rhErythropoietin-b as a tissue protective agent in kidney transplantation: a pilot randomized controlled trial.

BACKGROUND: Extended criteria donor (ECD) and donation after circulatory death (DCD) kidneys are at increased risk of delayed graft function (DGF). Experimental evidence suggests that erythropoietin (EPO) attenuates renal damage in acute kidney injury. This study piloted the administration of high dose recombinant human EPO-beta at implantation of ECD and DCD kidneys, and evaluated biomarkers of kidney injury post-transplant. METHODS: Forty patients were randomly assigned to receive either rhEPO-b (100,000 iu) (n = 19 in the intervention group, as 1 patient was un-transplantable post randomisation), or placebo (n = 20) in this, double blind, placebo-controlled trial at Manchester Royal Infirmary from August 2007 to June 2009. Participants received either an ECD (n = 17) or DCD (n = 22) kidney. Adverse events, renal function, haematopoietic markers, and rejections were recorded out to 90 days post-transplant. Biomarkers of kidney injury (neutrophil gelatinase-associated lipocalin, Kidney Injury Molecule-1 and IL-18) were measured in blood and urine during the first post-operative week. RESULTS: The incidence of DGF (53% vs 55%) (RR = 1.0; CI = 0.5-1.6; p = 0.93) and slow graft function (SGF) (32% vs 25%) (RR = 1.1; CI = 0.5-1.9; p = 0.73) respectively, serum creatinine, eGFR, haemoglobin and haematocrit, blood pressure, and acute rejection were similar in the 2 study arms. High dose rhEPO-b had little effect on the temporal profiles of the biomarkers. CONCLUSIONS: High dose rhEPO-b appears to be safe and well tolerated in the early post- transplant period in this study, but has little effect on delayed or slow graft function in recipients of kidneys from DCD and ECD donors. Comparing the profiles of biomarkers of kidney injury (NGAL, IL-18 and KIM-1) showed little difference between the rhEPO-b treated and placebo groups. A meta-analysis of five trials yielded an overall estimate of the RR for DGF of 0.89 (CI = 0.73; 1.07), a modest effect favouring EPO but not a significant difference. A definitive trial based on this estimate would require 1000-2500 patients per arm for populations with base DGF rates of 50-30% and 90% power. Such a trial is clearly unfeasible. TRIAL REGISTRATION: EudraCT Number 2006-005373-22 ISRCTN ISRCTN85447324 registered 19/08/09.

Recurrent tubulointerstitial nephritis and uveitis syndrome in a renal transplant recipient.

We report for the time a patient with recurrence of tubulointerstitial nephritis and uveitis (TINU) following renal transplantation. Our patient was diagnosed at the age of 8 years and, despite treatment with systemic steroids, developed established renal failure. At the age of 17 years, he underwent a live-related donor renal transplant. Immunosuppression included tacrolimus, mycophenolate mofetil and prednisolone. Having had normal renal function for 3 years after transplantation, he developed uveitis and decline in the graft function. A biopsy of the allograft demonstrated recurrent granulomatous interstitial nephritis. The recurrence of TINU following transplantation suggests a role for circulating autoantibodies in the disease pathology.

Extraperitoneal renal transplantation in small children results in a transient improvement in early graft function.

Renal transplantation is considered more technically challenging in small children compared to adults, especially when live donor adult kidneys are used. Transplanted kidneys have traditionally been placed intraperitoneally, although over the last decade extraperitoneal positioning has been attempted. The aim of this study was to establish whether there is a difference in kidney function and outcome dependent on the surgical approach to transplantation. The medical notes of all children under the age of six who received a renal transplant at our unit between January 1998 and October 2009 were reviewed. Demographic data, operation details, HLA mismatch, immunosuppression regime, complications, and function of the graft were analyzed. A total of 30 transplants were performed in children under six yr of age. The one-yr patient and graft survival were 97% and 93%, respectively. Eighteen were undertaken via an intraperitoneal approach, with the remaining being placed extraperitoneally. There were no significant differences in the number of complications observed between the two groups, and median length of stay was comparable (extraperitoneal 19.5 days vs. intraperitoneal 20.5 days). The plasma creatinine values for the two groups were compared using multivariate linear regression analysis and adjusted for age, weight, gender and baseline plasma creatinine. Between days 2 and 14 post-operatively, there was a significant difference in absolute plasma creatinine between the two surgical approaches. However, the trend of change in mean plasma creatinine values over time did not differ significantly between the two groups. Extraperitoneal kidney transplantation in small children is safe and technically feasible. From our series, there appears to be early improved function, although there is no long-term difference in function between approaches.

Native nephrectomy for autosomal dominant polycystic kidney disease: before or after kidney transplantation?

UNLABELLED: Study Type - Therapy (case series). LEVEL OF EVIDENCE: 4. What's known on the subject? and What does the study add? The indications and timing of native nephrectomy in patients with autosomal dominant polycystic kidney disease (ADPKD) is controversial, especially for those undergoing renal transplantation. Post-transplant unilateral native nephrectomy appears to be the preferred intervention compared to pre-transplant native nephrectomy. There seems to be substantial additive risk to bilateral over unilateral nephrectomy, especially prior to transplantation. Pre-transplant native nephrectomy should only be carried out when there are clear indications such as massive size preventing allograft placement, severe pain, early satiety, recurrent bleeding and infections, or suspected malignancy. OBJECTIVE: To analyse indications, timing and outcomes of native nephrectomy in autosomal dominant polycystic kidney disease (ADPKD) patients listed for kidney transplantation. PATIENTS AND METHODS: A retrospective analysis of all ADPKD patients who had a native nephrectomy prior to or following transplantation between January 2003 and December 2009 at a single centre, including those undergoing the sandwich technique (removal of the most severely affected native kidney prior to transplantation, and the other afterwards), was undertaken. RESULTS: There were 35 individuals in our cohort (M : F = 16 : 19), with a median age of 51.5 years (range 43-65). Twenty patients were in the pre-transplant nephrectomy group, 12 in the post-transplant group, and three underwent the sandwich technique. Indications for nephrectomy varied but were most commonly pain/discomfort, space for transplantation, ongoing haematuria, recurrent infections, and gastrointestinal pressure symptoms (early satiety). Seven individuals in the pre-transplant group and three in the post-transplant group required critical care admission after nephrectomy. Transient renal graft dysfunction occurred in two post-transplant bilateral nephrectomy patients. Two patients in the bilateral nephrectomy pre-transplant group and one in the bilateral nephrectomy post-transplant group died in the immediate post-operative period. No complications were noted in the sandwich technique group. CONCLUSION: Native nephrectomy in ADPKD is a major undertaking associated with significant morbidity especially in the pre-transplant group. Post-transplant unilateral nephrectomy appears to be the safest approach with fewest complications.

Management of transplant renal artery stenosis and its impact on long-term allograft survival: a single-centre experience.

BACKGROUND: Transplant renal artery stenosis (TRAS) is a recognized complication resulting in post-transplant hypertension associated with allograft dysfunction. It is a commonly missed but potentially treatable complication that may present from months to years after transplant surgery. In this retrospective study, we compared management strategies and outcomes of TRAS from 1990 to 2005. METHODS: Case notes of transplant recipients with TRAS demonstrated by angiography were reviewed. Angiography and was carried out when there was a clinical or Doppler ultrasound suspicion of TRAS. The clinical diagnosis of TRAS was based on uncontrolled refractory/new-onset hypertension and/or unexplained graft dysfunction in the absence of another diagnosis, such as rejection, obstruction or infection. The two-tailed Student t-test was used to analyse the differences between mean arterial pressure, serum creatinine, and estimated glomerular filtration rate before and after the intervention. RESULTS: Sixty-seven patients with angiogram-confirmed TRAS were included. Forty-four, 9 and 14 patients were managed with primary percutaneous transluminal renal angioplasty (PTRA), surgical intervention and conservative treatment, respectively. Uncontrolled hypertension was the most common presentation noted in 74.62%. Post-anastamotic single stenosis was the commonest occurrence (n = 53). Angioplasty had the highest 1- and 5-year graft survival rate of 91% and 86%, respectively. The worst prognosis was noted in patients treated with secondary PTRA after failed surgery or secondary surgery after failed primary PTRA. CONCLUSIONS: TRAS is a recognized complication resulting in loss of renal allografts. Early Doppler ultrasound is a good primary diagnostic tool. Early intervention is associated with a good long-term graft function.

Transplantation in adults with primary hyperoxaluria: single unit experience and treatment algorithm.

BACKGROUND: Kidney transplantation alone in Primary Hyperoxaluria is associated with a high rate of recurrence and in many cases early graft loss. Liver transplantation offers the possibility of correcting the metabolic defect. MATERIAL/METHODS: A retrospective review of five cases of Primary Hyperoxaluria managed at a major transplant unit was performed. RESULTS: The 5 patients had a mean age of 32.2 years (range 28-40) at time of first transplantation. 3 patients had kidney only transplants (one live donor, 2 deceased donor) and 2 had segmental liver followed by delayed kidney transplantation. All 3 kidney alone failed and one is now awaiting a live donor transplant, one underwent kidney alone retransplantation (failed 5 years later) and one had a combined deceased donor liver and kidney transplantation (remains well at 4 years). The 2 segmental liver sequential kidney transplant recipients remain well at 1 year and 3 years. CONCLUSIONS: Combined liver-kidney transplantation may be a better choice as the primary transplant procedure. The indication and timing for pre-emptive liver or liver followed by delayed kidney transplantation remains a matter of debate.

Negative pressure wound therapy used to heal complex urinary fistula wounds following renal transplantation into an ileal conduit.

Transplantation into an ileal conduit is an established option for patients with end-stage renal failure and a nonfunctioning urinary tract. Urinary fistulae are more common following these complex transplants. Urinary fistula in this scenario can cause substantial morbidity and even result in graft loss. The management options depend on the viability of the transplant ureter, the level of local sepsis and the overall condition of the patient. Urinary diversion with a nephrostomy and ureteric stents has been described in aiding the healing of urinary leaks in renal transplants into a functioning urinary tract. We describe the successful use of negative wound pressure therapy to eradicate the local sepsis and help the healing of a recurrent urinary fistula following kidney transplantation into an ileal conduit. To our knowledge these are the first such cases reported in the literature.

Noninvasive assessment of hepatic fibrosis and necroinflammatory activity in Egyptian children with chronic hepatitis C virus infection using FibroTest and ActiTest.

BACKGROUND: Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatic fibrosis. Liver biopsy, because of its limitations and risks, might be considered an imperfect gold standard for assessing the severity of chronic liver diseases. In this study, we aimed to prospectively validate FibroTest (FT) and ActiTest (AT) as noninvasive serum biochemical markers for assessment of the degree of hepatic fibrosis and necroinflammatory activity respectively, in pediatric patients with chronic HCV infection and compare them to liver biopsy. METHODS: Fifty patients, aged 2 to 18 years, with chronic HCV infection were prospectively enrolled. Two assessments were carried out, within 24-h duration, one of a liver biopsy specimen and the other FT and AT measured in serum sample. FINDINGS: A highly significant linear trend and correlation were found between FT-related fibrosis and fibrosis stage by METAVIR scoring on histopathological examination. A highly significant correlation was also found between AT and necroinflammatory histological activity using METAVIR as well. The FT area under the receiver operating characteristic curve (AUROC) is 0.97, SE=0.02 which can diagnose patients with mild stage of fibrosis, thus discriminating them from those with no (or minimal) fibrosis. The AT can successfully discriminate between patients with moderate activity and those with mild activity with AUROC=0.93, SE=0.06. CONCLUSION: FT and AT are potential noninvasive methods for assessment of hepatic fibrosis and necroinflammatory activity in pediatric patients with chronic HCV infection in comparison with liver biopsy.

Effect of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation.

Despite the potential tolerability advantage of enteric-coated mycophenolate sodium (EC-MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC-MPS permits mycophenolic acid dose to be increased or gastrointestinal side-effects to be ameliorated. In a randomized, multicenter, open-label trial, kidney transplant recipients experiencing gastrointestinal side-effects either remained on MMF or switched to an equimolar dose of EC-MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC-MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty-four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC-MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P < 0.001). At the final visit, 50.0% (34/68) of EC-MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients (P = 0.007). Kidney transplant patients receiving reduced-dose MMF because of gastrointestinal side-effects can tolerate a significant increase in MPA dose after conversion to EC-MPS. Patient-reported gastrointestinal outcomes with higher doses of EC-MPS remained at least as good as in MMF-treated controls.

Outcome of pancreas transplantation in recipients older than 50 years: a single-centre experience.

BACKGROUND: Pancreas transplantation (PT) remains the only treatment that can restore insulin independence among insulin-dependent diabetics. An ageing population in developed countries has led to an increasing number of older patients who may be suitable for PT. Some investigators argue that PT in recipients older than 50 years has an inferior outcome compared with the younger group. METHODS: The object of this study was to compare the outcomes of 31 PT in patients aged 50 and above 105 PT in recipients below 50 years performed between June 2001 and December 2007. RESULTS: The incidence of general posttransplant complications were similar in both; 60% in less than 50 vs. 58% in more than or equal to 50, P=0.539. So, as the incidence of other surgical complication in the more than or equal to 50 group compared with less than 50 (graft thrombosis 13% vs. 11.5%; bleeding 19% vs. 6.7%; abdominal abscess 23% vs. 19%; pancreatic leak 13% vs. 9.6%). There was no significant difference in the incidence of urinary tract infection and early rejection in either group. However, the incidence of respiratory tract infection was significantly higher in more than or equal to 50 (38.7% in >or=50 vs. 9.6% in <50, P=0.003). One-year patient survival was 88% in more than or equal to 50 vs. 92% in less than 50 group, P=0.399; and pancreas graft survival rate was similar (79% in the >or=50 and 74% in <50, P=0.399). CONCLUSION: This study demonstrates that it is feasible to safely transplant potential PT recipients aged 50 and above. However, good medical assessment and careful patient selection is strongly recommended.

Successful renal transplantation in children in the presence of thrombosis of the inferior vena cava.

Thrombosis of the inferior vena cava (IVC) has previously been considered to be a contraindication to renal transplantation in children because of the technical difficulties associated with surgery and the increased risk of graft thrombosis. We report three children with previous IVC thrombosis who underwent renal transplantation at our institution over the last 5 years. The pretransplant imaging of these patients included direct venography or magnetic resonance venography to evaluate venous outflow. Two children (19 kg and 36 kg) received deceased donor renal allografts with no surgical complications or delayed graft function. At the latest follow-up 3.0 and 4.6 years posttransplantation, respectively, they were well, with estimated glomerular filtration rates of 52 and 64 ml/min per 1.73 m(2), respectively. The third child underwent a live-related-donor renal transplant at the age of 4.9 years (weight 13.5 kg). There was primary graft nonfunction. Renal vein thrombosis was noted on postoperative day 12, with subsequent graft loss. Children with previous IVC thrombosis can be successfully transplanted with adult-sized kidneys provided detailed evaluation of the venous drainage has been performed. There is substantial risk of graft thrombosis, and detailed counselling regarding the specific risks of the procedure is essential.

Factors influencing glomerular filtration rate in renal transplantation after cyclosporine withdrawal using sirolimus-based therapy: a multivariate analysis of results at five years.

Changes in calculated glomerular filtration rate (GFR) from baseline to five yr were analyzed in relation to risk factors among renal transplant recipients. At three months after transplantation (baseline), 430 eligible patients receiving sirolimus (SRL), cyclosporine (CsA), and steroids (ST) were randomly assigned (1:1) to continue SRL-CsA-ST or have CsA withdrawn and SRL trough levels increased (SRL-ST group). For each risk factor, changes from baseline were compared within each treatment using a t-test and between treatments using ANCOVA. Univariate then multivariate robust linear regression analyses were also performed. In the SRL-ST group, changes from baseline were not significantly different for any risk factor. With the exception of cold ischemia time >24 h, GFR values declined significantly for all risk factors in SRL-CsA-ST patients. For all risk factors, except second transplant or cold ischemia time >24 h, renal function was significantly different between groups. By order of significance in the multivariate analysis, treatment (p < 0.001), donor age (p < 0.001), proteinuria (p < 0.001), and biopsy-confirmed rejection (p = 0.010) were significant predictors of GFR change from baseline. In conclusion, patients with risk factors for reduced renal function benefit from SRL maintenance therapy without CsA vs. those remaining on CsA.

Impact of changing trend in cold ischaemic time on operating times in renal transplantation.

INTRODUCTION: The European Working Time Directive (EWTD) is calling for reduction in the working hours of doctors. Renal transplantation is well-recognised as an out-of-hours specialty. Our study looks at whether our renal transplant centre's attempt to reduce cold ischaemic time (CIT) has impacted on the pattern of operating times since this may have implications on the surgeons' working hours. PATIENTS AND METHODS: We studied 883 adult cadaver kidney transplants performed between 1 January 1992 and 31 December 2002. CIT and time of surgery was obtained from a local audit database () and that held by UK Transplant. Time of surgery was divided into 07:30-17:59 (day),18:00-23:59 (evening) and 00:00-07:29 (night). RESULTS: CIT has decreased since 1992, with a significant reduction after 1998 (P = 0.0001). There was, however, no difference in the percentage of operations performed during the three time periods before and after 1998. Between 1999-2002, 51.4% of transplants took place out of hours (i.e. 18:00-07:29). CONCLUSIONS: Reduction in CIT does not appear to have impacted on our operating times. The large amount of out-of-hours work is, however, not compliant with EWTD requirements.

Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end-stage renal failure.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). It is characterized by a progressive, intra-abdominal, inflammatory process resulting in sheets of fibrous tissue that cover, bind, and constrict the viscera, thereby compromising the motility and function of the bowel. Although recent therapeutic approaches have been reported with variable success, the ability to detect reliably at an early stage patients at risk for EPS would be beneficial and allow treatment standardization. The aim of this study was to evaluate the clinical features of EPS and identify possible risk factors for its development in CAPD and APD patients. METHODS: This was a review of all cases of EPS in a single center over the last 5 years. RESULTS: There were 810 CAPD and APD patients, managed in our program over this period. We identified 27 cases of EPS, giving an overall of 3.3% in this population. The mean duration of CAPD before diagnosis of EPS was 72.6 +/- 39.7 months (range 16-172). Sixteen cases required surgical treatment and were classified as severe; others were treated conservatively (mild to moderate group). Ten patients received tamoxifen treatment with apparent benefit. The overall mortality rate was 29.6%. Eight patients from the severe group and the entire moderate group survived on hemodialysis or transplantation at 48.71 and 27.63 months follow-up, respectively. Peritonitis rates were not different between the 2 groups and peritoneal history was unremarkable compared to overall peritonitis rates in the unit. Data on small solute transport were not available in all patients in this retrospective analysis. CONCLUSION: EPS is a serious, life-threatening complication of CAPD. Most cases had PD duration of more than 4 years. Careful monitoring by CT scans of the peritoneal membrane in patients beyond 5 years, and early catheter removal in patients with peritoneal thickening should be considered for long-term CAPD patients. Treatment with tamoxifen may be of benefit in these patients.

Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: the "creeping creatinine" study.

BACKGROUND: This study determined whether cyclosporine A (CsA)-treated renal allograft recipients with deteriorating renal function ("creeping creatinine") secondary to chronic allograft nephropathy (CAN) benefit from the addition of mycophenolate mofetil (MMF) to their immunosuppressive regimen, followed by withdrawal of CsA. METHODS: In a controlled, open, multicenter study, CsA-treated renal allograft recipients with progressively deteriorating renal function were randomized to have their CsA discontinued with the concomitant addition of MMF to their regimen (group A) or to continue treatment with CsA (group B). The primary endpoint was the response rate over the 6-month period after withdrawal of CsA in group A or the equivalent time in group B. Response was defined as a stabilization or reduction of serum creatinine (SCr), as evidenced by a flattening or positive slope of the 1/SCr plot and no graft loss. Secondary endpoints included the incidence of acute rejection, graft and patient survival, and changes in selected metabolic parameters. RESULTS: The response rate in the primary intent-to-treat population (n=122) was 58% (36/62) in group A versus 32% (19/60) in group B (P=0.0060). The corresponding percentages of responders in the per-protocol population (n=107) were 60% (36/60) and 26% (12/47), respectively (P=0.0008). There were no acute rejections in group A during the study period. Patients in this group also experienced a significant decrease in total cholesterol. CONCLUSIONS: In patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.

Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients.

Cyclosporine (CsA) is a critical-dose drug for which a minor change in absorption can have important clinical implications. Generic formulations of CsA are becoming more widely available, but standard criteria for bioequivalence require only that a single study in healthy volunteers demonstrate that mean pharmacokinetic parameters fall within 80-125% of the mean values for Neoral, the reference formulation of CsA. However, CsA absorption is known to differ between healthy volunteers and transplant patients and between different types of transplant patients, such that standard bioequivalence testing may be inadequate to ensure interchangeability of CsA formulations in all patients. The limited available clinical evidence has shown that stable renal transplant patients receiving Neoral have a significant reduction in mean CsA trough level after transfer to the Cicloral formulation. Mean pharmacokinetic values have been reported as equivalent following transfer to Gengraft in one study, but mean CsA trough fell and mean serum creatinine rose significantly in a separate trial. The only clinical outcomes data available are from a retrospective study of de novo renal transplant patients, which reported a significantly higher incidence of biopsy-proven acute rejection in patents receiving Gengraf versus Neoral (39% versus 25%, P<0.05). Until robust clinical data demonstrate that different formulations of CsA are interchangeable, it is advisable to prescribe CsA by brand, and any transfer to a different CsA formulation should be undertaken with close supervision and only at the direction of the transplant physician.

Cold ischemia time, surgeon, time of day, and surgical complications.

BACKGROUND: Surgical factors are an important cause of early renal allograft loss and contribute to patient morbidity and mortality. The United Kingdom National Confidential Enquiry into Peri-operative Deaths has reported that operating out of normal working hours was associated with higher patient mortality because of inexperienced surgeons. In this study, we looked into whether operating outside normal working hours or the grade of the surgeon affected the incidence of surgical complications. We also examined the relationship between cold ischemic time (CIT) and likelihood of surgical complications. PATIENTS AND METHODS: We performed a retrospective review of 322 adult recipients who received their first cadaver kidney transplant in our center between January 1, 1998 and June 30, 2001. Information on surgical complications were collected from patients' records. CIT, time of surgery, and grade of the operating surgeons was obtained from a local audit database (www.nwkta.org.) and the database held by UK Transplant. RESULTS: Surgical complication(s) were less likely to occur if one of the surgeons was a consultant (P =0.002). We found no association between cold storage and incidence of surgical complication(s). The median CIT was 21.30 (range 3.3-43.5) hours, n=229, in the group without complications compared with 21.80 (8.8-47.9) hours, n=77, for those with complications. The incidence of surgical complications was the same regardless of whether the operation took place during the day, evening, or night. CONCLUSIONS: Prolonged CIT and operating out of normal working hours did not increase the incidence of surgical complications. Presence of a consultant did, however, reduce the likelihood of a surgical complication occurring.

Complete necrosis of allograft ureter after cadaveric renal transplantation.

Complete necrosis of a transplant ureter is a rare complication that needs to be considered early in cases of severe graft dysfunction if successful surgical intervention and restoration of graft function is to be achieved. We report on two cases of this complication occurring in children and discuss the surgical management. Surgical exploration of grafts where there is an early sudden decline in function is imperative as routine imaging will not exclude this potentially treatable problem.