Comparing Plasmapheresis plus IVIg with Plasmapheresis plus IVIg plus Rituximab on the Management of Suspicious Antibody-Mediated Acute Rejection in Kidney Transplant Recipients.

BACKGROUND: There is no treatment of choice for the management of acute antibody-mediated rejection (ABMR) in kidney transplant recipients. Plasmapheresis ± intravenous immunoglobulin (IVIg) ± rituximab has been used in different regimens with contradictory results. OBJECTIVE: To compare three regimens of acute ABMR management including plasmapheresis + IVIg ± rituximab in two different rituximab regimens. METHODS: In this prospective, observational study kidney transplant recipients with suspicious ABMR were categorized into three groups. Group 1 patients were treated with plasmapheresis + IVIg. Groups 2 and 3 received weekly rituximab at a dosage of 375 mg/m2 for either 4 doses (group 2 or high dose) or 2 doses (group 3 or low dose) in addition to plasmapheresis + IVIg. RESULTS: 8, 15, and 9 patients were categorized in groups 1, 2, and 3, respectively. There was no difference among the groups in terms of demographic and clinical characteristics of recipients and donors. Although, 1-year graft (37.5%, 60.0%, and 66.7% for groups 1, 2, and 3, respectively; p=0.308) and patients survival (75.0%, 86.7%, and 77.8% for groups 1, 2, and 3, respectively; p=0.730) were not significantly different among studied groups, graft survival was 22%-30% higher in rituximab-treated groups. Estimated glomerular filtration rate at 12th month of follow-up did not differ among groups (56.3±19.6, 57.3±20.6, 48.7±16.1 mL/min/1.73 m2 for groups 1, 2, and 3, respectively; p=0.683). However, kidney function steadily improved over time in rituximab-treated patients. CONCLUSION: Adding high or low doses of rituximab to plasmapheresis + IVIg comparably increased graft survival in suspicious acute ABMR kidney recipients and steadily improved kidney function among survived allografts over time.

Brain-dead Donation Rate in Month of Ramadan and the other Months: 2005-2014.

Regardless of the level of development, religion and beliefs have crucial impact on people's attitude towards organ donation. Although organ donation in Islam is obviously appraised, mainly due to lack of an appropriate infrastructure, post-mortem donation rate in Islamic countries is not comparable to successful settings. We conducted this study to assess the extent of contribution of factors that reduce the level of effectiveness, and also to determine the impact of altruistic feelings in the month of Ramadan on family refusal as the leading modifiable contributor to organ donation rate. All records of potential and actual brain-dead donors, referred to Organ Procurement Unit of the Iranian Tissue Bank, from January 1, 2005 to December 31, 2014, were analyzed. In each year, the number of potential and actual donors in the month of Ramadan was compared to the mean value in the remaining 11 months. Of 1758 total potential donors in 10 years, 464 cases became actual donors (26.4% as overall level of effectiveness). The reasons for non-effectiveness were medical contraindications (25.4%), cardiac arrest before referral or during maintenance (7.4%), family refusal (30.8%), judicial refusal (8.7%), etc (1.3%). Analysis showed no significant differences between donation rates (both potential and actual) in Ramadan and non-Ramadan months for potential (Δ=3.55, 95% CI: -6.7 to 13.8) and actual donors (Δ=1.35, 95% CI: -2.3 to 5). Despite the undeniable role of religion and beliefs in the establishment of organ procurement program from brain-dead donors, there was no monthly variability in post-mortem organ donation rate.

Carotid intima-media thickness as a marker of atherosclerosis in hemodialysis patients.

Atherosclerotic changes in carotid arteries of hemodialysis (HD) patients reflect global atherosclerotic changes in vasculature. Carotid intima-media thickness (CIMT) can be used for atherosclerosis prediction and assessment of cardiovascular risks in HD patients, and thus screening high-risk patients. In this cross-sectional study, CIMT was measured using ultrasonography (B-mode with 5-10-MHz multifrequency linear probe) in HD patients in our hospitals. Additionally, we assessed the relationship between their CIMT and some cardiovascular risk factors. A total of 62 HD patients (64.5% male) were included. Age, body mass index, low-density lipoprotein, fasting blood sugar, history of diabetes mellitus and cardiovascular disease, serum albumin, and duration and adequacy of HD in study patients had significant association with their CIMT. There were no significant relationships between CIMT and patient's gender, smoking, serum calcium, phosphate, calcium x phosphate product, hemoglobin, and uric acid level. More diagnostic modalities must be performed for detecting the impact of atherosclerosis on HD patients with high CIMT.

Human Tissue Processing and Transplantation in MESOT States: How to Promote?

Middle East, with more than 650 million inhabitants, has one the lowest mean donation rate in the world in the context of organ procurement from deceased donors with <2 per million population as actual deceased organ donation rate in 2014. Tissue processing and transplantation in this region are also restricted to a few countries among those representing Middle East Society for Organ Transplantation. Aiming to promote human tissue processing and transplantation in this region, as a life-enhancing therapeutic modality, we have to share our know-how and facilities in order so that the patients in different countries gain almost equal benefit of this vital procedure. To take different infrastructure of Middle Eastern countries into consideration and their plans to extend their activities, this intention will be come to the reality and materialized by primarily sharing the processed tissues among member states in a centralized manner and to offer processing services and banking to locally retrieved tissues.

Regenerative Medicine in Organ and Tissue Transplantation: Shortly and Practically Achievable?

Since the beginning of organ/tissue transplantation, the therapeutic modality of choice in end-stage organ failure, organ shortage has been the main problem in transplantation medicine. Given the so far unsolved obstacle, all hope-raising procedures to possibly tackle this long-lasting problem can draw attentions. In this context, "regenerative medicine" sounds to be more promising compared to other approaches. To consider the huge impact of hematopoietic stem cell transplantation on the treatment of some congenital or acquired hematological or metabolic disorders and some advances to produce tissue engineered materials on one hand, and to take all aspects of this emerging and costly interdisciplinary field of research into consideration, on the other hand, inevitably makes this reality unchanged, in particular in countries with low or middle income, that allograft (from deceased or living donors) will remain for years as the irreplaceable source of organ transplantation.

Comparison of various scoring methods for the diagnosis of protein-energy wasting in hemodialysis patients.

PURPOSE: The present study was designed to determine the cutoff points for the diagnosis of mild-to-moderate and severe protein-energy wasting (PEW) based on dialysis malnutrition score (DMS) and malnutrition inflammation score (MIS), and the sensitivity, specificity, accuracy, area under receiver operating characteristic (ROC) curve, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR(+)) and negative likelihood ratio (LR(-)) of DMS and MIS in comparison with subjective global assessment (SGA) in hemodialysis (HD) patients. METHODS: In this study, 291 HD patients were randomly selected from among 2,302 adult HD patients in Tehran hemodialysis centers. The PEW in these patients was determined by SGA, DMS and MIS. RESULTS: According to the cutoff points derived from the area under ROC curves, scores of 7-13 for DMS represented normal status or without PEW; 14-23, mild-to-moderate PEW; and 24-35, severe PEW. For MIS, scores of 0-7 represented normal status or without PEW; 8-18, mild-to-moderate PEW; and 19-30, severe PEW. In comparison with SGA, the sensitivity, specificity, accuracy, area under ROC curve, PPV, NPV, LR(+) and LR(-) of DMS were 94 %, 88 %, 92 %, 97 %, 93 %, 92 %, 7.8 and 0.07, respectively. Those of MIS were 87 %, 96 %, 91 %, 97 %, 97 %, 83 %, 22.0 and 0.13 in comparison with SGA, respectively. CONCLUSION: The results of the present study indicate that the DMS and MIS are almost similar to SGA for identifying PEW in HD patients, but it seems that the DMS is a more appropriate alternative tool for SGA in hospital routine assessments.

Rate of family refusal of organ donation in dead-brain donors: the Iranian tissue bank experience.

BACKGROUND: The growing gap between organ supply and demand remains a worldwide serious problem. Losing dead-brain donor organs can be attributed to several reasons including un-recognition of potential donor by ICU staff, death before official declaration of brain death and high refusal rate of deceased donors' families. OBJECTIVE: To study the trend of dead-brain patients' relatives refusal of organ donation from 2007 to 2011. METHODS: This study was a retrospective review of all patients who had been introduced as brain death to the organ procurement unit (OPU) of Iranian Tissue Bank between April 2007 and April 2012 according to preliminary neurological exam performed in the hospital of origin. The refusal rate of dead-brain patients' families and its reasons was evaluated. RESULTS: A total of 874 ICU admitted patients with severe brain injury (Glasgow coma score <7) was introduced to our center and were visited by the coordinator team during April 2007 to April 2012. 412 (47%) patients were excluded from the study mainly due to unsuitability for donation according to the approved medical protocols (n=205) and not fulfilling the brain death criteria (n=66). The families of the remaining cases (n=462) had been interviewed 343 (74.2%) of whom permitted donation. The mean±SD age of donors was 29.8±13.2 years; the male/female ratio was almost 2. The most common reason of brain death was traffic collision (n=120; 56.3%) and cerebrovascular accidents (n=40; 18.8%). The refusal rate from 2007 to 2011 has decreased respectively, from 30.4% to 20% in Tehran, and from 57.1% to 51.6% in other cities. The overall refusal rate was 25.8%. CONCLUSION: Our study confirmed that more level of expertise of the coordinator team and continuous public education, would result in higher rate of consent to organ donation.

Human split-thickness skin allograft: skin substitute in the treatment of burn.

BACKGROUND: Human skin allograft has been used as wound coverage for a long time; it is one of the most successful and widely used dressings for burn wounds in the world. OBJECTIVE: To prepare a freeze-dried human split-thickness skin allograft and evaluate its cytotoxicity, the structure and physical properties after processing methods and clinical efficacy in burn patients. METHODS: After ensuring tissue safety, we lyophilized human cadaveric partial thickness skin and exposed it to gamma radiation. Histopathological and immunohistochemical properties, tensile strength and in vitro cytotoxicity were assayed for the skin samples. Then, we tested the samples in 11 patients with deep skin burn. RESULTS: On histological and histopathological examinations, we found a normal skin structure. The tensile strength of the rehydrated freeze-dried human skin allograft was not lesser than the fresh human skin. Cell viability in MTT testing was more than 95%. None of our patients showed any signs of immunological reactions or complications. CONCLUSION: Gamma-irradiated freeze-dried human split-thickness skin is safe and non-toxic and can be used for the treatment of patients with deep skin burn.

Comparison of Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) with Serum Creatinine in Prediction of Kidney Recovery after Renal Transplantation.

BACKGROUND: Because of some insult to kidney during transplantation, assessment of kidney function after the procedure is essential. It would be ideal to find a marker better than creatinine to early predict the acute kidney injury. OBJECTIVE: To compare with creatinine the predictive value of serum neutrophil gelatinase-associated lipocalin (NGAL) in detecting kidney recovery after renal transplantation. METHODS: We studied 33 patients who received kidney transplantation (deceased [n=20] and live [n=13]) during a 6-month period in 2010. Serum NGAL and creatinine, hemoglobin, and blood glucose were measured at 0, 12, 24, 48, and 72 hours after transplantation. The need for dialysis and kidney function in one week were studied. RESULTS: There were 16 men and 17 women with the mean±SD age of 36.3±12.2 (range: 14-58) years. Of the studied patients, 6 had delayed graft function (DGF; hemodialysis within the first week of transplant); 9 had slow graft function (SGF; serum creatinine reduction from transplantation to day 7 <70%), and 23 had immediate graft function (IGF; reduction in serum creatinine ≥70%). At any time, serum NGAL, and creatinine levels were significantly higher among patients with DGF (p=0.024) and SGF (p=0.026) compared with those with IGF. However, in those who got IGF vs non-IGF, serum creatinine levels were not significantly different (p=0.59) but serum NGAL levels differed significantly(p=0.020). Receiver-operating characteristic (ROC) curve and area under curves (AUCs) of serum NGAL and serum creatinine levels on the first post-transplantation day had similar significance in predicting the patient's need to dialysis in the first week. However, using AUC of serum creatinine was not helpful in predicting non-IGF, compared to serum NGAL. The AUCs of the serum NGAL were 0.70 (95% CI: 0.52-0.89) and 0.76 (95% CI: 0.59-0.93) after 12 and 24 hours, respectively (p<0.05). The highest AUC (0.82) was attributed to serum NGAL of 24 hour (p=0.002). CONCLUSION: Serum NGAL level especially 24 hours post-transplantation, seems to be an early accurate predictor of both the need to dialysis and slow graft function within the first week of kidney transplantation.

Posttransplant diabetes mellitus: incidence and risk factors.

OBJECTIVE: Posttransplant diabetes mellitus (PTDM) is a common and serious complication of renal transplantation. Estimates of the incidence of PTDM after renal transplantation vary between 2% and 54%. The aim of the present study was to evaluate the incidence and risk factors for PTDM among our renal transplant patients. PATIENTS AND METHODS: In this study we evaluated 121 nondiabetic patients with end-stage renal disease (ESRD) who underwent kidney transplantation for the first time at our centers since 2005. All patients received the same protocol of immunosuppressive therapy. PTDM was defined according to the clinical practice recommendations of the American Diabetes Association. RESULTS: At 12 months following renal transplantation, 9.9% of patients developed PTDM. Patients with PTDM were significantly older (P = .013) and had higher body mass index (P = .001). There were significant differences (P

Proteinuria is reduced by inhibition of inducible nitric oxide synthase in rat renal ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion (IR)-induced nephrotoxicity is associated with proteinuria. There are reports on the involvement of inducible nitric oxide synthase (iNOS) in proteinuria in conjunction with renal disease. This study was designed to investigate the effect of N6-(1-iminoethyl)-L-lysine hydrochloride (L-Nil), a selective inhibitor of iNOS, to prevent proteinuria in IR injury. METHODS: Ischemia was induced by 40-minute clamping of the renal arteries followed by 6-hour reperfusion. Rats were administered either L-Nil (3 mg/kg intravenous bolus followed by infusion of 1 mg/kg/h) or saline. To monitor glomerular and tubular functional changes before and after treatment, we measured blood urea nitrogen, plasma creatinine, and urinary N-acetyl-beta-D-glucosaminidase activity. Total protein (TP), albumin, and low- (LMW) and high-molecular-weight (HMW) protein excretion rates were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis of urine samples. Kidney ultrastructure was examined through a transmission electron microscope (TEM). RESULTS: IR resulted in significant LMW and HMW proteinuria. L-Nil significantly prevented the IR-induced increases in TP, albumin, and alpha1-microglobulin excretion. TEM showed loss of microvilli of the proximal tubule cells, injured mitochondria, and foamy changes in the structure of nuclear and cytoplasm in IR group. L-Nil reduced IR-mediated renal ultrastructural changes and tubular proteinuria. DISCUSSION: This study suggested possible differences in the mechanism(s) of nephrotoxicity induced by iNOS in the glomeruli and tubular cells. The types of proteins excreted in the urine should be considered in the treatment strategy. In conclusion, this study suggested the involvement of iNOS in IR-induced tubular proteinuria.

Transplantation registry in Iran.

National registries provide valuable bases for comparisons and aid innovative policies. Iran, with 70 million inhabitants, has a governmentally supported system of organ and tissue procurement and transplantation. By two acts of legislation, first in 1997 regarding governmental rewarding living kidney donation and second in 2000 regarding cadaveric transplantation, this field has had remarkable growth in the last decade, under the supervision of the Ministry of Health. Since the beginning of each organ or tissue transplantation activity up to 2006, 21,359 kidneys, 338 livers, 122 hearts, 20 lungs, 7 pancreas, 1898 bone marrows, 28,838 corneas, 1380 heart valves, and 1366 bones were transplanted in our country. Increases in the number of live kidney transplantations are taking place, but cannot keep pace with the increasing number of patients. It is highly recommended that we try to increase cadaveric transplantation in coming years.

Pre-transplant calcium-phosphate-parathormone homeostasis as a risk factor for early graft dysfunction.

While good organ quality and ideal transplant conditions eliminate many of the know factors that compromise initial graft function (IGF), poor early graft function (EGF) still occurs after living donor kidney transplantation (LDKT). Uncontrolled pre-transplant hypercalcemia and hyperparathyroidism are associated with impaired allograft function. Between April 2004 and January 2006, data were collected on 354 LDKT recipients including 252 males and 102 females, to determine risk factors for poor EGF, defined as either delayed or slow graft function (DGF or SGF). Of the 354 recipients, 318 (89%) had IGF, 22 (6.2%) had SGF and 14 (4%) had DGF. Donor female gender (P = 0.04) and duration on dialysis (P = 0.02) were associated with poor EGF. Recipients with DGF had higher serum phosphate (P = 0.07) and calcium x phosphate product ( P = 0.01) than recipients with IGF and SGF. The serum parathormone (PTH) levels were higher in recipients with SGF and DGF although the difference was not statistically significant (P = 0.1). Serum calcium levels did not correlate with the occurrence of poor EGF (P = 0.9). Our study suggests that serum phosphate and calcium x phosphate product serve as risk factors for DGF while serum PTH level may play a role as a risk factor for SGF and DGF.

Infertility among female renal transplant recipients.

We studied 122 women with renal allograft transplantation to evaluate their reproductive systems. The patients were recruited from the three main kidney transplant surgery centers in Tehran, from September to October 2005. Fifteen (12%) patients were either in the menopausal stage or had hysterectomies, and the other 33(27%) were unmarried. Of the 76(62%) married women at the reproductive age, 10 (13.1%) had infertility that was defined as the failure of a married woman to conceive after 12 months of frequent intercourse without contraception. Three patients had male factor infertility, three others had ovulatory problems, and four cases were undefined. Only six cases were actively treated by ovulation induction +/- an intrauterine inducer (IUI); two patients became pregnant, while the other four refused infertility treatment. The reasons of unwillingness for infertility treatment included old age (40 years) in one patient, positive HBsAg in one, renal retransplantation in one, and previous clomiphene therapy failure in another. We conclude that the prevalence of infertility among female renal transplant recipients is the same as the general population, and the causes are mostly treatable. However, many are less motivated to be treated for this problem.

Sun protection in Iranian kidney transplant recipients: knowledge, attitude and practice.

BACKGROUND: Kidney transplant recipients (KTR) are at increased risk of developing skin cancer. The purpose of this study was to evaluate the knowledge, attitude, and practices of KTRs regarding skin cancer after transplantation and to identify the role of education in motivating these patients to practice sun-protective behaviours. METHODS: Two hundred and fifty KTRs in a referral hospital were interviewed using a questionnaire. All patients received a skin cancer information booklet after completion of the questionnaire. Six months later, these patients were invited and interviewed again about their skin cancer-prevention practices. RESULTS: The patients consisted of 153 men and 97 women patients with a mean age of 35.9 +/- 14.2 years and mean of 49.7 +/- 53.1 months after their transplantation. A total of 102 patients (40.8%) mentioned receiving skin care advice after transplantation. Nonetheless, the majority of patients did not have appropriate skin cancer-prevention practices. Patients who had received advice on skin care after transplantation were significantly more likely to do skin self-examination (chi-squared test; P < 0.001) and have less sun exposure daily (Mann-Whitney test; P = 0.019) than those who did not. Half of the patients (125 patients) participated in the second part of the study 6 months after the first interview and providing skin care instruction booklet. Although regular skin self-examination and sunscreen use was significantly increased (P = 0.006 and P = 0.001, respectively), but daily sun exposure was not changed significantly (P = 0.64). CONCLUSIONS: Post-transplantation education does not necessarily lead to patients' awareness about their increased risk of skin cancer, and subsequent motivation to practice effective sun protection. Health professionals and dermatologists in particular need to establish better methods of dissemination of information, repeatedly and at the proper time.

Antioxidant vitamins preserve superoxide dismutase activities in gentamicin-induced nephrotoxicity.

OBJECTIVE: The clinical use of gentamicin (G) is limited due to its known nephrotoxic actions. Generation of reactive oxygen species has been proposed as a causative factor of cell death in G-induced acute renal failure (ARF). Previous studies using superoxide dismutase (SOD) mimetics have indirectly suggested a role for the superoxide ion in G-induced ARF. In this study, we directly measured the enzyme activities using in situ isolated kidneys seeking to investigate the effects of antioxidant therapy on preservation of endogenous antioxidant levels in ARF. METHODS: Thirty-five male Sprague-Dawley rats were randomly assigned to 5 groups: control, Tyrode-perfused; G, gentamicin (200 mg/L) added to the perfusate; G + vitamin E (Vit E; 100 mg/100 g BW, IM); G + vitamin C (Vit C) added to the drinking water for 3 days (200 mg/L) and to the perfusate (100 mg/L); G + Vit E + Vit C. SOD activities were determined in renal tissues based on NAPDH oxidation at 340 nm by spectrophotometry. RESULTS: SOD activity was significantly reduced in the G group compared with the controls (P<.05). Administration of Vit E alone or in combination with Vit C significantly preserved enzyme activity levels compared with the G group (P<.05). CONCLUSION: Antioxidant vitamins have a role in preservation of renal endogenous antioxidant activities, namely SOD, in G-induced nephrotoxicity.

Cyclosporine effects on the antioxidant capacity of rat renal tissues.

OBJECTIVE: Cyclosporine (CsA) has been shown to improve long-term survival after organ transplantation. However, CsA therapy is associated with a variety of side effects, among which nephropathy is the major one. Recent studies have suggested increased oxidative stress as a cause of drug nephrotoxicity. Therefore, this study was designed to evaluate the effects of CsA administration on the antioxidant capacity of kidney tissue. METHODS: Adult male Sprague-Dawley rats were randomly assigned into 2 groups: one group received CsA (25 mg/kg/d, IP for 2 weeks) and a control group (no CsA administration). After 2 weeks, the kidneys of the rats from both groups were removed under anesthesia. A 50 mg fresh kidney tissue sample was homogenized in ice-cold phosphate buffer. Total antioxidant capacity (Ferric Reducing Ability of Plasma [FRAP]) in the homogenates was assayed based on the Benzie spectrophotometric method. RESULTS: FRAP in the kidney tissues had been significantly decreased by 2 weeks of CsA administration when compared with control rats (P<.05). CONCLUSIONS: These data suggested that CsA administration may decrease the antioxidant capacity of renal tissues. More studies on the evaluation of the protective effects of antioxidant therapy against CsA nephrotoxicity are underway.

The cost of kidney transplantation in Iran.

BACKGROUND: Kidney transplantation has gained widespread popularity by improving the outcome of end-stage renal disease (ESRD) patients. However, this is a highly complicated and expensive procedure that puts much pressure on the health system in developing countries. We report the costs in Iran model of kidney transplantation. MATERIALS AND METHODS: We reviewed the regulations for kidney transplantation using Dialysis and Transplant Patients Association (DATPA) information, 2005. All data regarding the cost of transplantation procedure, immunosuppression, and the money given to donors were included. The cost of transplantation procedure was categorized into personnel, drugs, paraclinics, hospital bed, and other expenses. To achieve more comprehensive results, all costs were converted into US dollars (1 USD = 9000 Rials). RESULTS: The total cost of kidney transplantation procedure was $9224. Of this, 65.8% ($6076) was related to the immunosuppression therapy in the first year, 22.2% ($2048) to the transplantation procedure, and 12% ($1100) to organ procurement. The details of donor nephrectomy were as follows: personnel, $183; accommodations, $107; drugs, $39; paraclinics, $23; and other, $22. These values for kidney recipient were personnel, $331; drugs, $367; paraclinics, $278; accommodations, $475; and other, $222. CONCLUSION: Compared with other countries, the kidney transplantation cost is low in Iran. The health system also pays for all the expenses. These, along with full medical insurance coverage of kidney recipients, make kidney transplantation available for every patient, regardless of the socioeconomic status due to its low cost. It is expected that a higher number of transplantation candidates with a low socioeconomic status will select transplantation.

Acid-base status determines cyclosporine-induced hypercalciuria.

OBJECTIVE: Cyclosporine (CsA) causes tubular dysfunction characterized by polyuria, calcium wasting, distal tubular acidosis, and hyperkalemia. The hypercalciuria induced by CsA administration is associated with an inhibition of calbindin D(28k) expression. It has also been shown that chronic metabolic alkalosis increased the expression of Ca(2+) transport proteins accompanied by diminished urine Ca(2+) excretion. The aim of this study, therefore, was to determine the effect of acid-base status on CsA-induced hypercalciuria. METHODS: Experiments were performed on male Sprague-Dawley rats. Metabolic alkalosis and acidosis were induced respectively by adding 0.28 mol/L NaHCO(3) and 0.28 mol/L NH(4)Cl in the drinking water for 7 days; control rats received regular tap water. Seven days after NaHCO(3) or NH(4)Cl administration, rats were treated with CsA (25 mg/kg, IP) daily for 14 days. To estimate glomerular filtration rate (GFR) over time, animals were placed in metabolic cages. Fractional urinary calcium excretion was determined by standard formula. RESULTS: The CsA group showed decreased serum calcium and increased fractional urinary calcium excretion compared with the control group. Creatinine clearance was also significantly reduced. Metabolic alkalosis alone did not affect GFR, but significantly prevented an increase in fractional urinary calcium excretion induced by CsA, whereas chronic metabolic acidosis resulted in the exact opposite effect. CONCLUSIONS: It is essential for nephrologists to fully understand the mechanisms of CsA-induced renal injury. In this study, metabolic alkalosis reduced CsA-induced hypercalciuria. Further studies are needed to elucidate whether this effect may be achieved pharmacologically by the expression of Ca(2+) transport proteins.