Gut microbiota and immune profiling of microbiota-humanised versus wildtype mouse models of hepatointestinal schistosomiasis.

Mounting evidence of the occurrence of direct and indirect interactions between the human blood fluke, Schistosoma mansoni, and the gut microbiota of rodent models raises questions on the potential role(s) of the latter in the pathophysiology of hepatointestinal schistosomiasis. However, substantial differences in both the composition and function between the gut microbiota of laboratory rodents and that of humans hinders an in-depth understanding of the significance of such interactions for human schistosomiasis. Taking advantage of the availability of a human microbiota-associated mouse model (HMA), we have previously highlighted differences in infection-associated changes in gut microbiota composition between HMA and wildtype (WT) mice. To further explore the dynamics of schistosome-microbiota relationships in HMA mice, in this study we (i) characterize qualitative and quantitative changes in gut microbiota composition of a distinct line of HMA mice (D2 HMA) infected with S. mansoni prior to and following the onset of parasite egg production; (ii) profile local and systemic immune responses against the parasite in HMA as well as WT mice and (iii) assess levels of faecal inflammatory markers and occult blood as indirect measures of gut tissue damage. We show that patent S. mansoni infection is associated with reduced bacterial alpha diversity in the gut of D2 HMA mice, alongside expansion of hydrogen sulphide-producing bacteria. Similar systemic humoral responses against S. mansoni in WT and D2 HMA mice, as well as levels of faecal lipocalin and markers of alternatively activated macrophages, suggest that these are independent of baseline gut microbiota composition. Qualitative comparative analyses between faecal microbial profiles of S. mansoni-infected WT and distinct lines of HMA mice reveal that, while infection-induced alterations of the gut microbiota composition are highly dependent on the baseline flora, bile acid composition and metabolism may represent key elements of schistosome-microbiota interactions through the gut-liver axis.

Renal function after 10 years' treatment with cyclosporin for psoriasis.

Renal function was assessed by measuring serum creatinine and glomerular filtration rate (GFR) in two groups of patients with chronic plaque psoriasis who had been treated with cyclosporin A (CyA), average dose 2.8 mg/kg per day (range 1-5 mg/kg per day). Group I was our original cohort of nine patients, seven of whom had received CyA for an average period of 10 years (range 9.5-11 years). These seven patients showed a persistent increase in serum creatinine > 30% from baseline measurement and four of the seven had persistent increases > 50%. The GFR, which was first measured after 2.5 years of treatment, showed at 10 years a decrease of > 30% in two patients and of > 50% in one patient. Three of the seven showed stable renal function while two had repeat renal biopsy because of deteriorating renal function and histology showed further evidence of CyA nephrotoxicity compared with that after 5 years' treatment. Two of the nine patients in group I had discontinued CyA 5 years previously after 5 years of treatment because of CyA nephrotoxicity on renal biopsy and impaired renal function. This impairment of renal function showed improvement during the 5 years of follow-up, implying reversibility of CyA nephrotoxicity. The second group of 20 patients had received CyA for an average duration of 6 years (range 5-8 years). Nine of the 20 patients showed persistent increases in serum creatinine of > 30% from baseline and five showed persistent increases of > 50%. The GFR showed a persistent decrease of > 30% in seven patients and of > 50% in two patients. This study has shown that nephrotoxicity is associated with long-term treatment with CyA. However, there is patient variation as to when nephrotoxicity commences and its speed of progression. On discontinuing CyA the impairment of renal function improves with time. Providing renal function is monitored with GFR and renal biopsy in addition to serum creatinine then long-term (5-10 years) CyA treatment can be justified in severe psoriasis not responsive to other treatments.

The diagnosis and racial origin of 394 patients undergoing renal biopsy: an association between Indian race and interstitial nephritis.

BACKGROUND: There is a high incidence of renal disease in the ethnically Indian population in the United Kingdom, the pathological basis for which is only partly understood. This study attempted to define associations between renal biopsy diagnosis and race. The aim was thereby to identify types of renal disease which may contribute to the observed predisposition to renal failure in the Indian population served by our centre. METHOD: A single-centre-based retrospective analysis of the final diagnosis and corresponding ethnicity in 394 consecutive patients undergoing native renal biopsy for the investigation of abnormal renal function or urinary sediment. RESULTS: A highly significant association between a diagnosis of interstitial nephritis and Indian race was observed. There were 30 cases of interstitial nephritis, of whom 17 were Indian. In 15 of the Indian patients no aetiology could be established. The clinical features, outcomes, and the effect of steroid therapy in the Indian patients with idiopathic interstitial nephritis are described. CONCLUSION: Idiopathic interstitial nephritis is associated with Indian racial origin. This pathology may significantly contribute to the high incidence of end-stage renal failure in Indian patients resident in the United Kingdom.

Magnetic resonance angiography of renal artery stenosis.

Renal artery stenosis is a common cause of renal impairment which in many cases may be potentially reversible. The diagnosis and follow-up of this condition is commonly carried out using the relatively invasive technique of intra-arterial angiography. Magnetic resonance angiography (MRA) is emerging as a possible alternative technique to conventional angiography. We have studied 60 patients who were referred for investigation of possible renal artery stenosis using both 3-D phase contrast MRA techniques and conventional digital arteriography. Studies were assessed prospectively and conventional angiography was assumed to be the gold standard for the purposes of this study. Calculated sensitivity and specificity results were 84% and 91% respectively, for 3-D phase contrast MRA of the renal arteries. We conclude that 3-D phase contrast MRA is a very promising technique for the noninvasive investigation of renal artery stenosis with high sensitivity and specificity levels acting as a screening test in the future for patients with this potential diagnosis, diminishing the amount of conventional angiograms that are performed.

Calcium metabolism following renal transplantation.

Abnormalities of calcium homeostasis are a recognized feature of end-stage renal disease. The treatment of choice is renal transplantation, but this does not always result in normalization of the biochemical profile. Persistent hypercalcaemia is well documented and our study was undertaken to investigate the status of the calcium regulating hormones in renal patients post-transplantation. Serum calcium, parathyroid hormone, 1,25-dihydroxyvitamin D (1,25(OH)2D) and osteocalcin concentrations were measured in post-transplant patients. Twenty per cent of the patients had subnormal 1,25(OH)2D concentrations while 55% had biochemical evidence of hyperparathyroidism but only 5% were hypercalcaemic. Time elapsed since transplantation was not correlated with any of the analytes investigated and there was no relationship between persistent impairment of renal function and abnormalities of calcium homeostasis.

Renal function and biopsy findings after 5 years' treatment with low-dose cyclosporin for psoriasis.

Renal biopsies were performed in eight patients with chronic plaque psoriasis who had been treated with low-dose cyclosporin (CyA) (range 1-6 mg/kg/day; average dose 3.3 mg/kg/day) for an average period of 5 years. In six of the eight patients biopsies showed features consistent with CyA nephrotoxicity. Tubular atrophy and arteriolar hyalinosis were present in all six, four had an increase in interstitium, and two showed an increased incidence of glomerular obsolescence. Two of the patients showed all of these features, two patients had three features, and the remaining patients had two features. Renal function was assessed by glomerular filtration rate (GFR) and serum creatinine. Both a fall in the GFR and a rise in the serum creatinine correlated with the severity of the features of CyA nephrotoxicity seen on biopsy. However, the best predictor of the biopsy findings was a failure of renal function to show significant improvement when CyA was discontinued for a month. CyA has been discontinued in two of the eight patients who had the most severe features of CyA nephrotoxicity on renal biopsy. In both patients there has been improvement of renal function after 1 year of follow-up.

Regulation of iron absorption in iron loaded subjects with end stage renal disease: effects of treatment with recombinant human erythropoietin and reduction of iron stores.

The effects on iron absorption of variation in erythroid activity, haemoglobin and iron stores were studied in six anaemic dialysis-dependent subjects in whom iron stores were increased from previous red cell transfusions. Gastrointestinal mucosal uptake and whole body retention of oral iron were measured at the beginning of the study, after starting treatment with recombinant erythropoietin (but before significant increase in haemoglobin), after partial correction of anaemia, after further reduction of iron stores by repeated phlebotomy, and when erythropoiesis decreased from the discontinuation of treatment with erythropoietin. Between successive measurements, valid comparisons were made in five subjects. Correction of anaemia decreased whole body retention of iron through decreased mucosal uptake (P = 0.032). Further reduction in iron stores through repeated phlebotomy whilst the increase in haemoglobin was maintained by treatment with erythropoietin, tended to increase whole body retention of iron through an increase in mucosal transfer (P = 0.010). With initial enhancement of erythropoiesis in anaemic iron-loaded subjects there was no change in any measured component of iron absorption. However, after correction of anaemia and reduction of iron stores, a decrease in erythropoiesis was associated with decreased whole body iron retention in all subjects through decreased mucosal transfer (P = 0.028). The data suggest that anaemia upregulates mucosal iron uptake, and that erythroid activity upregulates mucosal transfer but that this latter effect may be counter-balanced by iron overload which downregulates mucosal transfer.

Magnetic resonance angiography of renal transplants.

Stenosis of the artery of transplanted kidneys is an important cause of graft dysfunction. Diagnosis and follow-up of this condition normally requires intra-arterial digital-subtraction angiography (IADSA), which is invasive and may cause complications. A possible alternative to IADSA is magnetic resonance angiography (MRA), and we have assessed this technique in 50 renal transplant patients who were referred for investigation of possible renal arterial stenosis. In every patient, MRA was compared prospectively with conventional IADSA. Compared with IADSA, MRA had a sensitivity of 83% and a specificity of 97%, and when all images were graded retrospectively for severity of stenosis, the two techniques showed a significant correlation (r = 0.74, p less than 0.001). MRA can provide an accurate image of the renal transplant artery in a non-invasive manner with a high sensitivity and specificity.

Endoscopic placement of CAPD catheters: a review of one hundred procedures.

One hundred consecutive endoscopically placed peritoneal dialysis catheters inserted in 95 patients over an 18-month period have been reviewed. All catheters were placed for chronic dialysis (CAPD). Following insertion there were five early catheter failures (4 failed to drain, 1 perforated viscus) and 13 early complications (7 leaks, 3 tunnel bleeds, 2 scrotal oedema, 1 wound infection). In the long term six patients required transfer to haemodialysis (2 recurrent peritonitis, 2 pain on outflow, 1 unable to cope, 1 persistent vomiting). Overall probability of catheter survival as predicted by Kaplan-Meier analysis was 0.85 at 18 months. These results confirm that endoscopic placement of CAPD catheters is safe and reliable. In addition there is a low early failure rate and the long-term catheter survival figure is comparable with the best series reported. This procedure allows direct visualization of the peritoneal cavity, thus minimizing the risk of visceral damage. Furthermore, the procedure is well tolerated under local anaesthesia and allows early institution of dialysis because of the extremely low leakage rate (11%). Endoscopic placement of CAPD catheters is now the procedure of choice in our centre. General anaesthetic and mini-laparotomy are thus avoided in most of this high-risk group.

Studies of circulating parathyroid hormone following parathyroidectomy in renal osteodystrophy.

A study has been undertaken to document in detail some of the changes that occur following parathyroidectomy in chronic renal failure patients. In an attempt to predict more precisely the timing of the post-operative hypocalcaemia, serum parathyroid hormone (PTH) concentrations were measured in six patients with renal osteodystrophy undergoing subtotal parathyroidectomy [5] and total parathyroidectomy [1]. The values obtained were related to post-operative changes in serum calcium and albumin concentrations. The intact-PTH concentration in serum was shown to decline rapidly post-operatively while the C-terminal PTH followed a more gradual course. Neither total nor ionised serum calcium concentrations exhibited a correspondingly dramatic fall after parathyroidectomy and the serum albumin concentration remained unaltered.

Four years of experience with cyclosporin A for psoriasis.

Forty-four patients with severe psoriasis have been treated with cyclosporin A (CyA) for 2-50 months (mean 17 months). During the study, 31 (70%) of these patients achieved a greater than 70% reduction in PASI score, 39 (88%) achieved a greater than 60% reduction and 42 (95%) a greater than 50% reduction. The mean initial dose of CyA was 3 mg/kg/day and the mean dose was 3.3 mg/kg/day throughout the study. Twenty-five (57%) patients were maintained on less than or equal to 3 mg and six (14%) required greater than 5 mg/kg/day for limited periods to obtain significant improvement. In three of these patients, this was achieved with 6 mg/kg/day but, of the remainder, one required 7 mg and two required 10 mg/kg/day. Of the 44 patients, 32 (73%) are still taking CyA. Patients were discontinued because of: side-effects directly attributable to treatment (n = 4); remission of psoriasis (n = 4); death (n = I); defaulting (n = I); infrequent attendance (n = I); high doses of NSAID were necessary for arthritis (n = I). Before starting CyA, 39 patients were normotensive; 21 (54%) developed mild hypertension. In 28 patients where the GFRs were estimated before and during treatment, there was a 16% reduction (P less than 0.0001) during a mean period of 8 months. Two patients developed malignancies. The incidence of hypertension and percentage decrease in GFR were strongly correlated with the dose required to control the psoriasis.

Renal function after long-term low-dose cyclosporin for psoriasis.

Two groups of patients receiving cyclosporin A (CyA) for psoriasis had their renal function assessed by measurement of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). The first group comprised 13 patients who had taken low dose (average 3 mg/kg per day) CyA for an average period of 2.5 years. Seven of the 13 had a normal GFR of 108 (77-121) ml/min (median; range). In the other six patients the GFR was low at 63 (50-77) ml/min and CyA was discontinued for periods ranging from 3 to 17 weeks. The GFR rose in all six patients, to 79 (60-91) ml/min; this change was significant (P less than 0.05). The six patients restarted CyA because their psoriasis recurred and after a mean interval of 15 weeks the GFR had fallen in all six to 63 (46-80) ml/min (P less than 0.05) and the ERPF decreased from 339 (231-414) ml/min to 244 (177-321) ml/min (P less than 0.05). In the second group of 11 patients measurements were made prior to starting CyA and after taking CyA for a mean of 9 weeks. The GFR fell in eight out of 11 subjects, the GFR for the 11 patients being 117 (72-128) ml/min before taking CyA and 97 (51-122) ml/min after CyA (P less than 0.02). The ERPF was measured in nine of the 11 patients and fell in seven of the nine. The ERPF for the nine patients before CyA was 490 (296-642) ml/min and for the 11 patients after CyA was 410 (195-543) ml/min (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Use of hybridot assay to screen for BK and JC polyomaviruses in non-immunosuppressed patients.

Urine samples from 50 patients attending a genitourinary outpatient clinic and from 13 renal allograft recipients were investigated for evidence of infection with human BK and JC polyomaviruses using cytology and a new DNA hybridot assay. Forty four per cent of samples from the renal allograft recipients were positive by cytology and 75% by DNA hybridisation, indicating that hybridot assay is more sensitive than cytological screening. BK and JC viral DNA was found in 20% of the patients attending the genitourinary clinic, showing infection with BK virus and JC virus in a group of patients with clinical conditions not normally associated with immunological deficiency-a finding that has not been reported before.

Tuberculosis in renal failure: a high incidence in patients born in the Third World.

We report 11 cases of tuberculosis among patients with chronic renal failure being treated in our unit. All were born outside the United Kingdom, and represent 25% of the non-europid patients in the unit. This is about a seventy-fold increased incidence of tuberculosis in this group. Diagnosis is difficult and mortality high if the diagnosis is delayed. Culture of tissue biopsies is the most reliable investigation and chemotherapy should be commenced promptly or a therapeutic trial considered in doubtful cases. Chemoprophylaxis may be beneficial in patients from these ethnic groups or in any uremic patient with evidence of old tuberculosis. Three patients with advanced disease died despite antibiotic treatment, but in the remainder, triple therapy with normal doses of rifampicin, isoniazid and pyrazinamide proved safe and effective.

Effects of azathioprine therapy on the MCV of patients with renal grafts: evidence for alterations in the kinetics of erythropoiesis over a prolonged period.

The changes in MCV at various times after renal transplantation were studied in a group of patients with functioning cadaveric renal grafts who had received azathioprine from the time of transplantation and in a constant dose from 2-8 weeks later. A post-transplantation increase in the MCV was seen in the majority of the cases studied and in these cases the MCV did not reach a maximum value until as long as 11-40 months after transplantation. In most cases the MCV then feel although frequently not to within the normal range and in some cases it showed further fluctuations. These data suggest gradual alterations over a period of years in the various cytokinetic changes which serve to maintain a reasonably high output of red cells from the marrow despite the cytotoxic effects of azathioprine.