employed.

Estimation of cardiac output by bioimpedance cardiography.

Changes in thoracic electrical bioimpedance during the cardiac cycle have been related to the ejection of the stroke volume of blood during cardiac systole. Refinements in the recording and analysis of these changes permit estimation of cardiac output. Encouraging reports comparing results obtained by this method and those obtained simultaneously using the current standard invasive method have been published. While there are limitations, the advantages of this technique are sufficient to make bioimpedance cardiography attractive to the military physician. It is for these reasons that the principles of this technology are reviewed in this paper.