Underdiagnosis of diabetes mellitus in chronic dialysis patients on the renal transplant waiting list.

In diabetic patients long-term patient and graft survival after renal transplantation is reduced compared to nondiabetic graft recipients. Incidence and prevalence of diabetic patients on dialysis is rising continuously; however, there is a surprisingly low prevalence of patients with known diabetes mellitus on our local renal transplant waiting list. In a retrospective study we clarified the underestimation of diabetic dialysis patients on the transplant waiting list. Our local waiting list includes 46 diabetic patients among 377 (12.2%) candidates. Nine patients had type 1 diabetes and 37 type 2 diabetes. Surprisingly, only 20 of 37 patients (ie, 54%) were initially (at the time of wait-listing) classified as (type 2 diabetes mellitus). Primary renal disease in these 17 diabetic patients was classified in only eight patients, whereas the remaining nine were considered as chronic glomerulonephritis (not biopsy-proven and diabetic nephropathy not excluded). We conclude that among uremic patients on the renal transplant waiting list, the prevalence of diabetes mellitus and the number of patients with diabetic nephropathy are notably underdiagnosed.

Pre-transplant Th1 and post-transplant Th2 cytokine patterns are associated with early acute rejection in renal transplant recipients.

In this retrospective study, we tried to define pre- and post-transplant immunological parameters that identify patients at risk for early acute rejection. Lymphocyte subpopulations and plasma levels of cytokines and neopterin were determined pre- and post-transplant in 32 renal transplant recipients with biopsy-proven early acute graft rejection. Recipients without early acute rejection served as controls. High pre-transplant interferon-gamma (IFN-gamma) plasma levels (p = 0.006), consistently high levels of neopterin early post-transplant (p = 0.008), a post-transplant switch from a Th1 to a Th2 cytokine pattern with decreasing IFN-gamma (p = 0.02), low CD8+ lymphocyte counts (p = 0.006) and consistently high CD19+ B lymphocyte counts were associated with acute rejection. Our data suggest that patients with a pre-transplant Th1 and an early post-transplant Th2 cytokine pattern are pre-disposed for early acute rejection.

Differential early posttransplant cytokine responses in living and cadaver donor renal allografts.

BACKGROUND: Differences in early posttransplant immunologic responses between living donor (LDT) and cadaver donor transplant (CDT) recipients have not been thoroughly studied. This is the first study comparing lymphocyte subpopulations and plasma levels of different cytokines, soluble cytokine receptors, cytokine receptor antagonists, and neopterin during the first 2 posttransplant weeks. PATIENTS AND METHODS: Lymphocyte subpopulations (CD3, CD4, CD8, CD16, CD19, and CD25) and plasma levels of soluble (s) interleukin(IL)-1 receptor antagonist (RA), IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-8, IL-10, transforming growth factor-beta(2), tumor necrosis factor-alpha, interferon-gamma, and neopterin were studied in 52 CDT and 33 LDT recipients 1 to 2, 4 to 6, and 8 to 10 days after transplantation. RESULTS: The most impressive finding was a consistently higher neopterin plasma level in CDT than LDT recipients. Although plasma neopterin decreased during the second posttransplant week in both groups (CDT, P = 0.0001; LDT, P = 0.001), the difference in plasma neopterin levels 8-10 days after transplantation was highly significant (P = 0.005). In contrast, LDT had consistently higher sIL-1RA plasma levels during the first 2 posttransplant weeks. Whereas sIL-1RA plasma levels decreased in both groups during the first posttransplant week (CDT, P = 0.001; LDT, P = 0.005), they increased during the second posttransplant week in LDT (P = 0.02) but remained stable and low in CDT recipients. Eight to ten days after transplantation, the difference was highly significant (P = 0.002). CONCLUSION: These data suggest that transplantation of CDT is associated with strong monocyte-macrophage activation with consistently high neopterin plasma levels, whereas the effect of inflammatory cytokines seems to be down-regulated in LDT recipients by an increased release of antiinflammatory sIL-1RA.

[Incidence and clinical characteristics of renal insufficiency in diabetic patients]. / Inzidenz und klinische Charakteristika von Niereninsuffizienz bei Diabetikern.

BACKGROUND: In all Western countries there is a dramatic increase of diabetic patients who need renal replacement therapy. Very different figures for incidence and prevalence have been reported. There is a strong suspicion that the epidemiological dimension of the problem has been underestimated in many of the statistics. METHODS: In a retrospective analysis we assessed all patients admitted to the Department Internal Medicine Heidelberg from January 1(st) 1998 - December 31(st), 2000 for renal replacement therapy, i. e. hemodialysis or CAPD, because of acute or chronic renal failure. We counted the number of known diabetic patients (i) with signs of classical diabetic nephropathy (enlarged kidneys, proteinuria > 1g/24h +/- retinopathy), (ii) with atypical renal changes (contracted kidneys, proteinuria < 1 g/24 h) and (iii) diabetic patients with (coincident) primary chronic renal disease as well as (iv) the proportion of patients in whom the diagnosis of diabetes had been unknown when uremia had supervened. RESULTS: Dialysis treatment was started in 568 patients for acute (ARF; n = 341) or chronic (CRF; n = 227) renal failure. 95/341 (28 %) patients with ARF had diabetes. ARF occured in no less than 12/95 (13 %) of the diabetic patients after cardiological intervention. Diabetes was present in 111/227 patients with CRF (7 type 1, 104 type 2); in 12/111 patients the diagnosis of diabetes was established only after admission. Only 67/111 of the diabetic patients (60 %) had classical signs of diabetic nephropathy, in 14/111 (13 %) patients the classical signs of diabetic nephropathy were absent and in 30/111 (27 %) non-diabetic primary chronic renal disease was present. CONCLUSION: The study illustrates the importance of diabetes for the epidemiology of renal failure. A sizeable proportion of patients with acute renal failure have diabetes, typically patients with pre-existing nephropathy in whom this complication supervenes during diagnosis and treatment of late diabetic complications. In diabetic patients with chronic renal failure the presentation is frequently atypical and non-diabetic primary renal disease is present more frequently than expected by chance. In a sizeable proportion of patients diabetes had not been diagnosed by the time chronic renal failure occurred.

Compounds in development to combat hyperphosphataemia.

Hyperphosphataemia in haemodialysis patients is associated with secondary hyperparathyroidism and more importantly with an increased cardiovascular mortality in dialysed patients. Removal of phosphate during dialysis is less than net intestinal uptake. This imbalance results in a positive phosphate balance. To control serum phosphate concentration oral phosphate binders have to be taken to reduce net intestinal uptake. The use of classical phosphate binders such as calcium carbonate, calcium acetate and aluminium-containing phosphate binders is limited by their side effects. Hypercalcaemia aggravates vascular calcification and cardiovascular risk. Aluminium intoxication causes aluminium osteopathy, anaemia and encephalopathy. Therefore, the development of calcium- and aluminium free phosphate binders has become a challenge to clinical nephrology. Polyallylamine hydrochloride (sevelamer) is one of the new alternative compounds which has been shown to effectively bind phosphate in dialysis patients. A promising approach in the development of alternative phophate binders are trivalent-iron (Fe(III)) containing phosphate binders. They were not only successfully tested in experimental animals but have also been shown to reduce urinary phosphate excretion and serum phosphate concentrations in patients with preterminal failure and those on maintenance haemodialysis. This review outlines the experimental and clinical data on Fe-III based phosphate binders providing evidence that they will be as effective and safe as phosphate binders without the major side effects of classical phosphate-binding compounds.

Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement.

Successful maintenance therapy with mycophenolate mofetil (MMF) 2 g/d and low-dose oral corticosteroids (OCS) over a period of 15 mo was given to patients with Wegener's granulomatosis (WG) (n = 9) and microscopic polyangiitis (MPA) (n = 2). All patients had severe generalized disease with pauci-immune necrotizing glomerulonephritis and received standard induction therapy with oral cyclophosphamide and OCS for a mean of 14 wk until remission was achieved. Of 11 patients, only one WG patient relapsed in the 14th month of maintenance therapy. Maintenance therapy with MMF was able to further reduce grumbling disease activity as measured by the Birmingham vasculitis activity score (BVAS2) and proteinuria that were still present by the end of induction therapy. OCS could be reduced to a median daily dose of 5 mg and discontinued in three patients. Possible drug-related adverse effects were transient and included abdominal pain, respiratory infection, diarrhea, leukopenia, and a cytomegalovirus-colitis in one patient that was successfully treated with ganciclovir. It is concluded that MMF in combination with low-dose OCS is well tolerated and effective for maintenance therapy of WG and MPA. Long-term treatment with MMF in these diseases is attractive because of its low toxicity. MMF will have to be studied further and compared with cyclophosphamide or azathioprine maintenance therapy in randomized trials.

Advanced glycated end-products (AGE) during haemodialysis treatment: discrepant results with different methodologies reflecting the heterogeneity of AGE compounds.

BACKGROUND: There has been much recent interest in accumulation of advanced glycation end-products (AGE) in uraemic patients. Analysis of AGE has been difficult, because commonly used methodologies, i.e. immunodetection assays or fluorescence measurements, reflect group reactivity and are not specific for chemically defined substances. Some investigators measured individual AGE compounds, e.g. pentosidine, carboxymethyllysine, pyrraline or imidazolone, but a systematic assessment of known compounds using specific HPLC methods in diabetic and non-diabetic end-stage renal disease (ESRD) patients during treatment has not been performed. METHODS: For the present study, the concentrations of early and late products of the Maillard reaction in plasma and ultrafiltrate were monitored during high-flux dialysis sessions in diabetic and non-diabetic patients. AGE were analysed by fluorescence spectroscopy and size exclusion chromatography with fluorescence detection. Specific HPLC methods were used to quantify the Amadori product fructoselysine and the AGE compounds pentosidine and pyrraline in acid or enzymatic hydrolysates. RESULTS: Using size exclusion chromatography, we confirmed a similar fluorescent peak distribution for diabetic and non-diabetic ESRD patients. Main fractions were found at approximately 70, approximately 14 and <2 kDa, confirming results obtained by other authors. In diabetic patients, the fluorescence intensity of the low molecular weight fraction was higher. Uraemic patients differed from controls mainly by the fluorescence of the low molecular weight fraction. The peak spectrum in ultrafiltrates was similar to that in plasma regarding low molecular weight fractions and the 14 kDa peak, but no protein-bound fluorescence was found at 70 kDa. HPLC analysis revealed a significant reduction of plasma pentosidine during high-flux dialysis in non-diabetic (from 9.1+/-5.1 to 8.5+/-4.7 pmol/mg protein; P<0.05) and diabetic patients (from 10.0+/-9.1 to 6.8+/-4.0 pmol/mg protein; P<0.05). In contrast, plasma fructoselysine showed only a non-significant trend to decrease in diabetic (from 3.24+/-0.88 to 3.05+/-0.77 nmol/mg protein) and non-diabetic patients (from 2.69+/-0.52 to 2.56+/-0.50 nmol/mg protein). Pyrraline, a nonfluorescent late AGE product derived from reaction of 3-deoxyglucosone with lysine, could not be detected (detection limit approximately 40 pmol/mg protein). Comparing HPLC and size exclusion analysis, it was found that pentosidine accumulated in the range of low molecular weight substances and was removed by high-flux dialysis. CONCLUSIONS: High-flux dialysis reduces the plasma concentration of fluorescent AGE compounds, i.e. pentosidine, but the Amadori product fructoselysine is not removed, indicating that this compound is protein associated.

Stabilized polynuclear iron hydroxide is an efficient oral phosphate binder in uraemic patients.

BACKGROUND: There is a continuing need for non-aluminium and non-calcium-containing oral phosphate binders. A novel product, i.e. stabilized polynuclear iron hydroxide, has experimentally been shown to be an effective phosphate binder. The purpose of the study was to test the efficacy and tolerability of the compound in hyperphosphataemic patients with stable preterminal renal failure. METHODS: In an open uncontrolled study we examined a total of 13 patients with stable preterminal renal failure (median serum-creatinine 5.4 mg/dl, range 4.2-7.3 mg/dl) and hyperphosphataemia (median fasting plasma-Pi 2.2 mmol/l, range 1.95 3.0 mmol/l). Patients were given dietary advise to maintain a constant intake of phosphate and this was verified by measuring urinary Pi excretion. After 2 weeks on no oral phosphate binders, patients were given daily 3 x 2.5 g stabilized polynuclear iron hydroxide with meals for 4 weeks. In a blinded fashion plasma-Pi and urinary-Pi as well as 1,84 i-PTH, vitamin D metabolites, serum-iron and ferritin were measured in a central laboratory. RESULTS: Compared to baseline (no oral phosphate binders), the median per cent decrease of fasting plasma-Pi at day 14 was 20% (7.2-41%) (P<0.001 by Wilcoxon test) and the median per cent decrease of urinary P excretion was 37% (9.6-56.6%) (P<0.0003 by Wilcoxon test for paired differences). Ferritin levels did not differ significantly during the study. Apart from a certain laxative action and black discolouration of the faeces, no side effects were noted in this short-term study. CONCLUSION: Stabilized polynuclear iron hydroxide is a promising, efficaceous and well tolerated phosphate binder.

Phosphate binders on iron basis: a new perspective?

Uremic patients on maintenance hemodialysis are in positive phosphate balance. This is mainly the result of the complex elimination kinetics of phosphate during dialysis. Removal of phosphate is less than net dietary intake. Classical phosphate binders such as calcium carbonate, calcium acetate, and aluminum-based compounds are limited by side effects (hypercalcemia) and outright toxicity (aluminium). There have been numerous recent attempts to develop alternative phosphate binders, e.g., polyallylamine-hydrochloride (Renagel), lanthanum carbonate, and trivalent iron-containing compounds. The latter is based on old observations that iron salts may cause hyperphosphatemia and rickets in experimental animals and in patients. This idea has recently been taken up again, and effective inhibition of net intestinal phosphate uptake in non-uremic and uremic rats has been shown using simple iron salts (citrate, chloride, ammonium citrate) and complex compounds (cross-linked dextran and stabilized polynuclear iron hydroxide). In uremic rats, the latter compound reduces urinary phosphate excretion as an indicator of reduced intestinal phosphate uptake and has also been shown to be effective in subjects with preterminal renal failure. So far, no side effects or short-term toxicity has been observed. The compound appears promising and deserves further evaluation.

Safety of ultrasound-guided percutaneous renal biopsy-retrospective analysis of 1090 consecutive cases.

BACKGROUND: Ultrasound-guided renal biopsy with an automated spring-loaded biopsy device has become the standard method for kidney biopsy. Information on the success rate and safety of the routine use of this procedure from large series is not available. Such information is of interest for cost benefit considerations and for medicolegal purposes. We performed an audit of this procedure. SUBJECTS AND METHODS: From January 1993 to June 1997, 1090 percutaneous renal biopsies were performed in the renal units of Heidelberg (n = 557) and Karlsruhe (n = 533) using a spring-loaded biopsy device (Biopty; Radiplast AB, Uppsala, Sweden). After intensive local disinfection, biopsies were performed under local anaesthesia and direct visualization by ultrasound (Sonolayer SSH-140 A, Toshiba Inc., Japan). A puncturing adaptor was used (model UAGV 009 A, Toshiba, Japan). Of the 1090 biopsies 114 (10.4%) were performed on renal allografts and 976 (89.6%) on orthotopic kidneys. Biopsies were performed only if patients were strictly normotensive (<140/90 mmHg) and had normal coagulation parameters (PT, PTT, factor VIII, thrombocyte count, and bleeding time). All patients had been advised not to take aspirin or non-steroidal antiinflammatory agents for at least 5 days prior biopsy. We analysed (1) yield of diagnostically useful material, and (2) frequency of postbiopsy complications (e.g. macrohaematuria, haematoma, infections, and AV fistula). RESULTS: Except for one case requiring interventional radiology because of persisting blood loss and three cases requiring blood transfusions, no serious complications were seen in the 1090 consecutive renal biopsies, e.g. death, loss of kidney, life-threatening haemorrhage, or persisting haemodynamically relevant AV fistulae. The frequency of minor haematoma with an extension >2 x 2 cm, but no significant decrease of haemoglobin, was 2.2% (25/1090). Self-limited mild macrohaematuria occurred in 0.8% (9/1090). The incidence of small, haemodynamically irrelevant AV fistulae detected by Doppler ultrasound was 9% (48/533). Sufficient tissue for reliable histopathological diagnosis was obtained in almost all cases (1077/1090 = 98.8%). The median number of glomeruli per biopsy sample was 9 (range 1-37). CONCLUSION: If contraindications, especially high blood pressure and abnormal haemostasis, are respected, ultrasound-guided percutaneous renal biopsy with an automated biopsy device is safe. Skilled operators obtain satisfactory amounts of kidney tissue in almost all cases.

Tissue factor antigen is elevated in patients with microvascular complications of diabetes mellitus.

Patients with late diabetic complications have increased levels of parameters indicating activation of coagulation (Takakashi et al., 1989; Ceriello, 1993; Murakami et al., 1993; Kario et al., 1995; Shimizu et al., 1995; Yokoyama et al., 1996), endothelial cell damage (Jensen, 1989; Iwashima et al., 1990; Sernau et al., 1995; Gabath et al., 1996). TF is believed to activate the coagulation mechanism in patients with late complications of diabetes. We studied the TF antigen plasma levels in 72 patients with diabetes mellitus (36 type I, 36 type II) with respect to its relevance as a marker of microvascular diabetic complications. TF levels did not correlate with macrovascular disease, diabetes type or age. Sixty patients with decreased renal function not due to diabetes were studied for evaluation of the contribution of renal failure to TF antigen plasma levels. We did not find a significant correlation of TF with s-creatinine in non diabetic patients (r = 0.27, p > 0.05). However, TF levels were elevated in diabetic patients with microvascular disease. Patients with retinopathy had higher TF levels than without (0.30 ng/ml vs 0.11 ng/ml, p < 0.007). When patients were divided into subgroups according to the urine albumin concentration, TF antigen of patients without albuminuria (0.019 ng/ml, n = 25) did not differ from patients with microalbuminuria (0.095 ng/ml, n = 19 p > 0.05). However, TF levels were significantly higher in patients with macroalbuminuria (n = 28; 0.215 ng/ml, p < 0.005). Thus activation of coagulation in patients with microvascular complications of diabetes may be triggered by tissue factor.

Elevated levels of markers of endothelial cell damage and markers of activated coagulation in patients with systemic necrotizing vasculitis.

Activation of coagulation and endothelial cell damage was studied in 47 patients with small vessel vasculitis [Wegener's granulomatosis (WG) and microscopic polyangiitis (MP)] by measurement of thrombin-antithrombin III complexes (TAT), fibrin-D-dimers (D-dimers), von Willebrand-factor (vWF) concentration and plasma thrombomodulin (TM) levels. There was a close correlation between disease activity (DA) in patients with WG or MP and markers of endothelial cell damage (correlation TM/DA r = 0.46 for WG and r = 0.43 for MP) and activated coagulation (correlation TAT/DA r = 0.58 for WG and r = 0.55 for MP). Elevation of the markers of activated haemostasis and endothelial cell damage was reversed when remission was obtained by specific treatment. The markers studied were particularly helpful in cases where measurement of antineutrophil cytoplasmatic antibodies (ANCA) did fail to assess disease activity.

[Different autoimmunity in Wegener's granulomatosis and microscopic polyangiitis]. / Unterschiedliche Autoimmunität bei Wegenerscher Granulomatose und mikroskopischer Polyangiitis.

Wegener's granulomatosis (WG) and microscopic polyangiitis (MP) are "small vessel" vasculitides which can serologically be discriminated measuring autoantibodies directed towards different target antigens (ANCA). In the present study we can demonstrate increased autoimmunity in patients with MP, as evaluated by measurement of thyroid microsomal and cardiolipin antibodies. Neither thyroid microsomal- nor myeloperoxidase-, nor cardiolipin antibodies were correlated to each other.