Tools to detect and modify sickle cell nephropathy.

Placement of the development of a sickle cell nephropathy in a time/event line is helped by better measures of glomerular filtration rate, tubular dysfunction, and proteinuria. Preventing or slowing the nephropathy can improve the outcome of this complication of the devastating sickle cell disease.

Primary hyperoxaluria in infants: medical, ethical, and economic issues.

OBJECTIVES: Survey on the current medical approach to and the economic issues affecting infants with primary hyperoxaluria type 1. METHODS: Questionnaire to specialized centers worldwide. RESULTS: Seventy-eight infants were identified: 44% were of Muslim origin and 56% were not. The consanguinity rate was 76% and 0%, respectively. Thirty-three percent were treated in developing countries (group 1) and 67% in developed countries (group 2). Initial presentation (4.9 +/- 2.8 months) consisted of failure to thrive (22%), urinary tract infection (21%), and uremia (14%). Radiologic findings included nephrocalcinosis (91%), urolithiasis (44%), or both (22%). The diagnosis was based on family history, tissue biopsy, and urine oxalate level in most patients from group 1 and on urine oxalate and glycolate levels, alanine:glyoxalate aminotransferase activity, and DNA analysis in patients from group 2. Therapeutic withdrawal was the final option for 40% of children; financial reasons were given for 10 of 17 patients from group 1 and 0 of 9 from group 2. End-stage renal disease started at 3.2 +/- 6.4 years of age and was present in half of the patients at the time of diagnosis. Fifty-two percent of the patients died: 82% in group 1 versus 33% in group 2; 33% of patients who underwent transplantation died versus 71% of those who did not. CONCLUSION: The management of primary hyperoxaluria type 1 in infants is a major example of the ethical, epidemiologic, technical, and financial challenges that are raised by recessive inherited diseases with early life-threatening onset. In certain circumstances, oxalosis can be regarded as a condition for which therapeutic withdrawal may be an acceptable option.

Transplantation for primary hyperoxaluria in the United States.

BACKGROUND: Transplantation (TX) has become an acceptable treatment for renal failure in primary hyperoxaluria (PH). We have analyzed data from three U.S. sources to estimate the success or failure of different modes of management in PH patients. METHODS: The United States Renal Data System (USRDS) tapes provided coded medical record data, with PH assigned to 235 patients from 1974 to 1996. Another 45 patients were found from USRDS hospitalization records. We limited patients to those developing end-stage renal disease at <55 years of age after 1984 (95 PH patients). The North American Pediatric Renal Transplantation Cooperative Study (NAPRTCS) identified 34 (11 new) PH patients, and the United Network for Organ Sharing (UNOS) database identified PH in 34 (16 new, 5 more in both UNOS and NAPRTCS) patients. These secondary sources were used to correct some data from the USRDS and to add 32 more patients, with a total of 128 PH patients. Considering kidney TX (KTX) prior to combined kidney/liver TX (K/LTX) as a separate record for some calculations, the total "cases" were 138. RESULTS: By life table analysis, the 94 total TX patient survival was better than for the 34 NoTX patients (P<0.001). The 52 KTX patients' survival was better than either the 32 primary K/LTX (P<0.001) or the 10 K/LTX that following KTX (P<0.001). The 62 KTX cases' survival was better than the 42 K/LTX cases (P<0.005), which did not differ from the 34 NoTX (P<0.67). The overall survival of these 62 KTX patients was 76%. The survival of 42 K/LTX was 69%, and the survival of 34 NoTX patients was 44%. Kidney graft life table projected survival curves for TX patients did not differ between K/LTX (56% at 6 years) and isolated KTX (51% at 6 years, 35% at 10 years, P<0.91). CONCLUSION: KTX offers better patient survival in the United States then either K/LTX or NoTX. Graft survival does not differ between KTX and K/LTX. Because K/LTX can still follow a failed KTX, isolated living related donor KTX is still a reasonable first option for PH type 1 if a strictly managed protocol is followed.

Chronic renal failure: an overview from a pediatric perspective.

We present data on the costs and impact of chronic renal failure, the primary renal diseases leading to end-stage renal disease in children, and review the adaptive responses and the pathophysiology and complications of uremia in experimental animals and in man. A treatment strategy is summarized.

Recent data on results of isolated kidney or combined kidney/liver transplantation in the U.S.A. for primary hyperoxaluria.

Renal transplant for primary hyperoxaluria (PH) has been problematic. K/L-Tx is used almost exclusively in Europe. In USRDS data 235 patients had PH diagnosed at ESRD, another 47 found later. Since 1994, there were 176, since our modern management protocol, 96 under age 55. Of 82 non-K/L-Tx, 40 of 49 were alive after K-Tx, 14 of 33 without Tx. By lifetable analysis, survival was better for K-Tx (85% at 5 yrs, 75% at 10 yrs) than for non-Tx patients (40% at 5 yrs, 75% at 10 yrs) (P < .001). First Tx graft lifetable survival was 70% for LRD, 50% for CAD Tx at 3 yrs, both 40-45% at 5 years (N.S.). Twenty-eight K/L-Tx PH patients from the UNOS database had projected survival 50% at 5 yrs. Overall, transplant is better for patient survival than no transplant. While curative, K/L-Tx still has considerable risk in the U.S., but could follow failed K-Tx. Confirmation of PH and ruling out B6 sensitivity must precede K/L-Tx to justify its risk. Post Tx management for K/L-Tx must follow protocols developed to prevent oxalate recurrence for K-Tx.

Perspective of a pediatric nephrology program: an 18 year retrospective.

We analyzed the patient profile in a pediatric nephrology training program, along with data collected over an 18 year period, to determine whether there is merit in the proposition that clinical training can be obtained equally well in internal medicine nephrology training programs. We also compared the rate of patient referral in an U.S. metropolitan area with a population of 1.2 million, in the first 9 years without the "gatekeeper" health insurance system and the next 9 years with managed care competition. Finally, we discussed guidelines for renal biopsy in the child and approaches to treatment as practiced in a pediatric nephrology program of almost two decades. We used the same NIH clinical data form throughout the 18 years of data collection to record clinical, laboratory and biopsy diagnosis, dialysis/ transplantation and other treatment data of patients entering our outpatient and inpatient services. Between 1977 and 1996, 3,150 new patients were examined for disorders related to the kidney. Twenty-one per cent of the patients were in the first year of life and 50% were younger than seven years of age. The majority of the 389 percutaneous renal biopsies were done in children under 10 years of age. In addition, almost half of the 112 pediatric dialysis/transplant patients presented before 10 years of age. Thus, the majority of patients were in the early years of life, with an unique pattern of renal diseases and issues regarding therapy which are clearly different from adulthood. Therefore we concluded that the existing data did not support the proposition that pediatric nephrology training be absorbed into internal medicine nephrology programs. The introduction of managed care competition did not affect the rate of patient enrollment. In fact, the rate of referrals in the latter 9 years paralleled the first 9 years. The factors which contribute to this outcome are discussed. Such data should be useful to those trying to meet the challenges of this competitive era. Finally, we discussed guidelines for renal biopsies in children and approaches to specific diseases.

Neonatal edema.

Edema develops in the neonate from diverse clinical conditions; sometimes it heralds serious underlying disorders. In this review, we discuss the diagnosis and treatment of edema in the neonate.

IgA nephropathy: to treat or not to treat?

IgA nephropathy (Berger's disease) is thought to be the most common primary glomerulonephritis in the world. Characteristically, it presents with intermittent macroscopic hematuria in association with upper respiratory infections. The diagnosis is established by demonstrating predominant IgA deposits in the glomerular mesangium. One third of the cases progress slowly over 25 years to glomerulosclerosis and end-stage renal disease. This rate of disease progression has not been altered by any known treatment, including the use of corticosteroids or cyclosporine. The pathogenesis of this disease is unknown; however, recent data implicated oxygen free radicals in the development of IgA nephropathy. The recent controlled, double-blind, 2-year study from the Mayo Clinic showed that fish oil slowed the progression of IgA nephropathy. This contrasts with the previous studies where the use of fish oil either accelerated the rate of deterioration of renal function in patients with IgA nephropathy or showed no change compared to untreated subjects. Furthermore, in experimental uremia, marked renal functional deterioration with fish oil administration has been reported. Experimental models of IgA nephropathy have been developed in the past few years. In addition, molecular biology offers an unique opportunity to study kidney tissue obtained from patients and animals with IgA nephropathy. These advances will enable the identification of the critical sequence of events that result in renal injury and provide new insight into the pathogenesis and progression of IgA nephropathy. This will help clarify the role of free oxygen radical release on disease progression, and an understanding on the mechanisms of antioxidants, such as vitamin E, in preventing such renal injury.

Effects of uremia on growth in children.

Growth failure is a major complication of uremia in infancy and childhood. The influence of the primary renal disease leading to uremic growth retardation in children, the contributing factors leading to growth failure, such as metabolic acidosis, renal osteodystrophy, hyperparathyroidism, nutrition-endocrine and developmental disorders, are reviewed to update nephrologists on the complex issue of growth failure in children with uremia. The collaboration between endocrinologists and nephrologists in treating children with growth retardation is highlighted by a recently completed National Institutes of Health (NIH)-funded clinical trial on renal osteodystrophy plus the use of recombinant human growth hormone and insulin-like growth factor. Finally, this article concludes with a brief summary of an approach to reverse the effects of uremia on growth, including conservative nutritional management, treatment of anemia with erythropoietin, and selected aspects of growth and development after renal transplantation.

The kidney in acid-base balance.

The practitioner's approach to the pediatric patient with metabolic acidosis begins with calculation of the serum anion gap, which allows the clinician to place the patient in one of two categories of acid-base disturbance: a normal anion gap acidosis or high anion gap acidosis. Likewise, the patient with metabolic alkalosis can be categorized by urinary chloride concentration and the response to chloride replenishment as either chloride-responsive or chloride-resistant. The disease states associated with each category are reviewed in this article.

Hypercholesterolemia and growth hormone in renal diseases.

The interrelationships of hypercholesterolemia, progression of renal disease to renal failure, and to risks of nephrotic syntrouse are emerging. Both hypercholesterolemia and growth hormone are progression factors, and, in the chronically nephrotic patient, these factors may help to explain the progression to renal failure. Treatment of such patients with growth hormone even though growth retarded should be approached with caution.

Transplantation for primary hyperoxaluria in the USA.

US data were sought for transplantation in primary hyperoxaluria (PH). The USRDS recorded 194 patients since 1974. By lifetable analysis, survival was better for transplanted than for non-transplanted patients (P < 0.001), even after trimming data for age < 55 and end-stage renal disease since 1985 (63 patients, 39 transplanted, 24 not transplanted). Transplant survival was longer for living related donor (21) vs cadaveric (17) transplants. Twenty-nine kidney transplants in 22 children were registered in NAPRTCS. Interview data with physicians showed that eight of 17 living related donor kidneys functioned well, three were borderline and six were lost. All six cadaver kidneys were lost. Four of six kidney-liver transplants functioned, and two died. United Network for Organ Sharing recorded 13 kidney-liver transplants in 11 patients. Six initially functioned well; two were retransplanted. Ultimately seven lived and four died. Overall, transplant is better than no transplant; cadaver donation results are poor; living related kidney donation can succeed; and kidney-liver transplant is still problematic in the US, and rarely follows appropriate investigation. Until more cooperative effort can be achieved, isolated kidney living related donor transplant is preferable, and does not preclude kidney-liver transplant later.

Selection of transplantation procedures and perioperative management in primary hyperoxaluria type 1.

This paper outlines the different options of transplant procedures in patients with primary hyperoxaluria type 1. Isolated kidney, isolated liver and combined liver-kidney grafting are discussed. Combined liver-kidney grafting appears to be the preferred treatment for patients already in end-stage renal failure. The potential value of the two other procedures is outlined. Guidelines for perioperative care are given. These involve fluid regime, pyridoxine supplementation, immunosuppression and administration of crystallization inhibitors such as phosphate and citrate. Special emphasis is put on selection of appropriate dialysis procedures and reasons why haemodialysis and continuous haemodiafiltration are the methods of choice.

Primary hyperoxaluria.

Primary hyperoxaluria (PH) is a rare inborn error of amino acid metabolism, now genetically defined, that results in excessive production and urinary excretion of oxalate. It serves as a model of severe nephrolithiasis that requires management of urinary supersaturation to prevent the common outcome of renal failure, which can be the presenting finding: the continued oxalate excess than causes progressive systemic oxalosis (deposition). Routine kidney transplantation almost invariably fails, but a (live donor) protocol that reduces danger of the accumulated load of oxalate can reduce the risk of recurrence. The attractive (and curative) option of combined kidney/liver transplant has considerably greater risk of mortality (in the US), although the European experience is considerably better, often employed earlier in the course. Key to appropriate decisions are early recognition, certain diagnosis, testing for vitamin B6 response, and immediate planning for definitive therapy when renal function is failing. PH provides one example of the absolute need for workup of the metabolic causes of stone disease.

Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). Three unrelated PH1 patients, who possess a novel complex phenotype, are described. At the enzymological level, this phenotype is characterized by a complete, or nearly complete, absence of AGT catalytic activity and reduced AGT immunoreactivity. Unlike normal individuals in whom the AGT is confined to the peroxisomal matrix, the immunoreactive AGT in these three patients was distributed approximately equally between the peroxisomes and mitochondria. The peroxisomal AGT appeared to be aggregated into amorphous core-like structures in which no other peroxisomal enzymes could be identified. Mutational analysis of the AGT gene showed that two of the three patients were compound heterozygotes for two previously unrecognized point mutations which caused Gly41-->Arg and Phe152-->Iso amino acid substitutions. The third patient was shown to be a compound heterozygote for the Gly41-->Arg mutation and a previously recognized Gly170-->Arg mutation. All three patients were homozygous for the Pro11-->Leu polymorphism that had been found previously with a high allelic frequency in normal populations. It is suggested that the Phe152-->Iso and Gly170-->Arg substitutions, which are only eighteen residues apart and located in the same highly conserved internal region of 58 amino acids, might be involved in the inhibition of peroxisomal targeting and/or import of AGT and, in combination with the Pro11-->Leu polymorphism, be responsible for its aberrant mitochondrial compartmentalization. On the other hand, the Gly41-->Arg substitution, either in combination with the Pro11-->Leu polymorphism or by itself, is predicted to be responsible for the intraperoxisomal aggregation of the AGT protein.