Alok Kalia

The association of idiopathic hypercalciuria and asymptomatic gross hematuria in children

Seven children with asymptomatic gross hematuria are described. Six had recurrent hematuria; one had a single episode. Occasional global glomerulosclerosis and/or mesangial electron dense deposits were present in the three patients in whom renal bipsy was performed; the changes were felt to be insufficient to account for the hematuria. None of the patients had urolithiasis or any significant urinary tract abnormality. One was an adopted child; a family history of urolithiasis was obtained in the other six. Idiopathic hypercalciuria was documented in six patients; the seventh subsequently passed a calcium oxalate calculus. One patient is 10 weeks of age at the time of this submission. Of the remainder, three patients received no specific therapy; renal calculi developed six months, six years, and eight years later. Three patients were treated with a thiazide diuretic soon after onset of hematuria and confirmation of idiopathic hypercalciuria; there was complete cessation of hematuria within five days with no recurrence as long as therapy was continued. We suggest that measurement of urinary calcium excretion as part of the initial evaluation of a child with gross hematuria may, in some cases, obviate invasive investigations and allow for effective therapy.

Idiopathic hypercalciuria in children - How valid are the existing diagnostic criteria?

Idiopathic hypercalciuria is a common metabolic abnormality in children of all ages. There is evidence of an association of idiopathic hypercalciuria with nephrolithiasis, hematuria, and osteoporosis. However, much of this evidence is anecdotal and the precise role of hypercalciuria in the pathogenesis of these conditions is far from clear. Furthermore, the precise definition of idiopathic hypercalciuria has not yet been established. The methodologies for quantitating urinary calcium excretion have also not been standardized, adding another potential confounding factor to the accurate interpretation of urinary calcium excretion. Long-term studies on the natural history of unselected children with idiopathic hypercalciuria are needed to establish the true clinical significance of this condition. The focus of this review is to critically evaluate the methods currently being used to measure urinary calcium excretion in children and to assess the validity of existing criteria for diagnosing idiopathic hypercalciuria.

Role of transplant induction therapy on recurrence rate of focal segmental glomerulosclerosis

Abstract Individuals with focal segmental glomerulosclerosis (FSGS) are at risk for recurrence of disease following renal transplantation. The rate of recurrence has been estimated to range from 20% to 30%. The factors associated with an increased probability of recurrence are not known, although the rapidity of progression of disease, age at onset, and the presence of diffuse mesangial proliferation in the native kidney have all been implicated. We analyzed the data from 35 patients with FSGS who received 37 renal transplants at this institution between October 1968 and December 1997. Recurrence was diagnosed by the development of nephrotic-range proteinuria and a transplant biopsy compatible with the diagnosis. Sixteen recurrences were noted, with an overall recurrence rate of 43%. The risk of recurrence was associated with the use of antilymphocytic serum (ALS) for initial induction therapy; being 11% in those who received no induction therapy versus 53% in those who received ALS. Furthermore, in the latter group, the rate of recurrence was 88% in those who received antithymocyte globulin (ATGAM) versus 40% in those who received Minnesota antilymphocytic globulin. Factors such as race, sex, age at time of diagnosis, rapidity of progression to end-stage renal disease (ESRD), response to alkylating agents and/or cyclosporin therapy prior to ESRD, age at time of transplant, donor source, and triple or double immunosuppressive therapy did not appear to have an effect on the rate of recurrence. We conclude that induction therapy with ALS at time of transplantation increases the risk of recurrence of FSGS following renal transplantation.

Secondary resistance to cyclosporin A in children with nephrotic syndrome

Abstract. We investigated the phenomenon of secondary resistance to cyclosporin (CsA) in children with steroid dependent (SD) or steroid resistant (SR) nephrotic syndrome. Secondary resistance was defined as an initial response to CsA with relapse on withdrawal of therapy and absent or diminished response on reinstitution of the drug. Thirty-two children with nephrotic syndrome who were treated with CsA were included in the study. Twenty-two of the children (15 of 15 SD and 7 of 17 SR) responded while ten demonstrated primary CsA resistance. Of these 22 responders, 20 relapsed when therapy was tapered or discontinued. Cyclosporin was reinstituted in 19. Ten responded, demonstrating CsA dependence, and nine exhibited secondary CsA resistance. Focal segmental glomerular sclerosis (FSGS) was present in one patient with CsA dependence on the initial biopsy and in two of six on a subsequent biopsy. In comparison, seven of nine patients with secondary CsA resistance and ten of ten with primary CsA resistance had FSGS on the initial or subsequent biopsy (P=0.03). C4 and/or C1q were present on the initial biopsy in one patient with CsA dependence as compared to six of nine with secondary CsA resistance (P=0.02). Four patients with secondary CsA resistance had an accelerated progression to end-stage renal disease (ESRD). We conclude that the presence of FSGS, or of C4 and/or C1q, appears to increase the risk of secondary CsA resistance and some of these children rapidly progress to ESRD.

Prompt remission of post-renal transplant nephrotic syndrome with high-dose cyclosporine

A 2.8-year-old girl with focal segmental glomerulosclerosis had recurrence of nephrotic syndrome within 3 days of renal transplantation and the serum creatinine increased. Renal biopsy showed cellular rejection and also complete effacement of the epithelial cell foot processes. The rejection responded to methylprednisolone therapy but massive proteinuria persisted. An increase in the dose of cyclosporine A to 14 mg/kg per day was followed by immediate remission of the proteinuria. One month later, a second renal biopsy showed only focal fusion of foot processes. She remains free of proteinuria 2 years later. We propose that the higher dose of cyclosporine caused remission of the nephrotic syndrome.

Fungal peritonitis in children on peritoneal dialysis.

Continuous ambulatory peritoneal dialysis and continuous cycling peritoneal dialysis are extensively used in the management of children with end-stage renal disease and offer many advantages in comparison with hemodialysis. 1 However, peritonitis is a major complication of such therapy. Bacterial organisms are the most common causes of peritonitis, but a small percentage of the cases are of fungal origin. 2 The best treatment program for fungal peritonitis remains somewhat controversial. This is a report of our experience with nine children in whom fungal peritonitis developed during PD.

Sex of the parental donor and cellular rejection of renal allografts in children.

The survival of renal allografts of maternal and paternal origin has been assumed to be identical, and in reports concerning graft survival the outcome of parental transplants is not analyzed by sex of the donor. Fifty-five children received a parental kidney between January 1973 and March 1987 at one institution. There were 6 technical failures. Analysis of renal graft survival in the remaining 49 children indicates a disparity between maternal and paternal graft survival, with an increased propensity for loss of paternal grafts from cellular rejection. Nine of 22 paternal grafts are no longer functioning; 7 were lost from cellular rejection. In comparison, cellular rejection resulted in the loss of only 2 of 27 maternal grafts. This disadvantage of paternal grafts is most conspicuous in patients followed for 2 or more years; 7 of 15 paternal but only 1 of 20 maternal grafts were lost because of cellular rejection (P=0.01). With causes of graft loss other than cellular rejection treated as withdrawal, actuarial survival of the 27 maternal grafts at 1 and 5 years is 96% and 91%, respectively, while that of the 22 paternal grafts is 83% and 58% (P=0.017). Analysis of data from other centers will help determine whether our observation is of clinical significance.

Increased glomerular and urinary malondialdehyde in puromycin aminonucleoside-induced proteinuria in rats

Puromycin aminonucleoside (PAN)-induced proteinuria in rats may be mediated by reactive oxygen metabolites (ROM), which are injurious to several cell components including membrane lipids. Increased malondialdehyde (MDA) production is indicative of lipid peroxidation. We examined if MDA content of glomeruli and its urinary excretion were increased in rats administered PAN. Of three groups of 8 Sprague-Dawley rats each, group 1 served a control, group 2 animals received a single intravenous injection of PAN (5 mg/100 g body weight) and group 3 animals PAN with intraperitoneal injections of dimethylthiourea (DMTU), a free radical scavenger of oxidants such as hydroxyl radicals, for 4 days. The rats were sacrificed on day 8 after PAN injection. Increasing proteinuria, starting on day 4, developed in animals in group 2 but not in the others. The glomerular MDA (nmol/mg protein) in group 2 animals was 2.93±1.91, significantly higher than 0.87±0.63 and 1.26±0.76 in groups 1 and 3, respectively. urinary levels of MDA markedly increased in group 2 rats on day 3 and remained high thereafter, but no such increase occurred in the control animals and those administered PAN with DMTU; the latter was thus protective against PAN toxicity. Our observations support the view that ROM are involved in PAN-induced glomerular injury and that increased urinary MDA excretion can be a marker of ROM-mediated lipid peroxidation.

Preventing breast cancer in postmenopausal women by achievable diet modification: A missed opportunity in public health policy

The Diet Modification trial of the Womens Health Initiative studies was reported to be inconclusive as the overall risk reduction was not statistically significant at the 0.05 level. By our calculation, the trials demonstrated risk reduction at average adherence to a simple diet modification translates into avoiding 7.3% invasive breast cancers in post-menopausal women in the USA. The trial also demonstrated a clear dose response between diet modification and risk reduction, meaning a higher percentage of breast cancers can be avoided among women whose diet modification was better than average. Yet, the DM trial findings as reported and interpreted in public sent the message to post-menopausal women that reducing the fat intake does not reduce the risk of breast cancer. Clearly, a valuable opportunity to affect public health policy was missed because the contextual significance and policy implications of the findings were ignored.

Reactivated laryngeal coccidioidomycosis.

A 14-year-old Latin American male presented with 3 weeks of worsening hoarseness and progressive dyspnea. He denied fever, chills, cough, dysphagia, and odynophagia. At 31 months of age, after treatment with prednisone and cyclophosphamide for focal segmental glomerular sclerosis, he contracted laryngeal and pulmonary coccidioidomycosis, as diagnosed by laryngeal biopsy and tracheal aspirate culture (C. immitis). He was treated with amphotericin B for 4 weeks (total dose of 19 mg/kg) and ketoconazole (6.6 mg/kg/day for 1 year) and this disease went into remission. The clinical features of his illness have been published.1 He progressed to chronic renal failure and underwent a livingrelated kidney transplant from his father 4 months before presentation. His posttransplant course was complicated by severe acute cellular rejection, which was treated with intravenous Solu-Medrol and OKT3. His maintenance immunosuppressive regimen consisted of azathioprine 50 mg orally 4 times a day, tacrolimus 8 mg orally 4 times a day, and prednisone 13 mg orally twice a day. On physical examination, the patient had cushingoid features, biphasic stridor, and mild respiratory distress. Fiberoptic laryngoscopy revealed moderate edema of the supraglottis and glottis, with multiple submucosal nodules and sluggish vocal fold movement. Chest x-ray revealed calcified granulomas consistent with the previously treated pulmonary coccidioidomycosis. Lateral soft tissue neck x-ray suggested a normal subglottic airway. The patient underwent direct laryngoscopy and biopsy the following day. A photograph of the larynx is shown (Fig 1). The immediate subglottis was free of nodules. Biopsies were taken of nodules on the left aryepiglottic fold and laryngeal surface of the epiglottis. The patient was started on intravenous fluconazole empirically (300 mg daily) and demonstrated improvement in his voice and resolution of his stridor and dyspnea within 3 days of treatment. Final pathology demonstrated a mixed granulomatous and suppurative process. Acid fast bacteria and fungal stains and viral cultures of this tissue were negative. Fungal culture grew C. immitis. Coccidioides IgG antibody was positive and the complement fixation titer was 1:16. After 3 days of intravenous treatment, he was placed on oral fluconazole (200 mg 4 times a day) with intent to continue treatment for 1 year.