Factors influencing the clinical outcome of preimplantation genetic testing for polycystic kidney disease.

STUDY QUESTION: What are the factors influencing the success rate for couples undergoing preimplantation genetic testing (PGT) for polycystic kidney disease (PKD)? SUMMARY ANSWER: In our study cohort, the live birth delivery rate is significantly associated with female age while the male infertility accompanying autosomal dominant PKD (ADPKD) does not substantially affect the clinical outcome. WHAT IS KNOWN ALREADY: While women with ADPKD have no specific fertility problems, male ADPKD patients may present with reproductive system abnormalities and infertility. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study involves 91 PGT cycles for PKD for 43 couples (33 couples for PKD1, 2 couples for PKD2 and 8 couples for autosomal recessive PKD (ARPKD)) from January 2005 until December 2016 with follow-up of transfers until end of 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixteen single-cell clinical tests for PKD based on multiplex PCR of short tandem repeat markers, with or without a specific mutation were developed and applied for diagnosis of 584 Day 3 cleavage stage embryos. In 18 couples, the male partner was affected with ADPKD (=Group A) and 12 of them had a documented infertility status. Group A underwent 52 cycles to oocyte retrieval. For 18 other couples, the female partner was affected with ADPKD (=Group B) and four male partners from this group had a documented history of infertility. This group underwent 31 cycles to OR. MAIN RESULTS AND THE ROLE OF CHANCE: Genetic analysis resulted in 545 embryos (93.3%) with a diagnosis, of which 215 (36.8%) were genetically transferable. Transfer of 74 embryos in 53 fresh cycles and of 34 cryopreserved embryos in 33 frozen-warmed embryo transfer cycles resulted in a live birth delivery rate of 38.4% per transfer with 31 singleton live births, two twin live births and one ongoing pregnancy. The observed cumulative delivery rate was 57.8% per couple after five treatment cycles. Thirty cryopreserved embryos still remain available for transfer. The clinical pregnancy rate per transfer (fresh + frozen; 45.9% in group A versus 60.0% in group B, P < 0.05) and the live birth delivery rate per transfer (fresh + frozen; 27.0% in group A versus 42.9% in group B, P < 0.05) was significantly lower for couples with the male partner affected with ADPKD compared with couples with the female partner affected with ADPKD. However, a multivariate logistic regression analysis showed that only female age was associated with live birth delivery rate (odds ratio = 0.87; 95% CI: 0.77-0.99; P = 0.032). LIMITATIONS, REASONS FOR CAUTION: This study is based on retrospective data from a single centre with Day 3 one-cell and two-cell biopsy. Further analysis of a larger cohort of PKD patients undergoing PGT is required to determine the impact of male infertility associated with ADPKD on the cumulative results. WIDER IMPLICATIONS OF THE FINDINGS: Knowledge about factors affecting the clinical outcome after PGT can be a valuable tool for physicians to counsel PKD patients about their reproductive options. Males affected with ADPKD who suffer from infertility should be advised to seek treatment in time to improve their chances of conceiving a child. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Patient- and physician-level determinants of blood pressure response to treatment in normal weight and overweight patients (the PREVIEW study).

BACKGROUND AND AIMS: Obesity combined with hypertension places patients at greater risk for target-organ damage and cardiovascular disease. The purpose of this secondary analysis was to identify physician- and patient-levels determinants of blood pressure (BP) values and predictors of uncontrolled BP through subgroup analysis by body mass index (BMI). METHODS AND RESULTS: We conducted a subgroup analysis of 3006 patients with High-BMI (BMI >25 kg/m(2); n=2124) and Normal-BMI (BMI<25 kg/m(2); n=882) treated by 504 physicians and enrolled in PREVIEW, a Belgian prospective, multi-center, pharmaco-epidemiological study of 90-day second-line treatment with valsartan. Physician- and patient-level determinants of BP values and BP control were identified by means of hierarchical linear and logistic regression. Blood pressure values and control after 90 days of treatment were consistently lower for the High-BMI group. The 25.5% of variance in 90-day systolic and 28.3% of the variance in 90-day diastolic BP were attributable to physician-level determinants for the High-BMI group; versus 27.3% and 29.8% for the Normal-BMI group (ICC=0.273 and 0.298, respectively). Determinants of 90-day BP values and predictors of uncontrolled BP varied considerably by BMI status. CONCLUSION: Several common and unique patient- and physician-level determinants of BP values and control were identified for the High-BMI and Normal-BMI groups. These findings highlight the need for differentiating healthcare interventions to account for patient and physician variables, particularly with respect to effective BP management in vulnerable populations.

Gender-specific, multi-level determinants of outcomes of antihypertensive treatment: a sub-analysis of the Belgian PREVIEW study.

Gender-specific determinants of blood pressure (BP) values and control have not been the focus of clinical hypertension research. The purpose of this analysis was to identify gender-specific and multi-level (physician and patient) determinants of BP values and predictors of uncontrolled BP. We completed a subgroup analysis comparing men and women who participated in the Belgian PREVIEW study of second-line treatment effectiveness of valsartan, applying two-level hierarchical modelling of 90-day BP values and guideline-defined BP control. In total, 1665 women and 1525 men were treated by 504 general practitioners. Fewer women than men reached systolic BP (SBP) (P=0.015) and combined BP targets at 90 days (P=0.007). More than 26% of the variance in 90-day SBP (intra-class correlation coefficient (ICC)=0.270) and diastolic BP (DBP) (ICC=0.262) was attributable to physician-level factors for men; the physician-level ICCs for SBP and DBP were 0.259 and 0.268, respectively, for women. Determinants of 90-day BP values and predictors of uncontrolled BP varied considerably by gender. Many of the multi-level determinants of BP by gender are amenable to intervention, and the remainder can serve as warning signs to clinicians that patients may remain vulnerable to poor outcomes associated with sub-optimal BP control.

Methotrexate should not be used for patients with end-stage kidney disease.

Methotrexate is a widely used disease-modifying anti-rheumatic drug. Its effectiveness has been proven in placebo-controlled trials and in comparison with other disease-modifying anti-rheumatic drugs. The pharmacokinetics of methotrexate are highly variable and unpredictable. In patients with normal renal function, the recommended dose in rheumatoid arthritis ranges between 7.5 and 15 mg/week, but in recent years, even dosages up to 25 mg weekly are used. Toxicity includes myelosuppression, gastrointestinal adverse effects, hepatotoxicity and pneumonitis. Renal impairment and age are considered major risk factors for developing methotrexate toxicity, but studies show conflicting results. Whether methotrexate can be administered to patients with end-stage kidney disease has not been formally tested. The present case illustrates the severe side effects of low-dose methotrexate treatment in a patient with end-stage kidney disease. Seven other cases have reported similar and even more severe and irreversible consequences after low-dose regimen. In view of these side effects we strongly recommend to monitor toxicity rigorously in patients with stage 3 or stage 4 kidney disease and not to use methotrexate in patients with stage 5 kidney disease.

Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study.

BACKGROUND: A prognostic scoring system for hospital mortality in acute renal failure (Stuivenberg Hospital Acute Renal Failure, SHARF score) was developed in a single-centre study. The scoring system consists of two scores, for the time of diagnosis of acute renal failure (ARF) and for 48 h later, each originally based on four parameters (age, serum albumin, prothrombin time and heart failure). The scoring system was now tested and adapted in a prospective study. METHODS: The study involved eight intensive care units. We studied 293 consecutive patients with ARF in 6 months. Their mortality was 50.5%. The causes of ARF were medical in 184 (63%) patients and surgical in 108 (37%). In the latter group, 74 (69%) patients underwent cardiac and 19 (18%) vascular surgery. RESULTS: As the performance of the original SHARF scores was much lower in the multicentre study than in the original single-centre study, we re-analysed the multicentre data to customize the original model for the population studied. The independent variables were the score developed in the original study plus all additonal parameters that were significant on univariate analysis. The new multivariate analysis revealed an additional subset of three parameters for inclusion in the model (serum bilirubin, sepsis and hypotension). For the modified SHARF II score, r(2) was 0.27 at 0 and 0.33 at 48 h, respectively, the receiver operating characteristic (ROC) values were 0.82 and 0.83, and the Hosmer-Lemeshow goodness-of-fit P values were 0.19 and 0.05. CONCLUSION: After customizing and by using two scoring moments, this prediction model for hospital mortality in ARF is useful in different settings for comparing groups of patients and centres, quality assessment and clinical trials. We do not recommend its use for individual patient prognosis.

Aortic dissection and Turner's syndrome.

Cardiovascular malformations, especially coarctation of the aorta and bicuspid aortic valve, are common in patients with Turner's syndrome. Only 46 patients with aortic dissection and/or rupture have been described. All patients had associated aortic dilation or aneurysm. In all cases except three, involvement of the ascending aorta was present, making surgery often imperative. We describe a rare case of a DeBakey type IIIb aortic dissection (without involvement of the proximal aorta) in a patient with Turner's syndrome mosaicism. The dissection occurred two weeks after a caesarean section because of eclampsia. No aortic dilation or other cardiovascular malformations were found. The distal extension and uncomplicated nature of the dissection indicated medical management. After fifteen months of follow-up, she is clinically doing well and repeated CT scan shows a stable dissection of the descending and abdominal aorta without dilation.

Unilateral hydronephrosis and recurrent endometrial stromal sarcoma with review of the literature.

In this case we present a woman with arterial hypertension. Further examination showed an unilateral hydronephrosis caused by extrinsic compression. A tumoral mass, invading the caval inferior vein and the renal vein, is the very origin of the compression. This mass is a recidive of an endometrial stromal sarcoma for which she had a hysterectomy in 1984.

Intracaval extension of a recurrent low-grade endometrial stromal sarcoma.

We report the case of a patient undergoing successful removal of an intracaval extension of a recurrent low-grade endometrial stromal sarcoma sixteen years after complete surgical resection. Low-grade endometrial stromal sarcoma is rare uterine neoplasm with a excellent 5-year survival but with high incidence of relapse after a very long time. The tumour has a tendency for lymphatic and venous extension. Intracaval extension is an exceptional indication to perform caval surgery in the treatment of malignant neoplasm.

Odour perception in chronic renal disease.

BACKGROUND: The sense of smell plays an important role in the quality of life. Many studies have shown a declining odour perception in the elderly, as well as in subjects in poor health or nutritional state. Considering the high prevalence of poor nutritional state in renal disease and the importance of odour perception in nutrition and health, the relationship between renal function, nutritional state, and odour perception is explored in this study. METHODS: A total of 101 patients with chronic renal failure participated in the study. Thirty-eight haemodialysis patients (mean age = 64.3 years) were evaluated both before and after dialysis. Sixteen patients on peritoneal dialysis treatment (mean age = 64.0 years), 28 transplanted patients (mean age = 53.5 years, mean creatinine clearance = 64.0 ml/min) and 19 patients with varying degrees of renal insufficiency were also included (mean age = 63.7 years, mean creatinine clearance = 29.5 ml/min). Patients with cognitive deficits or upper respiratory airway diseases were excluded. A validated objective procedure was used to measure odour perception, by determining the detection threshold for isoamyl acetate (banana odour) as the lowest detectable odour concentration. RESULTS: Healthy control persons had significantly lower odour thresholds compared to patients on peritoneal (P = 0.001) and haemodialysis (P = 0.002). No significant difference was observed in odour perception between patients on peritoneal and haemodialysis (P = 0.779) and for patients on haemodialysis before and after a dialysis session. Transplanted patients had significantly better odour perception compared to matched patients on dialysis (P < 0.001). Odour perception of transplanted patients and matched healthy control persons was similar (P = 0.81). In patients with varying degrees of renal insufficiency, including healthy controls and transplanted patients, a significant positive correlation was found between odour perception and creatinine clearance (P = 0.02). A significant negative correlation was found between odour perception and serum concentration of urea (P < 0.001), serum phosphorus (P = 0.022) and protein catabolic rate (P < 0.05). Other parameters measuring nutritional status (albumin, BMI) were not correlated with odour perception. CONCLUSION: Our results show that the ability to smell is severely impaired in patients with chronic renal failure and is related to the degree of renal impairment and the degree of accumulation of uraemic toxins. After renal transplantation, patients have a normal odour perception, indicating the capacity of the olfactory system to recover once the concentration of uraemic toxins remains below a critical threshold. Acute removal of uraemic toxins by dialysis does not correct olfactory disturbances, suggesting a long lasting effect of uraemia on olfactory function.

Effect of amino acid administration on uremic muscle metabolism: a 31P-spectroscopy study.

The effect of a six-month peritoneal amino acid administration on muscle metabolism at rest and during exercise was examined in 12 patients (4 control and 8 amino acid treated) on continuous ambulatory peritoneal dialysis. 31P-magnetic resonance spectroscopy was used to measure several high-energy phosphates (PCr, Pi) in resting muscle and during exercise and recovery. At rest, no significant changes were detected between the non-treated (control) and the amino acid treated (experimental) group. Before the administration of amino acids, the exercise-induced fall in [PCr], the increase in [ADP] and [Pi] and the pH were not significantly different in the control and experimental group. The initial rate of PCr recovery and the calculated maximal rate of ATP-synthesis (Qmax) for the control subjects was not significantly different at the onset and the end of the study. In the treated group, however, the fall in [PCr] and increase in [ADP] after exercise were significantly lower after than before treatment, while [Pi] and pH were identical. The initial rate of PCr recovery and Qmax were also significantly improved. These changes indicate an improved oxidative phosphorylation under the treatment and suggest that the impaired oxidative metabolism of the dialysis patients could be the result of their bad nutritional state.

Effect of treatment with 1.25 and 1.75 mmol/l calcium dialysate on bone mineral density in haemodialysis patients.

The effect of two different dialysate solutions with a calcium concentration of 1.25 and 1.75 mmol/l was evaluated in 14 patients, using a cross-over design. Patients were treated with each solution during a period of 6 months. Treatment with calcium supplements, vitamin D and aluminium hydroxide was adapted weekly, according to the results of blood chemistry. PTH, SAP, and ionized calcium were determined monthly, bone density with DXA and QCT before and after 6 months of treatment. During treatment with both 1.25 and 1.75 calcium dialysate (cad), the control of serum calcium and phosphate was similar. PTH did not change during either treatment. SAP decreased during treatment with 1.75, but remained stable with 1.25 mmol/l cad. Bone density evaluated with DXA remained unchanged during both treatments. QCT measured bone density increased from 101.29 +/- 13.50 to 106.79 +/- 13.14 mg/ml in the 1.75 cad group, while it did not vary in the 1.25 cad group, (107.75 +/- 13.48 versus 108.97 +/- 13.40 mg/ml). It is concluded that lowering the calcium content of the dialysate does not negatively influence the control of serum calcium and phosphate, nor does it aggravate hyperparathyroidism when vitamin D is administered simultaneously. Under the present conditions, osteopenia and possibly bone mineralization improve only in the group dialysed with 1.75 Ca.

Legionnaires' disease and acute renal insufficiency: report of a case and review of the literature.

We report the case of a 73-year-old man, who developed acute renal failure in association with a Legionella pneumophila serotype 1 pneumonia. Renal biopsy revealed a tubulointerstitial nephritis. Treatment with erythromycin, rifampicin and haemodialysis resulted in a clinical resolution of the pulmonary and renal syndromes.

Kinin kinetics during different dialysis protocols with AN69 dialyser in ACEI-treated patients.

The effect of different dialysis modes on kinin kinetics was studied in seven stable haemodialysis patients treated with AN69 dialysers and ACE inhibitors (ACEI). AN69 haemodiafiltration with calcium-enriched substitution (HDF), AN69 haemodialysis with 1.75 (HD 1.75) and 1.50 (HD 1.50) mmol/l dialysate calcium, AN69 haemodialysis with 1.25 mmol/l dialysate calcium and substitution of 2.25 mmol/h calcium (HD+Ca), and cellulose acetate haemodiafiltration (CA HDF) were compared. Dialysis was uneventful in all patients. During dialysis, serum calcium, sodium, pH, albumin, and bradykinin were measured at the start and after 5 min at arterial, venous, and postinfusion side of the extracorporeal circuit. Serum predialysis bradykinin was 107 +/- 18fmol/ml (mean +/- SEM) in patients on HDF, 61 +/- 9 fmol/ml in patients on HD 1.50, 49 +/- 13 fmol/ml in patients on HD 1.75, 35 +/- 3 fmol/l in patients on HD+Ca, and 75 +/- 27 fmol/ml in CA HDF. No significant change of mean bradykinin levels occurred after 5 min at the arterial and venous side of the dialyser or postinfusion. Individual high bradykinin levels, up to 2672 fmol/ml, were observed but without clinical consequences, suggesting that the threshold value is difficult to determine. No significant correlations were evidenced between bradykinin levels and any of the biochemical measurements. The present data show an intraindividual variability of the bradykinin levels with variation coefficients ranging from 0.386 to 2.783. The present study illustrates that haemodialysis and haemodiafiltration with AN69 in ACEI-treated patients, under the present conditions, does not result in anaphylactoid reactions or in a clinically significant release of bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)