Post-transplant complications, patient, and graft survival in pediatric and adolescent kidney transplant recipients at a tropical tertiary care center across two immunosuppression eras.

BACKGROUND: We report pediatric PAKT patient and graft outcomes at a large tropical tertiary center spanning two transplant eras. METHODS: In this retrospective cohort study, all children ≤18 years who underwent kidney transplantation at our center between 1991 and 2016 were included. Data pertaining to their baseline characteristics, post-transplant events, and outcome were retrieved from transplant records and compared between transplant eras (1991-2005 and 2006-2016). RESULTS: A total of 139 children (mean age 15.2 ± 2.9 years) underwent PAKT during this period. The incidence of UTIs, CMV disease, BKVN, invasive fungal infections, new-onset diabetes after transplant, leucopenia, and recurrent NKD was higher in the 2006-2016 era (P < .001 for all), while 1-year cumulative BPAR was comparable (P = .100). Five-year graft and patient survival in the two eras were 89.9% and 94.2% (P = .365) and 92.1% and 95.3% (P = .739), respectively. Incidence of CMV disease, BKVN, graft loss, and death was lower in the calcineurin withdrawal group. Non-adherence accounted for 36% of graft loss; infections caused 43.7% of deaths. On multivariate Cox proportional hazards analysis, independent predictors for graft loss were UTIs and blood transfusion naïve status and for death were serious infections and glomerular NKD. CONCLUSIONS: PAKT in India has excellent long-term graft outcomes, though patient outcomes remain suboptimal owing to a high burden of infections. Current immunosuppression protocols need to be re-examined to balance infection risk, graft, and patient survival.

Peritoneal dialysis: Status report in South and South East Asia.

BACKGROUND: Peritoneal dialysis (PD) as a modality of kidney replacement therapy (KRT) is largely underutilized globally. We analyzed PD utilization, impact of economic status, projected growth and impact of state policy(s) on PD growth in South Asia and Southeast Asia (SA&SEA) region. METHODS: The National Nephrology Societies of the region responded to a questionnaire on KRT practices. The responses were based on the latest registry data, acceptable community-based studies and societal perceptions. The representative countries were divided into high income and higher-middle income (HI & HMI) and low income and lower-middle income (LI & LMI) groups. RESULTS: Data provided by 15 countries showed almost similar percentage of GDP as health expenditure (4%-7%). But there was a significant difference in per capita income (HI & HMI -US$ 28 129 vs. LI & LMI - US$ 1710.2) between the groups. Even after having no significant difference in monthly cost of haemodialysis (HD) and PD in LI & LMI countries, they have poorer PD utilization as compared to HI & HMI countries (3.4% vs. 10.1%); the reason being lack of formal training/incentives and time constraints for the nephrologist while lack of reimbursement and poor general awareness of modalities has been a snag for the patients. The region expects ≥10% PD growth in the near future. Hong Kong and Thailand with 'PD first' policy have the highest PD utilization. CONCLUSION: Important deterrents to PD underutilization were lack of PD centric policies, lackadaisical patient/physician's attitude, lack of structured patient awareness programs, formal training programs and affordability.

Aetiology, practice patterns and burden of end-stage kidney disease in South Asia and South-East Asia: A questionnaire-based survey.

AIM: There is paucity of data on the epidemiology of end-stage kidney disease (ESKD) from South Asia and South-East Asia. The objective of this study was to assess the aetiology, practice patterns and disease burden and growth of ESKD in the region comparing the economies. METHODS: The national nephrology societies of the region; responded to the questionnaire; based on latest registries, acceptable community-based studies and society perceptions. The countries in the region were classified into Group 1 (High|higher-middle-income) and Group 2 (lower|lowermiddle income). Student t-test, Mann-Whitney U test and Fisher's exact test were used for comparison. RESULTS: Fifteen countries provided the data. The average incidence of ESKD was estimated at 226.7 per million population (pmp), (Group 1 vs. Group 2, 305.8 vs. 167.8 pmp) and average prevalence at 940.8 pmp (Group 1 vs. Group 2, 1306 vs. 321 pmp). Group 1 countries had a higher incidence and prevalence of ESKD. Diabetes, hypertension and chronic glomerulonephritis were most common causes. The mean age in Group 2 was lower by a decade (Group 1 vs. Group 2-59.45 vs 47.7 years). CONCLUSION: Haemodialysis was the most common kidney replacement therapy in both groups and conservative management of ESKD was the second commonest available treatment option within Group 2. The disease burden was expected to grow >20% in 50% of Group 1 countries and 78% of Group 2 countries along with the parallel growth in haemodialysis and peritoneal dialysis.

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.

Enzobiotics-A Novel Therapy for the Elimination of Uremic Toxins in Patients with CKD (EETOX Study): A Multicenter Double-Blind Randomized Controlled Trial.

Design, participants, setting, and measurements: Predialysis adult participants with chronic kidney disease (CKD) and mean estimated glomerular filtration rate (eGFR) <45 mL/min per 1.73 m2) were recruited in 2019 to a multicentric double-blinded randomized controlled trial of enzobiotic therapy (synbiotics and proteolytic enzymes) conducted over 12 weeks. The primary objective was to evaluate the efficacy and safety of enzobiotics in reducing the generation of p-cresol sulfate (PCS) and indoxyl sulfate (IS), stabilizing renal function, and improving quality of life (QoL), while the secondary objective was to evaluate the feasibility of the diagnostic prediction of IS and PCS from CKD parameters. Results: Of the 85 patients randomized (age 48.76 years, mean eGFR 23.24 mL/min per 1.73 m2 in the placebo group; age 54.03 years, eGFR 28.93 mL/min per 1.73 m2 in the enzobiotic group), 50 completed the study. The absolute mean value of PCS increased by 12% from 19 µg/mL (Day 0) to 21 µg/mL (Day90) for the placebo group, whereas it decreased by 31% from 23 µg/mL (Day 0) to 16 µg/mL (Day 90) for the enzobiotic group. For IS, the enzobiotic group showed a decrease (6.7%) from 11,668 to 10,888 ng/mL, whereas the placebo group showed an increase (8.8%) from 11,462 to 12,466 ng/mL (Day 90). Each patient improvement ratio for Day 90/Day 0 analysis showed that enzobiotics reduced PCS by 23% (0.77, p = 0.01). IS levels remained unchanged. In the placebo group, PCS increased by 27% (1.27, p = 0.14) and IS increased by 20% (1.20, p = 0.14). The proportion of individuals beyond the risk threshold for PCS (>20 µg/mL) was 53% for the placebo group and 32% for the enzobiotic group. The corresponding levels for IS risk (threshold >20,000 ng/mL) were 35% and 24% for the placebo and enzobiotic groups, respectively. In the placebo group, eGFR decreased by 7% (Day 90) but remained stable (1.00) in the enzobiotic group. QoL as assessed by the adversity ratio decreased significantly (p = 0.00), highlighting an improvement in the enzobiotic group compared to the placebo group. The predictive equations were as follows: PCS (Day 0 = −5.97 + 0.0453 PC + 2.987 UA − 1.310 Creat; IS (Day 0) = 756 + 1143 Creat + 436.0 Creat2. Conclusion: Enzobiotics significantly reduced the PCS and IS, as well as improved the QoL.

Interventional nephrology and vascular access practice: A perspective from South and Southeast Asia.

South and Southeast Asia is the most populated, heterogeneous part of the world. The Association of Vascular Access and InTerventionAl Renal physicians (AVATAR Foundation), India, gathered trends on epidemiology and Interventional Nephrology (IN) for this region. The countries were divided as upper-middle- and higher-income countries as Group-1 and lower and lower-middle-income countries as Group-2. Forty-three percent and 70% patients in the Group 1 and 2 countries had unplanned hemodialysis (HD) initiation. Among the incident HD patients, the dominant Vascular Access (VA) was non-tunneled central catheter (non-TCC) in 70% of Group 2 and tunneled central catheter (TCC) in 32.5% in Group 1 countries. Arterio-Venous Fistula (AVF) in the incident HD patients was observed in 24.5% and 35% of patients in Group-2 and Group-1, respectively. Eight percent and 68.7% of the prevalent HD patients in Group-2 and Group-1 received HD through an AVF respectively. Nephrologists performing any IN procedure were 90% and 60% in Group-2 and Group 1, respectively. The common procedures performed by nephrologists include renal biopsy (93.3%), peritoneal dialysis (PD) catheter insertion (80%), TCC (66.7%) and non-TCC (100%). Constraints for IN include lack of time (73.3%), lack of back-up (40%), lack of training (73.3%), economic issues (33.3%), medico-legal problems (46.6%), no incentive (20%), other interests (46.6%) and institution not supportive (26%). Routine VA surveillance is performed in 12.5% and 83.3% of Group-2 and Group-1, respectively. To conclude, non-TCC and TCC are the most common vascular access in incident HD patients in Group-2 and Group-1, respectively. Lack of training, back-up support and economic constraints were main constraints for IN growth in Group-2 countries.

Impact of National Economy and Policies on End-Stage Kidney Care in South Asia and Southeast Asia.

BACKGROUND: The association between economic status and kidney disease is incompletely explored even in countries with higher economy (HE); the situation is complex in lower economies (LE) of South Asia and Southeast Asia (SA and SEA). METHODS: Fifteen countries of SA and SEA categorized as HE and LE, represented by the representatives of the national nephrology societies, participated in this questionnaire and interview-based assessment of the impact of economic status on renal care. RESULTS: Average incidence and prevalence of end-stage kidney disease (ESKD) per million population (pmp) are 1.8 times and 3.3 times higher in HE. Hemodialysis is the main renal replacement therapy (RRT) (HE-68%, LE-63%). Funding of dialysis in HE is mainly by state (65%) or insurance bodies (30%); out of pocket expenses (OOPE) are high in LE (41%). Highest cost for hemodialysis is in Brunei and Singapore, and lowest in Myanmar and Nepal. Median number of dialysis machines/1000 ESKD population is 110 in HE and 53 in LE. Average number of machines/dialysis units in HE is 2.7 times higher than LE. The HE countries have 9 times more dialysis centers pmp (median HE-17, LE-02) and 16 times more nephrologist density (median HE-14.8 ppm, LE-0.94 ppm). Dialysis sessions >2/week is frequently followed in HE (84%) and <2/week in LE (64%). "On-demand" hemodialysis (<2 sessions/week) is prevalent in LE. Hemodialysis dropout rates at one year are lower in HE (12.3%; LE 53.4%), death being the major cause (HE-93.6%; LE-43.8%); renal transplants constitute 4% (Brunei) to 39% (Hong Kong) of the RRT in HE. ESKD burden is expected to increase >10% in all the HE countries except Taiwan, 10%-20% in the majority of LE countries. CONCLUSION: Economic disparity in SA and SEA is reflected by poor dialysis infrastructure and penetration, inadequate manpower, higher OOPE, higher dialysis dropout rates, and lesser renal transplantations in LE countries. Utility of RRT can be improved by state funding and better insurance coverage.

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.

Cryptococcal granulomatous interstitial nephritis and dissemination in a patient with untreated lupus nephritis.

Infection is a significant cause of mortality and morbidity in systemic lupus erythematosus (SLE). There are many reports of cryptococcal infection in patients with SLE, on immunosuppression. However, untreated lupus with cryptococcal infection and dissemination is rare. CD4 lymphopaenia is not reported in such patients. We describe a patient with untreated SLE to be having cryptococcal granulomatous interstitial nephritis and dissemination with CD4 lymphopaenia.

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.

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.

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.

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.

Epidemiology of systemic mycoses among renal-transplant recipients in India.

BACKGROUND: Systemic mycoses have a high impact on tropical renal-transplant recipients. METHODS: Data from 1,476 primary renal-transplant recipients was prospectively recorded from 1986 to 2000 at a single center. Cumulative incidence of systemic mycoses, its time of occurrence, risk factors, outcome, and postmortem findings in 30 patients with systemic mycoses were analyzed. RESULTS: A total of 110 episodes of systemic mycoses occurred in 98 patients. The fungal genera Aspergillus, Cryptococcus, and Candida constituted 61% of pathogens, 45% localizing to the lungs. Cytomegalovirus (CMV) disease caused a 5-fold and chronic liver disease a 2-fold increase in systemic mycoses. Tuberculosis (TB) with or without nocardiosis was a significant coinfection. Cyclosporine (CsA) was associated with nearly a 4-fold risk of systemic mycoses less than 6 months from the time of transplantation as compared with prednisolone+azathioprine (PRED+AZA) therapy. Overall, the probability of survival with systemic mycoses was 73.4%, 60.8%, 39.5%, and 25.6% and was 92.5%, 87.5%, 80.0%, and 75.5% without systemic mycoses at 1, 2, 5, and 10 years, respectively (P<0.0001). An extended Cox model with time-independent and dependent covariates showed greater than 15 times the risk of death among those who develop systemic mycoses. Similarly, Posttransplantation (postTX) TB+/-Nocardiosis, preTX TB, CMV disease, diabetes mellitus, PTDM, chronic liver disease (>40 months), and Pred+AZA immunosuppression (>2 years) had 3.5, 1.5, 2.9, 1.9, 1.4, 1.6, 2.3 times the risk for death, respectively, as compared with those who did not have those risk factors. CONCLUSIONS: There is a recent predominance of Aspergillus among the transplant recipients. The risk factors for systemic mycoses are CMV disease, chronic liver disease, and hyperglycemia, and TB is an important coinfection. Systemic mycoses increased in the early postTX period with CsA. The risk factors for death are systemic mycoses, CMV disease, chronic liver disease (>40 months), diabetes mellitus, and Pred+AZA immunosuppression (>2 years). Overall, the probability of survival with systemic mycoses was poor; however, survival has recently improved.

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.

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.