A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy.

The chelator somatostatin analogue dota-D-phe(1)-tyr(3)-octreotide (DOTATOC), which is stably labeled with the beta-emitting radioisotope yttrium 90 ((90)Y), is used as internal radiotherapy for the treatment of patients with advanced neuroendocrine tumors. We report 5 patients who developed chronic renal failure, caused in 3 patients by biopsy-proven thrombotic microangiopathy (TMA). Twenty-nine patients (14 men, 15 women) with normal renal function before therapy were treated with divided intravenous doses of (90)Y-DOTATOC approximately 6 weeks apart (mean normalized cumulative dose, 165.4 +/- 36.4 mCi/m(2)). Twenty-two of 29 patients were administered a normalized cumulative dose of 200 mCi/m(2) without side effects. Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m(2), 5 patients (4 women, 1 man) developed renal failure. Increasing serum creatinine levels were observed within 3 months after the last (90)Y-DOTATOC injection. The evolution was rapidly progressive in 3 patients, resulting in end-stage renal failure within 6 months. The remaining 2 patients developed chronic renal insufficiency (mean serum creatinine level, 300 micromol/L an average 16 months after the end of treatment). Renal biopsies performed in 3 patients showed typical signs of TMA involving glomeruli, arterioles, and small arteries. Patients treated with high-dose (90)Y-DOTATOC internal radiotherapy (cumulative dose > 200 mCi/m(2)) are at high risk to develop severe renal failure caused by TMA lesions. The histopathologic lesions are identical to those found after external radiotherapy, which suggests a causal relationship between (90)Y-DOTATOC and renal TMA.

Sodium balance-neutral sodium profiling does not improve dialysis tolerance.

BACKGROUND: Modern haemodialysis monitors offer computerised ultrafiltration and sodium concentration profiles which promise better dialysis tolerance. This presumption was tested in chronic haemodialysis patients. METHODS: Using Fresenius MC 4008S monitors a group of nine patients were dialysed with a given ultrafiltration profile comparing sessions with decreasing sodium concentration (145 to 133 mmol/L) to sessions with constant sodium concentration (138 mmol/L) in random order. The built-in blood volume monitor recorded changes in haematocrit and blood volume during each dialysis. The analyses included dialytic weight loss, interdialytic weight gain and adverse symptoms (hypotensive episodes and muscle cramps). RESULTS: 321 dialysis sessions, 160 with and 161 without sodium profile, were available for analysis. No significant differences could be detected regarding changes in haematocrit, blood volume and weight in relation to sodium profiling. No significant difference in the incidence of hypotension or muscle cramping was observed with 55 symptomatic dialyses of 160 with sodium profile, compared to 52 symptomatic dialyses of 161 without sodium profile. Interdialytic weight gain and consequent weight loss during dialysis was higher in symptomatic dialyses both with sodium profile or without sodium profile. The same was true of increase in haematocrit and decrease in blood volume, which were greater for symptomatic versus symptom-free dialyses irrespective of sodium profiling. CONCLUSIONS: Sodium balance-neutral sodium profiling failed to improve dialysis tolerance in a group of stable chronic haemodialysis patients. This may be explained by the fact that vascular refilling as deduced from changes in haematocrit was uninfluenced by sodium profiling.

Evidence for disturbed S-adenosylmethionine : S-adenosylhomocysteine ratio in patients with end-stage renal failure: a cause for disturbed methylation reactions?

BACKGROUND: Elevated homocysteine concentrations have been associated with premature arteriosclerosis and with impairment of key methylation reactions through accumulation of the homocysteine metabolite S-adenosylhomocysteine. In end-stage renal failure high homocysteine concentrations are commonly found but thus far the concentrations of related adenosylated metabolites in plasma have not been assessed. METHODS: In this prospective study we determined plasma homocysteine and related metabolites in 25 patients on regular haemodialysis, and in 40 healthy volunteers. Blood samples from patients were drawn immediately before and in 10 patients additionally after the dialysis session. RESULTS: Folic acid and vitamin B12 in plasma were similar in patients (mean +/- SEM 25+/-2 nmol/l and 400+/-41 pmol/l respectively) and controls (24+/-3 and 324+/-23 respectively). In patients plasma homocysteine, S-adenosylmethionine and S-adenosylhomocysteine were markedly elevated (36.6+/-3.6 micromol/l, 381+/-32nmol/l and 1074+/-55 nmol/l respectively) compared to the control values (6.8+/-0.4 micromol/l, 60+/-3 nmol/l and 24.4+/-1.1 nmol/l respectively) whereas the molar ratio of plasma S-adenosylmethionine and S-adenosylhomocysteine was significantly decreased (0.36+/-0.02 and 2.7+/-0.2 in patients and controls respectively). Haemodialysis failed to normalize the abnormal levels of these metabolites. CONCLUSION: Since the ratio of S-adenosylmethionine : S-adenosylhomocysteine is closely linked to the activity of numerous enzymatic methylation reactions, these results suggest that methylation may be impaired in these patients.

Three consecutive day collection of dialysate and urine to identify non-compliance in CAPD patients.

BACKGROUND: Compliance with dialysis prescription is all important determinant of adequacy of CAPD. Several reports have suggested that non-compliance may be detected by a high creatinine excretion ratio (CrEx ratio = measured creatinine excretion in a 24-h collection of urine and dialysate/predicted creatinine excretion) and that it occurs in a substantial proportion of patients. However the validity of this screening method to identify non-compliant patients has been questioned, mostly because of the interindividual variation of creatinine excretion in a CAPD population. METHODS: Whenever possible we performed a 3-day collection of dialysate and urine in all patients on our CAPD programme, and calculated the daily CrEx ratio. Non-compliance was defined as a progressive and greater than 7.5% decrease of the CrEx ratio associated with a more than 7.5% decrease of serum creatinine during the test. RESULTS: Among 19 patients only one (5%) fulfilled both criteria for non-compliance and the subsequent interview revealed that he was truly non-compliant. The other patient admitting non-compliance had a significant decrease of CrEx ratio but showed only a slight decrease of serum creatinine. CONCLUSIONS: Our preliminary results suggest that this 3-day collection test, unlike previous procedures, identifies non-compliance with a good specificity. However, it may not be sensitive enough to detect a low level of non-compliance and has the disadvantage of being quite cumbersome. It may require further refinements to be clinically useful.

[Management of renal osteopathy in patients with chronic dialysis]. / Management der renalen Osteopathie bei Patienten mit chronischer Dialyse.

During the past decade considerable progress has been made in the field of calcium metabolism associated with chronic renal failure. The main factor influencing the pathophysiology of calcium homeostasis is its dependence on parathyroid hormone and active vitamin D metabolites. Among several new diagnostic tools, and to establish the diagnosis of renal osteodystrophy, only the measurement of i-PTH activity has any clinical relevance. The main goal in treating renal osteodystrophy is the lowering of PTH activity by correcting hyperphosphatemia and administration of calcitriol given either orally or intravenously. Furthermore, the need to lower the calcium concentration in the dialysate during calcitriol treatment is demonstrated. The clinical significance of adynamic osteodystrophy is still unclear.

Malignancies after renal transplantation: the EDTA-ERA registry experience. European Dialysis and Transplantation Association-European Renal Association.

The incidence of malignancies in recipients of renal transplants was compared to that in non-grafted patients on maintenance dialysis as reported to the EDTA-ERA Registry and in the general population as recorded by the cancer registries of England and Wales, of Sweden, of the (former) German Democratic Republic, and of Lombardy and Varese in Northern Italy. For tumours known to be associated with immunosuppression, namely Kaposi's sarcoma, non-Hodgkin lymphoma and the common malignancies of the skin (except melanoma), an increased incidence was confirmed for the transplanted population. Thyroid carcinoma and hepatoma were found to be more frequent in non-grafted patients on dialysis as well as after renal transplantation. An increased incidence of cancer of the cervix and of the body of the uterus was recorded only for young cohorts with a functioning graft but not for women after menopause. Most of the other malignancies had similar incidences in grafted and non-grafted populations which did not differ from those in the general populations of the cancer registries except cancer of the colon which was slightly more frequent, particularly at 10-20 years after the first transplant operation. Survival after diagnosis of cancer at the most frequent sites, such as bronchopulmonary, breast, oesophagogastric and colorectal cancer, did not differ between non-grafted patient groups on dialysis and those who developed the tumour while carrying a functioning renal transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term benefits and risks of cyclosporin A (sandimmun)--an analysis at 10 years.

To evaluate long-term benefits and risks of CyA therapy in renal transplantation, we analyzed the 10-year experience with all 59 patients who had received a first cadaveric renal graft until August 1983 and were immunosuppressed with CyA. We compared their actual graft survival with that of all 213 patients who had received a first cadaveric graft from 1967 until August 1983, but were immunosuppressed initially with azathioprine and prednisone (AzaP). For comparison of p-creatinine, proteinuria, blood pressure, lipids, uric acid and skin malignancies we evaluated the patients staying unchanged on initial therapy for 10 years (CyA = 12, AzaP = 53). RESULTS. (1) Actual graft survival at 10 years was 34% (20/59) with CyA and 27% (58/213) in AzaP treated patients (intention to treat) (P = .09 = ns). At 1 to 5 years, graft survival was 15% superior with CyA, but after 7 years the survival curve of the CyA-group has closely joined the chronic decline seen in the AzaP group. This behaviour could neither be explained by chronic CyA-nephrotoxicity nor by chronic rejection after switching from CyA to AzaP. (2) P-creatinine at 10 years was significantly (P < .03), but mildly elevated under CyA (130 +/- 52; AzaP = 109 +/- 65). (3) Proteinuria (g/d) at 10 years was not significantly different (CyA = 0.41 +/- 0.58, versus AzaP = 0.83 +/- 1.61). (4) Systolic blood pressure was higher at 10 years under CyA (152 +/- 19) than under AzaP (136 +/-) (P < .02), but diastolic pressure was not (89 +/- 10 versus 84 +/- 12; ns). Antihypertensive drug/patient was twice as high under CyA (1.25 versus 0.64 P < .02). (5) Cholesterol, triglyceride, HDL were not different. 75% of the CyA-patients were steroid free at 10 years, none of the AzaP-patients. (6) P-uric acid was not significantly different in both groups (494 +/- 192 vs 400 +/- 124), but 42% of CyA-patients were on uric acid lowering drug (given after at least one gout attack) as compared to 9% under AzaP (P < .006). (7) Seventeen percent of patients under CyA for 10 years had at least one skin cancer, not different from 15% of AzaP-patients. CONCLUSIONS. The main benefit of CyA was the better graft survival up to 5 years and the chance to stay free of steroids. The main risks of CyA were nephrotoxicity, hypertension and symptomatic hyperuricemia. No difference was found for hyperlipidemia and skin-malignancies.

Weight-independent dosing of cyclosporine--an alternative to the "mg/kg" doctrine.

Cyclosporine is usually prescribed as "mg CsA per kg body weight", and blood levels are used for guiding CsA therapy. The present study evaluated whether it is sensible to dose in "mg/kg" if one wishes to obtain specific CsA blood levels. In a retrospective analysis, 1071 consecutive CsA whole-blood trough levels from 164 renal transplant patients, measured by monoclonal parent RIA, were correlated with the respective oral CsA doses and several demographic parameters, including gender, age, weight, height, and time after transplantation. From this, we derived a concept of "weight-independent CsA dosing" which was prospectively tested in three series of patients during the first days after renal transplantation: 58 patients received 2x 100 mg/day CsA from day 0 with the intention to reach target levels of 40-80 ng/ml, 42 patients received 2x 200 mg/day CsA from day 4 (target: 100-200 ng/ml), and 38 patients received 2x 300 mg/day from day 4 (target: 100-200 ng/ml). In the retrospective analysis, the individual, patient-specific relation of CsA level to CsA dose (in mg) was found to depend only on height (P = 0.02) and time after transplantation (P < 0.001), but not on body weight (b. wt.). If the CsA dose was expressed in "mg/kg", patients < or = 55 kg b. wt. required nearly twice the doses of patients > or = 75 kg b. wt., whereas the mean CsA requirement was the same when expressed in "mg".(ABSTRACT TRUNCATED AT 250 WORDS)

End-stage renal failure due to analgesic nephropathy, its changing pattern and cardiovascular mortality. EDTA-ERA Registry Committee.

The changing pattern of prevalence and age distribution of analgesic nephropathy as a cause of end-stage renal failure (ESRF) in patients on RRT was analysed using the EDTA-ERA Registry's files. Comparing 1990 to 1981, the percentage of patients with analgesic nephropathy decreased in many European countries and the Registry's average came down from 3 to 2%. The highest prevalence was noted for Switzerland, which showed a decrease from 28 in 1981 to 12% in 1990. During the same interval the age distribution shifted to the right with an increase in median age from 57 to 63 at start of RRT for analgesic nephropathy. In Switzerland the age-specific acceptance rate to RRT for patients with analgesic nephropathy decreased to less than 1/3 in the age cohorts below 55 but increased in those aged 65 or older. This increase in the elderly cohorts appeared to be related to the growing acceptance rate to RRT of elderly patients in general rather than to an increasing incidence of ESRF due to analgesic nephropathy. Mortality in general and death rates due to cardiovascular causes were found not to differ in RRT patients with analgesic nephropathy from that of other standard primary renal diseases (excluding diabetic nephropathy and systemic diseases). Some 20 years after withdrawal of phenacetin from the analgesic market, analgesic nephropathy all but disappeared as a cause of ESRF in Sweden and Denmark, and the same may be expected to occur in countries like Switzerland, Belgium, and others in the not too far distant future.

[Pathophysiology of dehydration]. / Pathophysiologie der Dehydration.

The pathophysiology of dehydration is reviewed. The normal response to dehydration, i.e. decreased effective arterial blood volume or effective circulating volume is described. Due to water retention and drinking following stimulation of ADH secretion and thirst, osmoregulation is overruled by volume conservatory mechanisms, which lead to hyponatremia. Only patients with impaired mental function or those who are unable to drink will develop a progressive water deficit--with or without salt depletion--recognizable by hypernatremia. Decreased effective arterial blood volume and hypernatremia affect cerebral function in a way that perception of external stimuli as well as perception of pain will be impaired. Alert dehydrated patients are disturbed mainly by thirst and dryness of the mouth. Both symptoms are perceived more intensely by young than by elderly persons. Dryness of the mouth increase thirst on its own. Distress by thirst and oral dryness increases as a function of the level and the rapidity of developing hypernatremia. The simple act of filling the oral cavity with fluid and swallowing alleviates thirst in the absence of any change in plasma sodium concentration. Thirst quenching efficacy is increased by administering chilled hypotonic fluid with lemon or other fruit acid added (for stimulation of salivation).

Cyclosporin A-induced transient rise in plasma alkaline phosphatase in kidney transplant patients.

In 1981 cyclosporin A (CyA) became available and replaced azathioprine (Aza) as the immunosuppressive agent in kidney transplantation at the University Hospitals in Basel, Switzerland. Patients on CyA and prednisone (CyA/p) therapy frequently demonstrated an isolated rise in bone-derived serum alkaline phosphatase (aP) concentration, but patients on Aza and prednisone (Aza/p) therapy did not. On the basis of long-term aP concentration and using noninvasive means, the present retrospective study was designed to investigate biochemical markers and radiographic signs of bone disease after successful kidney transplantation in patients on Cya/p treatment. Similar investigations were performed in patients on Aza/p and the results were compared. Follow-up examinations included clinical examination, radiography of the hand, and biochemical analysis of serum and urine. In 139 renal transplant patients on CyA/p, aP increased transiently after successful grafting (at transplantation 84 +/- 43 U/l; on day 90, 112 +/- 82 U/l). In 50 patients aP levels were higher at the time of transplantation (120 +/- 80 U/l) and aP peaked after 8 +/- 6 months, at a mean concentration of 242 +/- 103 U/l. In these patients aP concentrations exceeded the normal range for 16 +/- 10 months. None of the patients on CyA/p showed symptoms of bone disease when aP was increased. Radiological surveys revealed more pronounced osteodystrophy in patients at the time of transplantation, which increased aP to above the normal range after transplantation. Despite this rise in aP, over the long term bone lesions improved radiographically while bone mass remained stable.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors influencing anaemia in dialysis patients. A special survey by the EDTA-ERA Registry.

The European Dialysis and Transplantation Association-European Renal Association (EDTA-ERA) Registry conducted a special study on anaemia in dialysis patients because it seemed important to elucidate the various factors that influence the degree of anaemia and the use of regular transfusions in dialysis patients before the introduction of recombinant human erythropoietin (rHuEpo) for larger groups of patients. In a 20% sample of all patients recorded to have been dialysed throughout 1987, statistically significant associations could be found by multifactorial analysis between haemoglobin (Hb) concentration and age, sex, primary renal disease, type of treatment, hours of dialysis per week, and number of years on renal replacement therapy. The type of dialyser membrane did not seem to play a role (although there was weak evidence of an effect of the dialyser). Mean Hb concentration for dialysis patients differed between countries as did the transfusion policy. In view of the high costs of the rHuEpo treatment and potential side-effects, factors such as method of dialysis and hours of haemodialysis per week should be taken into consideration in the treatment of anaemia in dialysis patients.

Risks and benefits of graft biopsy in renal transplantation under cyclosporin-A.

261 patients who received a kidney transplant under cyclosporin-A immunosuppression were reviewed in order evaluate the benefits and the risks of renal graft biopsies. 240 graft biopsies were performed in 124 of the 261 patients. The biopsy diagnoses were 103x rejection, 90x cyclosporin-A toxicity, 8x acute tubular necrosis, 8x glomerulonephritis, 9x different biopsy results, and 12 cases of normal renal tissue. In 214 cases the clinical course was well explained by the biopsy result. The histological results led to therapeutical changes in 199 cases. 221 of the 240 biopsies were performed without any complications. There was only one biopsy with irreversible and there were 19 biopsies with reversible complications.

[Bone and joint problems in long-term dialysis]. / Knochen- und Gelenkprobleme bei Langzeitdialyse.

Bone and joint pathology in patients undergoing long-term dialysis for end-stage renal failure is presented in the light of typical cases and a brief review of the literature. Osteomalacia with bone pain and fractures is caused mainly by aluminium overload due to enteral uptake from aluminium-containing phosphate binders. This is why calcium acetate or calcium carbonate should be used exclusively to lower enteral phosphate reabsorption. If--due to hypercalcemia--aluminium containing phosphate binders--cannot be entirely avoided, they should never be administered together with citrate (citrate-containing medication, fruit juice, etc.), which chelates aluminium and thereby massively increases enteral aluminium uptake. Secondary hyperparathyroidism with overt radiologically demonstrable bone disease develops in many patients on long-term dialysis despite efforts to maintain plasma calcium within or slightly above the upper normal range and concomitant treatment with calcitriol. Intravenous administration of relatively high-dose calcitriol or 1-alpha-OH-D3 (neither readily available at the present time), as well as the newly developed experimental vitamin D analogs such as 22-oxa-(OH)2-D3, which appear to suppress the parathyroid glands without increasing enteral calcium reabsorption, may in future reduce the high incidence of parathyroidectomy in patients on maintenance dialysis. beta 2-microglobulin amyloidosis is a new disease entity which develops in the majority of long-term dialysis patients. Apart from carpal tunnel syndrome, trigger fingers and tendon ruptures, it is associated with acute and chronic painful erosive arthropathy with joint effusions and fractures, particularly around the hip, due to cystic bone lesions where bone is replaced by nodular amyloid deposits.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressure dependent modulation of renin release in isolated perfused glomeruli.

The isolated perfused glomerulus technique was used to study pressure dependence of renin release in single, microdissected rabbit glomeruli with intact afferent arteriole and intact Bowman's capsule. Renin release from individual afferent-glomerular units was measured in 30 minute intervals while afferent arteriolar pressure was either decreased from 55 to 40 to 25 mm Hg or increased from 25 to 40 to 55 mm Hg. There was a clear, inverse relation of renin release and afferent pressure. Mean renin release rate was 3.2 times higher at 25 than at 55 mm Hg and 1.5 times higher at 40 than at 55 mm Hg. To evaluate the possible role of wall stretch in mediating this response, inner and outer afferent arteriolar diameters were measured by videomicroscopy. Outer afferent diameter remained constant between 25 and 55 mm Hg, whereas inner diameter exhibited a slight increase. Changes of afferent arteriolar wall stretch, however, did not correlate with changes of renin release. These data for the first time directly demonstrate the existence of a renin baroceptor at the level of the renal afferent arteriole. They furthermore suggest that this baroceptor is not a stretch receptor.