Jürgen Bommer

Mortality Risk for Dialysis Patients With Different Levels of Serum Calcium, Phosphorus, and PTH: The Dialysis Outcomes and Practice Patterns Study (DOPPS)

BACKGROUND Abnormalities in serum calcium, phosphorus, and parathyroid hormone (PTH) concentrations are common in patients with chronic kidney disease and have been associated with increased morbidity and mortality. No clinical trials have been conducted to clearly identify categories of calcium, phosphorus, and PTH levels associated with the lowest mortality risk. Current clinical practice guidelines are based largely on expert opinions, and clinically relevant differences exist among guidelines across countries. We sought to describe international trends in calcium, phosphorus, and PTH levels during 10 years and identify mortality risk categories in the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international study of hemodialysis practices and associated outcomes. STUDY DESIGN Prospective cohort study. PARTICIPANTS 25,588 patients with end-stage renal disease on hemodialysis therapy for longer than 180 days at 925 facilities in DOPPS I (1996-2001), DOPPS II (2002-2004), or DOPPS III (2005-2007). PREDICTORS Serum calcium, albumin-corrected calcium (Ca(Alb)), phosphorus, and PTH levels. OUTCOMES Adjusted hazard ratios for all-cause and cardiovascular mortality calculated using Cox models. RESULTS Distributions of mineral metabolism markers differed across DOPPS countries and phases, with lower calcium and phosphorus levels observed in the most recent phase of DOPPS. Survival models identified categories with the lowest mortality risk for calcium (8.6 to 10.0 mg/dL), Ca(Alb) (7.6 to 9.5 mg/dL), phosphorus (3.6 to 5.0 mg/dL), and PTH (101 to 300 pg/mL). The greatest risk of mortality was found for calcium or Ca(Alb) levels greater than 10.0 mg/dL, phosphorus levels greater than 7.0 mg/dL, and PTH levels greater than 600 pg/mL and in patients with combinations of high-risk categories of calcium, phosphorus, and PTH. LIMITATIONS Because of the observational nature of DOPPS, this study can only indicate an association between mineral metabolism categories and mortality. CONCLUSIONS Our results provide important information about mineral metabolism trends in hemodialysis patients in 12 countries during a decade. The risk categories identified in the DOPPS cohort may be relevant to efforts at international harmonization of existing clinical guidelines for mineral metabolism.

Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status.

BACKGROUND Poor nutritional status and both hyper- and hypophosphatemia are associated with increased mortality in maintenance hemodialysis (HD) patients. We assessed associations of phosphate binder prescription with survival and indicators of nutritional status in maintenance HD patients. STUDY DESIGN Prospective cohort study (DOPPS [Dialysis Outcomes and Practice Patterns Study]), 1996-2008. SETTING & PARTICIPANTS 23,898 maintenance HD patients at 923 facilities in 12 countries. PREDICTORS Patient-level phosphate binder prescription and case-mix-adjusted facility percentage of phosphate binder prescription using an instrumental-variable analysis. OUTCOME All-cause mortality. RESULTS Overall, 88% of patients were prescribed phosphate binders. Distributions of age, comorbid conditions, and other characteristics showed small differences between facilities with higher and lower percentages of phosphate binder prescription. Patient-level phosphate binder prescription was associated strongly at baseline with indicators of better nutrition, ie, higher values for serum creatinine, albumin, normalized protein catabolic rate, and body mass index and absence of cachectic appearance. Overall, patients prescribed phosphate binders had 25% lower mortality (HR, 0.75; 95% CI, 0.68-0.83) when adjusted for serum phosphorus level and other covariates; further adjustment for nutritional indicators attenuated this association (HR, 0.88; 95% CI, 0.80-0.97). However, this inverse association was observed for only patients with serum phosphorus levels ≥3.5 mg/dL. In the instrumental-variable analysis, case-mix-adjusted facility percentage of phosphate binder prescription (range, 23%-100%) was associated positively with better nutritional status and inversely with mortality (HR for 10% more phosphate binders, 0.93; 95% CI, 0.89-0.96). Further adjustment for nutritional indicators reduced this association to an HR of 0.95 (95% CI, 0.92-0.99). LIMITATIONS Results were based on phosphate binder prescription; phosphate binder and nutritional data were cross-sectional; dietary restriction was not assessed; observational design limits causal inference due to possible residual confounding. CONCLUSIONS Longer survival and better nutritional status were observed for maintenance HD patients prescribed phosphate binders and in facilities with a greater percentage of phosphate binder prescription. Understanding the mechanisms for explaining this effect and ruling out possible residual confounding require additional research.

Multicystic Transformation of Kidneys in Chronic Renal Failure

With real-time sonography, 120 nondialyzed uremic patients prior to hemodialysis, 108 patients on maintenance hemodialysis and 9 patients postdialysis after successful homotransplantation were examined for the presence of renal cysts. Even in incipient renal failure, multiple cysts were demonstrable in some patients (at a serum creatinine of 3 mg/dl in 22% of patients), particularly in patients with analgesic nephropathy. When hemodialysis was started (serum creatinine approximately 10 mg/dl), 35% of the patients had multiple cysts. On hemodialysis, the prevalence, number and size of cysts rose progressively with time. After 8 years of hemodialysis, 92% of the patients had multiple cysts. However, enlargement of the kidneys was observed in only 2/108 patients. No major clinical complications were noted with the possible exception of 1 case of renal cell carcinoma. No correlation was noted between hematocrit and presence or extent of cystic transformation, but the 2 patients with cystic enlargement of the kidneys were polyglobulic. In 8/9 patients after transplantation, cysts were demonstrable in the patients own kidneys after a median follow-up of 16 months. On light microscopy, cysts were lined by cuboidal or columnar epithelial cells with frequent papillary or adenomatous proliferations. The cyst lumen was filled with amorphous or lamellated organic material, which exhibited microfibrillar structure on electron microscopy. One kidney examined after ex vivo perfusion fixation showed multiple interconnected cavities on scanning electron microscopy. Ultrastructural studies showed epithelia with either the characteristics of proximal tubular cells (i.e. numerous microvilli, interdigitations and abundant lysosomes or mitochondria) or distal tubular cells (i.e. highly interdigitating processes) or finally collecting duct cells (i.e. no interdigitations and few microvilli).

Improving Outcomes for Dialysis Patients in the International Dialysis Outcomes and Practice Patterns Study

The international Dialysis Outcomes and Practice Patterns Study (DOPPS) is well suited to evaluate levels of deviation from emerging and established guidelines to clinical practice of hemodialysis, over time and by country. The DOPPS can also evaluate whether the target levels that are chosen in the guidelines are in agreement with outcomes such as elevated risk for mortality, hospitalization, and vascular access failure. At a special DOPPS symposium during the 2004 congress of the American Society of Nephrology, the authors presented such findings; key points from that symposium are presented in this article, focusing on vascular access, mineral metabolism, dialysis dose, and anemia management. Although an observational study cannot prove causality, DOPPS suggests large opportunities to improve care and outcomes of dialysis patients. The international perspective of DOPPS assists in the new efforts for international guidelines. Some encouraging trends in recent years are documented in these areas.

Hypercoagulability in the nephrotic syndrome

ZusammenfassungDas nephrotische Syndrom (NS) ist die intern-medizinische Grunderkrankung mit dem höchsten Risiko an venösen (Unterschenkelvenen-Thrombose, Beckenvenen-Thrombose, Cava- und Nierenvenen-Thrombose ggf. mit Lungenembolie) und arteriellen (Herzinfarkt, Cerebralarterien-Thrombose, periphere arterielle Thrombose) thromboembolischen Komplikationen. Aufgrund neuerer hämostaseologischer Untersuchungen können beim NS Defekte des plasmatischen Gerinnungssystems, der Fibrinolyse und der Plättchenfunktion festgestellt werden. Infolge der globalen Synthesesteigerung hepatischer Exportproteine ist die Plasmakonzentration der meisten Gerinnungsfaktoren (speziell Faktor I, II, VII, VIII und X) gesteigert; infolge erhöhten renalen Verlustes ist die Plasma-Konzentration des Inhibitors Antithrombin III vermindert. Die Änderung der Plasma-Konzentration ist das Ergebnis gesteigerter hepatischer Synthese und/oder renalen Verlustes im Rahmen der Proteinurie. Hinweise für eine intravasale Gerinnung fanden sich — im Gegensatz zu Angaben der Literatur — in eigenen Untersuchungen nur selten. Die Plasminogenkonzentration ist vermindert, während die Gesamt-Aktivität der Plasmin-Inhibitoren erhöht ist. Allerdings ist die Alpha-1-Antitrypsin-Konzentration wegen gesteigerten renalen Verlustes meist vermindert, was jedoch durch erhöhte Konzentration anderer Inhibitioren, speziell Alpha-2-Makroglobulin und Alpha-2-Antiplasmin kompensiert wird. Obwohl im Urin Material gefunden wird, welches in der passiven Hämagglutination wie Fibrinspaltprodukte reagiert, zeigten neuere Untersuchungen, daß dieses Material Fibrinogensplatprodukte darstellt (nicht selektive glomeruläre Proteinurie) und nicht Fibrinspaltprodukte infolge lokaler oder systemischer Fibrinolyse. Die Plättchenzahlen sind normal oder mäßig erhöht und die Plättchen-Überlebenszeit ist geringfügig verkürzt. Hingegen lassen sich deutliche Abweichungen der Spontanaggregation sowie der ADP- und Kollagen-induzierten Aggregation nachweisen. Desgleichen ist die Plättchen-Aggregation durch Arachidonsäure gesteigert und die Malondialdehyd-Bildung erhöht. Die Plättchen nephrotischer Patienten weisen nach Zugabe von Albumin ein normales Aggregationsverhalten auf, was auf eine erworbene Funktionsstörung hinweist. Das wichtige Gebiet der Plättchenfunktion bei NS ist derzeit noch wenig erforscht. Aus den klinischen und hämostaseologischen Befunden wird die Forderung abgeleitet, bei Patienten mit nephrotischem Syndrom in jedem Falle Plättchen-Aggregationshemmer zu verabfolgen; bei Vorliegen venöser Thrombosen ist eine Langzeit-Antikoagulation mit Marcumar anzuraten.SummaryThe risk of thromboembolic complications in patients with the nephrotic syndrome (NS) is higher than in any other condition encountered in internal medicine. Such thromboembolic complications comprise venous thromboses (calf, thigh, renal vein) with or without pulmonary embolism and arterial thromboses (coronary thromboses, cerebral artery thromboses, peripheral arterial thromboses). Several defects of the plasmatic coagulation system, fibrinolysis and platelet function had been recognized in the nephrotic syndrome. Increased hepatic synthesis causes a rise of coagulation factors, I, II, VII, VIII, X and increased renal loss causes lowering of the plasma concentration of antithrombin III concentration. There is little evidence for DIC. Plasminogen concentration is diminished, whereas total antiplasmin activity is increased. Low alpha-1-antitrypsin concentration secondary to renal loss is outweighed by increased concentrations of other inhibitors especially alpha-2-macroglobulin and alpha-2-antiplasmin. The common presence of material in the urine reacting as fibrin degradation products with passive hemagglutination techniques appears to be proteolytically degraded fibrinogen excreted as a result of non-selective glomerular proteinuria. Platelet counts are normal or slightly elevated and platelet survival time is slightly, decreased. Definite abnormalities of spontaneous aggregation and ADP- or collagen-induced aggregation are demonstrable. Furthermore, arachidonic acid induced platelet aggregation and malondialdehyde formation by platelets of NS patients are increased. Addition of albumin to platelets of NS patients normalises platelet aggregation. This finding points to some acquired defect of platelet function.There is a clearcut relation between the risk of thromboembolic complications and plasma albumin concentration: thromboses are particularly frequent at plasma albumin concentrations below 2 g/dl. Consequently, it is suggested, that NS patients with plasma albumin <2 g/dl should be given platelet aggregation inhibitors prophylactically. If there is a history of venous thrombosis, long term anticoagulation with dicumarol is indicated.

Amyloid kidney stone of uremic patients consist of Beta2-microglobulin fragments

Urinary stones with amyloid structure, obtained from uremic patients, were analyzed according to molecular weight, amino acid sequence, and antigenic content. A major protein of approximately 7 kD, designated AB protein, was isolated by size exclusion using HPLC in 60% formic acid. AB protein reacted in immunodiffusion only with an antiserum to beta 2-microglobulin, with beta 2m spurring over AB protein. N-terminal amino acid sequence analysis defined two fragments homologous to beta 2m. One fragment commenced with Ile at position 7 and the other with Ser at position 20, with a cleavage point subsequent to a lysyl residue in both. It is concluded that beta 2m is a precursor of urinary amyloid stones and intratubular concretions of patients with preterminal and terminal renal failure; limited proteolysis is involved in AB amyloid generation.

Silicone-induced splenomegaly: treatment of pancytopenia by splenectomy in a patient on hemodialysis.

SPLENIC sequestration of blood cells has been identified by several investigators as one cause of pancytopenia in dialyzed patients.1 , 2 In the case described below, a foreign-body reaction to sil...

Effects of parathyroidectomy on blood pressure in spontaneously hypertensive rats

The long-term effects of parathyroidectomy (PTX) on blood pressure, intravascular volume, pressor hormones, and on acute vascular effects of intravenous parathyroid hormone (PTH) were evaluated in spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WK) rats. PTX or sham operation (CO) were done at 4-5 weeks of age, and a high calcium diet was offered to PTX rats to study them at eucalcemic calcium levels. The cardiovascular effects of PTX, determined after 11-13 weeks, were qualitatively similar in SH and WK rats: mean arterial blood pressure (conscious unrestrained rats) was lower, intravascular volume was higher, total body sodium was slightly higher, and plasma angiotensin II or norepinephrine levels were not different from CO groups. The acute hypotensive and chronotrophic effect of intravenous PTH was unchanged in PTX groups. When parathyroid intact SH rats and PTX SH rats were both examined on an 1.6% Ca diet, blood pressure was significantly lower in PTX than in parathyroid-intact SH rats. The results are compatible with the hypothesis that PTH has a permissive action on blood pressure maintenance in eucalcemic SH and WK rats by mechanisms unrelated to volume status or circulating pressor hormone concentrations.

Dialysis Membranes and Coagulation System

Artificial membranes used for hemodialysis differ from endogenous membranes, i.e. endothelial cells, by their variable thrombogenicity. The key step in activation of the coagulation system by dialysis membranes is thrombocyte activation which is preceded by formation of a protein layer of critical thickness. Crucial questions concerning the quality of this protein membrane as a determinant of thrombocyte activation are not well understood. Activation of the contact phase of the intrinsic plasmatic coagulation system by dialysis membranes is well documented. Local action of thrombin in the membrane microenvironment is documented by release of fibrinopeptide A and deposition of fibrin on the membrane. Apart from thrombin, other mechanisms, e.g. PMN elastase, plasma-independent activation of blood cells, facilitatory action of erythrocytes etc., may play a contributory role. With respect to the polycarbonate membrane, some authors find less platelet extraction and unchanged platelet release reaction. In our own studies, polycarbonate membranes were not superior to cuprophane membranes with respect to thrombogenicity.

Metabolic bone disease in patients on maintenance hemodialysis.

Renal bone disease is the consequence of secondary hyperparathyroidism (P retention and PTH resistance) and of defective metabolism of vitamin D. The effects of these biochemical abnormalities in the