The management and outcome of propionic and methylmalonic acidaemia

The management of the severe variants of methylmalonic and propionic acidaemia remains difficult. With conventional therapy of diet, carnitine and antibiotics, mortality is high and long-term complications are common. Liver transplantation appears to be an important alternative.     

The kidney in children with tyrosinemia: sonographic, CT and biochemical findings

BACKGROUND: Tyrosinemia relates to a deficiency of fumarylacetoacetate hydrolase and presents early in life with central nervous system and liver abnormalities. Renal function is often impaired. Little is known about the architecture and function of the kidneys. OBJECTIVE: Imaging changes on US and CT are compared to the function of the kidneys in children with tyrosinemia, and followed after liver transplantation. MATERIALS AND METHODS: Renal sonography, CT and renal function tests in 32 children were reviewed. Renal length, volume, echogenicity and nephrocalcinosis were evaluated. Renal function was assessed by glomerular filtration rate, and the presence of aminoaciduria, acidosis and calciuria. Seventeen children had open renal biopsy during time of liver transplantation. Histology was reviewed. Statistical analyses relating renal structure to function were performed, and repeated after transplantation. RESULTS: The kidneys were enlarged (47 %), hyperechogenic (47 %) and showed nephrocalcinosis (16 %). There was delayed excretion of contrast medium at CT in 64 %. Aminoaciduria was present in 82 % of children, hypercalciuria in 67 %, tubular acidosis in 59 %, and low GFR in 48 %. Delayed excretion of contrast was associated with low GFR (P < 0.05). Renal biopsies showed dilated tubules (81 %), interstitial fibrosis (56 %), glomerulosclerosis (56 %) and tubular atrophy (56 %). During a mean observation period of 3 years following liver transplantation, GFR improved in 50 %, tubular acidosis in 50 % and hypercalciuria in 70 %. No change was noted in renal size or sonographic architecture. CONCLUSION: Renal architecture and function are abnormal in the majority of children with tyrosinemia. Liver transplantation improves renal function in about 50 % of patients, but abnormal renal size and architecture persist.     

An electroencephalographic study of disorders of amino-acid metabolism during the first days of life (author's transl)

The authors have attempted a systematic E.E.G. study in 32 neonates suffering from disorders of amino-acid metabolism, during the first days of life. These consisted of cases with ketosis (13 cases of leucinosis, 5 methylmalonic acidaemia, isovaleric acidaemia and 3 with hyperlactacidaemia) and cases without ketosis (6 cases of hyperglycinaemia and 3 with congenital hyperammonaemia). A study of the E.E.G. showed some characteristic features, the most typical of which were: -a periodic tracing with large sharps complexes intermingled with less active periods occurring in every case of hyperglycinaemia without ketosis, in 2 cases of leucinosis and 2 cases of methylmalonic acidaemia. This record indicates a poor prognosis. -a less stereotyped periodic tracing with variable evolution. -distinctive figures characterised by rapid Rolandic rhythms always found in cases of leucinosis compared with sharp spindles (between the 10th and 30th day). It is concluded that the E.E.G. patterns are not in close correlation with the anatomical lesions.     

Advances in the clinical management of pediatric kidney transplantation

Renal transplantation is the best form of renal replacement therapy for children reaching end-stage renal failure. The first human transplantation was performed by Dr. Voronoy from a cadaver donor in 1933; however, because of the lack of immunological laboratory assessments, this transplantation resulted in rejection. Progress in immunological evaluation and new immunosuppressive drugs have improved survival in renal transplantation. The first renal transplantation in Turkey was performed by Dr. Haberal et al. on November 3, 1975. This child was one of five siblings with juvenile nephronophytisis, and the mother was the donor. Dr. Haberal has thus pioneered renal transplantation in Turkey. In the following years Dr. Haberal initiated cadavral transplantation in our country in collaboration with Eurotransplant. He has also contributed to the law concerning transplantation in Turkey. Subsequently many transplantation centers have been developed in the country. In spite of marked progress in transplantation technology, pediatric transplantation has not improved as fast as adult transplantation. This is due to several factors, such as the difference in the etiological factors leading to chronic renal failure, technical factors, growth and sexual development, factors relevant to infections and vaccinations, and psychological problems.     

Truncation of betaA3/A1-crystallin during aging of the bovine lens; possible implications for lens optical quality

Recurrent infections are common features in patients affected by propionic acidaemia (McKusick 232000) and methylmalonic acidaemia (McKusick 251000). Since these disorders are biochemically characterized by tissue accumulation of propionic acid and methylmalonic acid respectively, it is possible that these compounds may act as immunosuppressants. We therefore investigated the effect of propionate and methylmalonate on cellular growth of human peripheral lymphocytes stimulated in vitro by phytohaemagglutinin, concanavalin A and pokeweed mitogen, a recognized test of cellular immunocompetence. Lymphocytes were cultured in flat-bottomed 96-well microplates at 37 degrees C for 96 h (phytohaemagglutinin and concanavalin A) or 144 h (pokeweed mitogen) in the presence of one mitogen at different concentrations and of one acid added at doses of 1.0, 2.5 or 5.0 mM. Cell blastogenesis was measured by the incorporation of tritiated thymidine into cellular DNA and compared with that of identical cultures with no acid added (controls). A consistent and progressive inhibitory effect of propionic acid with increasing concentrations in culture was identified with all mitogens and was more pronounced with pokeweed mitogen. Lymphocyte blastogenesis was not altered in the presence of methylmalonic acid. The effect of propionate was observed only when the drug was added at the beginning (phytohaemagglutinin-activated) or until 24 h (concanavalin A- and pokeweed mitogen-activated) of culture. The viability of lymphocytes after treatment with the drug, as assessed by the Trypan Blue exclusion test, revealed no change when compared with the same untreated lymphocytes, indicating no lymphocytotoxic activity. In conclusion, propionic acid, which accumulates in tissues of patients with propionic acidaemia, causes 'in vitro' immunosuppression, which may be related to the recurrent infections characteristic of these patients.     

The in vitro effect of vitamin D3 analogue EB-1089 on a human prostate cancer cell line (PC-3)

OBJECTIVES: To assess the impact of augmentation ureterocystoplasty on the success of cadaveric renal transplantation in children with dysfunctional bladders. METHODS: Two patients with end-stage renal failure secondary to dysfunctional bladders (one myelodysplasia and one posterior urethral valves) underwent augmentation ureterocystoplasty prior to renal transplantation in order to increase bladder capacity and improve compliance. RESULTS: Significant improvement of bladder storage function was achieved in both patients. By the use of megaureter for augmentation, untoward sequelae of enteric or gastric augmentation were obviated. Renal transplantation was successful in both patients. Both have normal renal function 4 and 3 years after transplantation. CONCLUSIONS: Renal transplantation into bladders previously augmented with megaureters is successful. The use of urothelial-lined biomaterial for augmentation avoids the potential complications of gastro- or enterocystoplasty, which are especially dangerous in transplant patients.     

Evaluation of the pediatric renal transplant recipient

Renal transplantation is the preferred therapy for children with end stage renal disease. A functioning renal allograft can dramatically improve a child's quality of life. Advances in immunosuppressive therapy and clinical practice approaches have significantly improved graft survival rates allowing children to attain near normal growth and development. Accurate assessment and appropriate nursing care enhances long-term survival of these young patients.     

Posterior urethral valves: long-term renal function consequences after transplantation

PURPOSE: We assessed the long-term efficacy of renal transplantation in children with posterior urethral valves. MATERIALS AND METHODS: We retrospectively compared the outcomes of renal transplantation in 66 children with posterior urethral valves and 116 with malformation uropathies (controls). RESULTS: Graft survival in the posterior urethral valves and control groups was 69 and 72% at 5 years, and 54 and 50% at 10 years, respectively (not statistically significant). A statistically significant increase in serum creatinine was noted at 10 years in children with posterior urethral valves but not in controls (p < 0.05). CONCLUSIONS: Renal transplantation in children with posterior urethral valves is not associated with a high rate of failure. However, long-term deterioration of graft function is likely related to lower urinary tract dysfunction.     

Reversible brainstem auditory evoked potential abnormalities in jaundiced Gunn rats given sulfonamide

Renal transplantation therapy performed for amyloid nephropathy is controversial because of the fatal effects of the disease. Amyloidosis is a relatively frequent disease and is generally associated with familial Mediterranean fever (FMF) in Turkey. Renal transplantation in the treatment of amyloid nephropathy started in January 1985. Till now, 18 (3.2%) renal transplantations have been performed on patients who had amyloid nephropathy. The mean follow-up period was 34.6 months. Fourteen renal grafts still function well (creatinine: 1-3.2 mg/dL). The overall 1-year patient and graft survival rates were 88.9% and 83.0%, respectively. These rates are not statistically different from renal transplantations done for other cases of renal failure. Therefore, patients with end-stage renal failure due to amyloidosis can be considered as appropriate candidates for renal transplantation.     

Distortion of size perception in visuospatial neglect

Renal osteodystrophy improves after renal transplantation but, after the procedure, other forms of bone disease emerge. We report a male patient that received a renal allograft four years before, who consulted for low back pain secondary to multiple vertebral compression fractures. The patient had good renal function, a parathormone independent hyperphosphaturia, normal 25-OH cholecalciferol, increased urinary hydroxyproline, decreased osteocalcin, reduced bone density and a bone biopsy revealing osteomalacia. The diagnosis of hypophosphatemic osteomalacia was reached and treatment with phosphates and ergocalciferol was started but, despite this, the patient suffered a new fracture two years later. Two mechanisms can produce hypophosphatemia after a renal transplantation: a parathormone excess due to the previous renal failure, that disappears during the first year after the transplantation or a derangement in renal phosphate transport that can be due to a generalized proximal tubule solute transport derangement (Fanconi syndrome), parathormone hypersensitivity or to an "idiopathic" hyperphosphaturia. Despite a good treatment, bone mass is not recovered and there is a high fracture risk. Mineral metabolism must be closely monitored after a renal allograft and its alterations must be quickly treated.     

Renal transplantation in patients with renal cell carcinoma and von Hippel-Lindau disease

This study reviewed the management and outcome of patients with von Hippel-Lindau disease (VHLD) who underwent renal transplantation after being rendered anephric to treat multifocal bilateral renal cell carcinoma (RCC). Five patients with bilateral RCC and VHLD underwent renal transplantation at our hospital. Initial treatment of RCC consisted of bilateral nephrectomy in 2 patients and unilateral nephron-sparing surgery with contralateral nephrectomy in 3 patients. All of the latter 3 patients experienced isolated tumor recurrence in the renal remnant at 48, 64, and 66 months postoperatively; this was managed by complete excision of the renal remnant. Renal transplantation was performed 11 to 24 months after initiation of dialysis. Postoperatively, all of the allografts functioned well with no further requirement for dialysis. Currently, 4 patients are alive at a mean post-transplant follow-up interval of 26 months (range, 7 to 66 months) with excellent graft function and no evidence of malignancy. One patient died 17 months following transplantation due to metastatic disease. Renal transplantation can provide satisfactory replacement therapy for patients with end-stage renal disease with VHLD and treated RCC.     

Torsion of intraperitoneal renal transplants: imaging appearances

OBJECTIVE: Torsion of a renal transplant is a rare complication with nonspecific clinical manifestations. Prompt detection is necessary to allow surgical treatment and to preserve renal function. We describe the radiologic appearances of torsion of intraperitoneal renal transplants in patients who have undergone simultaneous renal and pancreatic transplantation or dual renal transplantation. CONCLUSION: Renal transplant torsion should be suspected when a change in renal axis associated with abnormal perfusion occurs in an intraperitoneal kidney.     

Protective effect of N-acetyl-L-cysteine on the renal failure induced by inferior vena cava occlusion

BACKGROUND: Renal ischemia is produced during orthotopic liver transplantation when the inferior vena cava is clamped above the renal veins (inferior vena cava occlusion [IVCO]), and it often leads to postoperative renal failure. Although free radicals and nitric oxide (NO) have been implicated in the pathogenesis of ischemic renal failure, the effect of free radical scavengers in this model is unknown. METHODS: The effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, on the acute renal failure that follows IVCO were evaluated in pentobarbital-anesthetized dogs. The effect of NO synthesis inhibition with NG-nitro-L-arginine methyl ester (NAME) was also studied. Renal vascular endothelial function was tested by infusing acetylcholine (Ach) into the renal artery before the ischemia and during reperfusion. RESULTS: Renal failure developed during IVCO and persisted during reperfusion in all groups. However, in NAC-pretreated dogs, the glomerular filtration rate recovered progressively, reaching 31% of basal preischemic values 150 min after reperfusion. During reperfusion, fractional excretion of sodium increased above preischemic values only in the control group, which indicates a beneficial effect of NAC and NAME on the tubular dysfunction observed during reperfusion. The renal response to Ach was abolished in control dogs and in animals given NAME during reperfusion, which indicates endothelial dysfunction. However, in NAC-pretreated dogs, the renal response to Ach was preserved during reperfusion. CONCLUSIONS: These results demonstrate that NAC ameliorates the renal failure and renal endothelial dysfunction induced by IVCO. This protective effect was abolished by NAME, which suggests that NO is involved in the beneficial effects of NAC. These data also suggest that the use of NAC could be beneficial in ameliorating the acute renal failure observed after orthotopic liver transplantation.     

Renal artery angioplasty for renovascular hypertension and preservation of renal function: long-term angiographic and clinical follow-up

OBJECTIVE: Percutaneous transluminal angioplasty of stenoses of the renal artery can be used to treat hypertension and renal insufficiency. Although many studies have been published on the short-term results of this procedure, few long-term studies are available. SUBJECTS AND METHODS: One hundred ninety-five patients (123 men and 72 women 19-79 years old; mean age, 56 years) with stenosis of the renal artery and hypertension underwent renal percutaneous transluminal angioplasty at our institution. The stenosis was unilateral in 66% of patients, bilateral in 26%, and in a solitary functioning kidney in 8%. Renal insufficiency was present in 31% of patients. After renal percutaneous transluminal angioplasty, long-term clinical and angiographic follow-up was evaluated by life-table analysis. RESULTS: In patients with fibromuscular disease, blood pressure returned to normal in 57%, improved in 21%, and was unchanged in 21%. In patients with atherosclerotic stenosis, blood pressure returned to normal in 12%, improved in 51%, and was unchanged in 37%. After percutaneous transluminal angioplasty, renal function improved in 48% of patients with renal insufficiency due to bilateral stenosis or stenosis in the single functioning kidney, whereas none of the patients with unilateral stenosis of renal artery and renal insufficiency had any notable improvement. Long-term follow-up showed a high rate (82%) of patency of revascularized arteries and a low rate (21%) of hypertension recurrence at 5 years. CONCLUSION: Renal percutaneous transluminal angioplasty is useful for treating hypertension and for reestablishing renal function. Its effects on blood pressure and renal function are long-lasting in the large majority of patients.     

Renal replacement therapy in multiple myeloma and systemic amyloidosis

Renal failure frequently complicates both multiple myeloma and systemic amyloidosis. Renal replacement therapy (RRT) may be poorly tolerated and its role in such patients is not clearly defined. Of fifty patients (26 males and 24 females) referred to a single centre because of renal failure associated with multiple myeloma or systemic amyloidosis 37 progressed to end-stage renal failure and 30 of these patients received RRT. Nine patients have been treated by CAPD, 13 by haemodialysis, and 8 patients have required both forms of dialysis. Overall one year and two year survival rates were 66% and 57% respectively. The median duration on RRT was 7.5 months (range 1-96 months) with a 51% one year, and a 46% two year survival rate. Of 7 patients with amyloidosis who underwent renal transplantation, 3 died within 6 months of transplantation. Undiagnosed cardiac involvement contributed to this early mortality. We conclude that renal replacement therapy is appropriate for some patients with multiple myeloma and systemic amyloidosis who develop endstage renal failure. Careful assessment and selection of patients is necessary prior to renal transplantation.     

Patients surviving more than 10 years on haemodialysis. The natural history of the complications of treatment

BACKGROUND: The purpose of this survey was to describe the natural history of complications in 52 long-surviving haemodialysis patients to obtain a clearer picture of the impact these patients have on the dialysis population. This is important as they are often no longer suitable for transplantation and therefore are destined to remain on dialysis for the rest of their lives. METHODS: The patients who survived for more than 10 years on haemodialysis alone were studied. Information was obtained from patients' records and from the renal unit computer. RESULTS: Mean age at start of dialysis was 43 years and mean duration of HD 14.5 years. Renal failure was most commonly due to polycystic kidney disease or glomerulonephritis. Sixty-two per cent of patients developed cardiovascular disease, 78% complained of joint pains, 72% had a parathyroidectomy, and 50% developed carpal-tunnel syndrome. Two hundred and forty-five episodes of infection were recorded, 41% related to vascular access acquired in hospital or on immunosuppression. Only three infections occurred which could be described as opportunistic. Twelve patients were hepatitis C positive. In the 37 patients who have died, cardiovascular disease was the most common cause of death. Compared to other patients who started on dialysis before 1986 but who had a successful transplant the survival of patients on haemodialysis is much worse. CONCLUSION: Long-term survival on renal replacement therapy is dependent on successful transplantation. Complications, morbidity, and mortality are high after 10 years of dialysis.     

Hepatorenal syndrome

The hepatorenal syndrome is a severe and common complication of patients with advanced cirrhosis and ascites. It is characterised not only by renal failure but also by marked alterations in systemic haemodynamics. Renal failure is due to a marked hypoperfusion of the kidney secondary to renal vasoconstriction. Although the pathogenesis of hepatorenal syndrome is not completely understood, it is thought to be the extreme manifestation of the underfilling of the arterial circulation secondary to an arterial vasodilation, located mainly in the splanchnic circulation. Recently, a revised definition and diagnostic criteria of hepatorenal syndrome have been proposed. The prognosis of patients with hepatorenal syndrome is very poor. Liver transplantation is the only effective treatment but it is not applicable in most cases due to short survival. New therapies developed during the last years, such as the use of systemic vasoconstrictors or transjugular intra-hepatic portosystemic shunts appear to be promising, but prospective investigations are needed to delineate their real usefulness.     

Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus

Sirolimus (Rapamune; Wyeth-Ayerst, Philadelphia, PA) is a newer immunosuppressive drug with no known acute or chronic nephrotoxic effects; however, limited data are available in liver transplant recipients. We prospectively evaluated changes in renal function in liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus monotherapy. We measured serial serum creatinine levels in liver transplant recipients with chronic nephrotoxicity caused by calcineurin inhibitors before and after conversion to sirolimus therapy. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease formula. Change in eGFR over time, incidence of acute hepatocellular rejection, and adverse events while being administered sirolimus monotherapy were recorded. Mean interval between liver transplantation and initiation of sirolimus therapy was 310 weeks (range, 9 to 780 weeks). Of 21 patients included in our study, 18 patients were converted to sirolimus monotherapy and 3 patients were switched to sirolimus and low-dose steroid therapy. Patients were followed up for a mean of 66.8 +/- 38.9 (SD) weeks after conversion. Renal function improved in 71% of patients (15 of 21 patients). Median eGFR improved significantly from 34 mL/min/1.73 m2 at the time of conversion to 43 mL/min/1.73 m2 at the last follow-up (27% increase in eGFR; P = 001). Median monthly change in eGFR was from -0.25 mL/min/1.73 m2 pre-sirolimus therapy to +1.28 mL/min/1.73 m2 post-sirolimus therapy (P =.09). Adverse events were mostly mild and self-limited. Only 1 patient developed biopsy-proven acute cellular rejection, which was treated with sirolimus and mycophenolate mofetil. Two patients discontinued sirolimus therapy because of toxicity (oral ulceration, 1 patient; interstitial pneumonitis, 1 patient). Renal function improved significantly in the majority of liver transplant recipients with renal insufficiency caused by calcineurin inhibitors when converted to sirolimus therapy. Sirolimus monotherapy provided adequate immunosuppression with a low incidence of acute cellular rejection and minimal adverse events.     

Capillaries with fenestrations around regenerating muscle fibers in the soleus muscle of the dystrophic (dy) mouse

A 65-year-old woman developed nephrotic syndrome 7 years after receiving a cadaveric renal allograft. Renal biopsy and clinical laboratory evaluation revealed the underlying disease process to be AL amyloidosis. To our knowledge, this is the first reported case of de novo AL amyloid occurring in a renal allograft.     

Renal hemodynamics after lung transplantation. A prospective study

Renal function impairment is common after solid organ transplantation, due to the nephrotoxicity of cyclosporine. Moreover, in patients with severe respiratory failure, renal function is often impaired. This renal function impairment may predispose patients to further renal function impairment after lung transplantation. Therefore, renal hemodynamics were measured in 44 patients before lung transplantation and 1, 6, 12, 18, 24, and 30 months after transplantation. After transplantation, a decline in renal function occurred, with a progressive fall in glomerular filtration rate (GFR) of 33 +/- 4% at 12 months and 42 +/- 9% at 30 months. Effective renal blood flow fell by 22 +/- 5% at 12 months and remained stable thereafter. Changes in effective renal plasma flow (ERPF) were less pronounced than those of effective renal blood flow, due to a fall in hematocrit after transplantation. Blood pressure and renal vascular resistance increased significantly, consistent with the effects of cyclosporine. Prior to transplantation, renal function impairment with intense renal vasoconstriction had been found in a subset of the patients. Remarkably, the decrease in renal function after transplantation was less pronounced in patients with renal function impairment prior to transplantation, as indicated by significant negative correlations between pretransplantation GFR and the percentage change in GFR after transplantation, and pretransplantation ERPF and the percentage change in ERPF after transplantation. This suggests that the net course of renal hemodynamics after lung transplantation is the result of the opposed effects of cyclosporine nephrotoxicity and the favorable effects of the normalization of respiratory status. In conclusion, after lung transplantation a decline in renal function occurs that is less pronounced in patients with renal function impairment and intense renal vasoconstriction prior to transplantation. Such a renal function impairment, therefore, should not be considered a contraindication to lung transplantation.