Lessons from a pilot study of screening for upper tract urothelial cell carcinoma in Lynch syndrome.

BACKGROUND: Lynch syndrome is a hereditary disorder, with a very high risk of developing colorectal carcinoma (CRC) and a predilection to develop other cancers, including upper tract urothelial carcinoma (UTUC). We aimed to assess the prevalence of UTUC in a Lynch syndrome cohort undergoing screening for CRC, to determine the need for a UTUC screening programme. METHODS: Lynch syndrome patients were screened with urine dipstick for microscopic haematuria. Patients with confirmed microhaematuria were offered urine cytology, microscopy and culture, ultrasound (US) of their upper tracts and flexible cystoscopy. RESULTS: Of the 89 patients screened, 86 had an MLH1 mutation and two had an MSH2 mutation. Eleven of the 12 patients who had microscopic haematuria were female. Ten patients had urinary tract infections. One patient had follicular cystitis and another had a simple renal cyst. No patients had hydronephrosis on ultrasound. All urine cytology specimens were negative for malignancy. CONCLUSION: No cases of UTUC were detected in our cohort during this study. A more rational screening protocol in this group may be to screen patients for UTUC with known MSH2 mutations at an earlier age (over 35).

SabreSource™: a novel percutaneous nephrolithotomy apparatus to aid collecting system puncture - a preliminary report.

BACKGROUND: Successful percutaneous nephrolithotomy (PCNL) relies on a technically challenging, precise needle puncture of the renal collecting system. We aimed to compare, in an ex vivo model, the use of a real time image guidance system (the SabreSource™) and a mechanical stabilising device with conventional manual techniques for the accuracy of needle placement. METHODS: The SabreSource™ system (Minrad International Inc.; New York, USA) is a real time image guidance system. The system platform is mounted on a C-arm fluoroscope. It employs targeting cross hairs on the fluoroscopic image that can be easily positioned to target the desired renal calyx. The system directs a visible laser beam onto the patient which is precisely aligned with the cross hairs on the fluoroscopic image. This provides the correct "bull's-eye" angle of approach to the calyx, even after the x-ray source is turned off. The locator then stabilises the needle in the "bull's-eye" position so that only screening for depth is required. Objective assessment using a simulated PCNL puncture was performed by 7 urologic trainees on a kidney phantom with and without using the SabreSource™. Fluoroscopy screening time (FST) and amount of radiation (mGy) used to achieve successful puncture were compared. RESULTS: Simulated PCNL puncture was quicker and resulted in reduced radiation exposure when the apparatus was used. The mean FST for traditional "bull's-eye" vs SabreSource™ puncture was 17 vs 5 seconds (p = 0.01), and the mean radiation exposure to puncture was 0.7 vs 0.2 mGy (p = 0.03), respectively. CONCLUSION: The SabreSource™ is a novel assistant to achieving successful PCNL puncture. In combination with "the locator" the preliminary in vitro testing suggests that the device reduces fluoroscopy exposure and is quicker. The device warrants further evaluation in the clinical setting.

General and dietary oxalate restriction advice reduces urinary oxalate in the stone clinic setting.

BACKGROUND: Idiopathic hyperoxaluria is a risk factor for developing calcium oxalate nephrolithiasis. Dietary oxalate's effect on urinary oxalate is not well studied. The aim of this study is to assess the effect of advice focused on reducing dietary oxalate in a cohort of idiopathic hyperoxaluric patients. METHODS: Patients referred to the Groote Schuur Hospital Stone Clinic from 2015 to 2017 were considered eligible, if they were an idiopathic hyperoxaluric stone former, excreting > 40 mg/d of urinary oxalate on a pre-intervention 24-hour stone study urinalysis. Patients were asked to adhere to a diet sheet which included general stone prevention advice (low salt diet, increased fluid intake and moderate protein intake) and specific low oxalate diet advice. A post-intervention 24-hour urinalysis was performed at six weeks. RESULTS: Nineteen patients had hyperoxaluria (eight men and 11 women) with a mean age of 49 years (range 25-76 years). The mean BMI of the group was 28.4 kg/m2 (17.4-50). All patients had mean number of 1.9 range prior stone episodes (range 1-6 stone episodes). Fourteen (14/19) patients completed the study. The mean pre-dietary advice urinary oxalate was 53.2 mg/24 hours (n = 14), SD while the post-intervention was 29.6 mg/24 hours SD (p = 0.0002). Only 3/14 patients who completed the assessment failed to normalise their urinary oxalate on the diet. CONCLUSION: In the stone clinic setting, general advice of low salt diet, increased water intake, moderate protein intake and specific oxalate restriction can significantly reduce oxalate excretion in hyperoxaluric stone formers. Sustained reduction of oxalate excretion and longitudinal clinical benefit are worthy of study in larger cohorts.

Towards solving the riddle of nephrolithiasis: a South Africa perspective.

INTRODUCTION: South Africa has a rich tradition in urinary tract stone research. This paper asks what research originating from South Africa has contributed to the understanding of the pathophysiology of nephrolithiasis. Many of these contributions are based on the premise that ethnicity variation accounts for dramatic differences in the prevalence of nephrolithiasis and that South Africa represents an ideal place for investigating this variation. It needs to be noted that many of the papers dealing with this question, as Rodgers has put it, "demonstrate an insensitivity to racial terminology and classifications." We have nevertheless attempted to review these papers to understand what valid science this literature holds and how it can inform further work in the relatively under-investigated field of nephrolithiasis aetiology and pathophysiology.

Beware the bolus size: understanding intrarenal pressure during ureteroscopic fluid administration.

BACKGROUND: Flexible ureteroscopy (FURS) and laser lithotripsy for ureteric and renal calculi requires adequate irrigation for visualisation. This study aimed to evaluate how bolus administration of irrigant fluid impacts intrarenal pressure (IRP) during FURS. We also investigated how ureteral access sheaths (UAS) of varying sizes mitigate elevated IRP. METHODS: Using a porcine cadaveric model, IRP was evaluated using an arterial invasive pressure measurement system. Given a fluid column height (driving force) of 80 cm H2O, and varying bolus administration (1, 2, 3, 5, 10 ml), IRP was studied with and without a UAS. An IRP of < 40 mmHg was considered the cut off for "safe" FURS. The flow (drainage capacity) of UAS was also evaluated. At varying fluid column heights, three sizes of UAS were used, 10/12 French size (Fr), 11/13 Fr and 12/14 Fr, all 36 cm long. RESULTS: Bolus administration with a UAS of < 5 ml with a starting fluid column height of 80 cm H2O was "safe" (< 40 mmHg). In contrast, where no UAS was used, bolus sizes as small as 2 ml produced "unsafe" peak pressures. The flow through a 10/12 Fr UAS was poor but improved greatly with larger UAS diameters. CONCLUSION: This study suggests that 10/12 Fr UAS may be inadequate to maintain drainage from the kidney at acceptable pressures. Bolus fluid administration produces "unsafe" (> 40 mmHg) elevated IRP in the absence of a UAS. When a UAS is used, a fluid bolus of < 5 ml is likely "safe".

Investigating racial differences in clinical and pathological features of prostate cancer in South African men.

BACKGROUND: Men with West African ancestry living in Europe and North America are at higher risk of being diagnosed with prostate cancer, are diagnosed at a younger age, and have more severe disease characteristics. Published reports present a conflicting picture of the disease in sub-Saharan Africa. We aimed to study the clinical and pathological features of men undergoing prostate biopsy from different racial backgrounds in South Africa in an attempt to characterise the disease locally. Our hypothesis was that black African men presenting to our service had more severe disease characteristics than other patients. METHODS: All patients who underwent a prostate biopsy at Groote Schuur Hospital, Cape Town from July 2008 to July 2014 were studied. For each patient, data were collected on age, self-assigned race, presenting symptoms, prostate-specific antigen (PSA) level, prostate volume, and histological diagnosis. RESULTS: A total of 1016 patients were studied. 162 (15.9%) were black and 854 (84.1%) were coloured (mixed ancestry), white, or Asian. Black patients were compared as a group to the coloured, white and Asian patients. The black patients in the series had higher PSA values (mean 167.8 vs 47.7, median 16.4 vs 10.9, p < 0.001), were more likely to be diagnosed with cancer (57.4% vs 44.5%, p = 0.003), were more likely to present with locally advanced cancer (T3/4 16.1% vs 8.9%, p = 0.028), and were more likely to have high grade disease (Gleason ≥ 8 45.2% vs 30.5%, p = 0.011). There was no difference in age, presenting symptoms, or prostate volume. CONCLUSION: The black men diagnosed with prostate cancer at Groote Schuur Hospital had significantly worse clinical and pathological characteristics than the non-black men. Interpreting these differences as representative of a more common or aggressive disease among black men is not possible due to study limitations.

Outcomes of outpatient ureteral stenting without fluoroscopy at Groote Schuur Hospital, Cape Town, South Africa.

BACKGROUND: Ureteral stenting is generally a theatre-based procedure that requires a multidisciplinary team and on-table imaging. Limited hospital bed numbers and theatre time in our centre in Cape Town, South Africa, have led us to explore an alternative approach. OBJECTIVES: To see whether outpatient insertion of ureteric stents under local anaesthesia without fluoroscopy was a possible and acceptable alternative to theatre-based ureteral stenting. METHODS: Ureteral stenting (double-J stents and ureteric catheters) was performed with flexible cystoscopy under local anaesthesia and chemoprophylaxis, but without fluoroscopic guidance, in an outpatient setting. Every patient had an abdominal radiograph and an ultrasound scan of the kidney after the procedure to confirm stent position. RESULTS: Three hundred and sixteen procedures (276 double-J stents and 40 ureteric catheters) were performed in 161 men and 155 women. The overall success rate for the procedures was 85.4%, independent of gender (p=0.87), age (p=0.13), type of device inserted (p=0.81) or unilateral/bilateral nature of the procedure (p=1.0). Procedures with a successful outcome were performed in a significantly (p<0.0001) shorter median time (10 minutes (interquartile range (IQR) 5 - 15)) than failed procedures (20 minutes (IQR 10 - 30)). Patients with a pain score of >5 experienced a significantly (p=0.02) greater proportion of failure (27.3%) than patients with a pain score of ≤5 (12.5%). Difficulties were encountered in 23.7% of procedures, with a significantly higher proportion being registered in failed interventions compared with successful ones (82.6% v. 13.7%; p<0.0001). CONCLUSIONS: The procedure was easily mastered and technically simple, and represents savings in cost, time and human resources in our setting.

Investigating racial differences in clinical and pathological features of prostate cancer in South African men

Introduction: Men with West African ancestry living in Europe and North America are at higher risk of being diagnosed with prostate cancer, are diagnosed at a younger age, and have more severe disease characteristics. Published reports present a conflicting picture of the disease in sub-Saharan Africa. We aimed to study the clinical and pathological features of men undergoing prostate biopsy from different racial backgrounds in South Africa in an attempt to characterise the disease locally. Our hypothesis was that black African men presenting to our service had more severe disease characteristics than other patients. Methods: All patients who underwent a prostate biopsy at Groote Schuur Hospital, Cape Town from July 2008 to July 2014 were studied. For each patient, data were collected on age, self-assigned race, presenting symptoms, prostate-specific antigen (PSA) level, prostate volume, and histological diagnosis. Results: A total of 1016 patients were studied. 162 (15.9%) were black and 854 (84.1%) were coloured (mixed ancestry), white, or Asian. Black patients were compared as a group to the coloured, white and Asian patients. The black patients in the series had higher PSA values (mean 167.8 vs 47.7, median 16.4 vs 10.9, p < 0.001), were more likely to be diagnosed with cancer (57.4% vs 44.5%, p = 0.003), were more likely to present with locally advanced cancer (T3/4 16.1% vs 8.9%, p = 0.028), and were more likely to have high grade disease (Gleason ≥ 8 45.2% vs 30.5%, p = 0.011). There was no difference in age, presenting symptoms, or prostate volume. Conclusion: The black men diagnosed with prostate cancer at Groote Schuur Hospital had significantly worse clinical and pathological characteristics than the non-black men. Interpreting these differences as representative of a more common or aggressive disease among black men is not possible due to study limitations

Inguinal Herniation Containing Bladder, Causing Contralateral Allograft Hydroureteronephrosis-A Case Report and Literature Review.

We report the first documented case of an inguinal hernia containing bladder, resulting in contralateral allograft hydroureteronephrosis. A 39-year-old male patient presented with allograft dysfunction, a contralateral inguinoscrotal hernia, and marked hydroureteronephrosis on ultrasound (US). Percutaneous nephrostogram and a retrograde cystogram suggested bladder herniation with incorporation of the contralateral ureteroneocystostomy into the hernia. Paraperitoneal bladder herniation was confirmed at surgery and hernioplasty was performed. Six-week follow-up revealed normal renal function with no sign of hernia recurrence. Despite occurring rarely, transplant ureter or bladder herniation should be considered in the differential diagnosis of hydroureteronephrosis. This case illustrates that the contralateral position of hernia to allograft does not necessarily preclude the hernia as the source of ureteric obstruction.

Is there a role of C-reactive protein in red blood cell aggregation?

INTRODUCTION: Numerous clinical studies related the plasma level of C-reactive protein (CRP) to the erythrocyte sedimentation rate (ESR) independent of the kind of disease. The molecular regulation of the process is unknown. METHODS: We performed a meta-analysis of 10 previous studies and experimentally probed for a direct action of CRP on red blood cells (RBCs) by different methods including determination of a microscopic aggregation index, Ca(2+) imaging and analysis of sedimentation experiments. RESULTS: The meta-analysis revealed a statistically significant correlation (Pearson coefficient of 0.37; P < 0.0001), but we could not find any experimental evidence for a direct CRP-RBC interaction. Instead, we could confirm a correlation between fibrinogen level and ESR. CONCLUSION: Therefore, we concluded that CRP and ESR cannot account for nor replace each other as a diagnostic measure. The correlation between CRP level and ESR is most probably caused by fibrinogen, because its increase coincides with elevated CRP levels.

The plasma protein fibrinogen stabilizes clusters of red blood cells in microcapillary flows.

The supply of oxygen and nutrients and the disposal of metabolic waste in the organs depend strongly on how blood, especially red blood cells, flow through the microvascular network. Macromolecular plasma proteins such as fibrinogen cause red blood cells to form large aggregates, called rouleaux, which are usually assumed to be disaggregated in the circulation due to the shear forces present in bulk flow. This leads to the assumption that rouleaux formation is only relevant in the venule network and in arterioles at low shear rates or stasis. Thanks to an excellent agreement between combined experimental and numerical approaches, we show that despite the large shear rates present in microcapillaries, the presence of either fibrinogen or the synthetic polymer dextran leads to an enhanced formation of robust clusters of red blood cells, even at haematocrits as low as 1%. Robust aggregates are shown to exist in microcapillaries even for fibrinogen concentrations within the healthy physiological range. These persistent aggregates should strongly affect cell distribution and blood perfusion in the microvasculature, with putative implications for blood disorders even within apparently asymptomatic subjects.

B-type natriuretic peptide in the evaluation and management of dyspnoea in primary care.

OBJECTIVES: The rapid and accurate diagnosis of heart failure in primary care is a major unmet clinical need. We evaluated the additional use of B-type natriuretic peptide (BNP) levels. DESIGN: A randomized controlled trial. SETTING: Twenty-nine primary care physicians in Switzerland and Germany coordinated by the University Hospital Basel, Switzerland. SUBJECTS: A total of 323 consecutive patients presenting with dyspnoea. INTERVENTIONS: Assignment in a 1 : 1 ratio to a diagnostic strategy including point-of-care measurement of BNP (n = 163) or standard assessment without BNP (n = 160). The total medical cost at 3 months was the primary end-point. Secondary end-points were diagnostic certainty, time to appropriate therapy, functional capacity, hospitalization and mortality. The final diagnosis was adjudicated by a physician blinded to the BNP levels. RESULTS: Heart failure was the final diagnosis in 34% of patients. The number of hospitalizations, functional status and total medical cost at 3 months [median $1655, interquartile range (IQR), 850-3331 vs. $1541, IQR 859-2827; P = 0.68] were similar in both groups. BNP increased diagnostic certainty as defined by the need for further diagnostic work-up (33% vs. 45%; P = 0.02) and accelerated the initiation of the appropriate treatment (13 days vs. 25 days; P = 0.01). The area under the receiver-operating characteristics curve for BNP to identify heart failure was 0.87 (95% confidence interval, 0.81-0.93). CONCLUSIONS: The use of BNP levels in primary care did not reduce total medical cost, but improved some of the secondary end-points including diagnostic certainty and time to initiation of appropriate treatment.

Evaluation of human erythrocytes as model cells in photodynamic therapy.

The role of erythrocytes as targets in photodynamic therapy is a controversially discussed topic in the literature. Therefore five different, but well known photosensitisers (three zinc phthalocyanines, tetrabenzoporphine and pheophorbide a delivered in liposomes were used for photodynamic treatment of human erythrocytes. The phototoxic effect on these cells showed pronounced differences. It was in the range: zinc phthalocyanine = pheophorbide a > tetrabenzoporphine >> zinc octa-n-alkyl phthalocyanines. Data from the zinc octa-n-alkyl phthalocyanines were compared with photodynamic effects within cutaneous cell lines, treated under the same experimental conditions. The results show that erythrocytes are unlikely to make good models for predicting the efficiency of the photosensitiser in general, and the same applies to cells other than erythrocytes and in vivo. Possible reasons could be differences in dye accumulation. However, erythrocytes may well serve as model cells to explore the cellular and molecular mechanisms of photodynamic treatment.

Malaria parasite Plasmodium gallinaceum up-regulates host red blood cell channels.

The properties of the malaria parasite-induced permeability pathways in the host red blood cell have been a major area of interest particularly in the context of whether the pathways are host- or parasite-derived. In the present study, the whole-cell configuration of the patch-clamp technique has been used to show that, compared with normal cells, chicken red blood cells infected by Plasmodium gallinaceum exhibited a 5-40-fold larger membrane conductance, which could be further increased up to 100-fold by raising intracellular Ca(2+) levels. The increased conductance was not due to pathways with novel electrophysiological properties. Rather, the parasite increased the activity of endogenous 24 pS stretch-activated non-selective cationic (NSC) and 62 pS calcium-activated NSC channels, and, in some cases, of endogenous 255 pS anionic channels.

The non-selective voltage-activated cation channel in the human red blood cell membrane: reconciliation between two conflicting reports and further characterisation.

Using the patch-clamp technique, the non-selective, voltage-activated cation channel in the human red blood cell (RBC) membrane was further characterised. Activity of the cation channel could be demonstrated at a range of salt concentrations with the current-voltage characteristics for monovalent cations going from linear to superlinear functions, depending on the cation concentration in the range of 100-500 mM. The non-selective voltage-activated cation channel was demonstrated to be permeable to the divalent cations Ca2+ and Ba2+, and even Mg2+. The current-voltage relations for the divalent cations were superlinear even at 75 mM salt concentration, but indicated outward rectification in contrast to the I-V curve for monovalent cations. The degree of activation at a given membrane potential depended strongly on the prehistory of the channel. The gating exhibited hysteretic-like behaviour, since the quasi steady-state deactivation and activation curves were displaced by approximately 25 mV. This result fully explains apparent discrepancies between V0.5-values previously obtained by slightly different experimental protocols. The possible physiological/pathophysiological role of the channel is discussed in the context of the demonstrated permeability for divalent cations.

Non-selective voltage-activated cation channel in the human red blood cell membrane.

Using the patch-clamp technique, a non-selective voltage-activated Na+ and K+ channel in the human red blood cell membrane was found. The channel operates only at positive membrane potentials from about +30 mV (inside positive) onwards. For sodium and potassium ions, similar conductances of about 21 pS were determined. Together with the recently described K+(Na+)/H+ exchanger, this channel is responsible for the increase of residual K+ and Na+ fluxes across the human red blood cell membrane when the cells are suspended in low ionic strength medium.