R. A. P. Koene

Medication compliance after renal transplantation

Noncompliance is known to be an important cause of late graft failure after renal transplantation. We investigated prospectively the degree of compliance with immunosuppressive and antihypertensive drugs during the first year after renal transplantation by monthly pill counts. In addition, we examined whether noncompliance was related to a number of demographic and clinical variables or to the occurrence of rejections. The study population consisted of 127 patients who were involved in a randomized trial comparing cyclosporine monotherapy with azathioprine-prednisone treatment. Average compliance rates approximated 100%, although considerable variability within and between subjects was observed. Using an arbitrary limit to classify patients as compliers or noncompliers, the following frequencies of noncompliance were observed during the study year: cyclosporine, 23%; azathioprine, 13%; prednisone, 23%; atenolol, 36%; and nifedipine, 32%. Average compliance scores for all immunosuppressive drugs were superior to those of antihypertensive medication (P < 0.001). Except for a better compliance for prednisone in men as compared with women, we found no consistent relationship between compliance on the one hand and several demographic variables, graft function, or quality of life on the other hand. Patients who developed one or more acute rejection episodes showed a higher degree of undercompliance, especially for prednisone, than patients without rejections (P < 0.01). Following the occurrence of a rejection episode, compliance scores improved significantly. Keeping in mind the limitations of the pill count method, we conclude that noncompliance with immunosuppressive drugs is not a huge problem during the first year after renal transplantation. However, it is likely that noncompliance contributes to a certain number of acute rejection episodes.

Mannitol As An Indispensable Constituent Of An Intraoperative Hydration Protocol For The Prevention Of Acute Renal Failure After Renal Cadaveric Transplantation

With its incidence of about 40%, acute renal failure, (ARF) is a major problem after cadaveric renal transplantation. We have previously shown that, with moderate hydration (2.5 L) of the recipient, together with rapid infusion of 250 ml of mannitol 20% just before clamp removal, the incidence of ARF decreased to below 10%. Administration of mannitol without hydration was not effective. In a prospective randomized trial we have now investigated whether hydration without mannitol is sufficient to prevent ARF. For this purpose patients were randomly allocated to treatment with moderate hydration with or without mannitol. Furthermore, in both treatment groups recipients were randomized to treatment with cyclosporine or azathioprine. The allocation method used guaranteed an even distribution for 10 important prognostic factors. In the cyclosporine group, the percentage of ARF was significantly lower in mannitol-treated (n=32) than in glucose-treated patients (n=32) (19% vs. 54%, P < 0.01). In the azathioprine group the percentage of ARF was also lower in mannitol-treated (n=33) than in glucose-treated patients (n=34) (18% vs. 44%, P < 0.05). Overall incidence of ARF in both groups was significantly lower in mannitol-treated patients (P < 0.001). Thus, moderate hydration and administration of 250 ml mannitol 20% just before arterial clamp removal are both indispensable for optimal prevention of ARF after cadaveric renal transplantation.

Recurrence of type I membranoproliferative glomerulonephritis after renal transplantation : Analysis of the incidence, risk factors, and impact on Graft survival

BACKGROUND The information in the medical literature on the incidence of recurrence of type I membranoproliferative glomerulonephritis (MPGN) after renal transplantation and its impact on graft survival is limited because most data are derived from case reports or from studies involving a small number of patients. METHODS We analyzed the data from our transplant center. Among 1097 adult patients receiving their first allograft between 1977 and 1994, we identified 32 patients with type I MPGN. RESULTS A recurrence was detected in 9 of the 27 recipients of a first cadaveric graft (33%). The cumulative incidence reached 48% at 4 years after transplantation when patients with graft failure from other causes were censored. All patients with recurrent MPGN had clinically significant proteinuria (>1 g/24 hr) that was first observed at a median time of 20 months (range, 1.5-42 months) after transplantation. Graft survival was significantly worse in patients with recurrence as compared with patients without recurrence. Mean duration of graft survival after the diagnosis of recurrence was 40 months. We could not detect any clinical characteristics of patients or donors that were associated with recurrent disease. However, an increased risk of recurrence was observed in patients with the HLA haplotype B8DR3. Four patients received an HLA-identical graft from a living related donor. Recurrence occurred in three patients (75%), with ensuing graft loss in two. The only patient with a haploidentical living related graft did not have a recurrence. Five patients with a recurrence in the first graft received a second transplant. Recurrence was observed in four of these patients (80%). CONCLUSIONS Type I MPGN recurred after renal transplantation in half of the patients. The incidence may be even higher in recipients of an identical living related donor graft and in patients receiving a second transplant after having experienced a recurrence in their first graft. Recurrence of type I MPGN has a detrimental effect on graft survival.

Drug-induced nephrotoxicity: aetiology, clinical features and management

SummaryThere is a growing number of hospitalised patients who develop a drug-induced renal problem because increasing numbers of potent drugs have been added to the therapeutic arsenal in recent years. The 3 clinical syndromes that can be recognised in drug-induced nephropathy are acute renal failure, chronic interstitial nephritis and the nephrotic syndrome. The first can be caused by prerenal problems, acute interstitial nephritis, acute tubular necrosis and intratubular obstruction.The most important drugs that cause prerenal failure are NSAIDs, captopril and cyclosporin. NSAIDs inhibit the synthesis of prostaglandins, and consequently vasoconstriction of the afferent arteriole leads to lowering of the glomerular filtration rate (GFR); captopril blocks the formation of angiotensin II (which also leads to a lower GFR), and should be used with caution in patients with stenotic renal arteries; cyclosporin causes vasoconstriction of the afferent arteriole, which is probably mediated by the sympathetic system. Combinations of these drugs result in increased nephrotoxicity.The drugs most likely to cause acute interstitial nephritis are antibiotics and NSAIDs. Normally, signs of an allergic reaction are also present. Acute interstitial nephritis is usually self-limiting, but in some studies it is claimed that steroids may promote recovery.Four important causal agents of acute tubular necrosis are aminoglycosides, amphotericin B, radiocontrast agents and cyclosporin. Approximately half of the cases of drug-induced renal failure are related to the use of aminoglycosides: generally, 10 days after start of treatment a non-oliguric renal failure develops, with recovery after withdrawal of the drug in almost all cases. The aminoglycosides are particularly nephrotoxic when combined with other nephrotoxic drugs. 80% of amphotericin B-treated patients develop renal insufficiency, a percentage that increases as the cumulative dose exceeds 5g. It is because of its unique antifungal properties that there are still some indications for the use of this highly nephrotoxic drug; the high percentage of nephrotoxicity can probably be prevented in part by sodium loading. The nephrotoxicity of radiocontrast agents is largely dependent on renal function: from 0.6% in patients with normal renal function to 100% in patients with a serum creatinine above 400 μmol/L. Diabetes mellitus does not add greatly to the risk of radiocontrast nephrotoxicity. The nephrotoxicity of cyclosporin is dose-dependent and reversible, although there are some reports of irreversibility after long term use. Cyclosporin can also result in nephrotoxicity in combination therapy. Two mechanisms may be involved: some drugs increase the concentration of cyclosporin (e.g. ketoconazole), and careful monitoring is recommended; other drugs have an additive nephrotoxic effect and these combinations should not be used.Intratubular obstruction is often associated with chemotherapy, resulting in precipitation of urate, but can also be caused by precipitation of the drug itself (e.g. methotrexate). Chronic interstitial nephritis is also called analgesic nephropathy, and was formerly caused by phenacetin; paracetamol (acetaminophen), particularly in combination with other analgesics, can cause the same disease. Chronic nephritis can also be caused by cyclosporin. Drug-induced nephrotic syndrome is mostly immunologically mediated; membranous glomerulonephritis and minimal change glomerular disease are the most frequently encountered histological abnormalities. Drugs that can cause membranous glomerulonephritis are gold salts, penicillamine, captopril and mercury compounds, but after cessation of these drugs renal function recovers rapidly. Minimal change glomerular disease can be caused by NSAIDs and lithium. Nephrotic syndromes, not related to membranous glomerulonephritis or minimal change glomerular disease, can be caused by several other drugs, of which antiepileptic agents and heroin are well known. It is important to keep in mind that every renal failure of unknown origin may have been caused by drugs.

The effect of immunosuppressive drugs on quality of life after renal transplantation

This prospective, randomized study investigates the effect of two immunosuppressive treatment regimens on quality of life after renal transplantation. At 3 months after transplantation, patients treated with cyclosporine (CsA) and prednisone (Pred) were allocated to either withdrawal of Pred (n=60) or to conversion of CsA to azathioprine (Aza) (Aza-Pred, n=60). Quality of life was evaluated just before randomization, and at 6 and 12 months after transplantation using the Sickness Impact Profile (SIP), the Affect Balance Scale (ABS), the Center for Epidemiological Studies Depression Scale (CES-D), measures of satisfaction with several domains of life experience, and a population-specific physical symptoms questionnaire. In both groups, the overall SIP score as well as the scores on its physical and psychosocial dimensions improved continuously after transplantation, reaching levels that are comparable to those found in the general population. The occurrence of acute or chronic rejection had a significantly negative effect on SIP and CES-D scores. Intention-to-treat analysis showed no differences between groups for scores on SIP, ABS, CES-D, and satisfaction measures. Exclusion of 41 patients who did not strictly adhere to their originally designated therapy showed a tendency for better psychosocial SIP scores in CsA patients (P=0.05), which mainly resulted from a difference on the category of social interaction (P=0.01). This difference occurred despite a similar rejection rate and worse renal function in CsA-treated patients. Shortly after steroid withdrawal, a high proportion of CsA patients complained of stiff or painful muscles (CsA: 74%, Aza-Pred: 36%; P=0.002). Our data indicate that if successfully completed, CsA monotherapy from 3 months after transplantation may lead to a higher degree of psychosocial well-being as compared with conversion from CsA-Pred to Aza-Pred. It seems likely that this advantage is related to the withdrawal of Pred.

Anti-GBM nephritis in the mouse: severe proteinuria in the heterologous phase

Highly reproducible anti glomerular basement membrane (GBM) nephritis has been induced in the mouse after a single injection of rabbit or goat antibody against purified homologous GBM. The severity of albuminuria was closely related to the amount of antibody given. With doses of 4 mg or more, low serum albumin concentrations, sometimes accompanied by ascites and oedema, were observed after 1 week. Glomerular injury was characterized by an initial accumulation of polymorphonuclear granulocytes followed by thrombosis and necrosis, the extent of which defined the outcome of the glomerulonephritis. With high doses of antibody the exudative lesions entered a chronic phase, while at doses lower than 2 mg remission of the lesions occurred. Immunofluorescence studies showed prompt linear fixation of the injected anti-bodies to the glomerular capillary wall, accompanied by immediate binding of C3 in a fine granular pattern. Fibrin deposits appeared at 2 h in some glomeruli, increased thereafter, and were present after one day in more than 90% of the glomeruli in mice that had received 4 mg of antibody. This new reproducible model in the mouse is suited for the study of the relationship between activation of mediator systems, histological lesions, and proteinuria.

Oedema formation with the vasodilators nifedipine and diazoxide : direct local effect or sodium retention ?

Objective To determine whether the common side effect of ankle oedema with arteriolar vasodilators such as the calcium entry blocker (CEB) nifedipine and the potassium channel opener (PCO) diazoxide is the direct result of peripheral vasodilation or merely a consequence of renal sodium retention. Design In 12 healthy sitting volunteers we studied for 3 h the effects of 20 mg nifedipine, 150 mg diazoxide intravenously, 25 mg captopril and placebo on oedema formation and sodium excretion. Conclusions Foot swelling was determined with a new accurate device (coefficient of variation 0.30%), which uses Archimedes principle to measure water displacement induced by immersion of the foot. Blood pressures were recorded with a Hawksley random-zero sphygmomanometer. Results All of the active drugs decreased diastolic blood pressure (captopril by 9 ± 2%, nifedipine by 4 ± 3% and diazoxide by 2 ± 2%, compared with an increase of 5 ± 2% with placebo). Foot volume increased acutely after administration of nifedipine (by 2.6 ± 0.4%), whereas it remained stable with placebo and the other drugs. Administration of captopril and nifedipine induced increases of fractional sodium excretion (by 20 ± 9% and 40 ± 20%, respectively) in contrast to the decreases with placebo and diazoxide (by 13 ± 11% and 24 ± 10%, respectively). Only administration of nifedipine induced significant, albeit small, increases in haemoglobin and serum albumin levels. Conclusions Administration of nifedipine increased foot volume and natriuresis simultaneously, thereby supporting the hypothesis that development of ankle oedema with CEB is a local phenomenon at the site of vasodilation. The absence of a similar increase in foot volume with diazoxide administration should be interpreted with caution because of the rather minor effect of this dose of diazoxide on blood pressure. However, it could be indicative of a different mechanism of oedema formation with PCO.

Familial glomerulonephritis characterized by massive deposits of fibronectin

In recent years more than 150 cases of glomerulonephritis characterized by deposits of irregularly arranged fibrils have been documented. In the majority of these cases immunoglobulins and complement are the prime constituents of these deposits. We recently made a diagnosis of fibrillary glomerulonephritis without immunoglobulin deposition in two members of a family, a father and a son. In the father, proteinuria was first discovered 18 years ago. In 1985 he was referred to our outpatient clinic because of hypertension and increasing proteinuria. From that time onward he was regularly seen for blood pressure control. Nephrotic-range proteinuria persisted, without hardly any evidence of deterioration of renal function. Renal biopsies were performed in 1985 and 1993. His son underwent a renal biopsy in 1993 because of moderate proteinuria. The biopsies of both patients disclosed a distinct form of fibrillary glomerulonephritis that was characterized by massive deposits of a homogeneous, eosinophilic material in the mesangial and subendothelial areas. Staining for amyloid was negative. Immunofluorescence revealed that the biopsy specimens only stained faintly for immunoglobulins, complement factors C1q and C3, the extracellular matrix proteins, collagen IV, and laminin. However, they strongly stained for fibronectin. Using monoclonal antibodies specific for cell-derived fibronectin (IST-9) and plasma- and cell-derived fibronectin (IST-4), in the biopsy of the son we demonstrated that the fibronectin deposited in the glomeruli was mainly derived from the plasma, and to a lesser extent from resident glomerular cells. In addition, a moderate staining for amyloid P and vitronectin also was present. No or minor enhanced staining for collagen I, III, or V, heparan sulfate proteoglycan or its glycosaminoglycan side chains, tenascin, or thrombospondin could be observed. By electron microscopy the deposits in the mesangium and the subendothelial spaces appeared focally to be composed of irregularly arranged fibrils or microtubules 10 to 12 nm in diameter. Fibrillary glomerulonephritis with massive deposits of fibronectin represents a rare form of familial glomerulonephritis. In our patients the glomerulonephritis has an indolent course with hardly any deterioration of renal function.

Randomized, prospective trial of cyclosporine monotherapy versus azathioprine-prednisone from three months after renal transplantation

Cyclosporine (CsA) and prednisone (Pred) are the mostly used drugs for immunosuppression after renal transplantation, but both drugs have marked side effects. Either replacement of CsA by azathioprine (Aza) or withdrawal of prednisone (Pred) resulting in CsA monotherapy can be employed to circumvent the adverse effects in the long run. Both treatment regimens were compared to this prospective randomized trial in patients who were treated with CsA and Pred during the first 3 months after renal transplantation (CsA: n=64, Aza-Pred: n=63, median duration of follow-up: 3.9 years). Estimated graft survival rates at 5 years after transplantation (in patients with a functioning graft at 3 months) were 78% in the CsA group and 87% in the Aza-Pred group. The incidence of a rejection within 3 months after start of steroid withdraw or conversion from CsA to Aza was 30% and 25% respectively (NS). At 2 years after transplantation, serum creatinine levels were lower in the Aza-Pred group (126+/-35 micromol/L) than in the CsA group (180+/-78 micromol/L; P>0.001). There were no differences in blood pressure or incidence of infections between the treatment groups. Treatment-related costs were measured during the first year after transplantation and were lower in the Aza-Pred group (DFL 40,882+/-18,895 vs. DFL 53,484+/-44,828; 1 DFL [Dutch guilder] is about US

Identification of the component part in an epoetin alfa preparation that causes pain after subcutaneous injection

0.60; P<0.005). In conclusion, CsA monotherapy and Aza-Pred treatment from 3 months after renal transplantation are comparably effective immunosuppressive treatment regimens, although Aza-Pred therapy results in better graft function. Withdrawal of steroids and replacement of CsA by Aza both carry a substantial risk of rejection. The previously demonstrated cost effectiveness of CsA-containing therapies seems to be limited to the first phase after transplantation. Conversion to Aza-Pred at 3 months after transplantation reduces costs.