Idiopathic Recurrent Calcium Urolithiasis (IRCU): variation of fasting urinary protein is a window to pathophysiology or simple consequence of renal stones in situ? A tripartite study in male patients providing insight into oxidative metabolism as possible driving force towards alteration of urine composition, calcium salt crystallization and stone formation*

<p>Abstract</p> <p>Background</p> <p>In IRCU it is uncertain whether variation of urinary protein, especially non-albumin protein (NAlb-P), is due to the presence of stones or reflects alteration of oxidative metabolism.</p> <p>Aims</p> <p>To validate in a tripartite cross-sectional study of 187 ambulatory male patients, undergoing a standardized laboratory programme, whether stones impact on N-Alb-P or the state of oxidative metabolism interferes with IRCU pathophysiology.</p> <p>Methods</p> <p>In part 1 the strata low and high of fasting urinary excretion rate per 2 h of N-Alb-P, malonedialdehyde, hypoxanthine, xanthine, pH and other urine components were compared, and association with renal stones in situ evaluated; in part 2 the co-variation of oxidatively modulated environment, fasting urinary pH, calcium (Ca) salt crystallization risk and the number of patients with stones in situ was examined; in part 3, the nucleation of Ca oxalate and Ca phosphate was tested in undiluted postprandial urine of patients and related to the state of oxidative metabolism.</p> <p>Results</p> <p>In part 1, N-Alb-P excretion > 4.3 mg was associated with increase of blood pressure, excretion of total protein, hypoxanthine (a marker of tissue hypoxia), malonedialdehyde (a marker of lipid peroxidation), sodium, magnesium, citrate, uric acid, volume, pH, and increase of renal fractional excretion of both NAlb-P and uric acid; when stones were present, urinary pH was elevated but other parameters were unaffected. Significant predictors of N-Alb-P excretion were malonedialdehyde, fractional N-Alb-P and hypoxanthine. In part 2, urine pH > 6.14 was associated with unchanged blood pressure and plasma vasopressin, increase of blood pH, urinary volume, malonedialde hyde, fractional excretion of N-Alb-P, uric acid, Ca phosphate, but not Ca oxalate, supersaturation; this spectrum was accompanied by decrease of concentration of urinary total and free magnesium, total and complexed citrate, plasma uric acid (in humans the major circulating antioxidant) and insulin; the number of stone-bearing patients was increased. Significant predictors of urine pH were body mass index, plasma insulin and uric acid (negative), and urinary xanthine (positive). In part 3 low plasma uric acid, not high urinary malonedialdehyde or high ratio malonedialdehyde/uric acid was significantly associated with diminished Ca but not oxalate tolerance, with the first nucleating crystal type being mostly Ca phosphate (hydroxyapatite), in the rest Ca oxalate dihydrate; uricemia correlated marginally positively (p = 0.055) with Ca tolerance of urine, stronger with blood pressure and insulin, and negatively with urinary xanthine, fractional N-Alb-P, volume, sodium.</p> <p>Conclusions</p> <p>In IRCU 1) not renal stones in situ, but disturbed oxidative metabolism apparently modulates nephron functionality, ending up in higher renal NAlb-P release, urinary volume, sodium and pH of fasting urine; 2) etiologically unknown decline of uricemia may represent antioxidant deficiency and cause a risk of hydroxyapatite crystallization and stone formation in a weakly acidic or alkaline inhibitor-deficient and NAlb-P-rich milieu; 3) several observations, linking oxidative and systemic metabolism, are compatible with Ca stone initiation beyond tubules.</p

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Non-standard errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Contribution to the speleology of Sterkfontein cave, Gauteng province, South Africa.

The authors present more data about the speleological aspect of the Sterkfontein Cave, famous for its bone breccia which yielded abundant hominid remains. They also briefly review the previous voluminous studies by numerous authors, which are mainly dealing with the paleontology, stratigraphy and sedimentology of the breccia. The present investigations were oriented to hitherto poorly investigated aspects such as detail mapping of the cave, its country rock stratigraphy and recording the underground extension of the basal part of the breccia body. The cave consists of a complex network of phreatic channels, developed along joints in Neoarchaean cherty dolostone over a restricted surface of 250x250m. The combined length of all passages within this area amounts to 5,23km. The system extends over a height of about 50m and the dry part of it is limited downwards by the water-table appearing as numerous static pools. The fossiliferous breccia (= Sterkfontein Formation) forms an irregular lenticular mass 75x25m horizontally by 40m vertically, which is included within the passage network. It crops out at surface and in the cave, and resulted from the filling of a collapse chamber, which was de-roofed by erosion. The present investigation confirmed that the cave and the Sterkfontein Formation are part of a single speleogenetic event. The breccia resulted from cavity filling by sediments introduced from a pit entrance, whereas many of the phreatic passages around it, which are developed at the same elevation, were only partly filled or remained entirely open up to present. This filling took place mainly in a vadose environment. Taking into account the age of the Sterkfontein Formation (>3,3-1,5 My, from base to top), the geomorphic evolution of the landscape and the context of other caves in the region, it seems that the cave might have started to form 5 My ago. It has been continuously developing up to present as a result of a slow drop of the water-table

Contribution to the speleology of Sterkfontein Cave, Gauteng Province, South Africa

The authors present more data about the speleological aspect of the Sterkfontein Cave, famous for its bone breccia which yielded abundant hominid remains. They also briefly review the previous voluminous studies by numerous authors, which are mainly dealing with the paleontology, stratigraphy and sedimentology of the breccia. The present investigations were oriented to hitherto poorly investigated aspects such as detail mapping of the cave, its country rock stratigraphy and recording the underground extension of the basal part of the breccia body. The cave consists of a complex network of phreatic channels, developed along joints in Neoarchaean cherty dolostone over a restricted surface of 250x250m. The combined length of all passages within this area amounts to 5,23km. The system extends over a height of about 50m and the dry part of it is limited downwards by the water-table appearing as numerous static pools. The fossiliferous breccia (= Sterkfontein Formation) forms an irregular lenticular mass 75x25m horizontally by 40m vertically, which is included within the passage network. It crops out at surface and in the cave, and resulted from the filling of a collapse chamber, which was de-roofed by erosion. The present investigation confirmed that the cave and the Sterkfontein Formation are part of a single speleogenetic event. The breccia resulted from cavity filling by sediments introduced from a pit entrance, whereas many of the phreatic passages around it, which are developed at the same elevation, were only partly filled or remained entirely open up to present. This filling took place mainly in a vadose environment. Taking into account the age of the Sterkfontein Formation (\u3e3,3-1,5 My, from base to top), the geomorphic evolution of the landscape and the context of other caves in the region, it seems that the cave might have started to form 5 My ago. It has been continuously developing up to present as a result of a slow drop of the water-table