Giovambattista Capasso

Renal tubular transport and the genetic basis of hypertensive disease

Several monogenic hypertensive disorders are caused by genetic mutations leading to the deranged function and/or regulation of renal tubular NaCl transport, such as mutations of the renal epithelial Na+ channel (ENaC) in Liddle syndrome, of the kinase WNK1 (with no K) in Gordon syndrome, and of the mineralocorticoid receptor, or of 11β-hydroxysteroid dehydrogenase. Moreover, excessive formation of aldosterone in glucocorticoid-remediable hypertension leads to severe hypertension. Conversely, impaired function of the Na+,K+,2Cl− cotransporter (NKCC2), the renal outer medullary K+ channel (ROMK1), and the renal epithelial Cl− channel ClCKb/Barttin causes Bartter syndrome and defective Na+,Cl+ cotransporter (NCCT) Gitelman syndrome, salt-wasting disorders with hypotension. These monogenic disorders are rare, but illustrate the significance of renal tubular transport in blood pressure regulation. There is little doubt, however, that deranged renal salt reabsorption significantly contributes to essential hypertension polymorphisms of several genes participating in the regulation of renal Na+ transport have been shown to be associated with blood pressure and prevalence of hypertension. Two common genes will be discussed in more detail. The first encodes the renal Cl− channel ClCKb. A gain-of-function mutation of ClCKb, increasing channel activity by 7- to 20-fold is found in approximately 20% of unselected Caucasians and 40% of an unselected African population. The second common gene variant (prevalence, 3%–5% in unselected Caucasians), to be discussed in more detail, affects the serum and glucocorticoid inducible kinase SGK1, a kinase upregulated by mineralocorticoids and enhancing the activity of ENaC, ROMK, and Na+/K+ATPase. Both gene variants are associated with slightly increased blood pressure. SGK1 further stimulates the glucose transporter SGLT1, and the SGK1 gene variant correlates, in addition, with increased body mass index.

Risk factors for poor renal prognosis in children with hemolytic uremic syndrome

Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D−STEC− recovered normal renal function compared with 65%–76% of D+STEC+, D+STEC− and D−STEC+ patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D– but STEC+ patients have a significantly better prognosis.

A History of Salt

The medical history of salt begins in ancient times and is closely related to different aspects of human history. Salt may be extracted from sea water, mineral deposits, surface encrustations, saline lakes and brine springs. In many inland areas, wood was used as a fuel source for evaporation of brine and this practice led to major deafforestation in central Europe. Salt played a central role in the economies of many regions, and is often reflected in place names. Salt was also used as a basis for population censuses and taxation, and salt monopolies were practised in many states. Salt was sometimes implicated in the outbreak of conflict, e.g. the French Revolution and the Indian War of Independence. Salt has also been invested with many cultural and religious meanings, from the ancient Egyptians to the Middle Ages. Mans innate appetite for salt may be related to his evolution from predominantly vegetarian anthropoids, and it is noteworthy that those people who live mainly on protein and milk or who drink salty water do not generally salt their food, whereas those who live mainly on vegetables, rice and cereals use much more salt. Medicinal use tended to emphasize the positive aspects of salt, e.g. prevention of putrefaction, reduction of tissue swelling, treatment of diarrhea. Evidence was also available to ancient peoples of its relationship to fertility, particularly in domestic animals. The history of salt thus represents a unique example for studying the impact of a widely used dietary substance on different important aspects of mans life, including medical philosophy.

Beneficial Effects of Atrial Natriuretic Factor on Cisplatin-Induced Acute Renal Failure in the Rat

The organometal cisplatin has potent antitumor properties. However, its use is sometimes complicated by significant nephrotoxicity. This is characterized by tubular necrosis and impairment of the glomerular filtration rate (GFR). On the other hand, it has been demonstrated that atrial natriuretic factor (ANF) increases GFR in normal euvolemic rats. In the present study, we have therefore tested if this new potent natriuretic compound could restore some of the renal parameters affected by cisplatin. To investigate this issue, acute renal failure was induced in 9 rats by intraperitoneal injection of cisplatin 10 mg/kg body weight (b.w.). Renal function was studied 72 h later using the 3H-inulin clearance method and was compared with the renal function of 5 normal euvolemic rats. The cisplatin-treated rats showed high blood urea nitrogen levels, a 74% reduction of whole kidney GFR (0.308 +/- 0.047 vs. 1.17 +/- 0.08 ml/min/100 g b.w.) and a significant increase in the fractional excretion of urine, sodium and potassium. After 2 control clearances, synthetic ANF was administered intravenously as a prime (12 micrograms/kg b.w.) and then as a constant infusion (1 microgram/kg/min) to 6 cisplatin-treated rats. This promptly doubled the GFR (0.603 +/- 0.113 ml/min/100 g b.w.) and induced a significant increase in the excretion rate of urine, sodium and potassium. These results demonstrate that the administration of ANF has a beneficial effect on the experimental model of acute renal failure induced by cisplatin.

Function and Dysfunction of Renal Transport Molecules: Lessons from Electrophysiology

The availability of cloned transport molecules achieved by efforts in expression cloning has allowed their electrophysiological analysis in the Xenopus oocyte expression system. We describe the electrogenic uptake of various substrates by their corresponding transport molecules originally expressed in brush border membranes of proximal tubules. The functional properties of the following transport molecules are discussed: the sodium-coupled glucose transporter, the sodium-coupled phosphate transporter, the sodium-coupled sulfate transporter and the sodium-independent transporter of neutral and dibasic amino acids. Additionally, functional consequences of naturally occurring disease-causing mutations in some of these transport molecules are described.

Reabsorption of Bicarbonate Along the Nephron: Importance of Potassium

In order to assess the relationship between potassium and renal bicarbonate transport, micropuncture studies were carried out on superficial rat nephrons. The microcalorimetric method was used to quantitate bicarbonate reabsorption (JHCO3). Two segments were studied: 1) the loop of Henle and 2) the distal tubule. In the first set of experiments, superficial loops of Henle were microperfused in vivo from late proximal to early distal tubule. Three groups of rats were investigated: 1) control rats 2) rats maintained either on 2) low or 3) high potassium diets. The loops were perfused with solutions containing 2 or 4 mM K+. In control conditions JHCO3 was 150.3 ±5.0 pmol/min. This value was not affected by low or high potassium diet. In the second set of experiments free-flow micropuncture studies were carried out on superficial rat distal tubules. Experiments were performed in a) control conditions and b) during dietary potassium withdrawal. In normal conditions we observed highly significant, load dependent, net JHCO3. Distal bicarbonate reabsorption persisted in hypokalemic alkalosis and, at comparable early distal loads, hypokalemia exerted a powerful stimulation on distal JHCO3. These data demonstrate that along the loop of Henle, JHCO3 is unaffected by changes in potassium intake, while in the distal tubule JHCO3 is stimulated by potassium depletion.

The Effect of Parathyroid Hormone on Cisplatin Nephrotoxicity

The clinical use of cisplatin as an antineoplastic agent is limited by its nephrotoxicity that, in many cases, includes acute tubular necrosis and renal wasting of various electrolytes (1–4). Several studies have been performed to account for the various disorders of renal function induced by cisplatin. The decrease in GFR, for example, has been found to be related to a reduction in renal blood flow and to a lowered effective filtration pressure (5). The reported concentrating defect and the observed impaired sodium reabsorption have been associated to a defect in papillary hypertonicity found in cisplatin treated rats (6), while the potassium wasting effect is in part due to a negative potential difference induced by cisplatin in late distal segments (6). Finally the pathogenesis of cisplatin induced hypomagnesemia has been attributed to pathological changes confined to the straight portion (S3 segment) of superficial nephrons (7). On the other hand many therapeutic strategies have been tested to reduce its nephrotoxic action: the fall in GFR, for example, can be modified by hydration, mannitol diuresis (8) and by the administration of atrial natriuretic peptide (9); moreover compounds that provide SH groups have been reported to reduce the cisplatin associated renal injury (10).