The challenge of renal function in heart transplant children

Renal dysfunction may occur after pediatric heart transplantation and impacts on long-term prognosis. This study aims to review the incidence and mechanisms of chronic nephropathy following heart transplantation, and suggest therapeutic directions. The proportion of pediatric heart-transplant recipients with impaired renal function varies from 22 to 57%, and end-stage renal failure from 3 to 10%, depending on the method used for estimating the glomerular filtration rate. The pathophysiology of renal dysfunction is in part due to calcineurin inhibitor-induced renal vasoconstriction, through activation of the intrarenal renin-angiotensin system, TGF-β1 upregulation and TGF-β1 gene polymorphisms. Overproduction of angiotensin II, associated with angiotensin-converting-enzyme genotype, might be associated with poor prognosis and pharmacological factor gene polymorphisms, and may contribute to variation of calcineurine inhibitor exposure in the kidney. Strategies to prevent renal dysfunction include reducing calcineurine inhibitor exposure or delaying calcineurine inhibitor administration from the early post-transplant period. Calcium channel blockers and angiotensin-converting-enzyme inhibitors, blockade of angiotensin II, or anti-TGF-β1 antibodies might limit nephrotoxicity. No accurate marker can predict the potential of renal lesions to develop. Lowering calcineurine inhibitors levels with immunosuppressive agents that are either less nephrotoxic or non-nephrotoxic should be formally studied. Of high interest is the impact of genetic polymorphism on the development of renal dysfunction.     

Fatal cytomegalovirus disease in a high-risk renal transplant recipient

The incidence of CMV infection in pediatric renal transplant recipients has increased as immunosuppression levels deepen following the use of newer immunosuppressive agents. It has been thought that 3–5 months of anti-CMV prophylaxis offers sufficient protection for these patients. We present a case of late-onset fatal CMV disease in a pediatric renal transplant recipient who received prolonged anti-CMV prophylaxis while on ”quadruple” immunosuppression with daclizumab, mycophenolate, tacrolimus, and prednisone. Our case has prompted us to reassess CMV surveillance, prophylaxis, and immunosuppression levels in our pediatric renal transplant patients. Received: 11 February 2000 / Revised: 19 July 2000 / Accepted: 27 July 2000     

Non-steroidal anti-inflammatory drug-associated nephrotoxicity in Bartter syndrome

We have followed four patients with Bartter syndrome for a mean of 25.4 years (range 21.5–28.8 years) after diagnosis. All patients received non-steroidal anti-inflammatory drugs (NSAID). In all patients, various degrees of renal dysfunction were noted to be temporally associated with NSAID therapy. In two patients, renal dysfunction resolved after discontinuing NSAID therapy, while maintaining other chronic medications such as potassium-sparing diuretics. Renal dysfunction persisted after NSAID withdrawal in two patients. We report these cases as a warning that NSAID should be considered an important cause of either reversible or irreversible renal dysfunction in Bartter syndrome. Received December 2, 1997; received in revised form May 27, 1998; accepted May 29, 1998     

Enterohemorrhagic Escherichia coli infections: following transmission routes

Infections with enterohemorrhagic Escherichia coli (EHEC) are the major cause of hemolytic-uremic syndrome (HUS ), the most-common cause of acute renal failure in childhood. The mortality rate of HUS (0%–5% in most recent series and 10%–30% in individual reports) and residual chronic renal sequelae (in up to 50% of patients in long-term follow-up studies) emphasize the seriousness of HUS for public health. Several studies have described possible sources of EHEC infection. However, in the majority of cases the pathogen cannot be identified in food or animals and the routes of transmission remain unclear. In this review article the hypothesized routes of transmission are summarized. The medical data bases ”Medline” and ”Current contents” were screened for the years January 1966 through November 1998. The difficulties in following the chain of EHEC infection are discussed. A precise evaluation of the environmental aspects of the patient is a precondition for further analysis. Received: 11 September 1997 / Revised: 4 January 1999 / Accepted: 15 February 1999     

Yield of renal arteriography in the evaluation of pediatric hypertension

The prevalence of renovascular disease is estimated to be 3%–5% in pediatric patients with hypertension. The utility of non-invasive imaging tests has not been evaluated in children, and renal arteriography remains the diagnostic test of choice. However, there are no established guidelines for the application of this test and information is not available about the likelihood of detecting an abnormality if an arteriogram is performed in children with hypertension. Therefore, we reviewed the yield of renal arteriography in pediatric patients if the test was performed based on the following two criteria: (1) severe hypertension exceeding the 99th percentile for age and sex or (2) failure to control high blood pressure with one antihypertensive drug. During the period 1983–1998, 28 children (mean age 11.7 years) who satisfied one of the above criteria underwent renal arteriography to investigate hypertension. None of the patients were renal transplant recipients. The average duration of hypertension was 11 months and the peak blood pressure was 168/107 mmHg. The renal arteriogram was abnormal in 12 patients (43%). Unilateral renal artery stenosis was the most-common abnormality. When the patients were divided into two groups – those with an abnormal or normal test result – they did not differ in age, sex, or racial distribution. The peak systolic blood pressure was higher in children with an abnormal renal arteriogram (P<0.05). Among those undergoing the arteriogram on the basis of the first criterion, i.e., severe hypertension, 11 of 23 (48%) studies were abnormal. Five children had an arteriogram based on the second criterion – failure to control the blood pressure with one medication – and in 1 patient (20%) the test was abnormal. We conclude that the prevalence of renovascular disease in a population of hypertensive children subjected to renal arteriography is around 40%. Two clinical criteria – namely severe hypertension or failure to control hypertension effectively with one drug – are useful to guide the application of renal arteriography in children with hypertension. Received: 12 August 1999 / Revised: 24 November 1999 / Accepted: 28 November 1999     

Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity

Renal failure in cancer patients is a common problem in oncology; this complication is frequently multifactorial in origin. Several antineoplastic agents are potentially nephrotoxic; previous renal impairment as well as combinations with other nephrotoxic drugs may increase the risk of nephrotoxicity during administration of chemotherapy. Methotrexate-related renal damage most frequently occurs with high-dose therapy and can be avoided by forced alkaline diuresis and administration of folinic acid. Renal dysfunction secondary to semustine (CH3-CCNU) is clearly related to cumulative doses in excess to 1,200 mg/m2; the onset may be delayed and renal failure progress despite drug discontinuation. Streptozotocin is also nephrotoxic and may cause proteinuria and renal tubular acidosis; progressive renal failure can be predicted by a close monitoring of proteinuria and prevented by drug discontinuance. Mitomycin-associated renal failure frequently presents with signs of microangiopathic hemolytic anemia; renal failure is usually delayed but occasionally, it may be rapidly progressive despite drug discontinuance. Cisplatin nephrotoxicity is clearly dose-related and used to be considered dose limiting. Renal insufficiency can be prevented by hydration and forced diuresis; in addition, hyperhydration with mannitol-induced saline diuresis may allow administration of high doses and thus circumvent the dose-limiting effect of cisplatin-induced renal toxicity. Cisplatin-induced renal magnesium wasting occurs frequently and should be supplemented. Other approaches to reduce cisplatin nephrotoxicity are currently under investigation and are discussed.     

Kidney transplantation after a severe form of pseudotumor cerebri

Pseudotumor cerebri is a syndrome characterized by intracranial hypertension (intracranial pressure >200 mmH₂O) and a normal ventricular system. The diagnosis should be made as early as possible to prevent impairment of vision. Several diseases have been reported in association with pseudotumor cerebri in pediatric patients, and have been occasionally also noted with chronic renal failure, heart and renal transplantation. We report a 7-year-old boy who complained of severe headaches and visual impairment 2 years after hemodialysis for renal hypoplasia. Pseudotumor cerebri was suspected and, despite treatment with corticosteroids, acetazolamide, and lumboperitoneal diversion, visual impairment worsened. Bilateral optic nerve sheath decompression (ONSD) was performed without success and the child completely lost his vision within 2 weeks. He was successfully transplanted 2 months later. Two years post transplantation, the blind child has a normal renal function and school performance. Pseudotumor cerebri must be rapidly suspected in a child with renal failure suffering from headaches and papilledema. Visual loss may progress rapidly and ONSD seems to be the best surgical treatment when medical treatment fails. In this patient renal transplantation was well tolerated, with no deterioration in the neurological status over 2 years of follow-up. Received December 30, 1997; received in revised form April 23, 1998; accepted June 15, 1998     

Effects of an acute dose of L-arginine during coronary angiography in patients with chronic renal failure: a randomized,parallel, double-blind clinical trial

BACKGROUND: Contrast media (CM) are nephrotoxic and might further worsen renal function in patients with chronic renal failure. L-Arginine, the substrate of nitric oxide, protects kidney function and may improve endothelial function in patients with coronary artery disease. HYPOTHESIS: Acute administration of L-arginine in a subset of patients with combined coronary artery disease and impaired kidney function during coronary angiography might prevent superimposed acute renal failure. METHODS: A double-blind study of patients with mild/moderate chronic renal failure (Cr >1.7 mg/dl) undergoing coronary angiography (meglumine ioxaglate) was conducted. Patients received either L-arginine (300 mg/kg) or placebo and were followed for 48 h. Cardiac hemodynamic parameters, renal function and nitric oxide production were sequentially recorded. RESULTS--PRIMARY AND SECONDARY: Both groups experienced a decrease of creatinine clearance 48 h following the procedure (p < 0.05). Creatinine levels slightly increased following the administration of L-arginine (p < 0.05) but not in the placebo treated group. No changes of systemic and cardiac pressures, total peripheral resistance or cardiac output were recorded within and between the treatment and placebo groups. CONCLUSION: CM injection causes an impairment of renal function. Addition of intravenous L-arginine during cardiac catheterizations in patients with chronic renal failure does not prevent CM-induced nephrotoxicity and does not affect endothelial dysfunction in the particular population studied by the authors, i.e. patients with coronary artery disease (CAD) of various degrees, or suspicion of CAD and chronic mild renal failure.     

The impairment of true glomerular filtration rate in long-term cyclosporine-treated pediatric allograft recipients

We performed indium-111-DTPA plasma clearance studies in 61 pediatric kidney and liver recipients treated with cyclosporine to compare true glomerular filtration rate with calculated GFR (cGFR). The mean true GFR of 61.9 +/- 36.6 ml/min/1.73 m2 indicated renal impairment. The mean cGFR of 85.2 +/- 22.4 ml/min/1.73 m2 was significantly higher (P less than 0.001), and overestimated GFR by 38%. cGFR alone did not accurately reflect the degree of renal dysfunction. A group of 48 pediatric orthotopic liver transplant recipients was studied in more detail: 73% of these patients had a true GFR less than 70 ml/min/1.73 m2, while 85% had a true GFR below 90 ml/min/1.73 m2, the lower limit for normal GFR in children. The mean true GFR for patients treated more than 24 months with CsA was lower (P = 0.02) than patients treated with CsA for 12 to 24 months. OLT patients with normal true GFR (greater than 90 ml/min/1.73 m2) had significantly lower plasma CsA levels, and 50% of patients with a true GFR less than or equal to 50 ml/min/1.73 m2 had hypertension. There was no effect on true GFR of age, liver function, azathioprine use, or peritransplant treatment with other nephrotoxic drugs. We conclude that true GFR is significantly impaired in long-term CsA-treated allograft pediatric recipients. Calculations of GFR underestimate the degree of renal dysfunction. As patients treated greater than 24 months had the lowest true GFRs, the fall in GFR may be progressive.     

Retention of an albumin-bound furan dicarboxylic acid in patients with chronic renal failure or after a kidney transplant

BACKGROUND: 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propylFPA) is a furan dicarboxylic acid which accumulates in the plasmaof patients with renal impairment. 5-Propyl FPA is an inhibitorof the binding of drugs to albumin and is also implicated inother aspects of the uraemic syndrome. METHODS: Plasma concentrations of propyl FPA have been measured in non-dialysis-dependent,chronic renal failure patients and in renal transplant patientsby high-performance liquid chromatography. Concentrations ofhaemoglobin, albumin and creatinine were also determined. RESULTS: There was a positive correlation between serum creatinine and5-propyl FPA and a negative correlation between haemoglobinconcentration and 5-propyl FPA in chronic renal failure patients.There was a negative correlation between 5-propyl FPA and durationof transplant only when the serum creatinine was >200 µM.The mean plasma concentration of 5-propyl FPA in chronic renalfailure patients with plasma creatinine <200 µM wassimilar to controls but the mean concentrations were significantlyelevated in these patients and also in transplant patients whentheir plasma creatinine >200 µM. Despite a successfulrenal transplant the plasma concentration of 5-propyl FPA remainedhigher than in either controls or in patients with an equivalentdegree of renal impairment from miscellaneous causes. CONCLUSION: This retention of 5-propyl FPA may therefore reflect a specifictubular defect in renal transplant patients treated with cyclosporinand points to the possibility that 5-propyl FPA may serve asa marker of tubular dysfunction.     

Tuberculosis in children undergoing continuous ambulatory peritoneal dialysis

The incidence of tuberculosis (TB) is increasing worldwide. Due to an impairment of cellular immunity, patients with chronic renal failure are susceptible to reactivation of TB. Seventy patients were treated by continuous ambulatory peritoneal dialysis (CAPD) in our pediatric nephrology department during the years 1989–1997. TB was diagnosed in 4 patients, representing 5.7% of all CAPD patients in our department. One patient had extrapulmonary (TB osteomyelitis) and the others had pulmonary TB. All patients were treated with antituberculous drugs.Two patients with pulmonary TB were cured. Symptoms improved in the other 2 patients but they died at home for unknown reasons. We recommend that all children in regions of high prevalence of TB should be investigated for TB, especially if they have a cough or fever of unknown etiology. Received: 13 January 1998 / Revised: 7 December 1998 / Accepted: 11 December 1998     

Gentamicin-induced Bartter-like syndrome

Gentamicin is well known to be associated with nephrotoxicity, including acute renal failure and renal tubular dysfunction. A Bartter-like syndrome has also been described as a toxic manifestation of gentamicin therapy in adults, but this nephrotoxic syndrome has not been well characterized in children. In this report we describe the clinical course of four patients with gentamicin-associated Bartter-like syndrome. These patients ranged in age from 4 months to 17 years; they all demonstrated evidence of renal tubulopathy, primarily affecting the distal nephron. Hypocalcemia, hypomagnesemia, alkalosis, and hypokalemia were the main manifestations in these patients. After discontinuation of gentamicin, recovery of the renal tubular functions and resolution of the electrolyte abnormalities were complete in all patients. Received December 10, 1996; received in revised form May 5, 1997; accepted May 14, 1997     

Acute renal failure due to obstruction in Burkitt lymphoma

 Acute renal failure in Burkitt lymphoma is commonly the result of tumor lysis syndrome. We present a 15-year-old boy who developed hypertension, seizures, and acute renal failure due to extrinsic compression of the bladder and ureters by a large retrovesical Burkitt lymphoma. The causes of acute renal failure in Burkitt lymphoma and the incidence of acute urinary obstruction in this disease are reviewed. Received: 18 May 1998 / Revised: 30 June 1998 / Accepted: 1 July 1998     

Hyperuricemia and gout following pediatric renal transplantation

Hyperuricemia and gout are common complications in adult renal transplant recipients. In pediatric recipients, however, hyperuricemia seems to be rare, but data are scarce. Thirty-two children (21 males, 11 females) were investigated for a median time of 4.8 years (range: 0.4–11.2 years) following renal transplantation. The median age of this pediatric study group was 13.9 years (range: 5.7–20.3 years), and the calculated glomerular filtration rate (GFR) was 61 ml/min per 1.73 m² (range:12–88 ml/min per 1.73 m²). All patients were given calcineurin inhibitors, with 22 and ten children receiving cyclosporine A (CSA) and tacrolimus (TAC), respectively. The median plasma uric acid was 385 μmol/l (range: 62–929 μmol/l); 15 children (47%) were above the age-related normal range. Only one patient experienced gouty arthritis. There was a significant correlation between plasma uric acid concentration and both time span after transplantation and plasma creatinine, and an inverse correlation to GFR (p<0.05). No significant correlation was found between plasma uric acid and body mass index (BMI). Plasma uric acid concentrations were neither different among CSA- and TAC-treated children, nor did they correlate with drug exposure or blood trough levels of CSA or TAC. Plasma uric acid concentration was not different when compared to children with chronic renal failure (CRF) of a similar degree in native kidneys. We conclude that hyperuricemia is common among pediatric renal transplant recipients and rather a consequence of chronic renal transplant dysfunction than the use of calcineurin inhibitors. Gout, however, is rare.     

Renal epithelial polarity in health and disease

 Epithelial cells mediate the unidirectional movement of selective compounds from one biological compartment to another. This is accomplished by having biochemically, structurally, and functionally distinctive apical and basolateral surface membrane domains separated by the cells’ junctional complex. Derangement of this highly ordered situation can result in cell injury, dysfunction, and even death. For renal epithelial cells, both ischemia and polycystic kidney disease are known to result in a loss of surface membrane polarity. In both disease processes, this in turn plays an important role in cell and organ dysfunction. Received: 2 March 1998 / Revised: 13 May 1998 / Accepted: 18 May 1998     

BUPRENORPHINE DISPOSITION IN PATIENTS WITH RENAL IMPAIRMENT: SINGLE AND CONTINUOUS DOSING, WITH SPECIAL REFERENCE TO METABOLITES

The disposition of buprenorphine has been studied in two patientgroups to assess the influence of impaired renal function onthe metabolism of buprenorphine and two of its metabolites,buprenorphine-3-glucuronide (B3G) and norbuprenorphine (NorB).A single i.v. dose of 0.3 mg was given to 15 patients (ninewith dialysis-dependent renal failure) undergoing lower abdominalor peripheral body surface surgery. Blood was sampled up to24 h. Concentrations of buprenorphine, B3G and NorB were assayedby a differential radio-immunoassay technique. There were nodifferences in buprenorphine kinetics between anaesthetizedhealthy patients and those with renal impairment: mean eliminationhalf-lives 398 and 239 min; clearance 651 and 988 ml min^–1apparentvolume of distribution at steady state 313 and 201 litre, respectively.Both metabolites were undetectable following the single i.v.dose. In a second group of 20 patients (eight with renal impairment),buprenorphine was administered by continuous infusion for provisionof analgesia and control of ventilation in the ITU (median infusionrate 161 µg h^–1 (range 36–230 µg h^–1)for a median duration of 30 h (2–565 h). Buprenorphineclearance in patients with normal and impaired renal functionwas similar (934 and 1102 ml min^–1, respectively), aswere dose-corrected plasma concentrations of buprenorphine.In patients with renal failure, plasma concentrations of NorBwere increased by a median of four times, and B3G concentrationsby a median of 15 times.     

The use of pamidronate in three children with renal disease

The successful use of pamidronate, a bisphosphonate, for the treatment of hypercalcemia and/or osteopenia is reported in three children with renal failure or following renal transplant. Patient 1 was an 11-year-old post renal transplant male who received a single dose of IV pamidronate (0.5 mg/kg) for the treatment of acute hypercalcemia associated with a pathological fracture and subsequent immobilization. Prompt resolution of the hypercalcemia was seen. He received a second course of pamidronate (0.5 mg/kg per day for 3 days) for the treatment of osteopenia and has had a subsequent 15% increase in lumbar spine bone mineral content (BMC). Patient 2, a 14-year-old male on peritoneal dialysis, presented with symptomatic hypercalcemia associated with tertiary hyperparathyroidism. A single dose of IV pamidronate (0.4 mg/kg) was given with prompt resolution and prolonged control of his hypercalcemia. The third patient was a 16-year-old female, also in renal failure on peritoneal dialysis. Her course had been complicated by marked osteopenia. IV pamidronate (0.5 mg/kg per dose) was given on 3 successive days before and after renal transplant in an attempt to stabilize her bone mineral density (BMD) around the time of renal transplantation, when additional glucocorticoid was necessary. Her total body BMC and BMD remained stable pre and post transplant. The treatment was effective and well tolerated in all three patients. Hence pamidronate is safe and effective for the management of hypercalcemia and osteopenia in children with renal failure and/or renal transplant. Received October 13, 1997; received in revised form May 13, 1998; accepted May 15, 1998     

Can acute renal failure be prevented?

Correction of salt and volume depletion is paramount in the prevention of renal damage. Measures which stimulate intense filtration of glomeruli in acute renal failure, such as the use of atrial natriuretic peptide analogues, theophylline, dopamine, or growth factors should be regarded with caution, since they all increase metabolic workload in the outer medulla and hence aggravate medullary hypoxia. Neither frusemide, dopamine nor dopexamine have been shown to be better than aggressive saline loading in preventing acute renal failure in at risk patients. Until new clinical studies emerge, avoidance of nephrotoxic insults where possible, monitoring of circulating concentrations of potentially nephrotoxic drug levels and volume loading coupled with supportive measures is recommended. When volume depletion persists, usual blood pressure cannot be restored and patients remain oliguric, early referral to the intensive care unit is paramount. The mortality rate in patients with acute renal failure is high; therefore, measures which reduce the incidence and progression of renal dysfunction will be of benefit.     

Complement-mediated renal injury: Mechanisms and role of membrane regulators of complement

Conclusion Complement-mediated renal injuries occur not only in immune-mediated diseases, but also in nonimmune conditions. Membrane regulators of complement abundantly expressed in the kidney seem to play important roles in the maintenance of the normal function of the kidney under physiologic and pathologic conditions. We hope these findings have relevance to the development of therapeutic strategies for progressive renal injury. This paper was presented at the 2nd International Forum “The Frontiers of Nephrology,” Tokyo, May 10, 1998.     

Bisphosphonate-associated femoral fracture: implications for management in patients with malignancies

Reports of femoral shaft fractures in patients on long-term bisphosphonates (BPs) have raised important concerns on the safety for this class of drugs. Patients with malignancies are potentially at a higher risk for this complication considering the dose and the duration of treatment with BPs. In this report we describe the case of 56-year-old woman with multiple myeloma who developed a non-traumatic left femoral shaft fracture after treatment with high dose BPs for 6 years, following a bone marrow transplant. Intramedullary rod fixation of the fractured femur resulted in “splitting” of the fractured bone followed by poor healing and nonunion of the fractured bone. This case illustrates a potential problem in the management of patients with femoral shaft fractures from prolonged BPs, most especially those who are on high doses for malignant conditions. However, considering the number of patients who benefit from BPs, this complication should not discourage clinicians from using these agents in patients where treatment is indicated.