Pharmacokinetics of concentration-controlled mycophenolate mofetil in proliferative lupus nephritis: an observational cohort study.

BACKGROUND: Mycophenolate mofetil (MMF) has variable pharmacokinetics. This study examines the pharmacokinetic and clinical correlations in proliferative lupus nephritis. METHODS: Thirty-four patients were started on MMF, and the area under the concentration-time curve (AUC) was measured by limited sampling strategies, and dosing was adjusted to achieve an AUC of 30-60 mg·h·L. Twenty-seven patients had at least 2 measurements, and renal response was assessed within 1 year. RESULTS: About 61.8% of patients had mycophenolic acid (MPA) AUC <30 mg·h·L with an empiric starting dose of 30 mg/kg. About 79.4% of patients achieved renal response by 1 year, and the median time to renal response was 111 days. MMF dose per body weight had a weak correlation with the AUC and did not correlate with trough concentrations. The median dose was 1.5 g/d at entry and 2 g/d after dose modification during the induction phase. Trough concentrations had a weak correlation with AUC. Patients with serum albumin ≥35 g/L had a greater chance of having an AUC ≥30 mg·h·L. The between-patient coefficient of variability for dose-normalized AUC was 37.9% at entry and 31% within 1 year, whereas repeated measurements over time in an individual had a good intraclass correlation of 0.78. Infections occurred in 11.8% and toxicities in 5.9%. MPA exposure was not significantly associated with adverse events. Patients with an AUC ≥30 mg·h·L had greater renal response at 1 year. CONCLUSIONS: Lupus nephritis patients induced with concentration-controlled MMF had excellent renal response and fewer adverse events with lower than usual dosing. MPA exposure had high interpatient variability, requiring measurements for personalized dosing, and fewer adverse events. Long-term cost reduction is achievable with lower doses and good renal response in the majority of patients.

Can mycophenolic acid dose requirement during the first transplant help predict dosing for the second transplant?

We describe the pharmacokinetic profile of mycophenolic acid (MPA) in a patient receiving Mycophenolate mofetil (MMF) during her first and second renal transplantations. The MMF dose required to achieve a therapeutic range of MPA-AUC(0)(-)(12)(h) early following the second transplantation was 10 times greater than that required late following the first transplantation. Her MMF requirement then declined and continued to decrease even beyond 1 year. Intra-individual variability in MPA profiles precluded the ability to predict MMF dosing for the second transplant based on that during the first. Therapeutic drug monitoring of MMF should be continued beyond 1 year of transplantation.

Skin lesions in renal transplant recipients: a single center analysis.

BACKGROUND: The chronic use of immunosuppressants in renal transplant recipients (RTRs) predisposes them to a variety of skin manifestations. Studies on skin lesions in RTRs from India have been limited. AIM: To study the prevalence and clinical spectrum of skin diseases in RTR in patients attending the Nephrology clinic of a tertiary care hospital in South India. METHODS: Between October 2002 and June 2003, 365 RTRs were evaluated for skin lesions, including 280 examined after renal transplant (group A) and 85 examined once before and then monthly after transplant for a period of 6 months (group B). RESULTS: A total of 1163 skin lesions were examined in 346 RTRs (94.7%) including lesions of aesthetic interest (LAI) [62.3%] followed by infections [27.3%]. All LAI were drug-related manifestations, making it the most common skin lesion, while fungal (58.7%) and viral (29.3%) infections constituted majority of lesions caused by infection. Lesions related to neoplasms were relatively uncommon (2.1%) and all lesions were benign. Miscellaneous lesions constituted 8.3% of skin lesions, which included vaccine-induced necrobiotic granulomas at the site of Hepatitis B vaccination and acquired perforating dermatoses. CONCLUSION: Skin lesions among RTRs from India consist predominantly of drug-related LAI and infections and are different from the West in view of the paucity of neoplastic lesions.

Goodpasture's syndrome with positive C-ANCA and normal renal function: a case report.

INTRODUCTION: Goodpasture's syndrome consists of a triad of pulmonary hemorrhage, rapidly progressive glomerulonephritis and anti-glomerular basement membrane (anti-GBM) antibodies, either in circulation or fixed to the kidney. The absence of renal manifestations is uncommon. We present a case of biopsy proven anti-GBM antibody disease with normal renal function, mild urinary abnormalities and positive C-antineutrophil cytoplasmic antibody (C-ANCA) serology. CASE PRESENTATION: A 44-year-old female was treated for repeated episodes of hemoptysis and one episode of respiratory failure requiring ventilatory support. She had minor urinary abnormalities in the form of microscopic hematuria and non-nephrotic proteinuria. She also had positive C-ANCA. Her lung biopsy showed evidence of intra-alveolar hemorrhage with linear IgG deposits in the basement membrane of the alveolar capillaries. Owing to these lung biopsy findings, a kidney biopsy was carried out, which showed minimal thickening of the glomerular basement membrane and linear IgG and C3 deposits along the capillary walls. Her renal function remained persistently normal. CONCLUSION: Goodpasture's syndrome is a rare disease. Even though the classical presentation is that of rapidly progressive glomerulonephritis pulmonary hemorrhage and anti-GBM antibodies in the circulation and kidneys, in rare cases it can present with repeated pulmonary hemorrhage and minor urinary abnormalities. In all cases of repeated pulmonary hemorrhage, the possibility of Goodpasture's syndrome should be considered and investigated further.

Scleroderma with crescentic glomerulonephritis: a case report.

INTRODUCTION: Systemic sclerosis or scleroderma is an autoimmune rheumatic disease characterized by organ-based fibrosis. Renal involvement in scleroderma occurs mainly in the form of scleroderma renal crisis, affecting 5 to 10% of patients. It remains one of the most important and immediately life-threatening complications of scleroderma, but the prognosis improves considerably after treatment with angiotensin-converting enzyme inhibitors. Other renal pathologies can occur in scleroderma. These include scleroderma overlap syndromes with associated features of lupus nephritis, myeloperoxidase anti-neutrophil cytoplasmic antibodies (ANCA) or proteinase 3 ANCA-associated glomerulonephritis, or crescentic glomerulonephritis. These alternative pathologies should be suspected in any individual patient with a differing clinical picture and the patient should be appropriately investigated. Crescentic glomerulonephritis occurs very rarely in scleroderma. This report describes a patient with scleroderma and crescentic glomerulonephritis. CASE PRESENTATION: A 52-year-old woman with a known history of scleroderma and hypertension on angiotensin-converting enzyme inhibitors was referred to the nephrologist because of a rapid decline in renal function. Kidney biopsy was performed which revealed immune complex type crescentic glomrulonephritis. Cytoplasmic-staining ANCA was negative. Despite immunosuppressive treatment the patient rapidly went into end-stage renal failure and is still on hemodialysis. CONCLUSION: Scleroderma is a complex disease, and the best characterized renal involvement in scleroderma is scleroderma renal crisis. However, other renal pathologies can occur in scleroderma. These alternative pathologies should be suspected in any patient with a differing clinical picture and the patient should be appropriately investigated, as the clinical course and treatment are different from the more common scleroderma renal crisis.

Prevalence of proteinuria in rural adult population in Tamil Nadu.

BACKGROUND & OBJECTIVES: Presence of proteinuria is considered as an early marker of an increased risk of progressive kidney disease. Angiotensin converting enzyme (ACE) inhibitors (ACEi) and angiotensin II receptor blockers (ARB) treatment to persons with proteinuria and chronic kidney disease has been shown to decrease the progression to endstage renal disease. As the exact prevalence of proteinuria is not known in the general population, we undertook this study to estimate the same in a rural adult population in Vellore district, Tamil Nadu. METHODS: A convenient sample of 5,043 adults was included. All individuals were tested for albuminuria by albumin dipstick examination in an untimed urine sample. Individuals who tested positive for albuminuria underwent a second dipstick examination after a gap of one week. Individuals with persistent albuminuria on the second dipstick examination underwent further evaluation which included medical history, physical examination, 24 h urine protein estimation, total serum protein and albumin estimation. Ultrasound of the abdomen was done in patients with renal failure and renal biopsy was performed in selected patients. RESULTS: Of the total 5,043 individuals screened, 63.1 per cent were females. Mean age of the study population was 50.94 +/- 11.2 yr. First dipstick test identified 594 individuals positive for albuminuria. Repeat dipstick could be done in only 576, of whom 212 showed persistent albuminuria. Significant proteinuria was detected in 24 individuals of the 208 who had 24 h urine protein measured. Of these 24 patients, 3 were found to have chronic renal failure, 12 were presumed to have diabetic nephropathy clinically, one each had focal segmental glomerulosclerosis and biopsy proven diabetic nephropathy, and 7 patients had proteinuria of unknown aetiology. INTERPRETATION & CONCLUSION: The prevalence of proteinuria in this adult rural population was 0.47 per cent (0.30-0.67%). The detection and treatment of chronic kidney disease in 24 individuals is bound to reduce the rate of decline of renal functions. Screening programme for proteinuria in different parts of country may be an effective measure to bring a decline in rate of progression of chronic kidney disease in general population.

Characterization of kidney lesions in Indian adults: towards a renal biopsy registry.

BACKGROUND: In the absence of a renal biopsy registry, there is a paucity of data on the renal disease pattern seen in India. This study reviews the changing pattern of renal disease seen at a single center over the last 30 yrs. METHODS: Histopathological data of 5415 adequate native kidney biopsies performed on consecutive adult Indian patients presenting to our hospital from 1986-2002 were analyzed. This pathological demography classified according to the modified World Health Organization (WHO) classification was compared to the earlier published cohort collected from 1971-1985 (n=2827) to ascertain the changing trends. RESULTS: The indications for renal biopsy were comparable between the cohorts and included nephrotic syndrome (65%), nephritic syndrome (13%) and chronic renal failure (10.2%). Primary glomerular disease accounted for 71% of all biopsies. Non-immunoglobulin A (IgA) mesangio proliferative glomerulonephritis as a group was the predominant pathology (20.2%), followed by idiopathic focal segmental glomerulosclerosis (FSGS) (17%), minimal change disease (MCD) (11.6%), membranous glomerulopathy (MN) (9.8%), IgA nephropathy (8.6%) and membranoproliferative glomerulonephritis (MPGN) (3.7%). Of the patients with secondary kidney diseases, lupus nephritis (6.5%), diabetic nephropathy (2.5%), interstitial nephropathy (2.5%) and benign nephrosclerosis (2.2%) were notable. During the 31 yrs of the study period, there was a steady increase in FSGS prevalence (p<0.001), MN (p<0.0001), and post infectious glomerulonephritis (PIGN) (p<0.001). A reduction in the frequency of MPGN (p<0.001) and MCD (p<0.001) was observed. CONCLUSIONS: This is the largest series of renal biopsy data from India; and therefore, could reflect the demographic picture of renal diseases in this country. It discusses evolving patterns over 30 yrs and highlights differences with the developed world. This report represents the basis for the future of a renal biopsy registry in India.

Osmotic nephropathy resulting from maltose-based intravenous immunoglobulin therapy.

Intravenous immunoglobulin preparations are being used for an increasing number of indications. To minimize adverse reactions, sugar additives such as sucrose, maltose, and glycine are added to some preparations to serve as stabilizing agents. Intravenous immunoglobulin infusion induces acute renal failure (ARF) via a mechanism of osmotic nephrosis. Most reported cases are related to the use of sucrose-based intravenous immunoglobulin. Herein, we describe a patient with lupus nephritis treated with an immunoglobulin preparation containing maltose who developed ARF with histologic changes characterized by vacuolization and swelling of renal proximal tubular cells. Our case draws nephrologists' attention to the potential of maltose-based immunoglobulin in producing renal failure. Awareness and exercising caution in high-risk groups is elementary to the prevention of this condition.

Presentation, prognosis and outcome of IgA nephropathy in Indian adults.

BACKGROUND: IgA nephropathy (IgAN) is not well characterized in India. This retrospective study of 478 patients with IgAN was performed to clarify the presenting features, prognostic factors and the renal survival rates of the disease. METHODS: Three hundred and forty-seven patients who had been followed on average for 27 months after diagnosis were divided into two groups based on renal function at diagnosis. In group 1 (229 patients), the creatinine clearance estimated by the Modification of Diet in Renal Disease formula was <85 mL/min and in group 2 (118 patients) it was >/=85 mL/min. RESULTS: The predominant modes of presentation were nephrotic syndrome, hypertension and renal failure. Twenty-nine percent of patients had more than a 20% decline in renal function at the last follow up. Multivariate analyses with stepwise logistic regression identified hypertension (odds ratio (OR) 3.5), nephrotic range proteinuria (OR 3.4) and sclerosed glomeruli on biopsy (OR 4.1) to be independently associated with progression in group 1 and hypertension (OR 2.3) in group 2. Seventeen percent of patients progressed to end-stage renal disease (ESRD). Using multivariate analysis by the Cox model, four risk factors for developing ESRD were identified: hypertension (hazard ratio (HR) 3.1); nephrotic proteinuria (HR 1.9); interstitial fibrosis (HR 2.5); and sclerosed glomeruli (HR 1.8). The renal survival rates at 1, 5 and 10 years were 84, 55 and 33%, respectively, with a median renal survival of 61 months from the time of biopsy. CONCLUSION: The relatively rapid rate of progression of IgAN in India is suggestive towards a 'malignant' nature of the disease in this country.

Prediction of mortality in acute renal failure in the tropics.

Despite significant improvements in medical care, acute renal failure (ARF) remains a high risk for mortality. It is important to be able to predict the outcome in these patients in view of the emotional and ethical needs of the patients and to address questions of efficiency and quality of care. We analyzed the risk factors predicting mortality prospectively in a group of 265 patients using univariate and multiple logistic regression analysis. A prognostic model was evolved that included 10 variables. The model showed good discrimination [(receiver operating characteristic (ROC) area=0.91) and correctly classified 88.30% of patients. The variables significantly associated with mortality were coma odds ratio (OR)=9.8], oliguria (OR=4.9), jaundice (OR=3.7), hypotension (OR=3.1), assisted ventilation (OR=2.3), hospital acquired ARF (OR=2.3), sepsis (OR=2.2), and hypoalbuminemia (OR=1.7). Age and male gender were included in the model as they are clinically important. The score was validated in the same sample by boot strapping. It was also validated in a prospective sample of 194 patients. The model was calibrated by the Hosmer-Lemeshow goodness-of-fit test. It was compared with two generic illness scores and one specific ARF score and was found to be superior to them. The model was verified in different subgroups of ARF like hospital acquired, community acquired, intensive care settings, nonintensive care settings, due to sepsis, due to nonsepsis etiologies, and showed good predictability and discrimination.

Leflunomide therapy for cytomegalovirus disease in renal allograft recepients.

Leflunomide has excellent antiviral activity against cytomegalovirus (CMV) in animal models and is considerably less expensive than intravenous ganciclovir. We used leflunomide in four consenting renal allograft recipients with symptomatic CMV disease, who were unable to afford ganciclovir and would otherwise remain untreated. This is the first report of efficacy of leflunomide in humans with CMV disease. They received loading dose of 100 mg of leflunomide once daily on days 1-3 and then 20 mg once daily for 3 months. All four patients were followed up three times weekly with physical examination, total leukocyte counts, blood urea and serum creatinine for a minimum period of 6 weeks. None of the patients showed drug related adverse events, alteration in cyclosporine levels, or decreased graft function, except one who developed leucopenia. Preliminary data presented suggests that leflunomide therapy for CMV disease is effective and could be used with careful monitoring in allograft recipients who cannot afford intravenous ganciclovir therapy. The duration of treatment and the role of leflunomide in secondary prophylaxis and in situations of ganciclovir resistance need to be studied further.

Granulocyte macrophage colony stimulating factor augmented hepatitis B vaccine protocol for rapid seroprotection in voluntary kidney donors.

BACKGROUND & OBJECTIVES: Conventional hepatitis B vaccine protocols do not provide rapid seroprotection against hepatitis B. This randomized controlled trial was carried out to investigate the efficacy of granulocyte macrophage-colony stimulating factor (GM-CSF) augmented double-dose vaccine protocol in voluntary kidney donors prior to donor nephrectomy. METHODS: A total of 54 kidney donors, who had no history of hepatitis B infection, hepatitis B vaccination and tested negative for anti-HBs and anti-HBc antibodies were randomly allocated to the control or test groups. GM-CSF (300 microg) was administered subcutaneously on day 0, followed by 40 microg of recombinant hepatitis B vaccine intramuscularly on the same deltoid on day 1. The control group received only 40 microg of intramuscular hepatitis B vaccine. Anti-HBs titres were measured at the end of 4 wk. RESULTS: Of the 54 donors studied, there was a significant (P<0.003) seroconversion in the GM-CSF group (82%) compared to the control group (37%), after a single immunization with double-dose recombinant hepatitis B vaccine by 4 wk. Minor side effects such as fever in four patients and myalgia in three were noticed. INTERPRETATION & CONCLUSION: GM-CSF augmented double-dose hepatitis B vaccine could be used in unvaccinated patients when a rapid response is desired.

Sirolimus and ketoconazole co-prescription in renal transplant recipients.

Ketoconazole inhibits cytochrome P 3A4, leading to a 10-fold increase in sirolimus blood levels. Although it has not been reported in the clinical setting so far, sirolimus and ketoconazole co-prescription can lead to cost saving by reducing the dose of sirolimus administered. After informed consent was obtained, sirolimus and ketoconazole co-prescription was studied in six patients who could not afford the current recommended doses. Patients received one-eighth to one-fourth of the recommended dose of sirolimus (0.25-0.5 mg) with 100 to 200 mg of ketoconazole. Sirolimus levels were monitored, and the dose of ketoconazole was increased to achieve target levels of sirolimus. The loading dose was 3 mg of sirolimus with 100 mg of ketoconazole. After sirolimus rescue therapy was started, serum creatinine decreased in five patients. The mean serum creatinine for the group decreased from 2.6 +/- 0.3 mg/dL at the initiation of rescue therapy to 2.2 +/- 0.5 mg/dL on the last follow-up. Sirolimus ketoconazole co-prescription with monitoring of sirolimus levels is possible and safe and needs to be explored further.

Measurement of renal function in kidney donors using serum cystatin C and beta(2)-microglobulin.

BACKGROUND: The usefulness of serum cystatin C and serum beta(2)-microglobulin (B2M) as markers of glomerular filtration rate (GFR) were compared in kidney donors before and after nephrectomy. METHODS: Blood samples were taken from 28 donors (15 women and 13 men) for serum creatinine, urea, cystatin C and B2M estimation a median of 7 days before and 10 days after nephrectomy. RESULTS: Estimated GFR decreased from a median of 86.2 mL/min/1.73 m(2) to 60.3 mL/min/1.73 m(2), a median decrease of 28.6%. Serum creatinine increased by 40% and urea by 30.4%; serum cystatin C increased by 31.2% and serum B2M increased by 65.6%. Using published data on biological variation, critical values were calculated. An increase in serum creatinine above 18 micro mol/L detected the decline in renal function in 26/28 (92.9%) subjects. Increases in serum B2M greater than a critical value of 0.94 mg/L detected 24/28 (85.7%) of these subjects, but the critical value of 0.59 mg/L for cystatin C detected only 8/28 (28.6%). CONCLUSION: Using critical values, serial measurement of serum creatinine was better than serum B2M in detecting reduced renal function. Because of its large intraindividual variation, serial serum cystatin C estimation was very poor in detecting reduced renal function.