[Pathophysiology and diagnosis of renal tubular acidosis]. / Pathophysiologie und Diagnostik renal tubulärer Azidosen.

Intrinsic defects in tubular transport mechanisms of the kidney may cause impairment of urinary acidification or a loss of base equivalents, thereby inducing systemic metabolic acidosis. Different types of this disorder termed renal tubular acidosis (RTA) can be distinguished based on the localization of the disturbance along the nephron (proximal vs. distal) and their association with potassium transport (hypo-/hyperkalemic). Except for the proximal type RTA results in positive acid balance and negatively impacts on bone metabolism and the formation of kidney stones. The diagnosis is based on analysis of acid/base status, urinary pH and determination of ammonium excretion after an oral acid load. Both functional defects of specific tubular transport mechanisms and global impairment of renal tubular function can be causative of RTA. Their therapy is based on treatment of the primary disease process and correction of acidosis by alkali supplementation.

Prolonged course of pure red cell aplasia after erythropoietin therapy.

Pure red cell aplasia (PRCA) caused by neutralising anti-erythropoietin antibodies is a very rare disease. Since 1998, an increased incidence of PRCA in patients with kidney failure following treatment with recombinant human erythropoietin (rhEpo) has been reported, mostly in Europe. In most cases, PRCA was cured by immunosuppressive therapy, immunoglobulins, plasmapheresis or renal transplantation. We report an exceptionally prolonged course of PRCA over 68 months despite renal transplantation and different immunosuppressive regimens.

Renal pathology and premortem clinical presentation of Caucasian patients with AIDS: an autopsy study from the era prior to antiretroviral therapy.

PRINCIPLES: Renal disease in patients with HIV infection is becoming increasingly frequent. A particular form of HIV-associated nephropathy (HIVAN) has been found in patients of predominantly African-American and Hispanic origin. However, only limited data are available on renal pathology and premortem clinical presentation of kidney disease in Caucasian patients with AIDS. METHODS: To determine the prevalence, clinical presentation and aetiology of renal disease in Caucasian patients with AIDS at the time of death we have performed a prospective autopsy study with 239 patients who died of AIDS between 1981 and 1989. None of these patients had received HIV-specific antiretroviral therapy. Autopsies and histological analyses were performed on the basis of a standardised protocol. Clinical and laboratory data were gathered according to a uniform questionnaire. RESULTS: 95% of patients were of Caucasian race. 75% of all patients had extended AIDS (stage IV). Clinical signs of nephropathy prior to death were found in 36% of patients, including proteinuria (18%), abnormal urinary sediment (19.5%), and renal insufficiency (11%). Histopathological lesions were present in 43% of the autopsies, with two or more distinct structural lesions in 12.5% of patients. Of the pathological findings 28% were glomerular or vascular, 33% were non-glomerular, and 29% were combined lesions. The remaining 10% were renal infiltrations of infectious agents or neoplastic tissue. The most common findings were ischaemic changes and vascular scars (18% of patients), as well as pyelo- and interstitial nephritides (12.2%). Importantly, FSGS was present in only 1.7% of patients, and only a single African patient had classical HIVAN. CONCLUSIONS: Renal involvement in HIV disease is very common at the time of death among patients of Caucasian origin. However, classical HIV-associated nephropathy is absent in this population. These findings suggest that kidney disease affects all races and supports the hypothesis that HIVAN is specifically related to non-Caucasian ethnicity. The results reflect renal disease unaffected by HIV-specific antiretroviral therapy.

Renal safety of combined cyclooxygenase 2 (COX-2) inhibitor and angiotensin II receptor blocker administration in mild volume depletion.

PRINCIPLES: Drugs that either inhibit prostaglandin synthesis or antagonise angiotensin II effects are likely to impair renal function, especially in patients with an activated renin-angiotensin-aldosterone system. Of the former, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, and newer agents with cyclooxygenase 2 (COX-2) specific inhibition may have fewer renal side effects compared to non-selective NSAIDs. We therefore investigated whether combination of a COX-2 inhibitor with an angiotensin II subtype 1 (AT1) receptor blocker is safe with regard to preservation of normal renal function in a state of slight volume contraction. METHODS: Mild volume depletion was induced by a salt-restricted diet in 5 healthy volunteers who were then given a single dose of 400 mg celecoxib, a COX-2 inhibitor, alone or in combination with 150 mg irbesartan, an AT1 receptor blocker. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by measuring inulin and PAH clearance respectively, along with plasma renin activity (PRA) and urinary electrolyte excretion before and over 100 minutes after drug administration. RESULTS: PRA was high prior to drug administration, indicating slight salt depletion, and dropped by 65% after intake of celecoxib alone (p = 0.008) but only by 25% after combined intake with irbesartan (p = n.s.). GFR was not affected either by celecoxib alone or by combined administration with irbesartan. In contrast, ERPF increased by 28% 80 minutes after simultaneous drug intake (p = 0.029), but not after celecoxib alone. Renal sodium and potassium excretion did not significantly change under celecoxib alone or in combination with irbesartan. CONCLUSION: Selective COX-2 inhibition by celecoxib in combination with an AT1 receptor blocker (irbesartan) has no acute adverse effects on renal haemodynamics and renal salt handling in slightly volume-depleted subjects with normal renal function. Moreover, our data obtained in humans appear to confirm the co-regulatory interaction of COX-2 and angiotensin II in the control of renin release, as suggested by animal studies.

[Pediatric kidney transplantation and living donors--invaluable by virtue of necessity]. / Pädiatrische Nierentransplantation und Lebendspende--aus der Not eine Tugend.

UNLABELLED: Renal transplantation is the treatment of choice for paediatric patients with end-stage renal failure. Living donor transplantation (LDT) has become an important therapeutic option due to the shortage of cadaver donors and increasingly long waiting times. METHODS: Between 1992 and 1999, a total of 48 paediatric and adolescent patients underwent renal transplantation in Zurich. Of these, 21 patients (44%) received a kidney from a living related donor. 11 patients had been dialysed before LDT over a period of 0.2-5.7 years (median 0.6), and 10 were transplanted preemptively. Triple immunosuppression consisted of cyclosporine A, azathioprine or mycophenolate mofetil (MMF; since 1998), and prednisone. The observation period was 0.5-7.3 years (median 2). RESULTS: Recipients were 2-18 (median 10.5) years old at transplantation. One third had either a congenital malformation, an inherited disease, or an acquired disorder. One patient died of an associated cardiac disease at 4 months with functioning graft, and one functional graft loss occurred after 2.8 years. 9 patients were switched from cyclosporine to tacrolimus, 7 for biopsy-proven rejection and 2 for cosmetic reasons (hypertrichosis). No antibody preparations were used. Median glomerular filtration rate (51Cr-EDTA), measured after one year in 11 donor/recipients, was 64 (55-95) and 54 (32-82) ml/min/1.73 m2, respectively. The most recent estimated renal function (Schwartz formula) of 19 functioning grafts was 37-79 ml/min/1.73 m2 (median 63). Median body height of 16 patients with no associated extrarenal disease was -0.9 SDS (standard deviation score); the remaining 3--with serious extra-renal disease--were considerably growth retarded. Main complications were reversible rejection episodes in 19 (90%), arterial hypertension (16), CMV disease (2) and asymptomatic CMV infection (3), pyelonephritis (3), and recurrence of the primary renal disease, seizures, diabetes mellitus and non-compliance (one each). Actuarial patient and graft survival (Kaplan-Meier) after 3 years was 95 and 83% respectively. This was not statistically different from the cadaveric donor group (n = 27) with 100 and 80% survival respectively. Overall rehabilitation was excellent. The donors were 12 mothers, 8 fathers and one grandmother aged 31 to 50 (median 39) years; none of them experienced serious postoperative problems. CONCLUSIONS: The paediatric transplantation programme would no longer be feasible in Switzerland without LDT. The results are very encouraging; preemptive transplantation makes it possible to avoid dialysis in half of the patients. The risk for the donor is small, and careful evaluation without putting pressure on the family is essential.

Randomized trial of conversion from mycophenolate mofetil to azathioprine 6 months after renal allograft transplantation.

BACKGROUND: In the first year after renal allograft transplantation, triple therapy immunosuppression with cyclosporin (CsA), prednisone (P), and mycophenolate mofetil (MMF) is superior to a triple therapy treatment that includes azathioprine (AZA) instead of MMF. Whether long-term treatment with CsA-P-MMF is better than treatment with CsA-P-AZA is a matter of debate, as 3-year graft survival is similar in MMF- and AZA-treated patients. The purpose of the present study was to examine the short-term effect of changing MMF to AZA in low-risk renal allograft recipients 6 months after transplantation. METHOD: This was a randomized, open-label single-centre study, recruiting 48 low risk renal allograft recipients on CsA-P-MMF therapy 6 months after transplantation, comparing the outcome with continued MMF treatment (2 g b.i.d.) (group A, n=22) or switching MMF to AZA (1 mg/kg) treatment (group B, n=26). RESULTS: The outcome after a 6-months follow-up of patients in group A and group B was similar. Treatment failure rates (defined as clinically diagnosed acute rejection episodes) were 4.5% in group A and 3.8% in group B. There were no patient deaths and no graft failures during the 6-months observation period. Graft function was excellent and similar in both groups. CONCLUSION: Replacing MMF with AZA 6 months after transplantation in low-risk renal allograft recipients is safe and is not associated with altered graft function in the short term.

[Epidemiology of chronic hepatitis B and C among dialysis patients in Switzerland]. / Epidemiologie der chronischen Hepatitis B und C bei Dialysepatienten in der Schweiz.

BACKGROUND: Among patients with renal insufficiency undergoing chronic dialysis treatment, chronic hepatitis due to infection with viruses of the hepatitis B (HBV) or hepatitis C (HCV) type represents a serious medical problem. In contrast to other countries, detailed statistics on the prevalence of HBV and HCV infection are not available for dialysed patients in Switzerland. METHODS: The present study is based on a nationwide survey among the Swiss dialysis population which evaluated the prevalence of patients positive for either the HBs antigen (reflecting HBV infection) or anti-HCV antibodies (reflecting HCV infection) in 1999. From our survey we collected data on 1713 haemodialysis and 226 peritoneal dialysis patients, representing 92 and 65% of the respective dialysis populations in Switzerland. RESULTS: Of all patients (haemodialysis and peritoneal dialysis), 6.59% were HBV or HCV marker positive (HBV: 1.44%, HCV: 5.05%). In haemodialysis patients the prevalence was clearly higher for HBV (1.63%) and HCV (5.72%) compared to patients undergoing peritoneal dialysis (0.88 and 3.09% respectively). Laboratory parameters of hepatitis--as evidenced by an increase in liver transaminases--were present in 4% of the entire dialysis cohort, 0.6% having an increase in ALAT beyond 1.5 times the normal range. Patients undergoing treatment in haemodialysis units which do not implement additional precautions to prevent the spread of HCV among patients were more likely to be HCV marker positive with laboratory signs of hepatitis. A similar correlation was observed between HBV or HCV marker positivity and the number of patients treated per haemodialysis unit. Finally, the percentage of HBV/HCV marker positive patients on the Swiss kidney transplant list is comparable with that of HBV/HCV marker positive patients in the entire dialysis population.

Metabolic aspects of phosphate replacement therapy for hypophosphatemia after renal transplantation: impact on muscular phosphate content, mineral metabolism, and acid/base homeostasis.

Hypophosphatemia caused by renal phosphate loss occurs frequently after kidney transplantation. In assumption of systemic phosphorus depletion, the presumed deficit commonly is replaced by oral phosphate supplements. However, such treatment is debatable, because intracellular phosphorus stores have not been assessed in this setting and may not be accurately reflected by serum phosphate concentrations. Moreover, disturbances in mineral metabolism from chronic renal failure, such as hypocalcemia and hyperparathyroidism, may be prolonged with oral phosphate supplements. Conversely, a neutral phosphate salt might improve renal acid excretion and systemic acid/base homeostasis for its properties as a urinary buffer and a poorly reabsorbable anion. Twenty-eight patients with mild early posttransplantation hypophosphatemia (0.3-0.75 mmol/L) were randomly assigned to receive either neutral sodium phosphate (Na(2)HPO(4)) or sodium chloride (NaCl) for 12 weeks and examined with regard to (1) correction of serum phosphate concentration and urinary phosphate handling; (2) muscular phosphate content; (3) serum calcium and parathyroid hormone (PTH); and, (4) renal acid handling and systemic acid/base homeostasis. Mean serum phosphate concentrations were similar and normal in both groups after 12 weeks of treatment; however, more patients in the NaCl group remained hypophosphatemic (93% versus 67%). Total muscular phosphorus content did not correlate with serum phosphate concentrations and was 25% below normophosphatemic controls but was completely restored after 12 weeks with and without phosphate supplementation. However, the percentage of the energy-rich phosphorus compound adenosine triphosphate (ATP) was significantly higher in the Na(2)HPO(4) group, as was the relative content of phosphodiesters. Also, compensated metabolic acidosis (hypobicarbonatemia with respiratory stimulation) was detected in most patients, which was significantly improved by neutral phosphate supplements through increased urinary titratable acidity. These benefits of added phosphate intake were not associated with any adverse effects on serum calcium and PTH concentrations. In conclusion, oral supplementation with a neutral phosphate salt effectively corrects posttransplantation hypophosphatemia, increases muscular ATP and phosphodiester content without affecting mineral metabolism, and improves renal acid excretion and systemic acid/base status.

Gastric pouch acid secretion in response to physiologic digestive function.

OBJECTIVES: To evaluate acid secretion and histologic features of the gastric segment used for bladder replacement in bladder cancer. METHODS: Nine patients were investigated a mean of 36 months after gastric pouch surgery with modified shamfeeding and feeding. We determined urinary acidity, urinary pH, serum gastrin, and serum pancreatic polypeptide values and tried to find a relationship between feeding and acid secretion in the gastric pouch. In 6 patients, biopsy and histopathologic examination were performed. RESULTS: In 8 patients, urinary acidity increased after feeding following the rise of gastrin; in 1 patient no increase of gastrin or acidity was observed. In 7 patients, urinary acidity did not change after modified shamfeeding, indicating vagal denervation after surgery. This group showed a minimal urinary pH of above 4 after feeding. On the other hand, in 2 patients an increased acid secretion was observed after modified shamfeeding, indicating the possible presence of residual vagal innervation. In this group, the acid secretion in the pouch was higher, reaching the minimal pH level earlier after feeding. Histopathologic examination showed no major structural changes of gastric mucosa. CONCLUSIONS: Most patients are vagally denervated after gastric pouch surgery, and the gastric segment continues its original gastrointestinal function by a hormonal pathway. Our data indicate, however, that in some patients, the gastric pouch keeps a residual vagal innervation. We therefore suggest that nerve fibers present in the blood supply of the gastric segment be interrupted to avoid the complications associated with increased acid secretion of the gastric pouch.

Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil.

BACKGROUND: Several multinational controlled clinical trials have shown that triple therapy immunosuppressive regimens which include mycophenolate mofetil (MMF), cyclosporin A (CSA) and steroids (S) are superior compared with conventional regimens which include azathioprine (AZA), CSA and S, mainly because MMF reduces the rate of acute rejection episodes in the first 6 months after kidney transplantation. Post-marketing studies are useful to evaluate the general applicability and costs of MMF-based immunosuppressive regimens. METHODS: Based on the excellent results of the published controlled clinical trials, we have changed the standard triple therapy immunosuppressive protocol (AZA+CSA+S) to an MMF-based regimen (MMF+CSA+S) at our centre. To analyse the impact of this change in regimen, we have monitored 6-month patient and graft survival, rejection rate, serum creatinine and CSA levels, as well as the costs of the immunosuppressive and anti-rejection treatments, in 40 consecutive renal transplant recipients (MMF group) and have compared the data with 40 consecutive patients transplanted immediately prior to the change in regimen (AZA group). RESULTS: Recipient and donor characteristics were similar in the AZA and MMF groups. Patient survival (37/40; 92.5% in the AZA group vs 38/40; 95% in the MMF group), graft survival (36/40 vs 36/40; both 90%) and serum creatinine (137+/-56 vs 139+/-44 micromol/l) after 6 months were not significantly different. However, the rate of acute rejection episodes (defined as a rise in creatinine without other obvious cause and treated at least with pulse steroids) was significantly reduced with MMF from 60 to 20% (P=0.0005). The resulting cost for rejection treatment was lowered 8-fold (from sFr. 2113 to 259 averaged per patient) and the number of transplant biopsies was lowered > 3-fold in the MMF group. The cost for the immunosuppressive therapy was increased 1.5-fold with MMF (from sFr. 5906 to 9231 per patient for the first 6 months). CONCLUSIONS: The change from AZA to MMF resulted in a significant reduction in early rejection episodes, resulting in fewer diagnostic procedures and rehospitalizations. The optimal long-term regimen in terms of patient and pharmacoeconomic benefits remains to be defined.

Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).

In the absence of exogenous glucocorticoids, decreasing media pH (from 7.4 to 6.8) for 24 hours increased the Na+/H+ exchanger 3 (NHE3) activity in opossum kidney (OKP) cells. 10(-7) M and 10(-8) M hydrocortisone increased NHE3 activity, and in their presence, acid incubation further increased NHE3 activity. Hydrocortisone (10(-9) M) had no effect on NHE3 activity, but in its presence, the effect of acid incubation on NHE3 activity increased twofold. Aldosterone (10(-8) M) had no effect. In the absence of hydrocortisone, acid incubation increased NHE3 protein abundance by 47%; in the presence of 10(-9) M hydrocortisone, acid incubation increased NHE3 protein abundance by 132%. The increase in NHE3 protein abundance was dependent on protein synthesis. However, 10(-9) M hydrocortisone did not modify the effect of acid incubation to cause a twofold increase in NHE3 mRNA abundance. In the absence of protein synthesis, 10(-9) M hydrocortisone did potentiate an effect of acid on NHE3 activity, which was due to trafficking of NHE3 to the apical membrane. These results suggest that glucocorticoids and acid interact synergistically at the level of NHE3 translation and trafficking.

Regulation of renal phosphate transport by acute and chronic metabolic acidosis in the rat.

Metabolic acidosis results in impaired renal tubular phosphate reabsorption and proximal tubular apical brush border membrane (BBM) sodium gradient-dependent phosphate transport (Na/Pi cotransport) activity. In the present study we investigated the cellular mechanisms responsible for decreased Na/Pi cotransport activity following six hours to 10 days of metabolic acidosis induced by ingestion of NH4Cl. Urinary Pi excretion was significantly increased and BBM Na/Pi cotransport activity was progressively and significantly decreased by 18% at six hours, 24% at 12 hours, 32% at 24 hours, and 61% after 10 days of metabolic acidosis. The progressive and time-dependent decreases in BBM cotransport activity were associated with progressive decreases in BBM NaPi-2 protein (43% at 12 hr, 54% at 24 hr and 66% at 10 days) and cortical NaPi-2 mRNA (22% at 12 hr, 54% at 24 hr and 56% at 10 days) abundance. Interestingly, following six hours of metabolic acidosis, there was a significant 29% decrease in BBM NaPi-2 protein abundance that was not associated with decreases in either cortical homogenate NaPi-2 protein or cortical NaPi-2 mRNA abundance. In additional studies we found that the effects of chronic metabolic acidosis on Na/Pi cotransport activity were independent of endogenous parathyroid hormone activity, but were somewhat dependent on dietary Pi intake. In rats fed a high or a normal Pi diet metabolic acidosis caused significant decreases in Na/Pi cotransport activity, NaPi-2 protein and NaPi-2 mRNA abundance, however, in rats fed a low Pi diet the inhibitory effect of metabolic acidosis on Na/Pi cotransport were minimal and not significant. These results indicate that in chronic (> or = 12 hr) metabolic acidosis the progressive decrease in BBM Na/Pi cotransport activity is most likely mediated by decrease in BBM NaPi-2 protein and cortical mRNA abundance. In contrast, in acute (< or = 6 hr) metabolic acidosis the decrease in BBM Na/Pi cotransport activity is likely mediated by changes in the trafficking of the NaPi-2 protein that is, enhanced internalization from and/or impaired delivery of the NaPi-2 protein to the apical BBM.

Plasma hypercoagulability in haemodialysis patients: impact of dialysis and anticoagulation.

BACKGROUND: Thrombotic complications are common in patients with endstage renal disease and contribute substantially to the morbidity and mortality in this population. The aim of the present study was to: i) determine the prevalence and the extent of hypercoagulability in patients undergoing dialysis treatment by measuring parameters that directly reflect thrombin concentrations; ii) assess changes in coagulation status during haemodialysis (HD); iii) quantify the relative impact of heparin, dialysis and their combined effects on coagulation status and iv) detect factors that modify coagulation haemostasis in dialysis patients. METHODS: A total of 39 patients (HD: n = 29, CAPD: n = 10) was analysed for procoagulatory and fibrinolytic activity determined by measurements of partial thromboplastin time, prothrombin fragments F1 + 2, thrombin-antithrombin complexes and D-dimer concentrations. HD patients were investigated prior to and during dialysis. A subgroup of patients was infused heparin alone without dialysis or was dialysed without heparin administration. Furthermore, subgroup and correlation analyses were performed for the type of dialysis (HD vs CAPD), dialyzer and shunt, Kt/V, underlying disease and treatment with recombinant erythropoietin (rhEPO). RESULTS: Baseline levels of all parameters-procoagulatory and fibrinolytic--were substantially elevated in all patients, but to a higher degree among those on CAPD. Moreover, haemodialysis treatment increased procoagulatory markers even further, suggesting stimulated coagulation and/or insufficient anticoagulation during dialysis. However, after 3 h of dialysis thrombin concentrations, determined by quantification of prothrombin fragments, were inversely correlated with Kt/V. Selective heparin infusion diminished procoagulatory activity only slightly and incompletely, whereas HD without heparin resulted in excess thrombin accumulation. Finally, subgroup analyses revealed more pronounced thrombin formation among patients treated with polysulfon dialyzers, whereas erythropoietin dosage was positively related with lower procoagulatory activity. CONCLUSION: A majority of patients on dialysis are in a hypercoagulable state, which is further aggravated by the haemodialysis procedure itself and may not be sufficiently controlled with current anticoagulation regimens. Intensified heparin treatment and the use of rhEPO are likely to improve coagulation haemostasis, whereas the type of dialyzer should be considered as a relevant procoagulatory factor.

Quantification and predictors of plasma volume expansion from mannitol treatment.

OBJECTIVE: To determine the effects of acute hypertonic mannitol infusion on intravascular volume expansion and to identify potential predictors of hypervolemia. DESIGN: Measurements of plasma volume and volume regulatory hormones were performed in healthy volunteers before and over 90 min after acute infusion of 20% mannitol solution in a therapeutic dose of 0.5 g/kg body weight, equalling an average infusion volume of 180 ml. SETTING: Clinical research unit in an 800-bed teaching hospital in the eastern part of Switzerland. PARTICIPANTS: Eight normal male volunteers. MEASUREMENTS AND RESULTS: Baseline plasma volume was determined by the indocyanine green dye dilution technique. Serial plasma protein measurements were performed after mannitol infusion to calculate intravascular volume changes. Mannitol administration resulted in a plasma expansion that persisted for more than 90 min and peaked at 112% of the baseline plasma volume 15 min after infusion. Concomitantly, an increase in systolic blood pressure and a fall in plasma sodium concentration occurred. Pharmacokinetic analyses of mannitol distribution and elimination revealed a close relation between plasma volume expansion and mannitol serum concentrations. While renin activity and aldosterone concentrations were suppressed proportionally to the intravascular volume increase, antidiuretic hormone was increased despite notable volume expansion and hyponatremia. Similarly, a rise in atrial natriuretic peptide was detected. CONCLUSIONS: Therapeutic doses of hypertonic mannitol cause substantial plasma volume expansion, resulting in increased blood pressure. Plasma volume expansion is related to mannitol serum concentrations and mannitol clearance determines the time required to restore normovolemia. ADH and ANP are potentially aggravating factors of mannitol-induced hyponatremia.

Chronic metabolic acidosis increases NHE3 protein abundance in rat kidney.

Chronic metabolic acidosis increases the activity of the proximal tubule apical membrane Na/H antiporter, which is encoded predominantly by the NHE3 isoform. The present studies examined the effect of chronic metabolic acidosis on apical membrane NHE3 protein abundance in rats. Rats subjected to NH4Cl in their drinking water developed a metabolic acidosis, which decreased in magnitude over 14 days. During this time, renal cortical brush-border membrane NHE3 protein abundance, assessed by Western blot, increased progressively (28% at 3 days, 59% at 7 days, and 90% at 14 days). Immunohistochemistry revealed that the acidosis-induced increase in NHE3 abundance occurred in the apical membranes of the S1 and S2 segments of the proximal tubule and the thick ascending limb. NHE3 mRNA abundance was not significantly increased in these animals, whereas phosphoenolpyruvate carboxykinase and glyceraldehyde-3-phosphate dehydrogenase mRNA abundances were significantly increased. These studies demonstrate that the increase in Na/H antiporter activity seen in metabolic acidosis involves an increase in NHE3 protein abundance, which is distributed along the proximal tubule and the thick ascending limb. In addition, these studies suggest that a component of this adaptation is unrelated to changes in NHE3 mRNA abundance.

[Fulminant hepatitis: pathogenesis, clinical aspects and management]. / Fulminante Hepatitis: Pathogenese, Klinik und Management.

Fulminant hepatic failure may develop as a complication of liver disease of various etiology. Infectious agents, drugs and liver toxins represent the major causes of fulminant hepatitis. The function of many organ systems may be impaired during acute hepatic failure because of the crucial role of the liver in intermediary metabolism. The mortality of 50% or more is mainly due to cerebral edema, bleeding from the gastrointestinal tract or disseminated infections. In this review the causes, complications and pathophysiology of fulminant hepatitis are discussed, with particular reference to the prevention of complications and to therapeutic strategies. Moreover, criteria for assessment of prognosis are discussed. A case report illustrates the complex clinical picture and frequently fatal outcome of the disease.

Evidence for human DNA-mediated transfer of the suppressed phenotype into malignant Chinese hamster cells.

Genetic suppression of the neoplastic phenotype has been demonstrated in somatic cell hybrids between tumor and normal cells. Suppression in whole-cell and microcell hybrids cannot, as yet, be attributed to specific elements defined at the molecular level. To identify a gene capable of suppressing the neoplastic phenotype, we have introduced DNA of normal human cells into tumorigenic Chinese hamster Wg3-h-o cells. Primary and secondary transfectants which exhibit the suppressed phenotype similar to Wg3-h-o x embryonic fibroblast hybrids were selected. The cells require serum growth factors and anchorage for proliferation in vitro and show a reduced tumorigenicity in nude mice. Transferred human DNA segments were molecularly cloned from a secondary transfectant. Indirect evidence suggests that the cloned human DNA is associated with the expression of the suppressed phenotype.