Mohammad H. Malekzadeh

Focal glomerulosclerosis and renal transplantation

Eighteen patients with corticosteroid-resistant nephrotic syndrome developed end-stage renal disease and received one or more renal allografts. The lesion of focal segmental glomerulosclerosis and/or of focal glomerular obsolescence was demonstrable in the native kidneys of each patient. Following transplantation, nephrosis developed in three recipients. Two recipients developed nephrosis at two weeks and nine months posttransplant in association with rejection; the lesion of FGS was present in association with chronic rejection. Only one recipient developed recurrence of nephrosis and FGS unrelated to rejection. This was manifested by immediate onset of nephrosis in two successive allografts and histologic evidence of the lesion of FGS. The immediate recurrence in successive allografts suggests a circulating factor responsible for the renal lesion in this patient and indicates a separate etiology for a small number of patients with corticosteroid-resistant nephrosis and FGS.

Minoxidil therapy in children with severe hypertension.

Six children, from 1.3 to 18 years of age, with severe hypertension associated with the hemolytic uremic syndrome, periarteritis, and renal transplant rejection received minoxidil, an antihypertensive agent, for three to 36 weeks. All had severe hypertension resistant to oral antihypertensive medications; five required frequent intravenous diazoxide therapy prior to minoxidil therapy. The mean pretreatment systolic and diastolic blood pressures were 176 and 117 mm Hg, respectively. Following treatment, the mean systolic and diastolic blood pressures were 133 and 82 mm Hg, respectively. Concomitant antihypertensive medications were decreased in all six patients once optimal blood pressure control was obtained. The initial dosage of minoxidil was 0.1 to 0.2 mg/kg/day; maximal dosage for blood pressure was 0.3 to 1.4 mg/kh/day. Major complications of therapy were fluid retention and hirsutism. Transient asymptomatic pericardial effusions occurred in two patients. Three patients on prolonged minoxidil therapy had persistent increases in right ventricular end diastolic diameters. Minoxidil is an effective oral antihypertensive agent for treatment of severe hypertension in pediatric patients. Avoidance of fluid retention is mandatory to prevent congestive heart failure.

RENAL TRANSPLANTATION IN CHILDREN

During the past 7 years (Feb. 1967 - Feb. 1974) 96 children received 121 renal allografts from 87 cadaveric, 31 live related and 3 live unrelated donors. Seventy four of the 96 children (76%) are currently surviving with functioning allografts (58 first and 16 second), 12 have died (13%) and 10 are undergoing dialysis (11%) while awaiting a subsequent graft. The primary renal disease was end-stage in 32%, specific glomerulopathies (GN) in 28%, including 11 patients with membrano-proliferative GN; obstructive uropathy in 22%, including 2 patients with an ileal loop and 18% with miscellaneous diseases including 4 patients with cystinosis. Forty seven of the 121 allografts failed, 74% were immunologic failures. No evidence of recurrence of the original disease was present in any of the grafts lost. Medical complications including hepatic dysfunction, cytomegalovirus and unusual bacterial and fungal infections, hypertension, cataracts, orthopedic problems, growth retardation and psychosocial problems leading to noncompliance were frequently encountered. Systematic psychosocial followup documents that despite complications almost all patients who survive at least 1 year with a functioning allograft return to preillness level of adaptation.

The adverse effect of anticonvulsant therapy on renal allograft survival. A preliminary report.

Administration of anticonvulsant medication to recipients of cadaver renal allografts appears to be associated with decreased allograft survival. The one-and two-year actuarial graft survival rates for 20 index grafts was significantly lower than for 92 control grafts. Since phenobarbital and diphenylhydantoin increase the metabolism of corticosteroids, it is proposed that renal allograft recipients receiving these anticonvulsants may have ineffective immunosuppression, leading to a higher incidence of graft failure.

Cadaver renal transplantation in children with cystinosis.

Five children with end-stage renal disease resulting from cystinosis received seven cadaver renal allografts. Four recipients have functioning grafts eight to 55 months after receiving the transplant and one recipient lost two grafts at 17 and 26 months after the transplant. There was no florid recurrence of the Fanconi syndrome although proximal renal tubular dysfunction developed in two patients, in one in association with chronic rejection and in one without apparent etiology. Free cystine content of white blood cells, cultured skin fibroblasts and allograft tissue was significantly increased. Cystine crystals were observed in the mesangium of two grafts and in the interstitial tissue of all grafts; however, no cystine crystals were found in the tubules. The location of the cystine crystals, as well as the fact that the highest free level of cystine of allograft tissue was observed in the graft undergoing chronic rejection. led to the hypothesis that recipient cells infiltrating the graft were the source of cystine deposition. The data indicate that successful cadaveric transplantation does not correct the primary metabolic defect in cystinosis, thereby explaining the persistence of the extrarenal clinical manifestations, such as photophobia and hypothyroidism, after renal transplantation in cystinosis.

Human Immunodeficiency Virus-Associated Kaposi’s Sarcoma in a Pediatric Renal Transplant Recipient

An 11-year-old boy developed Kaposis sarcoma and progressive T lymphocyte deficiency 5 years after cadaveric kidney transplantation for end-stage renal disease. He had received 17 individual red blood cell transfusions prior to and during transplantation in 1980. Human immunodeficiency virus (HIV) was cultured from blood in cerebrospinal fluid and HIV antibodies were detected with enzyme immunoassay and immunoblot techniques. The recipient of the donors other kidney was well and HIV antibody-negative. The patient was treated with etoposide with excellent although transient regression of tumor. Allograft function has remained stable despite minimal immunosuppressive therapy and the need for high-dose anticonvulsant therapy. This case represents the first pediatric patient with acquired immune deficiency syndrome (AIDS) and Kaposis sarcoma following kidney transplantation.

Long-term cadaver allograft survival in the recipient with a positive B lymphocyte crossmatch.

Over a 2 1/2-year period, prospective standard, T, and B lymphocyte crossmatches were performed in 45 cadaver renal transplants using the microlymphocytotoxicity technique. Twenty-three of the 45 recipients had a positive B lymphocyte crossmatch. Cumulative graft survival rates did not differ between recipients with a positive and negative B lymphocyte crossmatch. High levels of presensitization in routine lymphocytotoxic antibody screening or transplant number did not adversely affect graft survival in recipients with a positive B lymphocyte crossmatch. Five recipients had moderately positive standard crossmatches which were attributable to anti-B lymphocytotoxicity. Four of these five grafts are presently functioning with normal serum creatinine levels 9 to 14 months post-transplant. A positive B lymphocyte crossmatch is compatible with good long-term cadaveric renal allograft survival. In addition, a weakly positive standard crossmatch is not a contraindication to transplantation when the positive crossmatch is attributable to anti-B lymphocyte antibody.

The Adaptation of Hydrogen Ion Excretion Associated with Nephron Reduction in Post-transplant Patients

Extract: The compensatory growth of the single and transplanted kidney is demonstrated by the improvement of glomerular filtration rate (GFR) of the single kidney to achieve 50–90% of the normal value. The compensatory renal tubular acid excretion is also studied. It is clearly demonstrated that in response to a standard ammonium chloride load (75 mEq/m2) systemic acidosis (tCO2 < 16 mEq/liter) occurs uniformly at 300–400 min but maximal renal acid excretion (98 ± 12 and 76 ± 17 μEq/min/1.73 m2) occurs in the normal and single kidney subjects, respectively, at 300–400 min, whereas, for the transplant subjects, maximal acidifications of 72 ± 34 and 74 ± 26 μEq/min/1.73 m2 are achieved at 800 and 1,400 min for live-related and cadaveric allografts, respectively. The slower and suboptimal renal response accounts for the persistence of metabolic acidosis in the transplant population.The studies document that the important limiting factor is the reduction in glomerular filtration rate in the transplant subjects. When the low net acid excretion in the two transplant groups are factored by GFR, they become comparable with the control (donor) group as well as the normal group (P > 0.95), i.e., each remaining nephron is excreting acid normally (or supernormally) and is supportive of the “intact nephron” hypothesis.The data show a marked difference in urinary pH during acidosis between the two transplant groups: 50% of the cadaveric allografts have an inability to lower urine pH below 5.4 compared with 10% only of the live-related allografts which show such a defect. This would imply that cadaver allografts are more susceptible to an acute acid load.Speculation: The ischemia sustained at the time of transplantation results in acute tubular damage and proportionate lowering of the glomerular filtration rate which account for the impaired acidification capacity in the kidney allografts. It is also possible that circulatory damage to the glomeruli may occur in the transplantation process. It is even possible that intrarenal circulation may be altered by either transplantation or nephrectomy; although, admittedly, this last possibility seems quite unlikely. It is open to speculation what effect the age difference between the donors and the recipients may have on their different responses to acute metabolic acidosis.

Hepatic dysfunction after renal transplantation in children

Nine of 63 (14 per cent) recipients of renal allografts developed clinical and/orbiochemical evidence of hepatic dysfunction. The etiology was considered to be azathioprine toxicity in eight children and cytomegalovirus hepatitis in one. Evidence of hepatic dysfunction abated in seven of eight children after lowering the dosage of or temporarily discontinuing the drug; the cytomegalovirus hepatitis remitted spontaneously without adjustment in immunosuppressive therapy. One patient died from fungal septicemia with persistent hepatic dysfunction despite discontinuation of azathioprine for 50 days. The data indicate the need for frequent surveillance of hepatic function in pediatric allograft recipients in order to determine the need for adjustment in azathioprine dosage.

Thyroid Function in Children with Chronic Renal Failure

Thyroid function was evaluated in 24 children (aged 4-18 years) with chronic renal failure either before institution of hemodialysis or after more than 3 months of hemodialysis. 22 patients were clinically euthyroid and 2 were hypothyroid; in one case hypothyroidism was secondary to cystinosis and in the other it followed radiation therapy. The 2 hypothyroid patients had subnormal levels of T4, T3, FTI and FT4 as well as elevated serum TSH levels. Mean values for T4, T3, FTI and FT4 for the remaining 22 patients were within the normal range, but were significantly decreased, (all p values less than 0.01) when compared to controls. TSH and TBG levels were not significantly different from those of the normal population. Eleven of the euthyroid patients (50%) had either T3 or FT4, but not both, below the normal range without elevation of their TSH levels. These findings suggest that in the absence of other causes of hypothyroidism, children with chronic renal failure are able to maintain a clinically euthyroid state with either normal FT4 or T3 serum levels and can respond to primary gland failure with elevated TSH secretion.