Reporting renal biopsies from Cyprus: a systematic approach.

BACKGROUND: The etiology of renal disease varies in different parts of the world. In the Middle East, half of all patients reaching end-stage are categorised as either unknown etiology or hypertension-related nephropathy. OBJECTIVES: To report a renal biopsy series, in a reproducible format and manner, so that data can be compared directly among other series. PATIENTS AND METHODS: Biopsies of native kidneys were performed in a 10-year period, at a tertiary referral hospital that provides the entire nephrology service for north Cyprus. Data are reported from 153 patients older than 17 years, who were either Turkish-Cypriot or from the Turkish mainland. RESULTS: Mean biopsy rate was 48 per million population (pmp) per year. Mean age was 45.7 years (range 18-78). Overall, the sex distribution was similar (male 51%). The most common histopathological categories were primary glomerulonephritis (GN) (56%), secondary GN (27%), and tubulo-interstitial disease (14%). Of those with primary GN, 29% had secondary (2o) focal and segmental glomerulosclerosis (FSGS) (29%), followed by IgA nephropathy (24 %), membranous 18% and a further 11 patients with 1o FSGS (12%). The incidence of IgA nephropathy was 6.3 per pmp/year. When expressed as a percentage of the annual biopsy rate, 14% of all biopsies showed IgA nephropathy. CONCLUSIONS: To compare data among centres, they must be expressed in terms of the population (incidence pmp/year) and the biopsy rate. In our population, secondary FSGS is common and uncharacterised and we believe many will be caused by monogenic disease.

Life expectancy with chronic kidney disease: an educational review.

Can renal prognosis and life expectancy be accurately predicted? Increasingly, the answer is yes. The natural history of different forms of renal disease is becoming clearer; the degree of reduction in glomerular filtration rate (GFR) and the magnitude of proteinuria are strong predictors of renal outcome. Actuarial data on life expectancy from the start of renal replacement therapy are available from renal registries such as the U.S. Renal Data System (USRDS), and the UK Renal Registry. Recently, similar data have become available for patients with chronic kidney disease. Data collected from a large population-based registry in Alberta, Canada and stratified for different levels of estimated GFR (eGFR) have shown that the reduction in life expectancy with kidney failure is not a uremic event associated with starting dialysis but a continuous process that is evident from an eGFR of ≤60 ml/min. Nevertheless, despite the poor prognosis of the last stages of renal failure, progress in the treatment and management of these patients and, in particular, of their cardiovascular risk factors continues to improve long-term outcome.

A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen.

BACKGROUND: Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts. METHODS: We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses. RESULTS: We identified a novel frameshift mutation, c.4611_4612insG:p.T1537fs, in exon 49 of COL4A1. This mutation predicts truncation of the protein with disruption of the C-terminal part of the NC1 domain. We confirmed its presence in 20 family members, 17 with confirmed haematuria, 5 of whom also had stage 4 or 5 chronic kidney disease. Eleven family members exhibited kidney cysts (55% of those with the mutation), but muscle cramps or cerebral aneurysms were not observed and serum creatine kinase was normal in all individuals tested. CONCLUSIONS: Missense mutations of COL4A1 that encode the CB3 [IV] segment of the triple helical domain (exons 24 and 25) are associated with HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and cramps). Missense mutations of COL4A1 that disrupt the NC1 domain are associated with antenatal cerebral haemorrhage and porencephaly, but not kidney disease. Our findings extend the spectrum of COL4A1 mutations linked with renal disease and demonstrate that the highly conserved C-terminal part of the NC1 domain of the α1 chain of type IV collagen is important in the integrity of glomerular basement membrane in humans.

Combinatorial Conflicting Homozygosity (CCH) analysis enables the rapid identification of shared genomic regions in the presence of multiple phenocopies.

BACKGROUND: The ability to identify regions of the genome inherited with a dominant trait in one or more families has become increasingly valuable with the wide availability of high throughput sequencing technology. While a number of methods exist for mapping of homozygous variants segregating with recessive traits in consanguineous families, dominant conditions are conventionally analysed by linkage analysis, which requires computationally demanding haplotype reconstruction from marker genotypes and, even using advanced parallel approximation implementations, can take substantial time, particularly for large pedigrees. In addition, linkage analysis lacks sensitivity in the presence of phenocopies (individuals sharing the trait but not the genetic variant responsible). Combinatorial Conflicting Homozygosity (CCH) analysis uses high density biallelic single nucleotide polymorphism (SNP) marker genotypes to identify genetic loci within which consecutive markers are not homozygous for different alleles. This allows inference of identical by descent (IBD) inheritance of a haplotype among a set or subsets of related or unrelated individuals. RESULTS: A single genome-wide conflicting homozygosity analysis takes <3 seconds and parallelisation permits multiple combinations of subsets of individuals to be analysed quickly. Analysis of unrelated individuals demonstrated that in the absence of IBD inheritance, runs of no CH exceeding 4 cM are not observed. At this threshold, CCH is >97% sensitive and specific for IBD regions within a pedigree exceeding this length and was able to identify the locus responsible for a dominantly inherited kidney disease in a Turkish Cypriot family in which six out 17 affected individuals were phenocopies. It also revealed shared ancestry at the disease-linked locus among affected individuals from two different Cypriot populations. CONCLUSIONS: CCH does not require computationally demanding haplotype reconstruction and can detect regions of shared inheritance of a haplotype among subsets of related or unrelated individuals directly from SNP genotype data. In contrast to parametric linkage allowing for phenocopies, CCH directly provides the exact number and identity of individuals sharing each locus. CCH can also identify regions of shared ancestry among ostensibly unrelated individuals who share a trait. CCH is implemented in Python and is freely available (as source code) from http://sourceforge.net/projects/cchsnp/ .

Incidence of end-stage renal disease in the Turkish-Cypriot population of Northern Cyprus: a population based study.

BACKGROUND: This is the first report of the incidence and causes of end-stage renal disease (ESRD) of the Turkish-Cypriot population in Northern Cyprus. METHODS: Data were collected over eight consecutive years (2004-2011) from all those starting renal replacement therapy (RRT) in this population. Crude and age-standardised incidence at 90 days was calculated and comparisons made with other national registries. We collected DNA from the entire prevalent population. As an initial experiment we looked for two genetic causes of ESRD that have been reported in Greek Cypriots. RESULTS: Crude and age-standardised incidence at 90 days was 234 and 327 per million population (pmp) per year, respectively. The mean age was 63, and 62% were male. The age-adjusted prevalence of RRT in Turkish-Cypriots was 1543 pmp on 01/01/2011. The incidence of RRT is higher than other countries reporting to the European Renal Association - European Dialysis and Transplant Association, with the exception of Turkey. Diabetes is a major cause of ESRD in those under 65, accounting for 36% of incident cases followed by 30% with uncertain aetiology. 18% of the incident population had a family history of ESRD. We identified two families with thin basement membrane nephropathy caused by a mutation in COL4A3, but no new cases of CFHR5 nephropathy. CONCLUSIONS: This study provides the first estimate of RRT incidence in the Turkish-Cypriot population, describes the contribution of different underlying diagnoses to ESRD, and provides a basis for healthcare policy planning.

Adult care of children from pediatric urology.

PURPOSE: In this article we highlight the difference, from established adult urology, in required approach to the care of adolescents and young adults presenting with the long-term consequences of the major congenital anomalies of the genitourinary tract. We review some abnormalities of the kidneys, progressive renal failure and disorders of bladder function from which general conclusions can be drawn. MATERIALS AND METHODS: The published literature was reviewed and augmented with material from our institutional databases. For renal function the CAKUT (congenital abnormalities of the kidney and urinary tract) database at University College London Hospitals was used, which includes 101 young adult patients with CAKUT in whom the urinary tract has not been diverted or augmented. For bladder function some data are from patient records at Boston Children's Hospital. RESULTS: Adolescents who grow up with the burden of a major congenital anomaly have an overwhelming desire to be normal. Many achieve high levels of education and occupy a wide range of employment scenarios. Babies born with damaged kidneys will usually experience improvement in renal function in the first 3 years of life. Approximately 50% of these cases will remain stable until puberty, after which half of them will experience deterioration. Any urologist who treats such patients needs to test for proteinuria as this is a significant indicator of such deterioration. In its absence, the urologist must have a reasonable strategy for seeking a urological cause. The most effective management for nephrological renal deterioration is with angiotensin converting enzyme inhibitors, which slow but do not prevent end stage renal failure. Renal deterioration is generally slower in these patients than in those with other forms of progressive renal disease. The bladder is damaged by obstruction or by functional abnormalities such as myelomeningocele. Every effort should be made to stabilize or reconstruct the bladder in childhood. A dysfunctional bladder is associated with or causes renal damage in utero, but continued dysfunction will cause further renal damage. Bladder function often changes in puberty, especially in boys with posterior urethral valves who may experience high pressure chronic retention. Dysfunction is managed with antimuscarinic drugs, clean intermittent self-catheterization and intestinal augmentation. Adult urologists must be able to manage the long-term problems associated with these treatments. CONCLUSIONS: Pediatric conditions requiring management in adolescence are rare but have major, lifelong implications. Their management requires a broad knowledge of pediatric and adult urology, and could well be a specialty in its own right. Therefore, adult urologists must remain aware of the conditions, the problems that they may encounter and the special management required for these patients to live normal lives.

Can we improve diagnosis of renal failure? A revised coding system for Middle East and North Africa.

INTRODUCTION: Reporting data on primary renal disease (PRD) causing end-stage renal failure (ESRF) is generally inconsistent and diagnostic groups poorly defined. METHODS: We have identified all papers published from the Eastern Mediterranean, Middle East, Arabia and North Africa during the decade 2000-2009 that report data on PRD in patients reaching ESRF in this region. RESULTS: We propose a system in which all diagnoses fall into one of 8 broad groups: ESRF of uncertain etiology, Congenital abnormalities of the kidney and urinary tract (CAKUT) and acquired Uropathy, Glomerular diseases, Tubulo-interstitial disease (TID), Other Congenital and Familial diseases, Diabetes, Renovascular disease, Other Specified Diagnoses. Each group has sub-headings, for instance, primary glomerulonephritis, secondary glomerulonephritis, and hereditary glomerular disease. And then for each sub-heading there is list of specific diagnoses similar to that used by EDTA and USRDS coding systems. We also recommend that 'etiology unknown' group should be reported in more detail as either 'glomerular phenotype' or 'tubular phenotype' and careful attention paid to evidence for a family history of renal disease. To improve reporting, all patients who are diabetic, and all who have evidence of familial inheritance, should be recorded and then a diagnostic category should also be chosen. So a diabetic patient is designated as 'diabetic nephropathy' only if they fulfil the case definition for that diagnosis. CONCLUSION: We know that collecting PRD data can be done much better as we have the example of the pediatric community which collects data that is very consistent, and has a low rate of 'unknown disease'.

Can we improve the diagnosis of renal failure? A revised coding system for the Middle East and North Africa.

We reviewed the regional data on primary renal disease (PRD) causing end-stage renal failure (ESRF) during the decade 2000-2009. Reporting was generally inconsistent and diagnostic groups were poorly defined. We propose a system in which all diagnoses fall into one of eight broad groups: ESRF of uncertain etiology, congenital abnormalities of the kidney and urinary tract (CAKUT) and acquired uropathy, glomerular diseases, tubulo-interstitial disease (TID), other congenital and familial diseases, diabetes, renovascular disease and other specified diagnoses. Each group has sub-headings; for instance, primary glomerulonephritis, secondary glomerulonephritis, and hereditary glomerular disease. For each sub-heading, there is a list of specific diagnoses similar to that used by the European Dialysis and Transplant Association (EDTA) and United States Renal Data System (USRDS) coding systems. We also recommend that "etiology unknown" group should be reported in more detail as either "glomerular phenotype" or "tubular phenotype" and careful attention be paid to evidence for a family history of renal disease. To improve reporting, all patients who are diabetic, and all who have evidence of familial inheritance, should be recorded and a diagnostic category should be chosen. Thus, a diabetic patient is designated as "diabetic nephropathy" only if he/she fulfils the case definition for that diagnosis. We believe that the collection can be done much better as exemplified by the pediatric community, where data collection is very consistent, and there is a low rate of "unknown disease".

Primary renal disease in young adults with renal failure.

BACKGROUND: No specific data have been published on primary renal disease (PRD) in young adults with end-stage renal failure (ESRF). For children, congenital abnormalities of the kidney and urinary tract (CAKUT) account for 50% of renal failure and other congenital and familial disease comprise 20%. This remains true for teenage children in paediatric registries. METHODS: To investigate the causes of ESRF in young adults, the UK Renal Registry data for the period 2000-2006 have been reviewed and PRD reported for all aged 18-39 years. For comparison, US Renal Data System (USRDS) results are available for age groups 0-19, 20-29 and 30-39 years. These data are also compared with data reported by the British Association of Paediatric Nephrology (BAPN). RESULTS: For the UK, there is a rise in the rate of 'aetiology uncertain' from 6% at 12-15 years to 21% by 18-21 years. This figure of 21% remains constant for the older patients in their third and fourth decades and can be increased by at least 5% by adding 'glomerulonephritis; histologically examined but unspecified'; but these figures compare with unknown rates of 36% for the US age group 20-29 years. In the UK, for those 18-21 years, 'glomerulonephritis' accounts for 28%, when 'Alport's disease' (6.5%) and 'unspecified' (4.5%) are excluded, which compares with age 12-15 of 26%. At age 18-21 years in the UK, there is a sharp decline in all CAKUT (26%) when compared with the BAPN incidence for the 12-15 age group of 45%. For those in their third decade, diabetes accounts for 14-18% of diagnoses, distorting our ability to compare data by percentage. CONCLUSIONS: These young adult data in the UK are consistent with the hypothesis that many of the undiagnosed cases must be CAKUT or tubular disease.

Stabilization of renal deterioration caused by bladder volume dependent obstruction.

PURPOSE: Previously published data from our unit show the detrimental effect of excessive bladder filling at normal pressure on renal function in chronically dilated renal units. Synchronous cystometry and dynamic renography identified a critical volume of filling that prevents upper tract drainage. In this followup study we determined whether maintaining bladder volume below this critical level would halt renal deterioration. MATERIALS AND METHODS: Followup data were collected on 20 patients in the original study. All had progressive renal function deterioration for which no other cause was identified. Creatinine measured nearest to the time of the study renogram served as a baseline and subsequent values were used to monitor renal function. Data were analyzed by the paired Student t test. RESULTS: Complete data were obtained on 14 patients with a mean age of 34.4 years (range 22 to 70). The mean glomerular filtration rate at entry to this part of the study was 42 ml per minute per 1.73 m(2) (range 18 to 69). Four patients had a neuropathic bladder, 4 had posterior urethral valves, 4 had bladder exstrophy, 1 had radiation cystitis, 1 had a solitary pelvic kidney and detrusor failure, 5 had a native bladder and 9 underwent cystoplasty. Drainage was via the native urethra and a Mitrofanoff channel in 7 cases each. Mean followup was 27 months (range 3 to 39). There was no significant difference in mean +/- SD creatinine at baseline vs latest followup (168 +/- 72 vs 185 +/- 90 micromol/l, p >0.05). CONCLUSIONS: In patients with bladder volume dependent renal obstruction function can be stabilized by consistently maintaining bladder volume below the critical level.

What do we know about chronic renal failure in young adults? I. Primary renal disease.

Paediatric registries worldwide report that congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately 50% of end-stage renal failure and other congenital and familial diseases account for another 20% (together 70%). Does the same hold true for young adults? Almost nothing has been published about primary renal disease in adults who have reached end-stage before 30 years of age. I have reviewed the UK renal registry (2000-2006) and the United States Renal Data System (USRDS) data base (2005) to answer this question. While paediatric registries have reduced the number of children with 'no specific diagnosis' from 39% in 1976 to fewer than 5%, the adult registries still report rates of 20-27%, which rise to 28-36% when all unspecified groups, predominantly 'glomerulonephritis (GN) (histologically not examined)', are considered together. For UK data, this rise in 'no specific diagnosis' mirrors a fall in CAKUT to 26% for the age group 18-21 years. According to USRDS data, CAKUT falls from 31% for ages 0-19 years to only 5% for ages 20-30 years. Nephrologists probably under-diagnose CAKUT in young adult patients, and this diagnosis can account for many of the 30% that currently have no specified primary renal disease.

What do we know about chronic renal failure in young adults? II. Adult outcome of pediatric renal disease.

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for more than half of all renal failure in children. For young adults with CAKUT two questions are paramount: what is the prognosis and what is the best management to improve outcome? The paediatric literature shows that prognostic factors are glomerular filtration rate (GFR) and the presence of proteinuria. We reviewed data from 101 young adult patients with either primary vesico-ureteric reflux and renal dysplasia or obstructive uropathy. Patients had an estimated GFR (eGFR) of 35 ml/min. The ACEI benefit increased with time. Rate of decline was slower than reported for other diseases and was only -2.4 ml/min per year for those reaching the start of dialysis. Outcome is predictable by the level of residual renal function (GFR). Nevertheless, function remains stable while proteinuria is minimal. Short-term studies overestimate rates of deterioration.

Hyponatraemia and hypokalaemia in adults with uncomplicated malaria in Thailand.

In a retrospective study of 1415 patients aged 15 and over, we determined the incidence of clinically important hyponatraemia and hypokalaemia in adults with uncomplicated malaria. On admission, serum concentrations of sodium (135-145 mmol/L) and potassium (3.5-5.0 mmol/L) were found outside these reference ranges in 81% of patients. Severe hypokalaemia (K+ <3.0 mmol/L) and severe hyponatraemia (Na+ <125 mmol/L occurred in 4.4% and 0.6% of the patients, respectively. For hypokalaemia (43%) and hyponatraemia (37%), hypovolaemia, blood urea to creatinine ratio and high serum glucose (>100 mg/dL) were all independent factors (P < 0.001). Other independent predictors for hypokalaemia were Plasmodium vivax infection, female gender; and for hyponatraemia, P. falciparum infection, male gender, concentrations of G-6-PD and serum bicarbonate.

Feasibility of dynamic 3-D color Doppler ultrasound for imaging penile vascular change in renal transplant patients with erectile dysfunction responding to sildenafil.

Renal transplant recipients (RTRs) have a high incidence of erectile dysfunction (ED). Differentiation of penile vasculogenic impotence from other causes is important for treatment. Conventional 2-D color Doppler assessment after intracavernosal stimulant injection often fails to produce reliable results because of limited views by the cross-sectional imaging and the painful procedure. In comparison to the findings in three healthy volunteers, we determined cavernosal vascular hemodynamics in eight RTRs with ED before and after oral sildenafil by using live 3-D ultrasound and dynamic 3-D color Doppler. Results showed that, before sildenafil, penile arterial flow signals could only be reliably detected in one patient. After sildenafil, all had reliably detectable flow with grades II to III erection. Our data suggest that 3-D volumetric changes of the penis and its vasculature during erection can be studied by this technique and that this method could be useful for the evaluation of new drugs and therapeutic biofeedback.

Rapamycin-induced remission of Kaposi's sarcoma is not associated with expansion of cytotoxic T-lymphocyte subsets.

We present a case of post-transplantation Kaposi's sarcoma (KS) successfully treated by conversion to rapamycin. Clinical and histological resolution was observed within 6 months of commencing rapamycin. Also, vascular endothelial growth factor (VEGF) staining in the biopsy samples resolved following rapamycin therapy. Interestingly there was no expansion in cytotoxic T-lymphocyte (CTL) subsets observed during this period, as might be expected if this remission was due to immune reconstitution following reduction in immunosuppression. These data suggest that the resolution of tumour with rapamycin could be the result of the antiangiogenic, antiproliferative effects of rapamycin.

Effect of the abnormal bladder when full on upper tract drainage using a combined cystometrogram-(99m)Tc-mercapto-acetyltriglycine renogram: a prospective study.

OBJECTIVE: To examine the relevance of bladder volume in patients with chronic hydronephrosis and abnormal bladder function who lose renal function even though the bladder or reservoir pressure is normal (<40 cmH(2)0). PATIENTS AND METHODS: In all, 20 patients (16 male; age range 17-67 years) were studied prospectively; 12 had a reconstructed bladder. All had progressive loss of renal function with a glomerular filtration rate (GFR) of >15 mL/min. The study was in three parts: a baseline (99m)Tc-mercapto-acetyltriglycine (MAG3) scan was performed with an empty bladder, then a combined full bladder cystometrogram (CMG) with (99m)Tc-MAG3 study was done supine, and finally repeated in the sitting position. The pressure and volume changes together with the (99m)Tc-MAG3 scintigraphic variables with and without a full bladder were compared. RESULTS: Of the 17 patients with normotensive bladders, 13 (77%) had functional obstruction of the kidneys with a full bladder. In seven this was threshold dependent and occurred at a total mean (range) bladder volume of 348 (135-720) mL for both positions. In the other six patients there was minimal drainage of isotope from the kidneys even with the bladder empty. When the sitting position was compared with supine, gravity was more important for upper tract drainage in the reconstructed bladders. In five patients the detrusor pressure at which drainage began was close to zero. CONCLUSIONS: In 13 of 17 patients (77%) the kidneys failed to drain with a full bladder despite 'normal' detrusor pressures. It remains to be seen whether bladder emptying designed to keep the urine volume below the obstructing threshold volume will prevent further loss of renal function.

Hyper-IgG4 disease: report and characterisation of a new disease.

BACKGROUND: We highlight a chronic inflammatory disease we call 'hyper-IgG4 disease', which has many synonyms depending on the organ involved, the country of origin and the year of the report. It is characterized histologically by a lymphoplasmacytic inflammation with IgG4-positive cells and exuberant fibrosis, which leaves dense fibrosis on resolution. A typical example is idiopathic retroperitoneal fibrosis, but the initial report in 2001 was of sclerosing pancreatitis. METHODS: We report an index case with fever and severe systemic disease. We have also reviewed the histology of 11 further patients with idiopathic retroperitoneal fibrosis for evidence of IgG4-expressing plasma cells, and examined a wide range of other inflammatory conditions and fibrotic diseases as organ-specific controls. We have reviewed the published literature for disease associations with idiopathic, systemic fibrosing conditions and the synonyms: pseudotumour, myofibroblastic tumour, plasma cell granuloma, systemic fibrosis, xanthofibrogranulomatosis, and multifocal fibrosclerosis. RESULTS: Histology from all 12 patients showed, to varying degrees, fibrosis, intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils, and sometimes eosinophilic aggregates, with venulitis and obliterative arteritis. The majority of lymphocytes were T cells that expressed CD8 and CD4, with scattered B-cell-rich small lymphoid follicles. In all cases, there was a significant increase in IgG4-positive plasma cells compared with controls. In two cases, biopsies before and after steroid treatment were available, and only scattered plasma cells were seen after treatment, none of them expressing IgG4. Review of the literature shows that although pathology commonly appears confined to one organ, patients can have systemic symptoms and fever. In the active period, there is an acute phase response with a high serum concentration of IgG, and during this phase, there is a rapid clinical response to glucocorticoid steroid treatment. CONCLUSION: We believe that hyper-IgG4 disease is an important condition to recognise, as the diagnosis can be readily verified and the outcome with treatment is very good.

Progressive neurological disease induced by tacrolimus in a renal transplant recipient: case presentation.

BACKGROUND: Tacrolimus and cyclosporine, both calcineurin inhibitors, can cause neurological side effects. While mild symptoms such as tremor are well recognised, severe complications including seizures and encephalopathy are poorly documented following renal transplantation. CASE PRESENTATION: We report a 42 year old man who received a cadaver renal transplant. He received tacrolimus and prednisolone. The course was uneventful for 6 weeks when he became intermittently confused, with unsteady gait and slurred speech. Following a grand mal convulsion he was admitted. He had no focal neurological signs, cerebrospinal fluid was normal; electroencephalogram was consistent with temporal lobe partial epilepsy. The magnetic resonance imaging of brain showed widespread changes with multiple areas of low signal intensity in brain stem and cerebral hemispheres. He was readmitted 3 weeks later after further fits, despite anti-convulsant therapy. He was psychotic with visual hallucinations, and rapidly became obtunded. Although his tacrolimus blood concentration had been kept in the normal range, his symptoms improved dramatically when the tacrolimus was stopped. CONCLUSION: Severe central nervous system toxicity from calcineurin inhibitors has been rarely reported in renal transplantation and we found only one report of tacrolimus-induced toxicity in an adult. We believe the condition is frequently undiagnosed. It is a very important diagnosis not to miss as the remedy is simple and failure may result in unnecessary brain biopsy, as well as irreversible injury.