The PTH (1-84)/non-PTH (1-84) ratio is a risk factor for cardiovascular events in hemodialysis patients.

BACKGROUND: We hypothesized that the PTH (1-84)/non-PTH (1-84) ratio (PTH ratio) might help to assess cardiovascular risk in hemodialysis patients. METHODS: In this prospective cohort study 70 prevalent hemodialysis patients were followed up to 4 years. The PTH ratio was determined at baseline. Primary outcomes were cardiovascular events (CVE) and all-cause mortality. Cumulative event-free survival was compared between patients with a ratio < 1 and those with a ratio > 1. The risk-association of the PTH ratio with CVE was examined using an adjusted Multiple Cox Proportional Hazards model. RESULTS: A PTH ratio > 1 was found in 34 patients (49%). During follow-up 26 patients suffered a CVE. Patients with a CVE showed a higher ratio than patients with event-free survival (p = 0.033). In patients with a ratio > 1 a significantly higher number of CVE occurred (53 vs. 22%; p = 0.013), and these patients showed a significantly shorter event-free survival (p = 0.032). In an adjusted Cox-proportional hazards model a higher PTH ratio was found to be independently associated with an elevated risk for CVE (HR = 3.2; 95% CI 1.06 - 13.63; p = 0.04). CONCLUSIONS: A higher PTH (1-84)/non-PTH (1-84) ratio is associated with an increased risk for CVE in hemodialysis patients and might therefore be useful for cardiovascular risk estimation in this population.

Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries.

BACKGROUND: The aetiology of atypical haemolytic uraemic syndrome (aHUS) is, in contrast to classical, Shiga-like toxin induced HUS in children, largely unknown. Deficiency of human complement factor H and familial occurrence led to identification of the factor H gene (FH1) as the susceptibility gene, but the frequency and relevance of FH1 mutations are unknown. METHODS: We established a German registry for aHUS and analysed in all patients and 100 controls the complete FH1 gene by single strand confirmational polymorphism and DNA sequencing. In addition, complement C3 and factor H serum levels were assayed. Demographic data at onset of aHUS and follow up were compared for the mutation positive and negative groups. RESULTS: Of 111 patients with aHUS (68 female, 43 male, mean age 33 years) 14% had FH1 germline mutations, including two of eight patients with familial aHUS. For each of these eight patients, both parents were tested, and we were able to trace the mutation for five cases. In the other three cases (one with the mutation 3749 C/T, one with 3200 T/C, and one with 3566+1 G/A), we could not detect the mutation in either parent, although paternity was proven by genetic fingerprinting, suggesting that these subjects have new mutations. C3 was decreased in five mutation carriers but also in two non-carriers, and factor H was decreased in none of the carriers, but elevated in six carriers and 15 non-carriers. Clinical parameters including associated medications and diseases, and outcome of aHUS and of post-aHUS kidney transplantation were similar in the mutation positive and negative groups. CONCLUSION: FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.

Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.

The highly atherogenic lipoprotein(a) [Lp(a)] is significantly elevated in patients with renal disease. It is discussed controversially whether Lp(a) concentrations decrease after renal transplantation and whether the mode of immunosuppressive therapy influences the Lp(a) concentrations. In a prospective study the Lp(a) concentrations before and on average 48 months after renal transplantation were measured in 145 patients. The determinants of the relative changes of Lp(a) concentrations were investigated in a multivariate analysis. Patients treated by CAPD showed a larger decrease of Lp(a) than hemodialysis patients, reflecting their markedly higher Lp(a) levels before transplantation. The relative decrease of Lp(a) was higher with increasing Lp(a) concentrations before transplantation in combination with an increasing molecular weight of apolipoprotein(a) [apo(a)]. That means that the relative decrease of Lp(a) is related to the Lp(a) concentration and the apo(a) size polymorphism. With increasing proteinuria and decreasing glomerular filtration rate, the relative decrease of Lp(a) became less pronounced. Neither prednisolone nor cyclosporine (CsA) had a significant impact on the Lp(a) concentration changes. Azathioprine (Aza) was the only immunosuppressive drug which had a dose-dependent influence on the relative decrease of Lp(a) levels. These data clearly demonstrate a decrease of Lp(a) following renal transplantation which is caused by the restoration of kidney function. The relative decrease is influenced by Aza but not by CsA or prednisolone.

Proteinuria and plasma total homocysteine levels in chronic renal disease patients with a normal range serum creatinine: critical impact of true glomerular filtration rate.

Conflicting data have been reported concerning the independent association between proteinuria and plasma total homocysteine (tHcy) levels, particularly among chronic renal disease (CRD) patients with a normal range serum creatinine. Studies of this potential relationship have been limited by failure to assess true GFR, failure to assess proteinuria in a quantitative manner, or arbitrary restriction of the range of proteinuria examined. We examined the potential independent relationship between plasma tHcy levels and a wide range of quantitatively determined proteinuria (i.e., 0.000-8.340 g/day), among 109 CRD patients with a normal range serum creatinine (range; 0.8-1.5 mg/dl; median=1.2 mg/dl). Glomerular filtration rate (GFR) was directly assessed by iohexol clearance, and plasma status of folate, pyridoxal 5'-phosphate, and B12, along with serum albumin, were also determined. Linear modeling with ANCOVA revealed that proteinuria was not independently associated with tHcy levels (partial R=0.127; P=0.201), after adjustment for potential confounding by GFR (partial R=0.408; P<0.001), age, sex, plasma B-vitamin status, and serum albumin. Moreover, descending across quartiles (Q) [from Q4 to Q1] of GFR, ANCOVA-adjusted (i.e., for age, sex, and folate status) geometric mean tHcy levels (micromol/l) were significantly increased: tHcy Q4 GFR=9.6; tHcy Q3 GFR=10.5; tHcy Q2 GFR=11.9; tHcy Q4 GFR=14.5; P<0.001 for overall Q difference. We conclude that across a broad spectrum of quantitatively determined proteinuria, after adjustment for true GFR, in particular, there is no independent relationship between proteinuria and tHcy levels among CRD patients with a normal range serum creatinine.

Chronic renal transplantation: a model for the hyperhomocysteinemia of renal insufficiency.

Renal transplant recipients (RTR) are considered representative of patients with chronic renal insufficiency (CRI) in general with respect to both reduced, progressively declining renal function, and increased risk for cardiovascular disease (CVD). In accord with this argument, we hypothesized that total (t) plasma concentrations of the putatively atherothrombotic amino acid homocysteine (Hcy) would be equivalent in RTR and CRI patients with comparable renal function. We determined plasma tHcy, folate, pyridoxal 5'-phosphate, and B12 concentrations, in addition to serum creatinine and albumin concentrations, in 86 chronic, stable RTR, and 238 patients with CRI. Within comparable ranges of serum creatinine (i.e. RTR=0.6-4.2 mg/dl; CRI=0.7-4.1 mg/dl), tHcy concentrations did not differ between the two groups (RTR=15.0 micromol/l; CRI=14.9 micromol/l, P=0.899). ANCOVA revealed that renal function, gauged as a simple creatinine measurement, was the major independent determinant of plasma tHcy concentrations, accounting for approximately 80-90% of the total variability in tHcy predicted by the full model (i.e. full model R(2)) containing, in addition to creatinine, the seven other potential explanatory variables. If controlled trials confirm that tHcy-lowering treatment reduces CVD events rates in RTR, these results should be applicable to CRI patients in general.

Influence of various heparin preparations on lipoproteins in hemodialysis patients: a multicentre study.

Recent studies have indicated controversial effects of low molecular weight heparin (LMWH) on lipid metabolism in patients on chronic hemodialysis as compared to unfractionated heparin (UFH). We therefore conducted a cross-sectional multicentre study comparing 153 patients treated with LMWH and 153 patients with UFH, matched for sex, age and diabetes mellitus. Both groups have been treated with LMWH or UFH for six months or longer (14.9 vs. 23.4 months). We observed no differences between the UFH and LMWH treatment groups for total cholesterol, LDL cholesterol, triglycerides, apoB, apoA-IV or Lp(a). The only significant differences were seen for HDL cholesterol and the corresponding apolipoprotein apoA-I, which were significantly higher in the UFH group (HDL cholesterol: 0.97 +/- 0.35 mM/l vs. 0.87 +/- 0.37 mM/l, p < 0.05; apoA-I 1.23 +/- 0.27 g/l vs. 1.15 +/- 0.27 g/l, p < 0.05). We conclude that the results of studies investigating the influence of LMWH on lipid metabolism are as heterogeneous as the substances themselves. This challenges the beneficial influence supposedly had by LMWH preparations on lipid metabolism.

Local botulinum toxin in the treatment of spastic drop foot.

Ten patients with spastic drop foot were treated by local injections of botulinum toxin A (botulinum toxin A haemagglutinin complex). The purpose was to improve stance and gait and/or to facilitate physiotherapy and patient care. Various calf muscles were injected using EMG guidance. The average dose used was 23 ng. Prior to and 4 weeks after treatment, positions of the upper and lower ankle joint at rest and the corresponding end positions of passive and active movement were determined. In addition, changes of spasticity and pain, the transmission phenomenon and stance and gait were evaluated. Most patients showed improvement of some aspects of the spastic drop foot. Positions of the upper and lower ankle joint were improved in most of the patients, as were the other parameters examined. Except for weakness of the injected muscles no side-effects were observed. The results appear promising and may be optimized in further trials by using higher doses of the toxin.

Variable parathyroid hormone(1-84)/carboxylterminal PTH ratios detected by 4 novel parathyroid hormone assays.

AIM: Parathyroidhormone (PTH) measurement is important in the evaluation of bone disease in patients with chronic renal failure. Large carboxyl-terminal PTH fragments (C-PTH) cross-react with second-generation PTH assays, lead to an overestimation of biologically active PTH, and are evaluated by a combination of second- and third-generation PTH assays. The aim of our study was to examine whether the use of 4 different PTH assays of putatively same specificity leads to comparable results detecting C-PTH fragments. SUBJECTS AND METHODS: In 70 chronic dialysis patients, total PTH and PTH(1-84) were measured in parallel by 4 novel PTH assays (Nichols Advantage Intact PTH and Bio-Intact PTH Chemiluminescence Assay, Nichols Institute Diagnostics, USA, DUO Total and CAP PTH IRMA, Scantibodies Laboratory, USA). The C-PTH concentration was quantitated by subtracting PTH(1-84) from total PTH. Consecutively, the PTH(1-84)/C-PTH ratio was calculated. RESULTS: Nichols Intact PTH and DUO Total PTH assays were highly correlated (r = 0.985), as well as Nichols Bio-Intact and DUO CAP assays (r = 0.984). However, total PTH values measured by the Nichols assay were 30% higher (median (range): 185 (9.9 - 2,332) versus 130 (2.3 - 1,271.1) pg/ml, p < 0.01). PTH(1-84) values, measured by the Nichols Bio-Intact PTH assay were 8% higher compared to the Scantibodies CAP assay (median (range): 79.6 (7.5 - 1,060.9) versus 73.7 (4.4 - 918.9) pg/ml, p = NS). Thirty-six patients had a ratio < 1 measured by the Nichols assays, whereas only 8 patients showed the same ratio when measured by the Scantibodies assays. In 28 patients (40%), contradictory PTH(1-84)/C-PTH ratios were found, showing a ratio < 1 when measured by the Nichols assays, but > 1 when the Scantibodies assays were used. CONCLUSION: In conclusion, our results suggest that the PTH(1-84)/C-PTH ratio cannot be equally used as a predictor of bone turnover when different PTH assays are used. Depending on those assays, differences in total PTH values mathematically lead to varying amounts of C-PTH fragments resulting in variable, even contradictory PTH(1-84)/C-PTH ratios.

[Bone scans in the diagnosis of renal osteopathy]. / La scintigrafia ossea nella diagnostica dell'osteopatia renale.

Biochemical tests (serum calcium, inorganic phosphate and alkaline phosphatase), as well as clinical, radiological, scanning and histological investigations were undertaken in 24 patients in chronic renal failure. The frequency with which the diagnosis of renal osteopathy could be made depended in the method of investigation, the biochemical findings proving to be completely unreliable. There were positive radiological signs in ten patients and clinical signs in 12, predominantly in the progressive stages of osteopathy. A positive scan was obtained in 23 patients, typical histological bone changes in an equal number. Since it correlates so well with the histological findings, bone scan is suitable particularly in the early diagnosis of osteopathy. Since this test is easily performed and hardly stresses the patient, it should routinely be the initial one for the diagnosis of renal osteopathy.

[Focal proliferation in reactive hyperplastic parathyroid tissue in end-stage renal failure--implication for autotransplantation after total parathyroidectomy]. / Fokale Proliferationen in reaktiv hyperplastischen Nebenschilddrüsen bei terminaler Niereninsuffizienz-Implikation für die Autotransplantation nach totaler Parathyreoidektomie.

Total parathyroidectomy with simultaneous autotransplantation may be associated with recurrence of graft-dependent hyperfunction due to excessive proliferation. We performed macroscopic tissue selection with a stereomicroscope prior to autotransplantation, which resulted in very low recurrence rates. As this technique greatly depends on experience, we investigated the possibility of additionally using proliferation staining (PCNA, MIB-1) for the detection of dysfunctional tissue. Selected tissue from 26 patients was investigated. Serial sections of freshly removed parathyroid tissue were correlated with their macroscopic appearance, HE and immunohistochemically stained paraffin sections, and with semithin Epon sections. The asymptotic growth mode of clonal proliferating regions was reflected by highest staining intensity (1-5%) in small to medium sized foci (diffuse, up to 3 mm in diameter) and very low staining in large areas (diffuse or nodular, 5-15 mm in diameter, from 0.03 to 0.003% positive cells). Thus, very large dysfunctional regions with (almost) no proliferation could not be detected by this method. However, they were very evident on macroscopic investigation. In conclusion, multiple fulminant recurrence after parathyroidectomy can be prevented by selecting tissue after proliferation staining. This may allow a delayed autotransplantation after total parathyoidectomy for those surgeons lacking experience in macroscopic tissue classification.

[Intraoperative blood sampling for parathyroid hormone measurement during total parathyroidectomy and autotransplantation in patients with renal hyperparathyroidism]. / Stellenwert der intraoperativen Blutabnahme zur Parathormonbestimmung während totaler Parathyreoidektomie mit Autotransplantation bei Patienten mit renalem Hyperparathyreoidismus.

Normalisation of intact parathyroid hormone serum level confirms sufficient resection of parathyroid tissue after total parathyroidectomy in patients with secondary hyperparathyroidism. The short half-life of the intact parathyroid hormone is such that complete resection may even be confirmed by intraoperative monitoring of the hormone, and operative exploration thus reduced. We tested intact parathyroid hormone serum levels in 9 patients during total parathyroidectomy, preoperatively, after the removal of each gland, after autotransplantation and 1 month postoperatively. The serum levels of the intact parathyroid hormone were significantly reduced after removal of each gland. The total percentage decrement after parathyroidectomy with autotransplantation was 77%. However intact parathyroid hormone levels had normalised in all patients one month after the operation. The absence of perioperative normalisation of intact parathyroid hormone serum levels in our patients cannot be defined as a predictor of incomplete resection in total parathyroidectomy. The definition of an intraoperative cut-off-level concerning the decrement of intact parathyroid hormone levels remains to be proven in further studies.

[Experiences with total parathyroidectomy and autotransplantation of intraoperatively selected parathyroid tissue in reactive renal hyperparathyroidism]. / Erfahrungen mit der totalen Parathyreoidektomie und Autotransplantation intraoperativ ausgewählten Parathyreoidea-Gewebes beim reaktiven renalen Hyperparathyreoidismus.

Surgery is indicated in cases of therapy-resistant reactive renal hyperparathyroidism with clinical symptoms and signs. The method of choice is total parathyroidectomy, with autotransplantation of parathyroid tissue into the forearm musculature. Twenty-two patients were parathyroidectomized. In 19 cases the intraoperative selection of tissue for autotransplantation was made by means of a stereoscopic magnifying glass. With one exception, only fragments of type 1a glands and type 1a-like areas obtained from type 2 glands were transplanted. In 18 of the 22 cases parathyroid hormone levels decreased from 1131 +/- 657 preoperatively to 87 +/- 53 pg/ml postoperatively. In 4 patients with postoperative values over 200 pg/ml a transplant-related recurrence of hyperparathyroidism or a remaining 5th gland in the cervical region was suspected. In all 22 patients serum calcium, as well as alkaline phosphatase levels returned to normal and the clinical signs of hyperparathyroidism disappeared.

A simple score predicts future cardiovascular events in an inception cohort of dialysis patients.

Vascular calcifications are very common in dialysis patients and have been shown to be associated independently with outcome. However, all of these studies used prevalent patients on dialysis since many years. We investigated vascular calcifications in an inception cohort of dialysis patients and followed them for cardiovascular disease outcomes during an average observation period of 66 months. One hundred and fifty-four Caucasian dialysis patients were enrolled in one Austrian dialysis center. Standardized plain radiographs from the pelvis and calves were carried out in all patients at the start of dialysis therapy. Vascular calcifications were assessed by a single radiologist. At the start of renal replacement therapy, 67.5% of the patients showed vascular calcifications. During follow-up, 29.9% of patients suffered a cardiovascular event. An additive 'vascular risk score', constructed from the presence of vascular calcifications and/or previous cardiovascular events before the start of dialysis treatment, showed the strongest independent association with cardiovascular events in the Cox regression model adjusted for various risk factors. The presence of each of these two conditions was associated with a hazard ratio of 2.03 (95% confidence interval 1.19-3.46) and a hazard ratio twice as high if both conditions were present. In summary, vascular calcifications on plain X-rays of pelvis and calves are largely present in incident dialysis patients. A history of a cardiovascular event in the predialysis period together with vascular calcifications at the beginning of dialysis therapy is a more powerful predictor of a cardiovascular event than age, smoking, diabetes, or other traditional risk factors.

[Low dosage intravenous calcitriol bolus therapy in chronic hemodialysis patients]. / Niedrig dosierte intravenöse Calcitriol-Bolustherapie bei chronischen Hämodialysepatienten.

Severe secondary hyperparathyroidism in patients on chronic renal replacement therapy is still an immense problem, even after the introduction of the oral calcitriol therapy. Because the current first choice treatment--intravenous calcitriol-bolus application--fails to decrease parathyroidhormone (PTH) in some patients, we decided to monitor 22 chronic hemodialysis patients receiving low dose therapy with 3 x 1 micrograms calcitriol per week for a period of 6 months. After 6 months the PTH increased from 430 +/- 318 to 573 +/- 508 pg/ml (p < 0.05), the serum calcium from 2.14 +/- 0.22 to 2.31 +/- 15 mmol/l (p < 0.01). There was no significant change in serum phosphate, alkaline phosphatase (APH) and osteocalcin. The patients were divided into 2 groups according to their basal PTH-levels. Group 1 (n = 7, PTH < 200 pg/ml) showed a significant decrease of the PTH-levels from 99 +/- 38 to 61 +/- 53 pg/ml (p < 0.05). There was no significant change in serum calcium, phosphate, APH and osteocalcin levels. In group 2 (n = 15, PTH > 300 pg/ml) the PTH increased significantly (p < 0.05) from 585 +/- 287 to 812 +/- 439 pg/ml. No significant change was found for APH or osteocalcin. Calcium and phosphate levels increased significantly from 2.11 +/- 0.20 to 2.31 +/- 0.12 mmol/l (p < 0.01) and from 2.29 +/- 0.47 to 2.74 +/- 0.60 mmol/l (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Mesangial lipidosis associated with cholesterol polycoria]. / Lipidose mésangiale associée à une polycorie cholestérolique.

Accumulation of glomerular foam cells were seen in a kidney biopsy of a 59-years old patient with persistent proteinuria and mild renal insufficiency. Further investigations revealed hypercholesterolemia, hypertriglyceridemia, normal activity of LCAT, absence of lipoprotein x. Foam cells which were shown by histochemical methods to be loaded with intracytoplasmic cholesterol were found in bone marrow. These findings strongly suggest cholesterol-ester-storage disease with glomerular involvement.

[Acute recurrent uveitis and idiopathic interstitial nephritis-- a nosologic entity (tubulo-interstitial nephritis and uveitis)]. / Akut rezidivierende Uveitis und idiopathische interstitielle Nephritis--eine nosologische Einheit (TINU-Syndrom).

So far 34 cases of idiopathic acute tubulo-interstitial nephritis and uveitis (TINU syndrome) have been reported by nephrologists. The patients have mainly been girls and only female adults. The authors describe a 53-year-old woman with this nosological entity, presenting with a granulomatous anterior uveitis and chronic course of nephritis. This is the first such case reported. All other cases described in the literature are compared and an attempt is made to locate the immune deficiency.

MR imaging in graft-dependent recurrent hyperparathyroidism after parathyroidectomy and autotransplantation.

The purpose of this study was to compare the value of MR imaging versus sonography in the detection of hyperfunctioning transplanted parathyroid tissue. After parathyroidectomy and autotransplantation of parathyroid tissue to the forearm, 14 patients were examined with sonography and MR imaging. Five of these patients had recurrent hyperparathyroidism. In three of these five, sonography found one echolucent nodule. MR imaging in all three patients detected, in addition to this nodule, other small nodules of hyperplastic parathyroid tissue, which were confirmed intraoperatively. In the other two patients, sonographic and MR imaging findings were negative. Further investigations showed that both patients had a fifth parathyroid gland. In the patients without recurrent hyperparathyroidism, sonography showed scar tissue only, whereas MR imaging found some tiny, contrast-enhancing structures in two patients, probably autograft material. MR imaging seems to be more sensitive than sonography in detecting hyperfunctioning autotransplanted parathyroid tissue.

[Headache and EEG changes caused by acetate and bicarbonate dialysis]. / Kopfschmerzen und EEG-Veränderungen unter Azetat- und Bikarbonatdialyse.

10 patients suffering from severe headache during Acetatedialysis were subsequently treated with Acetatedialysis (AD) and Bicarbonatedialysis (BD). During AD the headaches occurred more frequently and more intensely. After AD a deterioration of EEG-results was also seen more frequently than after BD. Urea, osmolarity and sodium in the blood as well as heart frequency and blood pressure showed no different variation. An essential difference was found in correction of the metabolic acidosis. After AD there could be seen a negative base excess and a fall in PaCO2, after BD the PaCO2 rose and the base excess was positive. Headaches and EEG-changes as signs of a cerebral dysfunction (disequilibrium syndrome) may perhaps be caused by a decrease of the cerebral blood flow. From our experience we recommend a change to BD for patients suffering from headaches during AD.

Alpha 1-antitrypsin phenotypes in patients with anti-neutrophil cytoplasmic antibody-positive vasculitis.

1. The genetic background of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis remains largely unknown. Recently a very high prevalence of medium and severe deficiency of alpha 1-antitrypsin was described in a small group of patients with Wegener's granulomatosis and c-ANCA. c-ANCAs are autoantibodies against proteinase 3, and alpha 1-antitrypsin is the main inhibitor of this enzyme. 2. alpha 1-Antitrypsin phenotypic polymorphism was determined by isoelectric focusing in 32 patients with c-ANCA-associated systemic vasculitis. Twenty-nine patients had Wegener's disease, two had microscopic polyarteritis and one suffered from idiopathic rapidly progressive glomerulonephritis. 3. Two patients were homozygous PiZZ and three were heterozygous PiMZ. These phenotype frequencies differed significantly from expected values, assuming Hardy-Weinberg equilibrium (P < 0.01). Compared with a control group of 868 healthy blood donors, these results meant a significant increase in the PiZ allele (0.0138 versus 0.1094, P < 0.001). 4. Furthermore, the serum of 47 patients with severe alpha 1-antitrypsin deficiency (PiZZ) was tested for the presence of ANCA. All sera were negative for c-ANCA and p-ANCA. None of the patients showed clinical signs of systemic vasculitis. 5. In conclusion, these data indicate that alpha 1-antitrypsin deficiency, despite being significantly more common in patients with c-ANCA-associated systemic vasculitis, is only a minor genetic risk factor for the development of this disease.