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Analgesic drug therapy in kidney patients needs special expertise. Patients with kidney disease frequently have pain and they have chronic pain more than others. Some analgesic drugs have a nephrotoxic potential and co-analgesics such as anticonvulsive, antidepressive and antipsychotic drugs need a dose adjustment to kindey function. When treating kidney patients with morphine, the accumulation kinetics of the M6 glucuronide must be observed. Otherwise, the risk increases for respiratory depression., Competing Interests: Peter Steffen gibt an, dass keine Interessenkonflikte bestehen. Frieder Keller hat einen Beschäftigungsvertrag beim Universitätsklinikum Ulm und einen Vertretungsvertrag beim KfH Kuratorium für Dialyse und Nierentransplantation., (Thieme. All rights reserved.)

Essential for drug dose adjustment is the glomerular filtration rate (GFR) not the serum creatinine level. In acute disease, a loading dose must be given that usually corresponds to the normal dose. The eliminated half-life is used to estimate the administration interval. For anti-infective drugs with a concentration-dependent effect, the target is the high peak such as for daptomycin, linezolide, and colistin. For anti-infective drugs with a time-dependent effect, the target is the high trough such as for piperacillin, meropenem and vancomycin. Such drugs with a time-dependent action should best be administered by infusion not by bolus dosing. With continuous renal replacement therapy (CRRT), the total filtration rate corresponds to a GFR of 30-50 ml/min and many antibiotics will not need a dose reduction on CRRT. After intermittent hemodialysis, a new loading dose should be given to ascertain sufficiently high concentrations in the interval until the next dose or next dialysis.

Pharmacokinetics and pharmacodynamics follow the logic of cause and consequence. Receptor-mediated and reversible effects can be distinguished from direct and irreversible effects. Reversible effects are capacity-limited and saturable whereas irreversible effects are limited only by the number of viable targets. In the case of receptor-mediated and reversible effects a threshold and a ceiling concentration can be defined. Antimicrobial drugs with concentration-dependent action are distinguished from drugs with time-dependent action. Concentration-dependent effects are associated with a high ceiling concentration and the target is the high peak. Time-dependent effects are associated with a high threshold concentration and the target is the high trough. During kidney dysfunction, alterations of drug response are usually attributed to pharmacokinetic but rarely to pharmacodynamic changes. Dose adjustment calculations, therefore, tacitly presume that pharmacodynamic parameters remain unchanged while only pharmacokinetic parameters are altered in kidney failure. Kidney dysfunction influences the pharmacokinetic parameters of at least 50% of all essential drugs. Clinicians usually consider pharmacokinetics when kidney disease is found, but pharmacodynamics is as important. Alterations of pharmacodynamic parameters are conceivable but only rarely reported in kidney failure. Sometimes surprising dosing adjustments are needed when pharmacodynamic concepts are brought into the decision process of which dose to choose. Pharmacokinetics and pharmacodynamics should both be considered when any dosing regimen is determined., (Copyright © 2018 by the American Society of Nephrology.)

BK virus-associated nephropathy (BKVAN) causes renal allograft dysfunction. The current management of BKVAN relies on pre-emptive adaptation of immunosuppression according to viral load monitoring. However, this empiric strategy is not always successful. Therefore, pretransplant predictive markers are needed. In a prospective longitudinal study, we enrolled 168 kidney transplant recipients and 69 matched donors. To assess the value of BKV genotype-specific neutralizing antibody (NAb) titers as a predictive marker for BKV replication, we measured BKV DNA load and NAb titers at transplant and followed patients for 24 months. After transplant, 52 (31%) patients displayed BKV replication: 24 (46%) patients were viruric and 28 (54%) patients were viremic, including 13 with biopsy-confirmed BKVAN. At any time, patients with high NAb titers against the replicating strain had a lower risk of developing BKV viremia (hazard ratio [HR], 0.44; 95% confidence interval [95% CI], 0.26 to 0.73; P =0.002). Each log 10 increase in NAb titer decreased the risk of developing viremia by 56%. Replicating strains were consistent with donor transmission in 95% of cases of early BKV replication. Genotype mismatch between recipients' neutralization profiles before transplant and their subsequently replicating strain significantly increased the risk of developing viremia (HR, 2.27; 95% CI, 1.06 to 4.88; P =0.04). A NAb titer against the donor's strain <4 log 10 before transplant significantly associated with BKV replication after transplant (HR, 1.88; 95% CI, 1.06 to 3.45; P =0.03). BKV genotype-specific NAb titers may be a meaningful predictive marker that allows patient stratification by BKV disease risk before and after transplant., (Copyright © 2018 by the American Society of Nephrology.)

Background: After the law on living will was released in 2009 in Germany, an increased use of advance directives was observed. Since patients with kidney diseases are facing the potential or real need for expensive and invasive renal replacement therapy, one could speculate that they will either less or even more frequently state an advance directive than patients with other diseases., Methods: A structured interviewing was performed of all patients on a nephrology ward where also patients with other general medical conditions are treated. The study was approved by our local ethics committee (protocol # 303/08). All admitted patients were successively included who could give signed consent. The investigation was performed between July 2009 and April 2010 by a single interviewer (FD)., Results: Among 505 admitted patients, 211 were included but 11 patients did not consent to the investigation. Of the 200 investigated patients, 121 had a renal diagnosis and 79 other medical diseases. Compared to other European studies, the frequency of advance directives was high (26 %), underlining its clinical relevance. Upon multivariate logistic regression analysis the odds ratio (95 % confidence interval, CI) for the presence of an advance directive was significantly increased only by the age (1.06; CI 1.03-1.09; p = 0.001), but not by the underlying diagnosis (1.47; CI 0.72-2.97; p = 0.287). Significantly more patients did forego resuscitation than did dialysis in their living will (16 vs. 4) while the majority was undecided (36 vs. 47; p = 0.01)., Conclusion: Age was found the more impacting variable than the renal diagnosis on the prevalence of advance directives. Patients with a renal diagnosis should be encouraged to make a statement on dialysis in their living will., (© Georg Thieme Verlag KG Stuttgart · New York.)

Contrast-induced nephrotoxicity (CIN) is a form of acute kidney injury that follows intravascular contrast media exposure. CIN may be preventable because its risk factors are well established and the timing of renal insult is commonly known in advance. However, contrast-induced nephrotoxicity is still the third leading cause of iatrogenic renal failure. This important complication accounts up to 10% of acute renal failure cases in hospitalized patients and it is associated with increased short- and long-term morbidity and mortality. Prolonged hospitalization follows and overall increases healthcare resource utilization. This paper will discuss the various prophylactic procedures tested in clinical trials.

In 2006, the German Society for Clinical Chemistry and Laboratory Medicine together with the Society of Nephrology founded a working group with the aim to develop diagnostic pathways for the detection and differentiation of renal diseases. Based on existing recommendations, these pathways may be structured to be a basis for implementation into hospital and laboratory information systems. The present paper describes the contents of these pathways regarding glomerular filtration rate, hematuria, leukocyturia and proteinuria.

Aim: Rituximab is increasingly being used in the treatment of patients with kidney disease. We evaluated our clinical experience at the Ulm University Hospital., Methods: Since 2004, we have administered rituximab as rescue therapy to twenty-seven patients with kidney disease non-responsive to standard treatment. Indications for rituximab were progressive loss of kidney function in thirteen cases; nephrotic syndrome in five cases; humoral rejection after kidney transplantation in five cases and single cases of catastrophic antiphospholipid syndrome (CAPS), pre-emptive removal of ABO incompatible antibodies, pre-transplant removal of panel-reactive antibodies (PRA), and post-transplant lymphoproliferative disease (PTLD). Sixteen patients were treated with both, plasmapheresis and rituximab., Results: Kidney function recovered in five of thirteen cases. Nephrotic syndrome response was observed in two of five cases. In two of five patients with humoral rejection, kidney transplant function could be preserved. Antiphospholipid antibodies, blood group A antibodies and panel reactive antibodies successfully were reduced, and remission was achieved in the case of the patient with PTLD. Four patients died (15%). Adverse events (N.=10) and infectious complications (N.=15) were most likely due to immunosuppression in general and not to rituximab alone. Toxic leukoencephalopathy was a serious but reversible complication in three cases and occurred particularly after the administration of high-dose rituximab (>375 mg/m2)., Conclusion: Rituximab rescue was successful in 48% of our cases (13 of 27). Rituximab did not increase the complication risk of standard immunosuppression. But toxic leukoencephalopathy was identified as a significant rituximab complication.

Background: The purpose of this study was to examine the efficacy of sodium 2-mercaptoethanesulfonate (MESNA), a reactive oxygen scavenger, in at-risk patients given radiographic contrast agents. Contrast-induced nephropathy (CIN) is a common complication of radiographic procedures; reactive oxygen species (ROS) could play a key role., Methods: We conducted a randomized, double-blinded, placebo-controlled trial in 100 patients with stable serum creatinine levels ≥ 150 µmol/l. They received an infusion of either 1,600 mg of MESNA (n = 51) or placebo (n = 49) plus 0.9% saline prior to and after contrast administration. CIN was defined as a ≥ 25% increase in serum creatinine after 48 h compared to baseline., Results: CIN occurred in 7 patients in the placebo group and none in the MESNA group (p = 0.005). The adjusted odds ratio for CIN was 0.17 (95% confidence interval 0.03 - 0.80, p = 0.026) in the MESNA group compared to the placebo group. Cystatin C concentrations decreased slightly in the MESNA group but increased in the control group (p < 0.05)., Conclusion: MESNA plus volume expansion before and during contrast exposure was effective in this single-center study for preventing CIN compared to volume expansion alone.

Objective: Our intention was to assess knowledge and requirements related to drug dose adjustment in patients with impaired kidney function., Method: In 2005, we sent a questionnaire containing 22 questions to nephrologists in Germany and Austria. With 77 responses, the study was not representative. However, it was probably of importance for the target group of practising physicians and potential users of a future drug information system., Results: Only 28% of the responding colleagues use the package inserts; these are obviously not considered to be an obligatory guideline for dose adjustment. The most common dosing problems (p < 0.05) were associated with anti-infective (48%) and anti-cancer drugs (25%). The greatest problems with dosing were encountered within intensive care units (29%). The risk of excessive dosing is estimated significantly more serious than the risk of underdosing (51% vs. 23%, p = 0.02). There was support for the statement that for cephalosporin antibiotics the trough levels are more important than peak levels (58% vs. 27%, p < 0.01). However, only 8% knew that in patients with impaired kidney function, trough concentrations of aminoglycosides and vancomycin need to be higher than in patients with normal kidney function for adequate peak levels to be obtained. Forty-five percent of respondents erroneously presumed that ceftriaxone must be adjusted to the kidney function. Half of the respondents were incorrect in assuming that ceftriaxone or moxifloxacin would be removed by dialysis., Conclusions: We see the need for more knowledge-based information on drug dosing in patients with kidney impairment and those in the intensive care unit. The risk to life posed by underdosage might be underestimated, especially for anti-infective drugs.

In people who are aged >65 years, pharmacokinetics are influenced more by the loss of kidney function than by the aging process of any other organ. A GFR of 30 to 60 ml/min, suggestive of stage 3 kidney disease, is observed in 15 to 30% of elderly people. Drug dosing must be adjusted to both changing pharmacokinetics and pharmacodynamics; the pharmacodynamics might be influenced by the aging of other organs, too. Using our NEPharm database, we extracted abstracts with pharmacokinetic parameters since 1999 from a weekly PubMed search. The recorded data were analyzed and compared with published recommendations on drug dosage and use in the elderly. Purely age-related changes in pharmacokinetic parameters were recorded from publications on 127 drugs. The analysis of our NEPharm records revealed an average (mean +/- SD) age-related prolongation of half-life of 1.39-fold (corresponding to +39 +/- 61%). Contrasting to common opinion, mean changes in clearance (-1 +/- 54%) and volume of distribution (+24 +/- 56%) were even less. The modest changes in pharmacokinetics do not suggest general dosage modifications in the elderly for most drugs. Changes in pharmacodynamics justify the common medication rule in the elderly-"start low + go slow"-especially for drugs that act on the central nervous system; however, in the case of anti-infective and anticancer therapy, the rule should be "hit hard = start high + go fast" to produce the target effect also in the elderly.

Unlabelled: Intensification of the conditioning regimen with a radioactively labeled anti-CD66 antibody is feasible before allogeneic stem cell transplantation. The use of radioimmunotherapy may deliver a significant dose of radiation to the kidneys. We therefore studied the incidence and clinical picture of bone marrow transplantation (BMT) nephropathy in our patients receiving radioimmunotherapy before allogeneic stem cell transplantation., Methods: This study was a clinical trial of 114 consecutive patients who received conditioning with a radiolabeled anti-CD66 antibody-188Re (n = 93) or 90Y (n = 21)-between 1998 and 2003., Results: Although BMT nephropathy has developed in none of the patients in the [90Y]anti-CD66 group, 6 of 93 patients receiving [188Re]anti-CD66 presented with signs of BMT nephropathy at a median of 11.5 mo after stem cell transplantation. The absorbed renal dose was significantly lower in the 90Y group (4 vs. 7 Gy, P < 0.0001). Of the patients receiving [188Re]anti-CD66 who are alive, BMT nephropathy developed in 19% (6/32). Five of 6 patients with BMT nephropathy received total-body irradiation. The patients presented with elevated serum creatinine, proteinuria, anemia, hypertension, and signs of microangiopathy. All 6 patients in whom BMT nephropathy has developed are alive at a median follow-up of 58 mo after stem cell transplantation, and 1 patient has entered a dialysis program., Conclusion: BMT nephropathy appears to be a significant problem after allogeneic stem cell transplantation with intensified conditioning using the 188Re-labeled anti-CD66 applied in this study, particularly when combined with total-body irradiation.

Aims: To compare raloxifene pharmacokinetics between renally impaired and healthy subjects., Methods: Raloxifene 120 mg was administered to 10 males with renal impairment (creatinine 2-4 mg dl(-1)) and to 10 healthy males. Data were analysed by two noncompartmental and one compartmental nonlinear regression methods., Results: The medians (95% confidence interval) of the area under the curves (AUC) were 35.1 (25.8, 74) and 20.5 (16.8, 28.0) h ng ml(-1) per mg kg(-1), P < 0.01, and of the clearances (CL/F) were 28.5 (13.5, 38.8) and 48.8 (35.8, 59.4) l h(-1) kg(-1), P < 0.01, in renally impaired and healthy subjects, respectively. 95% Confidence intervals on the differences for AUC and CL/F were 6.5-44.1 and -35.1 to -7.9, respectively., Conclusion: Exposure to raloxifene was twice as high in males with renal impairment compared with healthy subjects.

Background: The nephrotoxicity induced by contrast media remains a serious clinical problem, and the underlying mechanism has not been completely understood. Experimental and clinical investigations suggest that reactive oxygen species (ROS) are critical determinants of radiocontrast nephropathy (RCN), and that antioxidants can prevent this damage., Methods: Cultured human proximal renal tubule cells (HK-2) were exposed to hydrogen peroxide (H2O2) at different concentrations. H2O2-induced tubular DNA damage was examined in the presence of the antioxidant MESNA (sodium-2-mercaptoethane sulphonate). The induction of DNA damage was measured with the alkaline comet assay (single cell gel electrophoresis). We also studied 12 patients with stable renal impairment (median baseline creatinine 296 micromol/l; range: 203-495 micromol/l) undergoing cardiac catheterization/intervention prospectively. Patients received 800 mg MESNA intravenously 30 min before exposure to the contrast agent in addition to 0.9% saline hydration., Results: In the cell cultures, oxidative stress on HK-2 cells induced increased DNA migration in the comet assay. Treatment of tubular cells with the antioxidant MESNA prior to the addition of H2O2 significantly reduced DNA migration in the comet assay. In the clinical study, treatment of the patients with MESNA prevented the adverse renal effect of contrast media (median serum creatinine 293; range: 187-433 micromol/l) 48 h after coronary angiography/intervention., Conclusion: Both the in vivo and the in vitro studies suggest that the ROS-mediated renal injury could be inhibited by a potent antioxidant such as MESNA., (Copyright 2004 S. Karger AG, Basel)

Background: For patients with impaired renal function, dosage adjustment is necessary for many drugs. Adjustment with respect only to pharmacokinetic parameters may be insufficient., Objective: To apply the theory of pharmacokinetics and pharmacodynamics to derive a mathematical model that links the concentration-time course and the clinical response by means of the pharmacokinetic-pharmacodynamic parameter 'area under the effect-time curve' (AUETC), and to use this analysis and clinical data for aminoglycosides to calculate dosage adjustments in renal impairment., Methods: Model parameters were estimated for the antimicrobial and nephrotoxic effects of aminoglycosides on the basis of data from the literature. Effect parameters were calculated for various degrees of impaired renal function., Results: Use of the model parameters gave a high correlation between the predicted and the observed (literature) values for antimicrobial efficacy and nephrotoxicity. When calculating dosage adjustments in renal impairment, it was possible to hold only one effect (antimicrobial or nephrotoxic) constant by dosage adjustment, whereas the other changed unfavourably. This was explained by differences between the pharmacodynamic parameters for each effect. For high antimicrobial efficacy, a target peak concentration of 9 mg/L (for gentamicin) should be obtained every 48 hours in advanced renal impairment. For low nephrotoxicity, the peak concentration should not exceed 3 mg/L., Conclusions: The parameter AUETC could be a useful pharmacokinetic-pharmacodynamic surrogate marker for dosage adjustment in renal impairment. Using the AUETC method, the beneficial effect can be balanced against the adverse effect.

Schematic dosage adjustments for aminoglycosides, vancomycin, and ciprofloxacin were derived from published data on the prolongation of elimination half-lives in patients with renal impairment. Therapeutic drug monitoring was retrospectively evaluated with 84 severely ill patients, 29 of whom needed renal replacement therapy (35%). Mortality (n = 27) and antiinfective failures were high (n = 23). Toxicity was suspected in 5 patients, though it was demonstrated only in 1 case. As compared to the patients with normal renal function, patients with renal impairment exhibited peak levels that tended to be lower, although their trough levels tended to be higher; the aminoglycoside troughs even were significantly elevated in renal replacement patients (1.0 mg/l (0.6-1.4) versus 0.6 mg/l (0.3-0.8)). Seen in relation to toxicity, antiinfective failure was by far the greater problem even with dosage adjustments at high trough levels. Multivariate analysis showed antiinfective failure to be significantly correlated to 10 canonical variables (age, weight, leucocyte count, peak level, trough level, initial creatinine, increase in creatinine, fever, change of dosage, and renal replacement therapy). Among these variables, it were neither drug levels nor renal replacement, but only persistent fever and deteriorating renal function that independently contributed to antiinfective failure. For adjustment of antiinfective therapy, paradoxically we conclude that trough concentrations higher than normal must be allowed for to avoid underdosage in renal replacement patients.

Chronic kidney diseases are characterized by alterations in connective tissue turnover resulting in fibrosis. We measured circulating peptides related to type VI collagen and undulin in serum and urine of 125 patients with various kidney diseases, on chronic hemodialysis and after kidney transplantation. Using a double-armed ELISA technique (median, 95% CI), normal serum concentrations for type VI collagen were 50 ng/ml [46-63] with no type VI collagen detectable in urine. Normal values for undulin were 215 ng/ml [207-241] in serum and 240 micrograms/d [223-284] in urine. The serum concentrations of undulin were most significantly (477 ng/mg [358-737]) increased in 18 hemodialysis patients. A significant increase (330 ng/ml [306-368]) was also observed in patients with various kidney diseases not requiring dialysis. No differences were found between the various forms of glomerulonephritis, interstitial nephritis and other kidney diagnoses. Although very low in normals (1.16 ml/min [1.05-1.27]) renal undulin clearance was even significantly lower in patients with kidney diseases (0.5 ml/min [0.4-0.6]). Serum concentrations for undulin were in the normal range in the direct postoperative phase after kidney transplantation (207 ng/ml [167-306]), whereas in kidney transplant out-patient levels were elevated to 425 ng/ml [357-563]. There was a slight but significant correlation between serum undulin and creatinine values and between renal undulin clearance and creatinine clearance. Values of serum type VI collagen increased in analogy to those of undulin. We conclude, that type VI collagen and undulin are novel serum parameters of renal extracellular matrix turnover that merit further exploration in patients with chronic kidney diseases.

The basic law in nephropharmacology states that pharmacokinetic parameters depend linearly on renal function. Few exceptions to linear dependence have been reported, e.g. substances with saturable tubular reabsorption or secretion. A further example is cyclosporin, which was found to be eliminated according to log-concave nonlinear kinetics in 3 patients with hepatotoxicity after kidney transplantation. The nonlinear cyclosporin kinetics were computer-fitted to the integrated forms of the 1-exp function and the Michaelis-Menten equation by nonlinear regression analysis. The same maximal velocity (Vmax = 23 ng ml-1 h-1) and Michaelis constant (Km = 686 ng ml-1) were calculated for cyclosporin when applying either the 1-exp function or the Michaelis-Menten equation. The nonlinear elimination of cyclosporin, however, was described even more closely by the 1-exp function than by the Michaelis-Menten equation.

Analgesic nephropathy was the most frequent diagnosis in 324 haemodialysis patients (30%) and the second most frequent diagnosis in 900 transplant patients (17%) at the Klinikum Steglitz, Berlin. Analgesic patients were the oldest group among haemodialysis and transplanted patients; the analgesic patients on haemodialysis were significantly older than the transplanted analgesic patients (55.9 +/- 11.2 versus 50.5 +/- 7.5 years, P = 10(-6)). Patient and graft survival under cyclosporin treatment are not statistically different in 125 transplantations of 109 patients with analgesic nephropathy compared to 508 transplantations of 423 patients with other renal diseases (5-year patient survival, 83.3 +/- 5.1% versus 88.4 +/- 2.4%; 5-year graft survival, 53.5 +/- 7.4% versus 56.8 +/- 3.8%; NS). Acetaminophen in urine was found in two of 30 analgesic and in one of 54 other patients with a functioning transplant (6.7% versus 1.9%; NS). As a sign of compliance, the mean cyclosporin trough level of 17 patients with analgesic nephropathy did not differ significantly from that of 14 patients with polycystic kidney disease (136.4 +/- 16.4 versus 139.4 +/- 17.3 ng/ml; NS), nor did the mean standard deviation of the individual measurements (36.7 +/- 36.8 versus 27.5 +/- 20.7 ng/ml; NS). Urothelial carcinoma was significantly more frequent in patients with analgesic nephropathy than in those with other renal diseases despite cystoscopy and retrograde pyelography before transplantation (3.7% versus 0.32%; P = 0.001). Vascular disease was the cause of death in 19 of 44 analgesic transplant patients who died (43.2%).(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the clinical course of 700 renal transplantations, including 1,305 transplant histologies performed in 611 patients between 1970 and 1988, to estimate the influence of cyclosporine A (CsA) after kidney transplantation on the incidence of recurrent or de novo renal disease. Primary renal disease recurred in 11 of 583 functioning transplants (1.9%) with transplant loss in seven patients (1.2%): focal segmental glomerulosclerosis (FSGS, three patients); membranous glomerulonephritis (GN, one patient); mesangiocapillary GN (one patient); rapidly progressive IgA nephropathy (one patient); hemolytic-uremic syndrome (HUS, three patients); and oxalosis in two transplants (one patient). De novo renal disease occurred in six patients (1.0%), including mesangiocapillary GN type I (three patients); nonpurulent focal GN in septicemia (one patient); HUS (one patient); and nodular glomerulosclerosis in steroid diabetes (one patient). De novo membranous GN was seen in 14 additional cases (2.4%). No statistically significant difference could be established between the treatment groups without (n = 225) and with (n = 358) CsA in recurrent and de novo renal disease (n = 7/225 v 10/358, NS); in recurrent and de novo GN (n = 4/225 v 6/358, NS); in recurrent FSGS (n = 1/7 v 2/8, NS); in recurrent and de novo HUS (n - 1/1 v 2/7, NS); and in de novo membranous GN (n = 7/225 v 7/358, NS). Transplant loss by recurrent and de novo GN was higher without than with CsA (n = 4/4 v 1/6, P = 0.004). On the basis of our investigation, we conclude that recurrent and de novo renal disease in the transplant occur rarely and are not prevented by CsA. However, even if the incidence of transplant GN is unchanged by CsA treatment, its clinical course seems to be mitigated. CsA treatment also does not increase the incidence of HUS.

Measurements of elevated procollagen III peptide (PIIIP) levels are used to monitor fibrosing activity in hepatic and various other diseases. Elevated PIIIP levels have also been reported in renal failure patients without such diseases. Therefore, the serum levels and renal clearance of PIIIP were investigated in 17 healthy volunteers and 100 patients with different types of acute (n = 15) and chronic (n = 85) kidney disease. PIIIP was measured by conventional and Fab radioimmunoassays. Median PIIIP levels in serum (18, range 5-55 ng/ml) and urine (34, range 1-110 micrograms/day) were significantly higher in kidney patients than serum (9, range 6-14 ng/ml) and urine levels (17, range 6-24 micrograms/day) in normal volunteers (p = 0.01). No significant differences (Kruskal-Wallis H test) were found, however, within the different kidney disease groups (acute, chronic/glomerulonephritis, interstitial nephritis). Median renal clearance of PIIIP-related peptides in kidney patients (1.5, range 0.5-2.4 ml/min) did not differ significantly (Wilcoxon U test) from that in normal volunteers (1.3, range 0.4-2.2 ml/min). These findings indicate that PIIIP elimination does not depend on renal function. PIIIP-related peptides in serum and urine, however, increase with renal failure irrespective of the activity or type of renal disease. This can be explained most probably by enhanced turnover of collagen type III by the affected kidney itself.

The measurement of plasma drug concentrations provides no insight into the relationship between the free and the plasma-protein-bound fractions of drugs. Plasma protein binding may decrease in renal disease due to uremia, hypoalbuminemia, or due to drug interactions. Decreased plasma protein binding leads to an increase in free plasma fraction causing an increase in volume of distribution and a shorter elimination half life. The increase in the apparent volume of distribution and the shorter elimination half life cause a decrease in total plasma concentration. Therefore, the free drug concentration is more reliable than the total plasma concentration for therapeutic drug monitoring. However, the free amount in plasma and in tissue and the tissue-bound amount remain unchanged under steady state conditions. Thus, a decrease in plasma protein binding in renal disease usually does not lead to increased drug toxicity, and alteration of drug dosage is not required, although the total plasma concentration may be found to be considerably lower than normal. In addition to plasma protein binding, alteration of tissue binding must also be considered for the determination of the appropriate dosage of some drugs in renal disease.

The factors that influence the progression of renal failure in analgesic-associated nephropathy (AAN) still remain to be clarified. In this study, the actual analgesic intake (N-acetyl-p-aminophenol, NAPAP, i.e. acetaminophen in urine) and progression of renal failure (1/crea method) in 127 outpatients with various renal diseases were investigated over a period of 7-150 months. AAN was diagnosed in 57 of the 127 patients (44%). The NAPAP test was positive in 21% of the 57 AAN patients and in 3% of the 70 control patients with other renal diseases (p = 0.0001). The AAN patients presented with more advanced renal insufficiency, lost more weight, and had more severe hypertension as well as a higher mortality rate than the control patients (univariate analysis). Progression of renal insufficiency, as measured by regression analysis of the reciprocal of serum creatinine versus time and expressed as clearance loss per year, was more rapid in the AAN patients who were found positive for NAPAP (6.9 +/- 5.5 ml/min/year) than in the AAN patients who were found negative (4.1 +/- 11.0 ml/min/year) or in control patients with other renal diseases (5.1 +/- 14.9 ml/min/year). Multivariate analysis showed the more rapid clearance loss to be the most discriminating factor between the AAN patients who continued analgesic abuse of phenacetin-or acetaminophen-containing drugs and AAN patients who stopped. We therefore conclude that continued analgesic abuse promotes renal insufficiency in AAN. The progression of renal failure in AAN patients who stopped abusing analgesics, however, cannot be explained within the parameters investigated, i.e. urinary tract infection, hypertension, hyperalimentation, or papillary necrosis.

The important role of immunological factors, HLA typing and pretransplant blood transfusion on improved kidney graft survival is well established. Additionally, graft survival depends on risk factors such as diabetes and age of the recipient. The effect of other clinical risk factors on graft survival was evaluated in 187 patients who received kidney transplants at our centre between 1970 and 1981. Graft survival according to the life table method and statistical analysis according to the logrank test revealed 4 main risk factors. Graft survival is significantly lower in type I diabetics and analgesic nephropathy, whereas it is better in hereditary and other renal diseases. Additional risk factors are coronary heart disease and repeated grafting. Time of dialysis before transplantation and age of the recipient showed no detrimental effect on graft survival.

Transarterial renal embolization has been used in the management of renal cancer. We report on 9 patients who underwent selective and superselective renal arterial embolization for nonmalignant renal lesions. Embolization was done in 5 patients for hemorrhage owing to renal angiomas, renal artery, pseudoaneurysm, percutaneous renal biopsy and adult polycystic kidney disease, and in 2 patients with end stage renal disease because of massive proteinuria. Another chronic renal failure patient with severe hypertension was treated successfully with bilateral renal embolization. A postoperative renal arteriovenous fistula was treated successfully by catheter vaso-occlusion. Renal embolization may be a suitable alternative to surgery in poor operative risk patients and for technically difficult benign lesions. Renal infection is a contraindication to embolization.

In our haemodialysis centre patients (n = 144), we compared 48 aspects of morbidity in patients with analgesic-associated nephropathy (AAN) and patients with other kidney diseases to determine the presence of characteristic diagnostic features of AAN in addition to a history of habitual analgesic intake. The comparison between 48 AAN patients and the control patients revealed statistically significant differences (p less than 0.05) with regard to myocardial infarction (25% vs 7%), angina pectoris (63% vs 32%), atrial fibrillation (21% vs 4%), arteriosclerosis obliterans of the lower extremity (52% vs 33%), anaemia (mean haemoglobin, 8.38 vs 9.16 g/dl), renal osteodystrophy (67% vs 41%), carpal tunnel syndrome (23% vs 7%), peptic ulcers and erosive gastritis (54% vs 23%), colonic diverticula (15% vs 4%), and haemorrhoids (67% vs 28%). AAN patients therefore have significantly higher morbidity with a characteristic pattern than do patients with other renal diseases.

The knowledge of some characteristic findings on the personality of patients with analgesic-associated nephropathy (AAN) may facilitate diagnosis of the disease at an early stage. We therefore investigated the 144 patients at our hemodialysis center and compared the AAN patients (33%) with those having other kidney diseases (controls). Patients with AAN were older (60 +/- 10 vs 52 +/- 15 years, p less than 0.001) and predominantly women. Acetaminophen and metamizol metabolites were detected more frequently in blood from the AAN patients than in that from the controls (25% vs 3%, p = 0.002). More AAN patients were smokers, and they more frequently complained of vague symptoms (pain, sensitivity to changes in weather, insomnia) and also more frequently requested prescriptions for analgesics, hypnotics, laxatives, stomachics and antipruritics. Because they were older, AAN patients had fewer occupational and financial problems. The compliance of the AAN patients was significantly better with respect to important dialysis parameters such as weight gain between dialysis treatments (3.6 +/- 1.3 vs 4.0 +/- 1.3% body weight, p less than 0.05) and diastolic blood pressure (81 +/- 12 vs 86 +/- 12 mmHg, p = 0.025). Despite an older age and higher morbidity, the cumulative 17-year survival rate of the AAN patients did not differ from that of the controls. We conclude that AAN patients have characteristic personality traits. Their better compliance, adjustment to the hemodialysis situation and social conditions are responsible for their good survival on hemodialysis.

In progressive immunoglobulin (Ig)A nephropathy (IgAN), cyclophosphamide pulse therapy (CyP), high-dose intravenous immunoglobulins (IVIg) and mycophenolic acid (MPA) have been used to stop progressive loss of renal function, but disease progression may occur after the end of the initial treatment. Here, we report the long-term follow-up of patients with progressive IgAN with MPA as maintenance therapy after CyP (CyP-MPA). In a median observation time of 6·2 years, we analysed the slopes of the loss of renal function of 47 patients with biopsy-proven IgAN and treated with CyP. Thirty-one patients with further progression were treated with MPA maintenance for a median time of 5·2 years. Follow-up was compared with symptomatic therapy and IVIg as historically matched control groups. Median loss of renal function was reduced significantly from 0·9 ml/min to 0·1 ml/min per month with CyP ( P < 0·05), and with MPA in patients with a relapse from −0·4 ml/min to −0·1 ml/min per month ( P < 0·05) until the end of the study. Proteinuria decreased significantly from 1·6 g/l to 1·0 g/l after CyP, and during MPA treatment to 0·6 g/l ( P = 0·001 Friedman test). Median renal survival time was in patients with CyP 10·5 years (range = 3·2-17·8), with CyP-MPA 10·7 years (range = 8·3-13·1), with IVIg 4·7 years (range = 2·6-6·6), and in untreated patients 1·2 years (range = 0·8-1·6; log-rank test P < 0·01). In patients with progressive IgAN, our long-term follow-up observation indicates that sequential CyP-MPA therapy maintains renal survival significantly. [ABSTRACT FROM AUTHOR]

In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long-term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1·73 m2] followed for a median observation period of 8 years. In this single-arm, non-randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1·73 m2) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from − 1·05 ml/min per month to − 0·15 ml/min per month ( P = 0·024) and proteinuria decreased from 2·4 g/l to 1·0 g/l ( P = 0·015). The primary end-point (GFR < 10 ml/min or relapse) occurred 5·2 years (median; range 0·4–8·8) after the first IVIg pulse, and after 1·3 years (median; range 0·8–2·4) in the control group ( P = 0·043). In Kaplan–Meier analysis, the median renal survival time with IVIg was prolonged by 3·5 years (IVIg 4·7 years versus control 1·2 years; P = 0·006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN. [ABSTRACT FROM AUTHOR]

Pregnancies in women with renal disease, undergoing dialysis treatment or with kidney transplants are increasingly observed. Serious problems with drug dose adjustment may arise in pregnant women with renal impairment. This review gives a practical overview on the risks of drug use during gestation, the recommended drugs of choice (e.g. methyldopa, cyclosporin), and provides some proposals for dosage adjustments in pregnant women with renal impairment. In normal pregnancy, the glomerular filtration rate and plasma volume increase, whereas plasma protein binding and liver function may be impaired. An increase in dosage is needed for cyclosporin and for methadone because of increased hepatic clearance. The dosage of erythropoetin must be increased because of lower potency in pregnant women. Little more is known on the impact of gestation on drug dose, since pharmacokinetic studies are rarely done in pregnant women. The dosages of magnesium, lithium and morphine must be reduced in renal impairment. Dose adjustment to renal function is critical and is essential for anti-infective agents (e.g. ceftazidime, ganciclovir). Basing drug dose on estimated creatinine clearance might be the most practical solution in pregnant women with renal impairment. [ABSTRACT FROM AUTHOR]

Objective: Patients with diabetes and underlying renal insufficiency exhibit an increased propensitiy to develop radiocontrast agent-induced nephropathy after receiving radiocontrast agents for diagnostic and interventional procedure. In fact, radiocontrast-agent-induced nephropathy is currently a major leading cause of hospital-acquired renal failure. The underlying mechanisms for radiocontrast agent-induced nephropathy most likely involve the interplay of several factors, including vasoconstrictive forces resulting in medullary ischemia, direct effects on renal tubular cells, and damage caused by oxygen radicals. Data from experimental studies indicate that antioxidants, e.g. acetylcysteine, may prevent radiocontrast-induced nephropathy. Glutathion is an endogenous antioxidant primarily considered to be of importance in the erythrocyte antioxidant defense system function. The purpose of this study was to determine the development of radiocontrast agent-induced nephropathy in patients with moderate chronic renal insufficiency in dependence on their hemoglobin. Patients and Methods: We retrospectively studied 250 patients (age: 66.7 ± 10.1 years) with moderate chronic renal insufficiency (serum-creatinine concentration between 1.4 mg/dl (124 µmol/l) and 3.0 mg/dl (265 µmol/l)) who underwent coronary angiography with or without intervention from 1988 till 1999. Contrast-agent-induced nephropathy was defined by an increase in serum creatinine of 0.5 mg/ dL (44 µmol/l) or more than 25% compared to baseline levels within 48 to 72 hours of contrast-agent administration. First, hemoglobin and change of serum creatinine concentrations were correlated; in addition, patients were classified into two groups according to their hemoglobin (hemoglobin ≤12.0 g/dl group 1 [71 patients], hemoglobin ≥12,0 g/dl group 2 [179 patients]). Results: Hemoglobin (Hb) and change of serum creatinine concentrations (dKrea) were linear inverse correlated with a regression equation dKrea (µmol/l) = 137.2 - 8.887 x Hb, negative slope was significantly different from zero with p < 0.0001. There was no difference of serum creatinine between the two groups at baseline (173.5 ± 30.8 vs. 166.2 ± 31.1 µmol/l), in group 1 contrast-agent-induced nephropathy occurred in 39 of 71 patients (54.9%), in group 2 in 23 of 171 patients (13.5%), with a significant difference (p < 0.001) between the two groups. Also, absolute increase in serum creatinine was significantly differrent among the groups (group 1: 173.5 ± 30.8 → 222.6 ± 78.1 µmol/l; group 2: 166.2 ± 31.1 µmol/l → 173.2 ± 59.0 µmol/l; p < 0.001). Conclusions: In patients with moderate chronic renal insufficiency receiving radiocontrast agent for diagnostic and interventional procedures the presence of additional anemia rises the risk for radiocontrast agent-induced nephropathy. Further studies have to determine to what extent the primary antioxidant defense system of erythrocytes is important in this context. [ABSTRACT FROM AUTHOR]

Objective: In patients with advanced progressive IgA nephropathy (IgAN), CyP therapy has been shown to arrest progression to end-stage renal disease, but some patients show further progress after CyP. Mycophenolate mofetil (MMF) is a promising drug for salvage or maintenance in sequential therapy in autoimmune diseases. In this prospective, uncontrolled trial, we evaluated the effect of MMF salvage therapy on renal function after cyclophosphamide pulse therapy (CyP) in progressive or relapsing IgAN. Methods: Thirteen patients were treated for 21 months (median, range 8 to 63 months) with MMF salvage therapy (median dose 1 g/day) who showed further increase of serum creatinine (>10%), or proteinuria >0.7 g/l after CyP induction therapy. Results: In linear regression analysis of inverse serum creatinine the median loss of renal function was 1.6 % per year after CyP, but increased again to 12.7 % per year 5 months after end of CyP. MMF significantly reduced the loss of renal function to 3.5 % per year. Overall there was a trend to a decrease in proteinuria from 1.7 to 0.9 g/l after MMF and CyP therapy. Conclusions: In conclusion, sequential therapy with MMF is effective in salvage of renal function in a subgroup of patients with further progressive or relapsing IgAN after CyP induction therapy. [ABSTRACT FROM AUTHOR]

Objective: Intravascular administration of iodinated radiocontrast agent continues to be a common cause of hopital-aquired acute renal failure. Accumulating evidence suggests that radiocontrast-agent induced nephrotoxicity is associated with increased oxidative stress leading to renal tissue damage with DNA fragmentation. Still, oxidative DNA damage resulting from free radical attack remains a poorly examined field in radiocontrast-induced nephropathy. We therefore tested whether an iso-osmolar contrast agent (iodixanol) causes less oxidative damage to renal tubular cells than a low-osmolar contrast agent (iopromid). Methods: HK-2 cells (human proximal renal tubular cell line) were incubated (15 and 30 minutes) with different doses (100-300 ul/ ml) of the non-ionic iso-osmolar contrast agent iodixanol or of the nonionic low-osmolar substance iopromid. Oxidative DNA damage to renal tubular cells was measured by alkaline comet assay (single cell electrophoresis) in the presence or absence of FPG, a DNA repair enzyme, which detects DNA single strand breaks through 8-oxo-guanine lesions. Results: Both, iso- and low-osmolar contrast agents induced concentration- and time-dependent DNA fragmentation, But DNA migration was 3 times higher in cells exposed to the new iso-osmolar contrast medium iodixanol (tail moment 1.0 vs 3.5). Conclusions: This study demonstrates for the first time that both, iso- as well as low-osmolar radiocontrast agents can induce oxidative stress in HK-2 cells, but low-osmolar contrast agents exhibit less DNA damge compared to iso-osmolar substances. [ABSTRACT FROM AUTHOR]