S.N. Mehta

Prospective randomized control trial of isoniazid chemoprophylaxis during renal replacement therapy

Abstract: Background. Infectious diseases remain among the major morbid events in patients with end‐stage renal disease (ESRD) on renal replacement therapy (RRT). In developing countries, tuberculosis (TB) has been found to occur more frequently in these patients than in the general population. Efficacy of isoniazid (INH) chemoprophylaxis has been seen in other situations, such as human immunodeficiency virus infection. However, studies on INH prophylaxis in ESRD patients on RRT are limited.

Treatment of Acute Rejection in Live Related Renal Allograft Recipients: A Comparison of Three Different Protocols

We present our experience on the comparison of three different modes of steroid therapy, oral prednisolone (OP), intravenous dexamethasone (IVDX) and intravenous methylprednisolone (IVMP) in the treatment of acute rejection (AR) in renal allograft recipients. Between January 1980 and January 1992, 206 patients underwent live related renal transplantation. Before 1990, all received prednisolone (PRED) and azathioprine (AZA) only. After 1990, patients were given PRED, AZA and cyclosporine (CsA). After 1 year, CsA was stopped and patients were converted to a two-drug regimen only. Of the 206 patients, 180 (87.4%) were male and mean age was 30.3+/-8.7 years (range 14-63). During the mean follow-up of 43.5 months, 178 episodes of AR were seen in 121 patients. Each episode was considered as a separate entrant in the study. Conventional immunosuppression was given in 151 episodes and 27 episodes were on triple-drug therapy. Diagnosis of AR was made by clinical, sonography, nuclear scan with or without graft biopsy evidence. Of the 178 AR, 110 (61.8%) were within 3 months, 36 (20.2%) were between 3 months and 1 year and 32 (18%) were after 1 year. OP was given in 11 cases while IVDX and IVMP were given in 48 and 119 cases respectively. Overall, 154 (86%) showed either a complete or partial response to antirejection therapy. Response to therapy was 91, 90 and 85% in OP, IVDX and IVMP groups respectively. There was no statistical difference in response rate in different groups. There was also no difference in side effects in three different groups. Our data suggest that it is the high dose of steroid rather than mode of therapy which is responsible for therapeutic benefit in treatment of AR.

Results of conversion from triple-drug to double-drug therapy in living related renal transplantation.

Results of 34 recipients of living related renal allografts initially treated with cyclosporine, azathioprine, and prednisolone and later electively converted to AZA and PRED are presented. Thirteen (group A), 14 (group B), and 7 (group C) patients were converted before 9 months, between 9 and 12 months, and after 12 months, respectively. Thirty-four patients who were on AZA and PRED and had never received CsA served as controls. Of the 34 patients, 33 were HLA haploidentical with their donors and 1 was HLA identical. All patients received a mean 8.62 +/- 7.39 third-party blood transfusions. In the control group, 29 patients received haploidentical grafts. The number of blood transfusions given to this group was 7.09 +/- 9.13. Of the 34 patients receiving triple-drug therapy, 9 (26%) had acute rejection within 3 months after conversion, as compared with 5 (14.7%) in the control group (P > 0.05). Although 1 case had acute rejection before conversion, all recipients had stable graft function at the time of conversion. Of these 9 recipients, 7 had conversion over 4-7 weeks, while 2 had rapid conversion. Following treatment of the rejection episodes, 4 patients in the study group responded to therapy, as compared with 3 cases in the control group (P > 0.05). After a mean follow-up of 18.62 +/- 10.31 months (range 3-41 months) following conversion, 4 patients were normal, 4 had chronic rejection (mean serum creatinine = 3.0 mg/100 ml), and 1 was back on regular dialysis. Eventually, of the 34 patients who were converted from triple-drug to double-drug therapy, 25 were normal, 5 had stable chronic rejection, 2 were back on regular dialysis, 1 was retransplanted, and 1 died due to failed graft. At the end of follow-up, graft survival in the study group was 88.2%, as compared with 85.5% in controls (P > 0.05). We conclude that conversion from triple-drug to double-drug therapy is not without risk, even in living related primary renal transplantation. Degree of HLA matching, number of pretransplant blood transfusions, and rejection before conversion did not have any significant effect on rejections following conversion, and the graft loss following conversion is unpredictable.

Functional assessment of immune markers of graft rejection: a comprehensive study in live-related donor renal transplantation.

Abstract:  A better understanding of the immunobiological processes and predictors of graft rejection holds promise for the development of potential therapeutic strategies and also individualization of immunosuppression. The objective of this study is to analyze the clinical relevance of immune parameters such as antidonor antihuman leukocyte antigen (anti‐HLA) antibodies, monitoring of cytokines and their receptors on the graft outcome following live‐related donor renal transplantation. Flow cytometry‐based methods were used to detect antidonor antibodies (flow cytometry crossmatch, FCXM) and intracellular cytokines. Enzyme‐linked immunosorbent assay (ELISA) methods were employed to detect anti‐HLA class I and class II antibodies and quantitative serum‐soluble interleukin‐2 receptor (sIL‐2R) levels. The data revealed that patients with HLA class I‐specific IgG antibody experienced higher acute rejection (AR) episodes at 1 yr in comparison to the antibody negative group (82% vs. 56%, p = 0.01). On the contrary, donor‐specific class II antibodies (B+) did not have any influence on the graft survival. However, 15 recipients having both T‐ and B‐cell antidonor antibodies (T+B+) had significantly poor graft survival (60%) as compared to the antibody‐negative group (T−B−, 82%, p = 0.05). Additionally, patients having non‐donor but HLA‐specific antibodies (FCXM−/ELISA+) had poor graft survival as compared to the antibody‐negative group (64% vs. 88%, p < 0.05). Further, patients undergoing AR episodes had significantly higher expression of IFN‐γ‐producing T cells (19.16 ± 7.4% median 17.50) as compared to their pre‐transplant levels (5.68 ± 1.63%, Median 5.20) and the non‐rejecter group (5.97 ± 4.39%, median 4.3, p = 0.0004). Similarly sIL‐2 was significantly increased in AR episodes during the first month of transplantation (292 ± 131.5 pmol/L) as compared to those with well‐functioning grafts (p = 0.01) and healthy controls (p = 0.001). Evaluation of antidonor antibodies by flow cytometry is found to be relatively more sensitive and a better predictor of graft outcome. Further monitoring of cytokine expression profile of primed peripheral T‐helper cells and quantitative analysis of sIL‐2R offer additional valuable diagnostic and prognostic tools for follow‐up of transplant subjects and a better alternative for functional assessment of immunosuppression.

Urinary Sporotrichosis in a Renal Allograft Recipient

Dr. Sanjay K. Agarwal, Assistant Professor, Department of Nephrology, Aiims, New Delhi-110029 (India) Dear Sir, We are reporting a case of urinary sporotrichosis in a renal transplant recipient. The patient had a radiolucent calculus with recurrent urinary tract infection. A 23-year-old male, having chronic glo-merulonephritis with end-stage renal failure underwent renal transplantation in July 1985. His mother was the donor with one haplotype match with the recipient. Postoperatively his renal function did not improve steadily. Ultrasound examination of the abdomen showed moderate hydronephrosis of the graft with narrowing of the lower end of the ureter. After confirming the finding on radionucleid scan on the 7th postoperative day, he was reoperated and a ureteroneocystostomy was done. Postoperatively he developed supra-pubic urinary leak which was managed conservatively. Following surgery his renal function improved slowly and on the 17th postoperative day serum creatinine was 106 μmol/l (1.2 mg/dl). He continued to have recurrent urinary tract infections which were treated according to the urine culture and sensitivity. On the 75th day following transplantation, a follow-up ureterocystoscopy was done which was essentially normal. However, his symptoms of lower urinary tract infection continued to persist even though the urinary cultures were repeatedly normal. In April 1986, although a plain radiogram of the abdomen was normal, the patient passed a stone per urethra, which was mainly made of ammonium phosphate with traces of calcium and oxalate. Keeping the possibility of a radiolucent calculus he was admitted for investigations. While in the hospital, he had acute retention of urine associated with enlargement of the graft which spontaneously got relieved within 12 h. However, a repeat ultrasonogram still showed hydroureterone-phrosis of the allograft with an echoic shadow at the lower end of the ureter. An antegrade pyelography performed at this time showed a dilated ureter (1.2 cm) and a stone at the lower end of the ureter. As the stone could not be dislodged, a percutaneus nephrostomy was done. Once the acute stage was over, he was operated for ureterolithotomy. During surgery multiple small yellowish calculi were found at the lower end of the ureter with a large stone 2 cm proximal to the vesicour-eteric junction

Clinical Profile and Course and Outcome of Late Acute Rejection Episodes in Living-Related-Donor Renal Allograft Recipients

We prospectively monitored clinical data and renal function at monthly intervals in 165 patients who had received living-related-donor renal allografts in our institution between January 1981 and December 1991 and had a functioning allograft for 1 year or longer. During a mean follow-up period of 47.2 (range 13-155) months, 32 patients (17.2%) developed late acute rejections, of which 14 (43.7%) were asymptomatic. Amongst the symptomatic late acute rejections, worsening of hypertension was the commonest finding, being present in 11 (61.1%) patients, followed by oliguria in 8 (44.4%) and weight gain in 7 (38.8%) patients. Of these 32 late acute rejections, as many as 28 (87.5%) showed a response to antirejection therapy with high-dose steroids: 5 (15.6%) a complete response and 23 (71.9%) a partial response. The response rate was 100% if it was the first acute rejection (20% complete and 80% partial), 78.6% if it was the second (14.3% complete and 64.3% partial), and no or only a partial response to treatment if it was the third acute rejection episode. On long-term follow-up, patients who had responded to to antirejection treatment had a significantly better graft survival as compared with nonresponding patients: 76 and 27%, respectively. Our observations suggest that routine monitoring of the renal function at frequent intervals is essential for early diagnosis and treatment of acute rejections, even during the late posttransplant period. The chances of a response to antirejection therapy are higher during the first episode of late acute transplant rejection as compared with second or a third late rejection event.

Neoral monitoring by limited sampling area under the concentration time curve in stable indian renal transplant recipients

The optimization of cyclosporine (CsA) immunosuppression remains a challenge because of the narrow therapeutic window and highly variable pharmacokinetics (PK). The highly variable PK were improved by the introduction of the current microemulsion preparation Neoral. However, the best clinical benefit of this CsA microemulsion can only be obtained by regular PK monitoring. During the past decade, various PK strategies have been proposed, such as C(0), C(2), level monitoring, abbreviated or limited sampling approach, and various prediction algorithms to replace the conventional area under the curve (AUC). In this study we evaluated the Neoral PK in stable Indian renal transplant recipients using a limited sampling approach. The C(0) (mean +/- SE) was 175 +/- 15 ng. mL(-1); C(max) 970 +/- 101 ng. mL(-1), and the AUC (0-4) 2734 +/- 258 ng. h. mL(-1). The C(0) showed a poor relationship to AUC (0-4) (r =.65) but high correlations were obtained with C(2) (r = 0.93) and C(3) (r =.96). Our finding suggest that stable Indian renal transplant recipients should either be monitored using C(2) or C(3).

AZATHIOPRINE-INDUCED PURE RED BLOOD CELL APLASIA IN A RENAL TRANSPLANT RECIPIENT

Dr. Sanjay K. Agarwal, Assistant Professor, Department of Nephrology AIIMS, Ansari Nagar, New Delhi 110029 (India) Dear Sir, We report a case of pure red blood cell aplasia (PRBCA) induced by azathioprine (AZA) in a renal transplant recipient. K.L.T., a 30-year-old male, presented with chronic glomerulonephritis with end-stage renal failure in 1984 and underwent renal transplantation in March 1985. He was put on predniso-lone and AZA (2 mg/kg/day). On the 15th postoperative day he developed leucopenia. The dose of AZA was temporarily decreased to 1.5 mg/kg/day. In spite of his normal renal function, his haemoglobin (Hb) continued to remain low near 7-8 g% even 6 months after transplantation. Slowly his Hb picked up, but in November 1986 it dropped again to 8.3 g%. At this time detail investigations revealed: Hb 8.5 g%, total leucocyte count 6,300/mm3, reticulocyte count 3.3%, red cells showed anisocytosis, poikilocytosis and macrocytes. Mean corpuscular volume was 108 mm3. Red blood cell count was 5.2 million/mm3. Coomb’s test was negative. Bone marrow aspiration was normal. In view of the macrocy-tosis, a trial of vitamin B!2 and folic acid was given. His Hb slowly increased to normal within 2 months. The Hb remained normal till 8 months later, when it dropped to 8.2 g%. Treatment with vitamin B12 and folic acid was restarted, but this time his Hb did not increase. Considering AZA-induced toxicity cyclosporine was started in the dose of 2 mg/kg/day, and AZA was decreased to 0.75 mg/kg/day. His Hb increased to 12.5 g%, but to avoid long-term nephrotoxicity, cyclosporine was stopped, and the patient was put again on AZA (2 mg/kg/day). Within a few months his Hb dropped again to 7.6 g% with a reticulocyte count of 1.5%. Bone marrow biopsy at this time revealed normal myeloid and megakaryocytic elements but severe paucity of erythroid cells. AZA was stopped, and cyclosporine was started (2 mg/kg/day). His Hb became 12.6 g% in a month’s time. At this time a repeat bone marrow biopsy was normal. AZA can commonly cause leucopenia, predominantly granulocytopenia and mega-loblastic erythropoiesis [1], but PRBCA has also been reported in the past. The first 2 cases of PRBCA

Recurrence of idiopathic membranous nephropathy in HLA-identical allograft.

Dr. S.C. Dash, Aditional Professor & Head, Department of Nephrology, AIIMS 110029 New Delhi (India) Dear Sir, We report a case of recurrent membranous nephropathy (rMGN) in an allograft, out of 200 live-related renal transplant (LRT) we have operated so far. S.S., a 49-year-old male first presented with idiopathic nephrotic syndrome (NS) in 1984: blood pressure was normal. He was empirically treated with prednisolone (1 mg/ kg/day) for an adequate period without any response. Renal biopsy done later in November, 1985, revealed MGN. Thereafter, he received only symptomatic treatment. He developed ESRD by the end of 1987 and underwent renal transplantation in March, 1988, the donor being his HLA-identical brother sharing A2, A10, B21 and B40 antigens. On the 17th postoperative day, he was discharged from the hospital with normal renal function and urinary protein 1.3 g/day. He remained asymptomatic till the 8th month, when he developed NS with a proteinuria of 8.5 g/day and creatinine clearance of 78 ml/min. Percutaneous graft biopsy done showed MGN. Since the first case report in 1975 [1], 28 cases of rMGN have been reported so far, including the present case. Details of 23 cases could be found in the literature. Of the remaining 5 cases, in 1981 Pirson et al. [2] and Blanc-Brunat et al. [3] reported 2 cases each. In the same year, Cosyn et al. [4] also reported a de novo MGN which recurred in the 2nd and 3rd transplant. Cases of rMGN have been published mostly as case reports. In three major series, First et al. [5] reported 1 of 14 cases, Montagnino [6] 3 of 9 cases and Mirzyeka [7] 4 of 7 cases of rMGN. These cases had usually an agressive primary disease; mean duration between diagnosis and ESRD being 4.0 years. Recurrent MGN is common in males and in LRT. Patients with LRT develop rMGN earlier than patients with cadaver renal transplants (CRT). Of 23 cases, 11 allografts were from LRT, 8 being 100% HLA-matched. In cases of rMGN from haploidentical donors, A2 antigen is common in all 4 cases where HLA of patients are known. Montagnino [6] reported 3 of 6 cases of rMGN while on ciclosporin and steroid for the first time in 1989. rMGN presents as early posttransplant variable proteinuria. Hypertension has been frequently found. Renal function at onset was normal. Prognosis of rMGN is relatively poor in LRT as compared to CRT. At 3-year follow-up, our case had heavy proteinuria (6.0-8.0 g/day) with abnormal renal function (serum creatinine 4.5 mg%). It appears that a group of idiopathic MGN patients have a rapid progressive course leading to ESRD in the short period. It may be reasonable to

Results of Renal Transplantation Using Living-Related HLA-identical Donors

Dr. Sanjay K. Agarwal, Assistant Professor, Department of Nephrology, A1IMS, Ansari Nagar, New Delhi – 110029 (India) Dear Sir, We present the results of 10 renal transplant patients on conventional immunosuppression who received transplant from living-related HLA-identical donors. Mean age of these patients was 33 years, and 9 out of 10 were males. The basic disease in 6 patients was chronic glomerulonephritis and 1 case each had polycystic kidney disease, diabetic nephropathy, bilateral renal artery stenosis and membranous glomerulopathy with chronic glomerulonephritis. Four patients belonged to blood group 0 and 2 each to A, B and AB. Each patient received a mean number of 50 haemodialyses before transplantation and 5-12 (mean 6) pretransplant third-party blood transfusions. Four patients had acute rejection (AR) episodes. Patient 1 had AR at the 3rd month, was antirejected with high-dose steroids, to which he did not respond, and lost his graft at the 5th month and subsequently died. Case 2 had 2 AR at the 13th and 20th month and lost his graft in the third year. Case 3 had 2 AR episodes at the 3rd and 6th week. He did not respond to steroid therapy followed by monoclonal antibodies and lost his graft at the 6th month. He was subsequently retransplanted. Case 4 had AR episodes at the 7th, 9th and 16th month and each time responded partially to steroids. He lost his graft at the 2nd year and died of renal failure. Case 5 who never had AR lost his graft at the 2nd year due to recurrence of membranous nephropathy. He was also re-transplanted. At the mean follow-up of 49 months (range 12144), 5 patients had lost their graft, 4 due to rejection and 1 due to recurrence of basic disease. Of these 2 died, 2 were retransplanted and 1 is being managed conservatively. HLA-identical donors for renal transplantation have been used since the early renal transplant period with excellent outcome [1]. The results have been the gold standard (1-year graft survival of nearly 90-95%) with which the results of HLA-nonidentical living-donor renal transplantations are compared [2]. Few studies have examined the potential benefits of cyclosporine (CsA) in HLA-identical transplants with inconclusive results [3,4]. Because of the controversy of the role of CsA in HLA-identical transplantation, most authors advocate only prednisolone and azathioprine (AZA) in this patient group [5,6].